114 MCQs +Mid+Final PTech Syllabus-Merged-Merged

MCQs 10.
The cross linking of the Polymers in hydrogels is designed to

a
1. The mechanism of the release of drug from Matrix or a make it more gelatinous Hydrogel nature
Reservoir system can be applied to predict released through b making linking of drug with Polymers stronge
particular drug delivery as well c none of these
True d make it more hydrophilic
False e control the release of the drug
2. The osmotic pump Alzet works only on the principle of 11. Which of the following is not the clear advantage Novel
diffusion and dissolution controlled release of the drug Drug Delivery System
True
False a none of these
b target the drug release
3. Hydrogels are hydrophilic cross linked swelled high molecular c increase patient compliance
weight and water insoluble gels to control the release of drugs d increase dosing frequency
over time e control the drug release
True
False 12. Similar to disintegrants binders are also added to the
granules for tablet manufacturing in two parts that is before
4. Generally dry granulation has number of formulating steps granulation and after granulation
than in wet granulation True
True False
False
13. Implants can be delivered as per oral Matrix controlled
Dry granules can also be used prepared from fluidized bed devices
granulator True
True False
5. Why granules are denser than the other constituent of the 14. Segregation may reduce dust hazards and ultimately may
parent mixture increase the health of the personnel.
a inter particulate void or volume is reduced true
b because the flow property is improved false
c cause the particle size is increased
d none of these 15. Basic difference between osmotically controlled and
e the particle size is increase as well as inter particulate void or swellable control system is that the size of dosage form in terms
volume is reduced of imbibition of the former is not increased Unlike the latter.
true
6. Segregation may improve the flow properties of a powder false
mix
True 16. Choose the odd type of preparation methods of granules
False
a wet granulation
8. Granules intended to be administered orally are b dry granulation through slugging
comparatively coarser than the granules prepared for tablet c dry granulation through roller compactor
compression d direct compression method for tableting
True e none of these
False
18. flow property parameters are not as much important while
9. Disintegrant Substance may reduce the need of lubrication manufacturing granules for oral administration compared with
glidant or any of these from the Powder mix the granules for tablet manufacturing
True true
False false
19. Handling granules while production of tablet may cause 32:- Polyamino acids are generally biodegradable
more material loss compared with powder • True
True /false • False
20. The local sev baseplate in the Nitro dur is designed to inhibit 33:- Most polymers are non biodegradable because they
or reduce the environmental contact with the dosage form contain branched chains of Carbon atoms
• True
True/False
• False
21. Glycolic acid and polyethylene are biodegradable polymers

34:- According to the definition of the polymer. Magnesium
True /False
stearate is a polymer.
• True
22. Man made Polymers examples of natural and semi synthetic • False
polymers
True /false 35:- The behavior of polymer in terms of viscosity or sustained
action can be manipulated by changing number of polymer
23. The final drying of wet granules performed through gral units in polymer chain
mixer can be dried in simple tray drier • True
True/False • False
24.The smaller blade in gral mixer is not designed to eliminate 36:- Degradation rate of no biodegradable can not be controlled
dead spots present in the container • True
37:- A biodegradable can be delivered in dosage form to oral

25.Fluidized bed granulator can intake liquid feed for the
route
preparation of final wet granules
• True
26.Unheated blown air can be used to used to dry wet granules 38:- Polyamides are classic examples of condensed polymers
prepared through fluidized bed granulator • True
27.The exhaust filters in fluidized bed granulators is designed to 39:- One type of the monomer is the main chain while other
reduce granular or powder loss from machine type of monomer is present in the branch attached to the main
True/False chain in
• Graft copolymer
28.Oscillating granulator can not mix the slurry of binder with • Alternating copolymer
the rest of the dry powder for granulation • Branched copolymer
• Block copolymer
True/False
40:- Polyethylene is composed of repeating units of ethene

29.The final dried wet granular mass from simple tray dryer
• True
attained for tabletting purpose resembles pendular stage a it • False
contain slight amount of moisture
True/False 41:- The final dried wet granular mass attained for tableting
purposes resemble pendular stage as it contain slight amounts
30.Albumin and globulins are example of natural biodegradable of moisture
polymer • True
31.Cross linked polymers form more densely interconnected 42:- The flow properties of wet granules appears to be less
chains of monomers than branched controlled by changing the formulation factors or machine
True/False factors compared to the wet granules
• True
• False
43:- In Gral Mixer the mixing as well as granulation of the wet 53:- For delayed release and immediate release coating layers
mass is achieved through the blunt paddles only of the coating polymer.The immediate release layer will not be
• True encapsulated inside the delayed release layer
• False a)True
b)False
44:- All steps of prepared wet granules can be performed in
pneumatic spray dryer as compared to other wet granulating 54:- All of following are the advantages of Novel Drug Deliveries
machine except
• True a)Reduce extent of the associated ADRs
• False b)Reduce the free drug concentration in blood
C None of these
45:- Out of all mixers containg paddles for the production of wet d)Reduce half life
granule the most vigilant and agitation producing mixer is e)Reduce frequent dosing
Hobart mixer/granulator
True/False 55:- For delayed release and immediate release coating layers
of the coating polymer,the immediate release layer will not be
46:- Suspension of powder mixer is used as raw material for the encapsulated inside delayed release layer
preparartion of wet granules in fludized bed granulator True/False
True/False
56:- Coating may be applied to matrix cores to form matrix
47:- The compaction property can be well built in the nature of microcapsules.
hollow dried granular product obtained from pneumatic spray True/False
dryer
True/False 57:- If the release of the active substance is mainly influenced
by the presence of macro molecules and biochemicals present
48:- The exhaust filter in fluidized bed granulator is designed to in the present in the solvent,it is termed as :
reduce granular loss by seggregation Solvent of action
True/False None of the
Dissolving it under particular conditions e.g enteric release
49:- The smaller blade in gral mixture is designed to optimise Melting the wall
the mixing of components of powder mixture Hydrolysis
a)True
b)False 58:- The basic aim of formulating microencapsulation is to
discover new dosage forms
50:- Little ford mixer can perform granulation at a faster rate True/False
than oscillating granulator because it is high speed mixer
True 59:- Encapsulated particles having a particle size of 1250mm will
be termed as
51:- The efficacy of high speed mixers lies in the additional small Macroparticles
paddles at the periphery of of the container to eliminate dead None of these
spots Microencapsulated particles
a)True Microspheres
b)False Micro pellets
52:- If the release of the active substance is mainly influenced 60:- All of the following are advantages of novel drug
by the presence of macromolecules and biochemical present in deliveries;except
the solvent it is termed as Reduce half life
a)Hydrolysis Reduce extent of associated ADRs
b)non of these None of these
c)solvent action Reduce the free drug concentration in blood
d)melting the wall Reduced dosing frequency
e)Dissolving it under particuler conditions e.g enteric release
61:- If the encapsulating layer of the polymer broken down due 71:- Not more than one layer of shell material can be coated on
to the action of water molecule into simpler monomers,then the microencapsuted particle
the predictable release mechanism will be • True
Chemical reaction • False
Hydrolysis
Solvent action 72:- Polyethylene glycol (PEG) exists in liquid as well as solid in
Melting the wall
appearance depending upon the moleculer weight of the
None of these
polymer chain.
• True
62:- Shellac is insoluble in enteric and acidic pH
• False
True/False
63:- All of the following are advantages of novel drug deliveries ; 73:- Biodegradable polymer cannot deliver targeted drug
except ? delivery through oral route.
Reduced frequency dosing • True
Reduce the free drug concentration in blood • False
None of these
74:- Cross linked polymers generally faster the release of drug
Reduce half life
than linear polymers in dosage form.
Reduce extent of associated ADRs
O False
64:- A higher extent of powder dust is associated with health
safety of working personnel
• True 75:- The overall surface area of particles is reduced as the size of
• False the granular particle is increased with fixed volume of air
entrapped.
65:- Zein can be used as enteric release agent in the coating
O True
layer in microencapsulation or other coatings
• True O False
• False
66:- Polyurethane is used as an ingredient in oral drug delivery 76:- Implants can be delivered as per oral matrix controlled
• True devices.
• False
O True
67:- Strict compliance in terms of flow property is not required O False

for granules that is packed in sachet and intended to be
delivered through per oral route 77:- Cellulose or its derivatives can be used as super
• True disintegrant in tablet formulations.
• False
True /False
68:- According to the definition of the polymer, hydroxypropyl
cellulose is a polymer ? 78:- Biomolecules are generally more preferred because the
True polymers are biologically degradable
O True
69:- According to the definition of a Polymer, vinyl alcohol is a O False
polymer ?
• True 79:- In reservoir type diffusion controlled mechanism, the drug
• False release is not only be controlled through the matrix network but
also through the semipermeable membrane encapsulated the
70:- Carrageenan gum is not one of the components of dosage form.
seaweeds . O True
• True O False
• False
80:- Which of the following forms more densely connected 87:- Hydrogels can be used as Matrix system as well as
monomers: controlling membrane for the release of medicinal substance
O a. condensed polymers True

O b. None of the options False
O c. branched and cross-linked polymers
O d. branches polymers 88:- In microencapsulation the drug release cannot be
O e. linear polymers prolonged
81:- Segregation of "granules" is a term that explains the true

existence of fine powder in the form of aggregated particles false
again.
89:- Basic difference between osmotically controlled and
O True swellable controlled system is that the size of dosage form (in
O False term of imbibtion) of the former is not increased,unlike the
latter
82:- Which of the following is not the clear advantage Novel True/False
Drug Delivery System
90:- Carboxymethyl cellulose is an example of natural polymer
O a. none of these True/False
O b. Target the drug release
O c. Control the drug release 91:- Average particle size of the granular batch become
O d. increase dosing frequency different when the purpose of granulation or intention to be
O e. increase patient compliance delivered for various route of administration differs
True/False
83:- When different monomers are arranged in an organised
manner representing alternating arrangement it is termed as 92:- The cross linking of the polymer in hydrogels is designed to
none of these
a homopolymer make it more hydrophilic
b alternating polymer making linking of drugs polyer stronge
c graft copolymer control the release of the drug
d copolymer make it more gelatinous (hydrogel) in nature
e branched copolymer
93:- Microcrystalline cellulose is the sustained form cellulose
84:- The osmotic pump Azlet works only on the principle of with good filler properties in solid dosage form. Select one:
diffusion and dissolution controlled release of drug a) True
b) False
True
False 94:- Which of the following polymer is used as swelling agent
Select one:
85:- The flow properties of wet granules is more easy to control a. None of these
compared with the dry granules b. Cellulose
c. polyethylene
true d. polyethylene glycol
false e. polyethylene oxide
86:- Which of the polymer is not soluble in water 95:- For moisture sensitivity of granules on storage, wet method
of granulation is inferior to dry granulation method. Select one:
a hydroxypropyl cellulose True
b none of these False
c hydroxy ethyl cellulose
d ethyl cellulose
e hydroxypropyl methylcellulose
96:- The occlusive base plate in the Nitro-dur ® is designed to 106:- Flow property parameters are better controlled in wet
inhibit or reduce the environmental contact with the dosage granulation.
form. Select one: True
True False
False
107:- Buna S is an addition based polymer
True
97:- Liquid core substance can also be microencapsulated.
False
Select one:
True
108:- For granules the action of binder and disintegrant can only
False
be mediated in the presence of water
True
98:- Polymer is said to be biodegradable when its backbone False
chains of carbon atoms are metabolized in to degraded
products. Select one: 109:- Pectin and collagen are biodegradable polymer obtained
True from plant source
False True
False
99:- Coating material should be hygroscopic in order to provide
good stability of product during shelf life. Select one: 110:- Glycolic acid and polyethylene are biodegradable
True polymers
False True
False
100:- Polyacrylic acids have generally poor adhesive properties
111:- The physical properties of polymer cannot be manipulated
Select one:
by changing number of monomer units in the polymer chain
True
True
False False
101:- The shape of produced granules of which of the following 112:- Alginic acid is an example of natural polymer
machine is easy to identify: Select one: True
a. planetory mixer
b. slugging 113:- Generally hydrogels are hydrophilic cross linked swelled
c. pneumatic spray dryer high molecular weight and water insoluble gels to control the
d. None of these release of drugs over time
e. oscillating granulator True
False
102:- Which of the following machines can process all steps of
wet granulation including drying ? 114:- Which of the following polymer is not obtained from plant
Oscillating wet granulator source
Starch
103:- If the drug is released feom the dosage form through ion Pectin
exchange present in the lumen in GIT it is termed as dissolution Guar gum
controlled mechanism. Cellulose
True None of these
False
104:- The initial step of formulating granules through wet and

dry methods are almost same
True
False
105:- The oscillating granulator can mix the slurry of binder with
the rest of powder mix
False
PHARMACUTICAL TECHNOLOGY MID SYLLABUS
CHAPTER 1
Pharmaceutical Technology:
Branch of pharmaceutical sciences that deals with/include knowledge of
1 Active pharmaceutical ingredients(API) drugs:
• Organic chemistry
• Medicinal chemistry
• Phyto chemistry
By these chemistries discovery of new chemical substance and modification (in pre -
existing drug molecule)/ alteration.
2.Excipients:
Came the knowledge by
• Pharmaceutics
• Physical pharmacy
• Dispensing
3.Technological process:
Characterization and evaluation of API excipients and dosage form. We get this
knowledge from Qc, instrumentation.
Chromatography:
• HPLC
• TLC
Spectroscopy:
• Thermal analysis
• Transmittance
• Gas chromatography
4.Manufacturing process:
We get this knowledge from
• Dispensing
• Industrial pharmacy
5.Manufacturing Equipments:
• Pharmaceutical engineering examples Mixer, Tablet forming etc
• Dispensing
Also include maintain equipment and working.
➢ We can conclude that Pharmaceutical Technology include multiple disciplines

like
1
• Instrumentation
• Qc
➢ In development and use of pharmaceutical products
Dosage form & Drug:

A drug can be changed to dosage form but a dosage form cannot be
changed into a drug.
Drug:
Any agent or a substance intended for use to:
1-Diagnose
2-Mitigate
3-Treat
4-Cure
5-Prevent
diseases in human beings and other animals
DOSAGE FORM:
Finalized shape of finished products for presentation of drug substances.
Drug substances are administered in combination of one or more non medicated
agents(pharmaceutical agents).These pharmaceutical agents perform varied and
specialized functions like to dilute thicken stabilize solubilize suspend emulsify
suspend colour flavour and fashion the drug product to obtain an efficacious and
appealing dosage form in order to develop a proper design and formulation of a
dosage form requires the considerations about physical, chemical and biological
characteristics of active pharmaceutical agents and dosage form.
The products should be manufacture under appropriate conditions or measures of
quality control and packed in container that contribute to product stability.
40 Dosage Form Names:
1. Linimints 15. Solution 28. Emulsion

2. Lotions 16. Spirits 29. Elixrs
3. Lozenges 17. Suppositories 30. Dusting
4. Magmas 18. Suspension powders
5. Mouthwash 19. Syrups 31. Drops
6. Ointments 20. Tablets 32. Draught
7. Pastes 21. Tincture 33. Douches
8. Pastille 22. Aerosol 34. Injections
9. Pessary 23. Aromatic 35. Pellets
10. Pill waters 36. Capsules
11. Laster 24. Gargle 37. Creams
12. Poultice 25. Gels 38. Boluses
13. Powders 26. Extracts 39. Inhalation
14. Premixer 27. Enema 40. Fluid extract
2
Why we need dosage form?
• To protect the drug from destructive influences of atmospheric oxygen or
humidity (coated tablets)
• To protect the drug from destructive influence of gastric acid and after oral
administration
• To cancel the bitter salty or offensive taste or odor of drug
• To provide liquid preparation of substances that are either insoluble or
unstable in the desired vehicle(suspension)
• To provide clear liquid dosage forms of substance
• To provide rate-controlled drug action
• To provide optimal drug action from topical administration sites
• To provide for placement of drugs directly in the blood stream or body
tissues
• To provide for optimal drug action through inhalation therapy
Evolution In dosage form/Drug delivery or Transition periods of dosage form

Two ways
➢ Primitive ways of drug delivery
1. chewing
Roots e.g glyceriza glabra
Rhizomes e.g termaric,ginger
Stem e.g ephedra (ephidrine)
Bark e.g Cinammon,cinchona
Leaves e.g peppermint ,cena ,neem
Flowers e.g rose
Fruit e.g papitta,avocado
Seeds e.g clove
Anther e.g sefron
2. Snuffing :
Snuffing powder in nostrils like afeem , cocaine
3. Inhaling:
4. Smoking:
Tobacco, chars
5. Soots/ sooting/ soots (Particals in smoke):

Luman
6. Secretion / Eadate:
Xanthum, acacia, tragacanth Gums, resins, oleogum, resins,
Drawbacks of primitive ways:
• No content uniformity
3
• No dose accuracy
• No selectivity
• No accuracy in results
• Greater or higher chances of toxicity
To overcome these drawbacks go to modern ways

Modern ways of drug delivery:
In this we extract the desire part or element that we need to use.
Reasons why we moved to modern drug delivery system:
Goals and Aims:
There are two types of terminologies used to understand this:
1. Spatial placement:
Derived from word space defined as delivery of smallest required amount of

drug to the required area or required space e.g 5mg of drug in heart.
2. Temporal delivery:
Derived from the word time defined as smallest required amount of drug
to a specific area/space at specific rate for a specified period of time e.g 5mg/hr/ml
for 48 hrs at cancerous site. 100% of temporal delivery cannot achieved and produce
maximum effect. This idea proposed by a pharmacist Paul Ehrlich also called Majic
Bullets.
Modern ways of drug delivery system can be classified into different generations:
1) 1st generation drug delivery system
2) 2nd generation drug delivery system
3) 3rd generation drug delivery system
4) 4th generation drug delivery system
1. 1st generation Drug delivery system:
In late 19th century it was introduced;

• Tablet
• Capsule
• Solution
• Elixirs
Advantages:
• content uniformity
• Dose accuracy
• Selective
• Accuracy in result
• Less chance of toxicity
• Patient compliance
4
Disadvantages:
• Chances of toxicity
• Side effects
• Degradation of drug
The dosage form belongs to 1st generation has less patient compliance because of
dose frequency. There are chances of degradation of drug by GIT environment.
Certain drugs disturbed GIT causes ulcer etc. We have many quality control tests still
there are chances of over dosing are contents uniformity as well. To remove all the
drawbacks of 1st generation DDS move towards 2nd generation DDS.
2nd Generation DDS:

Also known as sustained release DDS. Came in the market in 1950’s. With
passage of time advancement in pharmacokinetics, Biopharmacokinetics, Physiology
and anatomy and there application to drug formulation and development leads to
modification in drug molecules and in dosage forms. In order to include patient
compliance and get benefits approved in a better way.
Goals:
• For better patient compliance.
• To reduce dose frequency.
• To protect drug from hostile environment (e.g. destructive environment).
• To enhance bioavailability (the measure and extent of drug that reaches the
systemic circulation and is available at the site of action).
• To prolong the action of drug.
Bioavailability:
In the measurement of rate and extant of drug that reaches the blood
circulation and available at the site of action.
The release of drug from 2nd DDS try to mimic the zero order kinetics in order to
achieve a steady state concentration in plasma but cannot achieve a 100% zero
order kinetics (release of drug is independent from concentration of drug,
environmental factors).
The release of drug from 2nd generation DDS follow pseudo zero order kinetics. E.g.
enteric coated tablets and capsules, sustained release tablets and capsules. With the
advancement in pharmacokinetics, biopharmaceutics, human physiology and
anatomy the new drug formulations which leads towards an improvement in dosage
form for patient compliance and to get maximum benefits for human beings.
3rd Generation DDS:

Came in 1960’s. Also known as controlled release DDS.
Goals:
• To achieve steady state concentration of drug in plasma.
• When a drug follow zero order kinetics then we can say that release of drug is
independent.
5
• No fluctuation in concentration of drug in plasma for a prescribed period of
time.
4th Generation DDS:

Once we administer the D.D you have no control on the release of drug and fate of
the drug.
Drawbacks:
• Narrow therapeutic effects. High chances of toxicity and decreased safety
range.
• Anticancer drugs, the cancerous cells are abnormal body cells.
• We cannot deliver drug when we require and where we require.
• A contraindicated drug cannot be administered, e.g. a sustained release drug
is already present in the body and we cannot deliver another drug.
• Due to renal failure, we cannot stop the release of drug.
4th generation drug delivery system further classify into 3 classes:

1. Targeted/ site specific drug delivery system:
It is desirable in order to achieve maximum patient compliance to achieve drug
safety and efficacy and to reduce drug toxicity.
There are two types:
i. Simple targeting:
We can achieve simple targeting by applying the drug on diseased skin, eyes, and
nose.
ii. Sophisticated targeting:
We have to deliver drug at required organ or tissue or specific receptors.
Components of targeted drug delivery system:
• Drug/API
• Carrier
• Binding moiety /molecule
E.g. Liposomal preparation of Doxorubicin
2. Pulsatile/ modulated drug delivery system:
There are certain requirements for DDS in case of pulsatile DDS, it is the best
delivery system for the formulation. In pulsatile DDS the delivery of drug or release
of drug from dosage form should mirror certain physiological needs or physiological
release. There should be a condition, the release of drug should be in response of
certain physiological needs. No continues release of drug.
There are hundreds and thousands of physiological needs.
➢ Chronotherapeutics:
The branch of medicinal science that deals with administration of drug according to
schedule which correspond to daily, weekly or monthly circadian changes of living
organism in order to minimize side effects and maximize health benefits.
➢ Circadian rhythm:
6
24 hourly, weekly or monthly cyclic changes in physiology, biochemistry and
behavior of human beings and animals.
Melanin secretion more exposure to sun more melanin secreted

Melatonin Sleep inducer
12:00 (Noon)
(Melatonin secretion stops) 7:30 am
9:00 pm(Melatonin secretion start)
12:00 (Mid-night)
E.g. In arthritis patients the joints of patients stiffs so melatonin drugs are given.
3. Bio responsive /self-regulated /feedback drug delivery system :

There is a complete control after administration. There is a condition or
requirement that condition is available than we can formulate bioresponsive DDS.
There should be a known relationship between plasma level and pharmacological
effects. There should be a natural secretion .e.g. Insulin releases in our body and
have direct pharmacological effect release in response of glucose level. A condition
that is fulfill in diabetes patients.
Drugs with narrow therapeutic effect, we do not change them.
Classification:
1. Close loop system with biosensor and pump
2. Close loop system with which releases drug by self-regulating mechanism
3. Close loop system with microencapsulated or drugs
1. Close loop system with biosensor and pump:
This system has 3 components:
➢ Biosensor
➢ Algorithm
➢ A pump
A probe that is inserted in vessels of patient. That probe detects glucose level in
plasma and sends information to Algorithm which is mathematical formulas based
software that calculate the dose according to the information provided by sensor.
The algorithm sends that calculations towards the pump which inject the calculated
dose into the patient. The pump has a step motor, a drug reservoir and a catheter.
2. Close loop system with which releases drug by self-regulating mechanism:
7
In this system we use sensitive polymers these polymers are sensitive towards ph
and glucose on the disturbance of glucose level the polymer senses it and self
regulate it.
3. Close loop system with microencapsulated or drugs:
Here in this system living cells from natural sources are microencapsulated and
are inserted in the patient of body e.g islets of langerhans or drug that release insulin
are microencapsulated and inserted into the body.
This system:
• is not available in the market
• are not available
• in market and not FDA approved
5th generation DDS:

It is based on genetic engineering or gene therapy or biotechnology. Gene therapy is
intended to treat the cause of the disease rather than the symptoms. It is essentially
the redesign of cell by introducing therapeutic agent made by genes.
8
CHAPTER 2
Modified release drug delivery system:
Delivery system from which the rate of release of drug is modified or
altered for required period of time.
Classification:
Generally there are 3 types:
1) Delayed release DDS
2) Extended release DDS
3) Targeted release DDS
1.Delayed release DDS:

In delayed release drug delivery system there is no immediate release of
drug from the symptoms but release of drug occurs after required delay in time
period e.g enteric coated
2. Extended release DDS:

Classified into 2 classes;
A. Sustained release DDS:
The sustained release drug delivery protects the drug from hostile
environment it increases the patient compliance and it reduces the dose frequency it
also enhances the bioavailability of drug and prolongs the action of the drug.
B. Controlled release DDS:
The controlled release drug delivery system is used to achieve the
steady state concentration of the drug in control release drug delivery system the
release of drug is independent.
Repeat action DDS:
Also called tri layer tablet or tablet in tablet/compressed coated tablet/kinetic/poly
pills.
3. Targeted release DDS:

It is desireable to release drug at our required targeted diseased site.
Targeting may be organ targeting in which we target an organ for the release of drug
e.g heart targeting/brain targeting.
Targeting may be of receptor in which drug is released at certain receptor sites e.g
alpha receptor, beta, muscurinic, nicotinic receptor.
9
CIRCADIAN RYTHMS
CIRCADIAN RYTHMS
Definition(By sir):
It can be defined as;
24 hourly, weekly or monthly cyclic changes in physiology, biochemistry, and
behavior of living organism
• Physical
• Mental
• Behavioral
That follows a 24-hours cycle

Responding primarily to LIGHT and DARKNESS in an organism’s environment.
Suprachiarmatic Nucleus (SCN):
Function Of SCN:
SCN controls the production of Melatonin, a hormone that make you sleepy. It is
located just above the optic nerve, which relay information from the eye to the
brain, the SCN receives information from incoming light.
When there is less light-like at night- the SCN tells the brain to make more melatonin
to make person drowsy.
Circadian rhythm can change
• Sleep-wake cycle
• Hormonal release
• Body temperature
• Other important functions
Graph 1:
Plasma Melatonin (pmol/L)
10
Core Body Temperature (oC):
Plasma cortisol (nmol/L):
11
Body clock Guide
The Body clock Guide to Better health; by Michael Smolenshy and Lynne
Lamberg, Henry, 2000
Time Situation
12:00am Midnight
2:00am Deepest sleep
4:30am Lowest body temp
6:45am Sharpest BP rise
7:30am Melatonin
secretion stops
8:30am Bowel movement
likely
10:00am Highly alertness
12:00pm noon
2:30pm Best coordination
3:30pm Fastest reaction
time
5:00pm Greatest CV
efficiency of
muscle strength
6:00pm evening
6:30pm Highest Bp
7:00pm Highest body temp
9:00pm Melatonin
secretion starts
10:30pm Bowel movement
suppressed
Graph 2: Alertness level: Dim light, physical repair, psychological repair
Factors effecting circadian rhythm
12
Graph: 3(a): Normal Sleep curve (sleep urge, Nap, sleep needed)
Graph: 3(b): missed Sleep : Increased sleep burden (awaken early, sleep urge, sleep
needed):
Graph: 3(c): NAP Taken: Decreased sleep needed (sleep urge, Nap, sleep needed)
13
CHRONOTHERAPEUTICS
The study of circadian rhythm is called chronobiology.

Chronotherapeutics is a delivery of a medication in concentration that vary
according to physiological need at different times during the dosage period.
First Chronotherapeutics agent for hypertension and angina pectoris, controlled
onset, extended release (COER-24) Verapamil, has been developed and registered in
US, Brazil, Canada and Mexico. The theoretical advantage of the formulation is that
delivery of the active drug verapamil has been tailored to the typical circadian
rhythm of bp and heart rate in patients with hypertension and angina to better cover
the early hours when CV need appear to be the greatest.
14
Pharmaceutical technology characteristics of active pharmaceutical ingredients pharmaceutical
P.Tech is the branch of pharmaceutical sciences that deals with agents and dosage form.
/ include The product should be manufuctuirng under appropriate condition or
Knowledge of measure of quality control and packed in container that contribute to
product stability
i:- active pharmaceutical ingredient
Why we design dosage form?
( API ) Drugs
Tablet Mouth wash Inhaler
Organic chemistry Capsule Ointment Nebulizer or atomizer
Medicinal chemistry Lozenge Cream Ophthalmic ointment
Discover Pastilles Gel Ear drop
Modification (in pre existing drug molecules) Pental cone Poultice Nasal drops or spray
ii:- technological process Pills Paste Infusion
characterization and evaluation of API , excepents and dosage form Granules Dusting powder Extracts
we get the knowledge from QC instrumentation Powder Liniments Tincture
Syrup Lotion Douches
Oral solution Colloion Mixture
iV:- manufacturing process
Emulsion Paint Lintises
we get this knowledge from
Suspension Aerosols Drugght
Dispensing Elixir Suppository Pellets
Industrial pharmacy Linctures Enema Irrigation
Physical pharmacy Drops Pessary Stips
What are the steps Gargle Injection Patches
Whatis the senence
V:- manufacturing eqipments to protect the drug substance from the destructive influences of
.industrial pharmacy atmospheric oxygen or jumidity ( coated tablets )
.pharmaceutical engineering to protect the drug substance form the destructive influence of
Chromatography Spectroscopy gastric acid after oral administration
Paper IR to conceal the bitter, salty or offensive taste or ador of a drug
TLC FIIR
to provide liquid preparation of substances that are either
HPLC transmittance
insoluble or unstable in the desired vehicle (suspension)
GAS chromatography Thermal analysis
IGA to provide rate controlled drug action
we can conclude dote p.tech include multiple disciplines like to provide optimal drug action from topical administration sites
Organic chemistry to provide for placement of drugs directly in the blood stream or
Medicinal chemistry body tissue
Instrumentation to provide for optimal drug action through inhalation therapy
Q.C
Development and use of pharmaceutical product Evolution in dosage form/drug delivery or
Transition periods of dosage form two eways
Dosage form drug 1:- primitive ways of drug delivery
A drug can be changed to dosage form but a dosage form cannot be 2:- modern ways of drugs delivery
changed into a durgh i)chewing
Drug roats  glyceriza glabra
Any agent or a substance intended for use to: rhizomes  turmeric ginger
1:-Diagnose :- a pharmacist dose not diagnose stems  ephedra ( ephidrile)
Isotopes bark  cinaman cinchona
2:- mitigale :- symptomatic treatment leales  neem cena , peppermint
3:- treat :- reliving or increasing the disease flowers  rose
4:- cure :- sample evolution of disease fruit  papptta ,avocado
5:- prevent -> vaccines seed  clove
Disease in human being and other animals anther  sefron
Dosage form (ii) seuffina .  snoffing powder in nos tril

Firalised shape of finished product for presentation of drug (iii) inhling afeem , cocaine
substances. (iv) smoking obtain from opium
Drug substances are administered in combination of 1 or more Tobacco , chars
medical agent (pharmaceutical agent ) these pharm. Agents perform Obtained from cannabis
varies and speciallzed functions like to dilute thicken stabilized (v) scorts / sooting / soots – luman
soluble suspend emulsify suspend color flavour and fashion the drug (vi) gums . resins, oleogum resms / secetions
product to obtain an efffeaious and appealing dosage form in order Xanthum
to develop a proper design and formulation of a dosage form require Acacia
the consideration about physical chemical and biological Tragacanth
v:- to prolong the action of drug
Drawbacks of primitive ways
i:- no content uniformity the measure of extent of drug that reaches the blood systemic,
ii:- no dose accuracy circulation & is available at the site of action.
iii:- no selectivity To prolong that action of drug
iv:- no accuracy in results
v:- greater / higher chaces of toxicity The release of drug from 2nd DDS to mimic the zero order
kinetics in order to achieve a steady state conc in plasma but
2:- modern ways of drug delivery can not achieve a 100% zero order kinetics
Reasons why we moved to modern ways Release of drug is independent from conc of drug
Goals / aims environmental factors
1:- spatial placement The release of drug from 2nd G DDS follow psedo zero order
Derived from word space defined as delivery of smallest req. kinetics
amount of drug to the req area or required space e.g enteric coated tab & cap
e.g 5 gm of drug in heart . sustained release tab & cap
2:- temporal delivery With the advancement in pharmacokinetic biopharmacetic
Derived from word time . defined as smallest req. amount of human physiology & anatomy the new drug formulation
drug to a specific req. area/ space at specific rate & for a remerse which lead towards an improment in dosage form for
specified period of time patient comphiance & to get maximam banefits for human
e.g 5gm / ml/ for 48 hrs at cancerous site beings
magic bullet 3rd Generation DDS

proposed by payl ehrlich Came in 1960 ‘s
modern way of drug delivery sys Goals :- to achieve steady state conc of drug in plasma
can be classified into diff generation When a drug follow zero order kinetics than we can say that
1st generation DDS release of drug is independent
2nd generation DDS No fluctuation in conc of drug in plasma for a prescribed period
3rd generation DDS of time
4th Generation DDS Graph
5th generation DDS 4th Gen DDS
1st + 2nd + 3rd + 4th = dosage form once we administer the DS you have no control on the release of
5th = genetic engineering drug. & fate of drug.
DRAW BACK.
1st Generation DDS Narrow therapeutic effects:
In 19th century was introduced High chances of toxicity & decreased safety range.
Tablet Anti- cancer drugs
Capsule The cancerous cell are abnormal body cell
Solution We cannot delivery drug when we require it
Elixirs Where we want it
a contraindicated drug cannot be administered e.g a sustained
Advantages Disadvantages
I:- content Patient compliane release drug is already present in the body & we cannot deliver
uniformity Chances of toxicity another drug
Ii:- dose accuracy Side effects Due to renal failure we can not stop the relase of drug
Iii:- selective Degradation of
Iv:- accuracy in drug 4th Generation DDs
result 1:-Targeted/Site specific DDS
V:- less chance of Its desireable in order to achieve max patient compliance to achieve
toxicity drug safety & efficacy & to reduce drug toxicity
Two type
i:- simple targeting
2nd generation DDS ii:- soffisticated targeting
Also known as sustained release DDS came in market in 1450’S 2:- pulsatile / modulated DDs
Goals 3:- bioresponssive/ self regulated/ feedback DDs
i:- for better patient compliance i:- STC simple targeting
ii:- to reduce dose frequency we can achieve s.t by applying the drug on diseased skin, eyes nose
iii:- to protect drug from hostile environment= from a cidic ii:- soffisticated targeting
environment dissolution disinleration we have to deliver drug at required organ or tissue or specific
e.g destative environment receptor
iv:- to enhance bioavailability
components of targeted DDs
(i)Drug API i:- is available in market, FDA approd
(ii)Carrier ii:- are not available
(iii)binding moiety / molecule iii:- in market & net FPA approat
e.g liposomal preparation of poxurubicin
liposome  carrier binding moiety folale 5th Gen DDS
It is based on generic enginnering or gene therapy or
2:- pulsatle bictechnology Gen therapy is intended to meat the cuase of
There are certain requirement for DDS in case of pulsatile DDs, the disease rather than the symptom it is essentially the sign of
it is the best delivery system in pulsatile DDs the delivery of cell by introducing therapeutic gens into genetically disabled
drug or release of drug form dosage form should mirror certain cells to dieliver therapeutic agent meal by genes
physiological needs or physiological release
Chapter #02
Chronothertrapeutics Modified release DDs
Branch of medical sciences that deal with administer of drug Delivery system from which the rate of release of drug is
according to schedule which come to daily weekly or monthly modified or altered for require period of time
circadian changes. Of living organism in orcher to minimize side Classification
effects & maximize health benefits Generally there a 3 types
1:- delayed release DDs
Circadian Rhythm 2:- extended release DDS
24 hourly weekly or monthly cyclic changes in physiology 3:- targeted release DDs
biochemistry & behavior of human being and adhr animal
1:- Delayed Released DDS
Melanin secretion pigment =- more exposure to sun more melanin is
Delayed release there is no immediate release of drug from the
secreted
Melatonin sleep inducer system but the release of drug occur other a required delay in
e.g in arthritis patients the joint of the patient stiffs so melatonin time period
drug are given e.g enleviccoated
Bioresponsive DDs 2:- extended release DDS

There is a cond or req if that cont is available dey we can formulate Classified into 3 types
bicker DDs Sustained relsease the DDs protects the drug from hostile
And is there should be aknown relashnship between plasma level & environment it increase the patient compliance and it reduce
pharmacological effect but level & pharmacological effect but it mean the dose frequency it also enhances the bioavailability of the
there should be a biomuther in body in secretion drug and prolong the action of the drug.
Drug with narrow therapeutic effect we do not change them into d
Control release
e.g relase of hormone . secretion
The control release DDs is used to achieve the steady state
insulin .. when plasma level has a therapeutic effect
this type of system can be designed for diabetes concentration of the drug in control release DDs the release of
can be classified into 3 classes drug is independent.
1:- close loop system with biosensor & pump
2:- close loop system which release drug by self regulating 3:- targeting release
3:- close loop system with microencapsulated cells/ drug Is decrease to release drug at our required targeted diseased
1:- CLSW B&P site. Targeting may the organ targeting in which we target an
This sys has 3 main compartment organ for the release of drug
I:- biosensor ……..> a prche that is inserted in the blood vessel of the e.g targeting & brain targeting
patient that senses the glucose level of the patient and send these targeting of receptor in which may is released at contain
information to algonrthrm
receptor sites
e.g malelaraclly based software that cal. The dose on the bases of
e.g alpha receptor beta muscarinic .
information received from biosensor & finally the pump inject the
calculated dose in the body of patient the pump consret of step
motor drug reserror and label
ii:- in this system we use sensitive polymers these polymers are

sensitive pH & glucose on the disturbance of glucose level the
polymer senses it & self regulate it
iii:- hence this drug system living cells from natural sources are
microsenulated and are inserted in the patient of body
e.g islets of langethans or drug that release insulin are
microncapulated and inserted into the body
Granulation
Ch. Sherjeel Adnan
B.Sc., B-Pharm B.Z.U
M.Phil. (Pharmaceutics) I.U.B
Ph.D (Pharmaceutics) B.Z.U
CHEE 440 1
Objectives
 Granulation
 Why?
 Granulation techniques
 Particle bonding
 Granulation mechanism
 Equipments
CHEE 440 2
Granulation
 Any process whereby small particles are gathered into
large masses in which the original particles can still be
identified. or
 Granulation is the process in which primary powder
particles are made to adhere to form larger, multiparticle
entities called granules.
 Pharmaceutical granules ranges between 0.2 and 4.0 mm

 The granulation by direct size enlargement of primary particles, or size
reduction from dry compacted material.
CHEE 440 3
CHEE 440 4
Why granulation?
 Done to
 For tablets  increase the uniformity of drug distribution in the
 In encapsulation product
 densify the material
 Modified release  enhance the flow rates and rate uniformity
dosage form  facilitate metering or volumetric dispensing
 improve the appearance of the product
 improve compression properties of the mix
 prevent segregation of components in powder mix
 reduce production of toxic dust/ reduce dust
 reduce possibility of ‘cake’ formation
 increase convenience of transport
CHEE 440 5
Most Frequently Used Pharmaceutical
Granulation Techniques
Wet
 Divided into two types: wet  Low shear mixer
methods which utilize a liquid in
 High shear mixer
the process, and dry methods in
which no liquid is utilized. Wet  Fluid bed granulator
granulation technology is the
 Spray dryer
more common
 Extrusion/spheronization
 Continuous fluid bed
 Wet
granulator
 Dry
 pelletizers
 Others/advance
CHEE 440 6
Dry Others/advance
 Slugging  Steam
 Roller compactor  Melt
 Foam
 Moisture activated dry
 Thermal adhesion
granulation process
CHEE 440 7
Particle bonding mechanisms
 Adhesion and cohesion forces in immobile liquid films
and b/w individual powder particles
 Interfacial forces in mobile liquid films within granules
 Solid bridges
 Attractive forces between solid particles
 Form-Closed Bonds or Interlocking Bonds
CHEE 440 8
Bonding Mechanisms in Wet
Massing
 The mechanisms of bonding in the
wet state depend on capillary and
interfacial forces between the
particles
 These four states are termed:
pendular, funicular, capillary, and
droplet or suspension state
 The mechanism of agglomeration
can be considered as a gradual
change from a triphasic stage (air-
liquid-solid) in which most
granules are in pendular and
funicular states, to a biphasic
(liquid-solid) particulate assembly,
in which the granules will be in the
capillary and droplet states.
CHEE 440 9
CHEE 440 10
Granulation mechanism
 Nucleation
 Transition
 Ball growth
o Coalescence
o Breakage
o Abrasion transfer
o Layering
CHEE 440 11
Equipment for wet granulation
CHEE 440 12
Low shear/planetary
CHEE 440 13
High shear mixer/granulator
Diosna
 Little ford lodige mixer
 Little ford MGT mixer
 Diosona
 Gral
CHEE 440 14
Collette gral
CHEE 440 15
Granulators with drying facilities
 Fludized bed
 Spray drier
 Double core and twin shell blenders with
liquid feed and drying capabilities
 Day nauta mixer
 Topo granulator
 CF granulator
CHEE 440 16
Fludized bed dryer
CHEE 440 17
CHEE 440 18
Spray dryer
CHEE 440 19
Extrusion/spheronization
 Used for multiparticulate controlled drug delivery
 Spheronizers/pelletizer/extrusioner
 Steps
o Dry mixing
o Wet massing
o Extrusion
o Spheronization
o Drying
o Screening
CHEE 440 20
CHEE 440 21
Spheronization
CHEE 440 22
Spheronizer
CHEE 440 23
CHEE 440 24
Rotogranulator
CHEE 440 25
Dry Granulation Equipment
 sluggers
 roller compactors
CHEE 440 26
CHEE 440 27
Other /advance
 Steam granulation
 Melt
 Foam
 Thermal adhesion granulation process
CHEE 440 28
CHEE 440 29
 You never will be the person you can be if
pressure, tension and discipline are taken out of
your life.
 You see things; and you say "Why?" But I dream
things that never were; and I say "Why not?“
 “You are rewarding a teacher poorly if you remain
always a pupil.
 The good teacher makes the poor student good and
the good student superior. When our students fail,
we, as teachers, too, have failed.
CHEE 440 30
CHEE 440 31
MICROENCAPSULATION
Ch. Sherjeel adnan
B.Sc. , B.Pharm (BZU)
M.Phil Pharmaceutics (IUB)
► Microencapsulation is defined as the application of
a thin coating to individual core materials that
have an arbitrary particle-size range from 5 to
5000 µm (Nokhodchi and Farid 2002)
► MICROENCAPSULATION is a process by which
very tiny droplets or particles of liquid or solid
material are surrounded or coated with a
continuous film of polymeric material.
► For solids, liquid and gases
Microcapsules
Microcapsules are small particles (liquids,
solids,solutions or disperssions) that can
contain an active substance coated by
natural or synthetic polymer of varying
thickness. Generally the active substance is
called CORE & the coating is called WALL
MATERIAL.
Microcapsules vs. Microspheres
A Microcapsule has a drug A Microsphere has its drug
located centrally within the dispersed throughout the
particle i.e. the internal
particle, where it is encased structure is a matrix of drug
within a unique polymeric and polymeric excipients
membrane
Microspheres
► Microspheres are
defined as solid,
approximately
spherical particles
ranging in size from
about 1-1000 µm
(Burgess and Hickey
2002) and are widely
used as drug carriers
for controlled release
Reasons for microencapsulation
► To make the formulation sustained or controlled
release.
► To mask the taste & odour of bitter drugs
► A mean of separating incompatible materials
► To protect the drug from environmental conditions
(light, moisture & oxidation)
► For converting liquid into free flowing powders
► To prevent the gastric irritation of certain drugs
► Water solubility or dispersability
Different Dosage Forms
The microencapsulated drugs from different
pharmacological classes can be given in the
form of free flowing powders in hard & soft
gelatin capsules, tablets, suspensions, rectal
& vaginal suppositories, ointments, creams,
aerosols, plasters and dressings.
General methods of preparation
Determined by some formulation ► Nature of polymer
and technology related factors
► Drug
► The particle size requirement.
► Intended use
► The drug or the protein
should not be, adversely ► Duration of therapy
affected by the process
► Reproducibility of the release
profile
► No stability problem.
► No toxic products associated
with the final product
► Solvent evaporation (Emulsification-Evaporation)
Oil-in-water emulsion (o/w)
Multiple emulsions: Water-in-oil-in-water (w/o/w):
Nonaqueous emulsions: Oil -in -oil (o/o)
► Polymerization techniques
Normal polymerization
► Bulkpolymerization
► Suspension polymerization
► Emulsion polymerization
Interfacial polymerization
► Phase separation coacervation technique
► Spray drying and spray congealing
Solvent evaporation
(Emulsification-Evaporation)
► Fully developed at end of 1970
► Based on the evaporation of the internal phase of an emulsion
by agitation
DEFINITION : Process of microencapsulation in which
deposition of coating material or polymer around drug or core
material is carried out by the evaporation of volatile solvent in
which polymer is present. Actually creation of insufficiency of
solvent for polymer by evaporation of solvent results in
precipitation of polymer around core material & formation of
microcapsules. Aggitation is required during this process
Method of preparations by
solvent evaporation process
Two major techniques are used for
microencapsulation by solvent evaporation.
► Single emulsion solvent evaporation
technique (O/W & O/O)
 Oil in water emulsion technique
 Oil in oil emulsion technique
► Multiple emulsion solvent evaporation
technique. (W/O/W)
Oil-in-water (o/w) emulsion
► Water as nonsolvent to the polymer are in
general preferred.
► Extremely economical and negate the
recycling of the external phase
► Suitable for the encapsulation of lipophilic
active principles
► Microencapsulation of hydrophilic active
principles by this process can pose problems
Multiple emulsions: Water-in-
oil-in-water (w/o/w)
► For the efficient encapsulation of water-soluble
active principles
► Organic phase acts as a barrier between the two
aqueous compartments preventing the diffusion of
the medicine toward the external aqueous phase
► This process proves much more effective when the
water solubility of the medicine is high (>900 mg/
mL) and prevent partioning of drug into organic
phase
► Sometimes viscosity of primary emulsion is
increased to prevent partioning
Nonaqueous emulsions: Oil-in-
oil (o/o)
► Continuous & discontinuous phase are oil and
immiscible with each other
► For drugs having high hydrophilicity and gives
highest yield
► For drugs/polymers that are degraded in presence
of water
► More expensive than aqueous methods
► Difficult to recycle oil phase
► Traces of oil possesses problems
Interfacial Polymerization
Definition; interfacial Polymerization is
atechnique in which polymerization of two
monomers, one oil soluble and other water
soluble, takes place and a polymer is formed at
the interface of two immiscible substances.
This tech is mostly used for the encapsulation of
liquids rather than solids b/c penetration of
monomer to polymerization zone is much easy
from the liquid state rather than the solid state.
General method of Preparation
► The process consists of bringing two reactants at the
interface of the dispersed phase and the continuous
phases in emulsion system
► This is usually accomplished by emulsifying the liquid
containing first reactant (dispersed phase) into continuous
phase, which is initially devoid of second reactant
► Additional continuous phase containing the second
reactant is then added. The interfacial polymerization
reaction produces a continuous film of the polymer around
the drug.
► Microcapsules can be recovered by spray drying or
filtration
Procedures adopted for interfacial
polymerization
► Procedure for water immiscible liquid core
► Procedure for water miscible liquid core
► Procedure for solid core
Procedure for water
immiscible liquid core
When the core material is lipophilic liquid, the
monomer is dissolved in the liquid core.
Usually isocyanate or acid chloride is user as
monomer. Then this solution is disperesed
in aqueous phase (containing 2nd monomer)
this prpduces poolymerization of monomers
at the interface & results in formation of the
capsule wall
Procedure for water miscible
liquid core
Aqueous solution of water soluble drug (dispersed
phase) containing monomer is dispersed in to an
organic phase (continuous phase) which contain
the emulsifier to form W/O emulsion. When
additional oil containing 2nd monomer is added to
W/O emulsion, polymer membrane is formed.
Then microcapsules are separated by different
techniques
Procedure for solid core
Solid cores are encapsulated by vinyl monomers that

polymerizes by free radical reaction.
► Different solvents used
o CCl4
o Chloroform
o Methanol
o Water
► Different monomers used
Polyamines (hexamethylene diamine) polyphenol (hydroxy
phenol propane) polybasic acid halide (sebacoyl chloride)
Applications of interfacial
polymerization
Some important applications are as follows;.
► Enzymes
► Proteins
► Artificial cells
► Pharmaceuticals
► Adsorbants
► Hormones and antibiotics
► Pigments, oily liquids & polyelectrolytes
Coacervation Or phase separation
technology
Coacervation is derived from Latin word
acervus means aggregation and the prefix
co indicates the preceding union of the
colloidal particles.
This term was first used to described the
phenomenon of phase separation in
colloidal system and thus it was defined as
A process in which aqueous colloidal solution
separate upon alteration of thermodynamic
condition of state into two liquid phases,
one rich in colloid i.e. the coacervate & the
other containing little colloide.
Deposition of this coacervate around drug or
core material form the embryonic capsule &
then appropriate gelling of coacervate
resulted in microcapsules.
Core material
The core material or drug which can be
encapsulated by coacervation can be solid,
liquid, gas, liquid slurry, suspension or
emulsion and analgesics, antibiotics,
antihistamine, tranquillizers, iron salts and
vitamins
Wall material
► The coating material can be selected from a variety of
natural and synthetic polymers depending on the core
material to be encapsulated and the desired
characteristics.
► The amount of coating material used ranges from 3%-
30%of the total weight.
► Both natural and synthetic colloids can be used,
Hydrophobic colloids are used for encapsulating water
soluble drugs whereas Hydrophobic colloids are used for
encapsulating water insoluble drugs.
Methods employed for
coacervation
Following methods can be used for coacervation & the choice
of method depend upon the polymer and the set of
conditions which are being used;
► Temperature change
► Salt addition
► Nonsolvent addition
► Incompatible polymer addition
► polymer-polymer interaction
Temperature change
By temp. change, phase separation of dissolved polymer

takes place in the form of immiscible liquid droplets, if drug
is present these droplets surround the core & form
microcapsules.
A system that utilizes ethyl cellulose & cyclohexane at high
temp. is an example of thermally induced
microencapsulation. Ethylcellulose is soluble in cyclohexane
elevated temp. but insoluble at room temp. first of all
ethylcellulose is dispersed in cyclohexane & then mixture is
heated to boiling point so that a homogenous polymer
solution is formed. Then core material is added in the
solution with continous stirring & mixture is allowed to
cool.
This results in phase separation of ethylcellulose &
microencapsulation of core material. Furthuf cooling of
mixture to room temp. causes gelation & solidification of
the coating.
Salt addition
Soluble inorganic salts can be added to aqueous solution of
water soluble polymers to cause phase separation. A
gelation-water-sodium sulphate is an example. In this
system, phase separation/coacervation is induced by
adding dropwise 20% solution of sodium sulphate.
Nonsolvent addition
A liquid that is a nonsolvent for a given polymer or does not
dissolve the given polymer can be added to a solution of
polymer to induce phase separation. The resulting
immiscible liquid polymer is used for encapsulation of an
immiscible core.
Fro example;
Cellulose acetate+ methyl ethyl ketone -------- solution of
polymer--------- addition of drug (scopolamine) -------
addition of isopropyl ether (nonsolvent for polymer) -----
---- phase separation & microencapsulation of suspended
drug occur.
Incompatible polymer interaction
Methylene blue-ethylcellulose-liquid polybutadiene is an
example of microencapsulation by incompatible polymer
addition.
Ethyl cellulose is dissolved in toluene to form polymer
solution. Then methylene blueis dispersed in polymer
solution. Phase separation is carried out by adding liquid
polybutadiene which is soluble in toluene but incompatible
with ethyl cellulose. Thus causes demixing of ethyl
cellulose & phase separation occur.
Polymer-polymer interaction
Interaction of two oppositely charged polyelectrolyte can
result in the formation of a complex having such reduced
solubility that phase separation separation occur.
e.g. gelatin & acacia are examples of oppositely charged
polyelectrolyte because gelatin has positive charge
whereas acacia possess a negative charge. Gelatin-gelatin,
gelatin-CMC are examples of other oppositely chaeged
polyelectrolyte used in microencapsulatio.
Description of coacervation
Coacervation method is divided into two main
groups
► Aqueous phase separation
 Simple coacervatio
 Complex coacervation
► Organic phase separation
CHARACTERIZATION
► Recovery of formed microspheres
► Hydration of microspheres
► Drug loading
► Encapsulatipon efficiency
► Rheological properties
► Morphology (SEM,TEM)
► FTIR
► XRD
► TGA/DSC
► Drug release
► Drug release kinetics
Water immiscible liquid / O/W Emulsion
water insoluble particles
Or
Simple CoaCervation +
Aqueous Suspension of Solid
Aqueous coating solution Particles
(gelatin in water)
Gel colloid by pouring Then add 20% w/w Na2SO4

Filter and wash coacervate coacervate solution with continuous
with cold water to remove salt Mix in to 70 % w/w Na2SO4 stirring to produce
solution Cacervation
Treat filtered material with Filter and wash particles with

Dry to remove remaining
formaldehyde to harden cold water to remove
solvent
coacervate hardening agent
Complex Water immiscible liquid /
O/W Emulsion
CaCervation water insoluble particles
Or
+
Aqueos coating solution
Particles
(accacia in water)
Pour coacervate mixture in to Add warn water until Then add gelatin solution
cold water coacervate is produced with stirring
Remove aggregates of
Then treat coacervate with Dry and comminute
encapsulated material and
formaldehyde solution aggregated material
wash with water
Water immiscible liquid /
W/O Emulsion
organiC phaSe +
Or
Separation Polymer in organic solvent
Suspension of Solid Particles
(in solid particles)
(PLA in methylene chloride)
Cooling of microcapsules to Phase separation Then addition of non solvent

solidify PLA coating (microcapsule are produced) for polymer (mineral oil)
Then further treatment with

Wash and dry
non solvent for hardening
Applications of coacervation
► Antibiotics;amoxicillin, ampicillin,
bacampacillin, cephalexin, cephradine,
erythromycin, clarithromycin,
chloramphenicol
► Anti-inflammatory drugs; diclofenac sodium,
ibuprofen, naproxen, mefenamic acid &
flufenamic acid.
► Bronchodilators; theophylline & terbutaline
sulphate.
► Sulfa drugs; sulfadiazine, sulfamerizine &
sulfamethoxazole
► Diuretics; furosemide, chlorothiazide &
sulfonamide
► Urinary antiseptics; nitrofurantoin & nalidixic
acid
► Antiepileptic drugs; phenytoin sodium,
beclamide
► Antihypertensive;isosorbide mononitrate,
captopril, propranolol &nicardipine
► Analgesics; acetyl salicylic acid
► Anticancers; mitomycin, bleomycin &

mercaptopurine.
► Tranquilizers; diazepam & oxazepam.
► Electrolyte replenisher; sodium chloride &
potassium chloride.
► Vitamins & metal salts; A, B1, B2, B6, B12,
C & D and mineral salts like Zinc sulphate.
► Converting liquids into free flowing
powders; Cod liver oil, benzaldehyde &
other citrus essential oils.
► Recovery of formed ► Hydrationof
microspheres microspheres
► Rheological studies
► Drug loading
► Encapsulation efficiency
Ethylene Glycol Dimethacrylate co-
vinyl acetate microspheres
► Polyhydroxybutyrate-
co-valerate (PHB-HV)
FTIR & XRD of PCL-PVP
microspheres
DSC
► 5-FU microspheres
Drug release
Equation for drug release kinetics
• Zero order release Qt  k0 t
• First order logQt  logQ0  k1 t
• Higuchi,s model Qt  k H t 1/ 2
1/ 3 1/ 3
• Hixson-Crowell Q0  Qt  k HC t
• Korsmeyer-Peppas M t
 k KP t n
M 0
Application
Potential applications of
microspheres
► Taste and odor masking
► Conversion of oils and other liquids to solids for ease of
handling
► Protection of drugs against the environment as moisture ,
light ,heat , oxidation etc and vice versa i.e. prevention of
pain of injection
► Delay of volatilization
► Separation of incompatible materials
► Improvement of flow properties of powders
► Safe handling of toxic substances
► Aid in dispersion of water insoluble substances in aqueous
media
► Production of sustained release, controlled release and
targeted medications
► Reducing dose dumping potential compared to large
implantable devices (Burgess and Hickey 2002).
► If you stand for a reason, be prepared to
stand alone like a tree and if you fall on the
ground , fall as seed that grows back to
fight again
► Whenever you get really attached to some

one more than anyone else, then that
person is surely going to heart you more
than any one else
INTRODUCTION
Conventional dosage forms are the basic dosage forms which have abrupt release of drugs and there
is no modern technique in them.
Example :
Tablets, capsules, syrups, emulsions, gels etc
These may have organoseptic issues. Drug itself is not soluble
 Drug soluble in medium = Soluble form
 Drug insoluble in medium = Aggregates on bottom
Doxorubicin (Doxarubicin) = cause cardiotoxicity so shifted to nyosomal (noisome ) dosage

form
 Tablets have least bioavailability
 Peak height is decrease for narrow therapeutic index drugs.
 Drug molecule is not changed while properties can be altered
 Maxius (maxial) lozenges = poor permeability
 Ranitidine = moisture sensitive
GASTRO-RETENTIVE DRUG DELIVERY SYSTEM: (GRDD)

Floating System :
Remains floating on fluid
Sinking System :
Sink to the bottom an swell
Gastric mucoadhesive :
Adhere to mucous
Swellable system :
Fragments are formed
P.Tech :
Focus on advancement of techniques/technologies
 Ingredients properties
 Pharmaceutical drug properties
 Methods of preparation
 Problem in dosage form
Example :
Diclofenac sodium => forms a complex with beta-cyclodextrin (solubility and permeability
enhancer) => formation of complex will decrease ulceration and duration is prolonged.
This complex formation is called solid dispersion technique.

Definition :
P.Tech is the branch of pharmaceutical sciences that deals with the knowledge API active
pharmaceutical ingredients, excipient, equipment and dosage forms .
Conventional dosage form does not have their own techniques for
 Increasing bioavailability
 Increasing solubility
These are basic dosage forms.
P.tech is a merge of 2-3 product basically

 There is no compulsion of proving large scale production in P.Tech.
Primitive ways of remedy :
Ways Examples
1)Chewing Roots (glycyrrhiza)
Rhizomes
Stem
Bark(cinchona bark)
Leaves (digitalis, senna)
Flowers (rose, clove)
Fruits (apple, mango, tomato)
Seeds(sunflower , seasame, flex)
Anther (saffron)
Tobacco , cannabis , alcoholic beverages
Cocaine
Ash flakes , volatile oil , rose water ,thymol ,eucalyptus
2)Smoking
3)Snuffing
4) Inhalation
Disadvantages :
1)chances of toxicity
Example glycyrrhiza cause tachycardia
2) no content uniformity of ingredients
3) no accuracy of dose
4) no uniformity of active ingredients
5) no selectivity or specificity of drug towards the disease
Modern way of drug delivery :
Two Theories
Theory#1 (Spatial) related to space => drug delivery to the space of receptor, there is no
need of time
Theory#2 (Temporal) related to time => drug should be on receptor for time or drug
molecule should be on receptor for specific time.
Temporal Theory :
It is delivery of small, specific or minimum amount of drug to be required at body space
(receptor) for a required period of time at a required rate.
Example :
Vaccine
Spatial Theory :
Delivery of small or specific amount of drug to or required at specific body place.
Example :
Vaccine & 5mg of drug for beta receptor
Generations:
Drug delivery systems are classified into 4 generations
 1st Generation : simplest dosage form and conventional method of delivery of drug.
Example : decoctions, infusions , tablets , pills , troches , poultices
5th Generation is genetically engineered.
Advantages :
Content uniformity
Active ingredient
Decreased chances of toxicity to the primitive method
Disadvantages:
No selectivity/specificity
Pharmaceutical instability is not cleared e.g BCS classification
Increase dose frequency
1st order kinetics
Patient compliance was comparatively good than primitive method
Patient compliance of acute diseases
1st order kinetic non linear pharmacokinetics and toxicity occurring in body
Lipophilic agent = non-linear
Non linear : there can be a sudden absorption or excretion
Hydrophilic drugs : cause more toxicities to kidney . For example : gentamycin and
amikacin
Absorption should be shifted to zero order, all other on 1st order.
Infusion is zero order.
When body system is saturated the kinetics of drug will be zero order => because there
will be no further filling in receptors.
0 hour 100mg => 1 hour 90 mg => 2 hour 80 mg ( Excretion 10mg/hour)
Constant manner => zero order
While in 1st order => there is so much layer
Release in-vitro level = zero order
Release in-vivo level = 1st order
Medicinal + pharmacology = development of drug
2 important disciplines
 Pharmaceutics
 Pharmaceutical technology ( equipment & preparation of process)
We give drug in dosage form because we need dose response curve over time.
Biodegradable : body has mechanism to degrade any substance. If not biodegraded it

becomes carcinogenic
Biocompatible : substance does not harm the body or cause any instability
Aims of dosage form :

 To deliver drug
 To protect drug from environment
 Set the BA according to design
 Need to protect drug substance from environment characteristics example vitamin c
 To protect drug from gastric fluid
 To provide liquid preparation e.g suspensions
 To provide rate controlled drug reactions (all body reactions are 1st order , sustain release
are 1st order , control release are zero order )
 Body systems not saturated is 1st order
 Body systems saturated is zero order
 To provide optimize action of the drug
 To provide insertion into body cavity
Polymer
1)Hydrophilic (Polymer) capability to dissolve in water , PEG 200 dissolve in water ,PEG 400
increase viscosity cause water dispersion , HPMC hydroxypropyl methylcellulose , CMC
carboxymethyl cellulose , Acacia
2)Lipophilic Hydrophoic (Polymer) ethyl cellulose
Knowledge of
 Raw materials and excipients
 Equipment and machine
 Method of preparation
 Basic and physiochemical properties of drug
Parameters to be focused :
 BA
 Solubility
 Permeability
2nd Generation : (Sustain Release Drug Delivery System ) SRDDS

 1950s
 Sustain release (slow release)
 Addressed drawbacks of 1st generation
 Polyer that retard the release of drug
 Load more than 1 dost (make sustained release dosage form => slowly release of drug)
 In-vitro release is 1st order ( 8-12 hours SR Tablets )
 In 1st generation
 Dosing frequency was too high
 Cmax fluctuates which effects side effects and efficacy
 No patient compliance
THEREFORE SUSTAINED RELEASE TABLETS WERE INTRODUCED
Focus : To attain zero order
Disadvantages :
Don’t follow zero order
No specificity
Advantages :
Less frequency
Patient compliance
Example : Enteric coated tablets and sustained release
3rd GENERATION
 Control release
 After 1960s
 We want to shift drug to zero order and it happens when drug is
independent of initial concentration
 In this generation zero order achieved
Example :
Osmotic pumps (osmotic control drug delivery system , hydro capsules,
micro-capsules, diffusion control system , ion exchange resin)
 Dose indivisualisation
 Control release to stop fluctuations in narrow therapeutic index potent
drugs
Hydrocapsules :
When water touches gets inside and show swelling behavior and drug is
release
Drug release => 1) Gel erosion Dissolution

2) Diffusion
Capsule solvent inside swelling drug release Gel erosion or diffusion
Osmotic DDS :
 Adalat (Nifedipine)
 Holes by laser (very minute holes)
 Water inside through hole hydrodynamic pressure created inside drug is
release
Ion Exchange:
 Water inside polymer + drug GIT ions attaches to polymer drug release by
polyer
3rd Generation:
 Nano liposomes, nanoparticles
 To increase selectivity/specificity decrease toxicity
 Drug should reside at receptor site for clinical response is called specificity
 Focus on adjusting that is targeted
 Main Focus Specificity and selectivity is enhanced
 Drug
 Binding agent/dosage form
 Drug carrier (whole particle carry to site of action)
 Targeting occur at nano levels
Particle Design as
 Nanoparticles
 Nanosomes
 Lyposomes
 Microcapsules
Example : Cancer (nuclear ratio increase in cell than cytoplasm ) Uptake the
hyaluronic acid cancer cell HA load on particle surface
Anticancer drug Release Drug (anti-cancer) rotated towards tumor

binding surface
Sometime overlook degradation
Virosome :
 The head separates and anti-viral is added to it then closed taken by other
viruses for replication Replication of this head and causes degradation anti-
viral effect
Types of 4th Generation :

 Targeted DDS ( cell tissue organ)
 Pulsatile DDS (4-5 layer) release pulses into GIT and environment one by
one layer is released .
Bioresponsive DDS:
 Dosage form as it is in body e.g insulin dependent on sugar depends on pH
and temperature
 Drug release depends on biological stimulus
In site Preparation :
Change in consistency of dosage form e.g gels into solution
Advantages :
 Drug selectivity / specificity e.g DNA drug delivery must be deliverd
intracellularly
 Reduced toxicity
 Increase clinical response / outcome / efficacy
 Patient compliance
Disadvantages:
 Costly procedure
 Reproductibility (not everyone is able to make nanoparticle)
 Toxicity (polymer is not biodegradable)
 4th generation produce mostly parenterals
5th Generation :
 Genetically engineered DDS
 Alteration of genes for betterment of people
 Does not deliver drug but alter the DNA / gene
 Reaches to intracellular spaces
 DNA has sensitivity , any change may cause destruction of DNA
 To treat cancer #1 anti cancer kill cells i.e Increase hazards and increase resistance
#2 DNA delivery normal gene decline replace oncogene and express itself produce
protein wraps DNA incorporates on nucleus
 DNA is combined with plasmid (bacterial DNA) Delivers the DNA to desirable point
 Check extent of gene expression
Advantages:
 Cancer cells are killed effectively
 Almost no side effects
 Drug delivery pathologically
 Wide drug delivery upto cellular level
Disadvantages:
 Not 100% effective
 Reproductibility concern
 Costly
 Indivisualised drug delivery system
Drug discovery and product development :

Drug discovery refers to any drug or substance having therapeutic activity from natural
source.
Drug is chemical structure
Sources :
 Natural sources
 Synthetic sources
 Semi synthetic sources
Natural sources :
Plants , animals , minerals and mircrobes
Semi Synthetic source:
Natural but are somehow modified foe example a polymer natural is taken and modified.
E.g Morphine natural - Acetyl morphine (semi synthetic)
Synthetic Source :
Synthesis of drug molecule from zero and is artificially prepared . The material for this can
be taken form natural sources but it is synthesized in lab.
 A drug must have biological activity
Product discovery :
 Clinical pharmacist
 Pharmacologist
 Medicinal chemist
 Biologist
 PTech scientist
 Animal toxicology specialist
 Chemist
Required to develop a drug.
New molecular entity NME —> If passed by criteria preliminary and shifted to human level —
>Investigational new drug IND
Aims of dosage form
1. To deliver drug
2. To protect drug
3. To set bioavailability according to design
4. Need to protect drug substance from environmental characteristics
5. To protect Drug from gastric acids
6. To provide Liquid preparations for example suspensions.
7. To provide rate controlled drug reaction
All body reactions are first order
Sustained release 1st order
Controlled release 0 order
Body system not saturates 1st order
Body System saturate 0 order
8. Sometimes We need optimal dosage form of a drug
9. To provide insertion to body cavity
Requirement for pharmaceutical technology

Knowledge of excipients equipment techniques drugs.
Critical point for Pharmaceutical Technology
bioavailability solubility permeability.
Ways of drug discovery

Random screening
Molecular modification
Mechanism-based discovery
Random screening
No logic
Natural
We performed test on whatever we get
Can take many molecules and Test and we assume that one of these May contain a drug molecule
We check “folk curves”
E.g Glycon discovered—> added to syrups etc
Advantages
May discover a molecule. For example penicillin
Disadvantages :
extensive money and time wastage
Page#22
Molecular modification (semisynthetic)
Molecules discovered—> If any side-effects due to any functional group—>Change that group or
replaces—>Effect modified—>In vivo toxicity and invitro solubility.
For example
Omeprazole —> Esomeprazole
Ampicillin —> Hydroxy ampicillin
Medicinal chemist, Biology in pharmacology involved in all stages.
Mechanism based discovery:

Disease identified by biologist/clinician —> mcEnnis of disease—> inhibit the stimuli that causes the
disease—> Study attachment activity —>That where and which things attaches to receptor site and
the substance that bind is considered as drug.
In Silico modelling:
Drug modelling
In Silico means Taking help of a software.
Software is given the receptor detailed information And software is asked to design molecule
possibilities Are further testing. This is called docing.
Random screening is natural source.

Molecule modification is semisynthetic.
Mechanism-based research is natural and synthetic and semisynthetic.
In silico Drug modelling is synthetic.
Page#24
Product/drug development;
Lead compound—> Basic nucleus is known—>Containing desirable properties
Lead compound is representative compound on mother compound
By medicinal chemist
NME Compound
#1 Biological study invivo
Toxicity main effects in animal body.
#2 In vitro—> preformation—> Preliminary study physio chemical properties
1&2 leads to Submitted as IND —> official approval for human trials.
Pre-clinical study—> parental—> for immediate response
Phase 1–> suspensions, tablets,capsule

Page#25
Information to FDA —> 3 to 10 months review if failed.

3 to 10 months review if passed —> NMDA —> NDA Drug —> Enter phase 4 —> Product surveillance
and development.
The formulation
Discovered drug is delivered. Drug is formulated at two levels.
Level#1 preclinical—> Pre-formulation—>Simple solution is injected to animals and Doses are

checked —> No need for tablet and only Peranteral are given—> therapeutic value divine.
Level#2 Clinical->Delivered to human—> Made in advance forms —> For example syrups, suspension
are formed —> Therapeutic window previously defined should be maintained.
Page#26
Test for preformulation:

1) Bulk characterisation:
Crystallinity or polymorphism
Hygroscopicity nature
Particle characterisation
Thermal effects
Flow properties
2)Solubility analysis:
Ionization constant PKA
BH solubility profile
Common ion effects
Partition coefficient
Solution
3) Stability analysis
Solid-state stability
Solution phase stability
Excipient compatibility study
Bulk characterisation
1)Polymorphism;
Shape of crystal varies in a drug. Amorphous is more easily soluble because bonding is loose.
How much effect is on change and crystal structure.
Effect on Invitro. Release and than In blood serum levels is checked.
2) Hygroscopicity:
To check if there is any change in stability or solubility due to hygroscopic nature of drug
Less effect on solubility
Degradation of drug is affected by hygroscopicity of Drug
Degradation has direct contact with moisture absorbance
3) Particle characterisation:
Overall an average particle size—> Effect of change on dosage form.
4)Thermal effects;
What is the effect on drug of Thermal Variation at different temperature changes. We study the
physical examination.
5) Flow properties;
flow properties required for the flow of drug At scale up level
We check the speed of the drug to flow out of machine
Bulk and tap density etc
Solubility Analysis
In which range and solvent the drug is soluble
1) ionization constant
Important profile
PH= Extent of hydrogen ions
pKa= PH in which 50% drug is ionised. Related to drug stability.
2) PH solubility profile:
Range made of different pH’s
Buffer made
If drug is pH specific or check PH where drug is stable , Ionizable, degrade etc
3). Common ion effect :

If drug added over some PH, How much of it can be settled
All this information is helpful and stability studies
Setting—> Precipitation—>Instability
Partition coefficient;
How much drug has ability to be lipophilic or hydrophilic
It affects the permeability of a drug
Value low = hydrophilic properties
Value high= lipophilic properties
Value increase than 10= Drug has irregular unpredicted permeability
5)Solubilization:
Molecule is soluble in which kind of Solvent -> For in vitro testing and advanced drug delivery—
>Different concentration of drug in different solvent.
Solvents:
Water, ethanol,Methanol , Isopropyl alcohol than Use surfactants
Check different concentration of solubility—>. Indifferent Solvent concentration
Water—>methanol —> surfactant salability—> In vitro level
6)Dissolution:
Same in vivo condition as in in-vitro.
Works on Ph(in-vivo). On which drug is to be delivered
Stomach 0.1N Hcl
Intestine 6.8 phosphate-buffers
Tears 5.5
Skin 7.2
In dissolution
1) We observe rate of drug taken to release from dosage form
2)Precipitation of the drug
0.5% SLS = Surfactant is a different drug is not soluble
PH adjusted
Maintain thinking conditions of dissolution medium
3) stability analysis:
Deliver in solid form so added in solid excipients—> so stability should be maintained in solid-state
Expiry should be more than two years (range 2-5 years)
Solution phase stability:

Drug molecule if solid in liquid then stability should be maintained according to the conditions.
Excipients compatibility studies:

Drugs are guest in dosage form—>Patient buy the medicine—>Release form their dosage from after
ingested
Drug excipients interaction—>. Replaced with a different excipients.
Analysis and excipients by :

1) FTIS (Fourier Transform infrared spectroscopy)
2) DSC (differential scanning calorimetry)
3) NMR ( Nuclear magnetic resonance at molecular level)
4) UV (Qualitative analysis)
Preclinical studies;
Animal toxicity study is done to check
Therapeutic response of study
Chemical or biological molecule—>Drug is called
1) Mutagenic study :
Capability of drug molecule to alter or effect DNA. In animals cell cultures are done—> Labelled
different cells then it is stored—> Drug concentration is injected and animal is saved.
DNA 1) DNA damage 2)Change the sequence of DNA.
2) Carcinogenic studies:
Oncogenes activation or conversion of normal genes to cancer cells.
Either normal cells are affected or not?
3)Reproduction studies:
It includes Fertility, reproductive performance, tetratology, pre-and post natal studies, multi
generation effects.
Fertility;
Does the drug maintain the jam cells or cause the jam cells to lose their activity.
Reproductive performance; normal physiology process is maintained or causing any problems?
Tetratology:
Fetus toxicity or not?
Pre-and post natal studies:
Pregnant animals is injected with drug and check if fetus is getting infected or not.
Multi generation effects:
In multiple generation, drug effects are observed in germ cells and genes.
4)Acute toxicity studies:

General symptoms of toxicity
Organ toxicity separates each organ with the help of biomarker and anatomical studies and it is then
compared with normal organs.
5) Subacute Or subchronic toxicity studies:
Low doses Are given and their affects our observed
Physiological behaviour of animal is observed and compared with normal behaviours.
6)Chronic toxicity studies

Check effect of drug molecule at lower dose for longer period of time observe the duration after
which animal show toxicity.
MICROENCAPSULATION
pellets are slightly big and define shape. Granules do not have define shape and are
irregular. Dosage form in the particle form is called particulate drug delivery system. Particle level
or size these may be nano from range 1-500nanometer which are called nano drug delivery system
Submicron more than 500 and less than 1000 nanometer while the others are the micron which are
visible to eyes and range from the 500-800nanometer are called micron drug delivery system.
MICROENCAPSULATION
Drug protected in a protective layer if it is done at micron level it is called microencapsulation. Drug
is encapsulated into a polymer or shell and it is done at micron level. Lipid based dual layer is called
liposome. If the layer is purely a cholesterol layer it is called Noisome. Nanosphere particle is
absolutely sphere do not have shell. Nano capsule drug is enclosed inn shell. Nanoparticle no define
shape and no shell is present.
ADVANTAGES OG MICRONENCAPSULATIN
1)protect the drug from gastric pH, taste, degradation or oxidation.2) to target a point. 3) sustain or
control release of the drug. 4) improve patient compliance.
DISADVANTAGES OF MICROENCAPSULATION
 Time consumption method. 2) expensive 3) consistency of the product may be irregular.
APPLLICATION OF MICROENCAPSULTION
1)To hide the core or drug. Moisture sensitive drug is enclosed in moisture impermeable
shell called shellac. 2) Taste masking with sweeting agent. 3) to avoid gastric irritation which
may include to enhance pharmaceutical activity and for sustain or control release by varying
no of coating, thickness of coating, use polymer which control the release.
Drug loading in the core and drug coating in the shell. Coating polymer coating properties
are provided. Core polymer are including bulking agents, form complex with drug, drug +
sustain release.
REASON TO FORMULTATE MICROENCAPSULATION
1)to protect reactive substance from the internal and external environment e.g. vit c 2) to convert
liquid active form to solid form 3) to separate incompatible components of the ingredients 4) to
protect the immediate environment to microcapsule e.g. drug is anticancer or antibiotic. intravenous
+ oral drug delivery system. For moisture impermeable layer shellac is used. 5) isolation of core from
its surrounding. 6) retarding evaporating of volatile core. 7) for safe handling of toxic compounds. 8)
to control release of active component. 9) mask the odor or taste of the core 10) to increase the B.A
of the drug. 11) exertion of duration of activity.
PULSATILE DRUG DELIVERY SYSTEM one

layer will release the drug at a specific time (lag time). Expensive method and machines.
pharmaceutical process is not applicable in industrial level. As particle size is in nano size as no
mixing is possible. Machines are not capable. Decease side effects by effecting the site and increase
efficiency.
REASONS FOR MICROENCAPSULATION
7.sea back thorn and sofosbuvir (antiviral) very sticky material which is difficult to handle so add an
inert material which get stick to the material. Toxic materials are also coated like anticancer and
thyroxin (6.25microggram) disturbed significantly in body thyroxine hormone. Protect from GIT
content like penicillin’s and vitamins.
TWO PARTS involving core (pure drug + additive) and shell (covering). Polymer + coating material is
applied while core + coating material dissolve in polymer (vehicle)
MICROENCAPSULE in which one is core depot form (reservoir system) while in another core is
not continuous (matrix system).
ORGANIC SOLVENT inflammable, expensive, not economical, toxic so prefer aqueous media. spray
method gelatin water spray is the core material.
MONONUCLEAR define shell single depot or reservoir core.
POLYNUCLEAR define shell multiple cores, discrete patches of core, presence of vesicles or large
particles.
MATRIX 3DSTRUCTURE, core exit in small particles. core material is mixed with the shell/polymer, no
define shell.
RELEASE MECHANISAM
 by pressure or shear stress.

Water diffuse into microcapsule and create hydrostatic pressure by producing shear stress
on inner walls of the capsule then rupture or crakes or leaks on the wall and release of core in
GIT.
 By melting the wall which is made of hydrophilic materials.
Coating layer touches the solvent layer and coating layer will remove or melted then core is
exposed.
 BY dissolving It under particular condition.
Like in enteric coating the shell dissolve in enteric medium.
4)Drug coating
No drug loading, drug is present in coating layer, drug + coating layer mixed and particles are coated
in GIT body fluid when touches the coating layer, the drug is released.
5)By solvent action.

Body can digestive enzymes, water molecules biomolecules hydrophobic substance
in solvent system on interphase of material is solubilize the coating layer.
6) By enzyme attack.
In enzyme attack enzyme should convert a substrate into product like polysaccharides coated layer
in enzymes eat the layer which cause holes or punches, pores core it will released.
7)By chemical reaction.
Non enzymatic reaction polymer may DE gradated or react with body components and get
disrupted. Coating layer has elastic appearance. polymer, may break down or converted by chemical
reaction.
8)By hydrolysis or slow disintegration.
Coating material starts to worn out, coating layer gets disintegrated in the GIT, coating layer it is
controlled as the coating layer is dissolved only then core is released.
MICROENCAPSULATION TECHNIQUE
General method one is core solution and the other is the coating solution which is always in organic
phase as it gets evaporated, it may coat material get insoluble including precipitate and deposits,
while the coating layer deposits on the core.
Dispersion phase in this particle form in the solution, Solubility phase having coating layer and clear
solution.
METHODS
Spray drying basic principle coating is emulsified in organic phase, core is first emulsified into
coating solution.
Colloidal dispersion uniformly distributed.
Aggregates non uniformly distributed or clumps or separated by ppt or settle down in this emulsion
is form in continuous phase or coating solution.
PROCEDURE. Fill the mixture in the tank the blow through the atomizer into drying chamber with
pressure through atomizer thus increase the surface area by increasing the drying and organic phase
evaporates while decreasing the pressure hot air is also introduced. change geometry effect on flow
properties limits the type of shell material coating material cannot be dissolve in water and cannot
form emulsion as it requires two phases done with organic solvent, solid drug is used because liquid
material is not responded properly.
INTERFACIAL POLYMERIZATION.
Not spray, core material + coating material placed in a tank after sometime polymers are formed
monomers functions as polymer production and polymer encapsulation either centrifuge or filtered
to separate the coated particles like drying.
SOLVENT EVAPORATION
Whole reaction take place in water media core particles are uniformly dispersed in water media
coating polymer with organic solvent, both are combined at stirred at high speed organic phase is
evaporated and droplets of coating material form solubility decrease and coating the core material
and microencapsulation is achieved. If organic solvent remains make the system unstable may
solubilize the coating layer and can cause toxicity.
PREPARE PARTICLES ARE COLLECTED
BY centrifugation with high speed centrifugation at specific rpm material is rotted and different
layers are separated and thus collected or by filtration in which filtering media is used to completely
separate the liquid vehicle phase.
If still any few moisture is left then freeze-drying freeze particles at 0 temperature the complete
moisture is removed. In these limitations are involving like expensive and multiple steps and
laborious. Matrix type coating polymer form polymeric network and the spaces are embedded with
drug molecules and used for sustained release Dispersion type when core material is not solubilizing
in the coating polymer it will be dispersed not a matrix type network.
Desolation solubility is reduced polymer is soluble then changing condition lead to precipitation
LIQIUD MANUFACTURING VEHICLE two solutions like polymer rich coating solution conc solutions
polymer poor phase core or diluted solution, includes the three immiscible phases like polymer poor
solution, LMV, and polymer rich solution including homogenous solution forming emulsion or
suspension. examples are chitosan and Carbopol
Only particles are formed by this method then we have to separate and dry particles causing
increase no of steps for biological molecules core phase to aqueous phase
Changing factors or conditions directly effect the coating polymer
COACERVATION may be simple or complex simple including as coating polymer setup on core
material complex as electrostatic interactions is involve in the settling of coating polymer on the
core
COMPLEX COASERVATION same as simple conservation only difference is coating polymer and core
polymer combine to bind with the help of electrostatic interaction
DESOLVATION dissolve out settle down or slow precipitation. SOLVATION the capability to dissolve
something
Novel Drug Delivery System (DDS)
Novel means something new

3rd 4th and 5th Drug Delivery System
totally new Drug Delivery System
recently discovered system
control release
drug release is independent of the initial concentration
sustained release
drug release is dependent on the initial concentration
non erodible
dosage form will not erode drug release slowly
Erosion
drug dosage form will be eroded or disintegrated
Erosion is of two types
surface erosion and bulk erosion
surface of the dosage form eroded not internally while in bulk erosion occurs internally as well all
the dosage form is eroded
control release delivery
 Diffusion controlled
diffusion of the drug from dosage form into the body cavity and drug releases
drug pass through the membrane
 dissolution controlled
until the drug is dissolved from the dosage form only then it will be released dosage form is
converted into
Reservoir or matrix
Reservoir—combine with polymer hydrophobic polymer is preferred from dispersion
Matrix – polymer embeds a drug and form network hydrophilic
No membrane is involved
outer surface area of the dosage form + solvent/ fluid of the lumen ~ dissolve and go into the body
polymer ~ controls the release of the drug
Matrix ~ release slowly
 Diffusion and dissolution Control
rate limiting factor - membrane
dosage form converts into solution form
in the core release of drug is controlled by dissolution
once drug is in soluble form membrane is crossed by diffusion
DRUG ABSORPTION
Instantly dissolve dosage form to soluble form released
for drug in soluble in Drug Delivery System solvent comes and solubilized the drug and release
 Water penetration controlled

Osmatically controlled - entry of H2O will result in the release of drug
swelling controlled—dosage form is in the dry form hydrophilic Polymers are used
entry of water inside the dosage form – and moves outside with osmotic pressure by water
for example
ADALAT LA – nifidipene releases in a specific manner
Core
coating polymer
water impermeable membrane
Laser guided hole
water penetrate through the laser guided hole - drug is solubilized-water produce pressure osmotic -
maximum pressure achieved - water moves out along with the drug from laser-guided hole
swelling control
If swelling is not controlled then along with the hydrophilic polymer some quantity of hydrophobic
polymer ethyl cellulose can be used for example sodium alginate 13 to 40% doses are used.
The drug is in the dry form - water penetrates into the dosage form--swelling results as a network
formation
HYDROGELS
Hydrophilic Polymers are converted into hydrogels during the formation or manufacturing for
example carbopol and sodium alginate hydrogels (gel or Jelly like appearance)
water penetrates due to the formation of network, if the network is hard than the water exist of
water from Matrix in the hydrated form
 ION Exchange method
Sticky appearance
Exudative
have some charge on it resin and drug will have opposite charges resin maybe and ionic or cationic
anionic resins have negative charge
while cationic resins have positive charge
drug is binded by ionic binding example when the drug is administrated in the GIT it contain a
negative charge and for example chlorine have negative ions interchange with the drug resin + drug
will give us CL- as a result drug is released
ions in the lumen an get exchanged and the drug and is released from the resin.
 Chemically controlled
 Erodible
drug or drug embedded in polymer
either it will be chemically eroded breakup or chemical polymer itself erode
chemical polymer breakdown into different compounds. compound should not be toxic This
breakdown results in the release of drug for example polysaccharides or lipoproteins
Lipoproteins are divided into small pieces or units that results in the drug release.
 DRUG polymer conjugate
Drug plus polymer gives conjugated through the covalent bond
Once the drug reaches to a specific target or the site in the lumen either pH enzymes temperature
catalyst may break up the bond drug is released and get absorbed
Reservoir types DDS
Polymeric membranes rate controlling is the embryonic membrane
 Core + polymer + additives are present in it
 impermeable to solid particles polymeric membrane is known for a small membrane
size drugs and diffuse semipermeable membrane is comparatively larger molecular size
drugs can penetrate through it
Outset – zero order kinetics
Outset pilo 20 or outset pilo 40
Release rate 40g/h
Titanium dioxide ring maintains the shape of the dosage form
drug from Reservoir diffuses through the polymeric membrane and then enters the lackrymal fluid
and released
mixture of pilocarpine- higher release rate and is not included para
Matrix type DDS

E. G Nitro-dur -
When applied on intact skin for Hypertension continuous transdermal infusion of nitroglycerine daily
dose 0.5 gram per CM square use for angina
Absorbent pad - drug is take to it as a base - drug permeates or diffuse through skin into the
bloodstream
In case of lipophilic polymer the permeability of a drug increases
while in the case of hydrophilic polymer the drug absorbs the moisture dissolves in it and is released
Matrix may be produced by
 Finely grounded drug particles
Blind with viscous liquid or semi solid - The Matrix or Cross linking of the polymer
ii- solid drug + melted polymer gives mixed solidifies - give define shape
 Fabricated
Polymer chain + drug - form specific pattern and the drug is released
drug + polymer dissolved in a common solvent
The solvent evaporated – complex form remains
No mathematical equations
Solvent casting for hot melted
adhesive Polymers molded into a define shape for gels and films
OSMOTIC PUMPS
Surface is impermeable membrane
delivery port is the laser guided whole water Entry from here from lumen into the internal body of
Reservoir
protect the membrane from pressure generated by water
based on the principle of osmosis
decreased dose frequency as the drug is loaded in the Reservoir
For increased consistency - cellulose Acetate membrane is used
DIFFUSION
Drug movement controlled by membrane of the polymer is called diffusion
Intrauterine devices (IUD)

Drug release for years
low dose is delivered
delivery of contraceptive steroidal hormones
intrauterine devices act as carrier effective antifertility agents for example copper bearing IUDs or
progesterone releasing IUDs
Advantage
prolonged release
no Side Effects
increased B. A
copper and other metals like zinc cadmium and lead enhances the contraceptive effectiveness of
intra uterine device
T shaped polyethylene plastic device with 30 mm square of copper wire – pregnancy rate declined
up to 5%
progesterone releasing devices
continuously release 65 MG progesterone daily inside uterine cavity achieve contraception for 1
year drug in nomograms
IMPLANTS
Depot / reservoirs form is delivery or placed on skin and external intramuscular subdermal or other
route for longer period of time for example 6 months or 2 years
loaded drug should be potent in micrograms over nanograms
minor fluctuation can worsen the condition for example anticancer morphine implant transdermal
for 5 years
it is a reversible method
in the case of increased drug concentration or when required
implants can be parenteral or nonparenteral
parenteral implants are biodegradable biocompatible and are of polymer type these are viscous
liquid or semi solid
CLASSIFICATION
Transdermal implantable systems
Subdermal implantable systems
Implantable polymeric matrix
Implants used in chronic therapy mostly compressed disc biodegradable material for example poly
lactic co glycolide inside forming gels body cavity precipitate and release in the body diffusion
method
implants follows the zero order kinetics
initial burst of the drug is followed by the slower release due to the release of the drug deposited on
the surface of implant avoided by coated the implant with drug impermeable polymeric material.
HYDROGELS
Hydrogels are already swollen/ hydrated form
the cross link Slow Down its dissolution
hydrophilic Polymers imbibe water content from 30 to 90%
INSITU gelling system
 Ph
The change in pH causes the gel to swell and the drug is released
ii. Thermoresponsive hydrogels
when the desirable temperature is achieved the polymer start releasing the drug
iii- glucose responsive
in situ gelling glucoseenters the dosage form and the drug is released.
GRANULATION
Clumping of individual particles or powder into aggregated form is known as granulation
individual fine powder adhesive particle granulated size decrease surface area
granule size is 0.2 to 4.0 mm smaller than 0.2 is the micro particles
PALLETS
Pallets have define shape generally rounded usually hollow and are helpful when particles are
compressed into tablets
GRANULES
Clumping of particles and it is not of define shape should have a size range can be identified on this
basis
DISPENSING OF GRANULES
Bulk granules for internal use for example ORS
divided granules for example NSAIDs and risek are in the fine form
insufflation - in granulation form – increases secretion
powder for reconstitution into injection for example 3rd Generation cephalosporin
dry powder for topical use/preparation for example cicatrin
POWDER – PROCESS – SEGGREGATE (SEPERATES)
Based on density the particles separate content uniformity poor flow properties weight variation in
compression
Pallets have define geometrical shape
no content uniformity
apply coating
interspaces are not present
spray- increased smooth surface
less denser
AGGREGATES/ GRANULES – NOT SEGGREGATED

Uniform flow properties by converting powder into aggregate
increased average particle size
enhanced compression
least segregation enhanced flow properties
granule does not have define shape
clumping occurs
Cannot be coated
interspaces are present but least
and it is denser
there are two variables in granulation technology machines and material both can be selected as
desired
why granules?
because there are no disintegration in the Powder
hygroscopic material
air tight container
Silica Gel packs
GRANULES can be coated
ADVANTAGES
Low dust hazard
useful in cytotoxic drugs certain antibiotics and corticosteroids and sex hormones
make hydrophobic surface more hydrophilic for example suspension
aggravated- intensity
hydrophobic – to avoid its exposure court with hydrophilic material
DISADVANTAGES
Expensive
time consumption
loss of material
might stick with machines or blade
METHODS
 Dry granulation
 Wet granulation
 Direct compression
Adjust particle size adjust flow properties then the material is compressed
Such ingredients are selected which have binding properties in the dry form /, powder form
if the particle is moisture sensitive and temperature sensitive dry granulation is used
IPA isopropyl alcohol is used in the wet method
Wet method-- we can adjust the factors such as flow property, bulk and tap density and angle of
repose hardness and friability ate achieved according to the Desire
Differences between wet granulation and Dry Granulation:

Dry Granulation:
Heat sensitive/ moisture for dry
Drying Is required in wet granulation
Steps Are more in wet granulation than dry granulation.
Less time is required in dry granulation
Less labour is required in dry granulation.
Wet granulation
Quality is more in wet granulation, flow properties, distinctive dissolution
Granulation parameters
Particle size is accurate in wet granulation

In Moist granulation water act as a Binder.
In wet granulation production Technology is more advanced.
When to choose dry method?

Form aggregates for clumps without the addition of the moisture.
STEPS OF DRY GRANULATION

 Mixing
Polymeric components + drug - mixed well
 Compaction
Powder or particles and large aggregates under high pressure
 Milling
Roller compactor breakdown of large aggregates into smaller particles
gentle force is used to reduce particle size as desired
 Screening
Screening is done to obtain desired size
Dry Granulation Method

By slugging and roller compaction.
Dry method
1- heat and moisture sensitive polymers.
2- no drying
3- less time consuming
4-less laborious process
5- conventional slugging
Wet Granulation
1-Solvent + binder
2- drying is required to remove moisture.
3- more advanced techniques
4-accurate particle size achieved.
5- water can be used as a binder.
Slugging
:- batch production
:- large tablets without the interest of it's shape are formed which are then milled in to smaller
particles.
:- reduce slug particles leads to difficult to break size.
:- no define shape so it should have increase particle size that break down ideally.
Milling
1- Not finer powder
2- coarse particles are desired and produce.
Chilsonator roller compactor
A roller compactor generally consists of three major units:
 A feeding system, which converts the powder to the compaction area between the rolls.
 A compaction unit, where powder is compacted between two counter rotating rolls to a ribbon
by applying a force.
 A size reduction unit, for milling the ribbons to the desired particle size.
Working:
Step 1:
Put all material in the feeding hopper. With the help of the machine feeding auger, material will
move to the rolling system.
Step 2:
Once the material reaches the rolling system, it will compress the material into a ribbon. Remember,
the machine will direct the material into the gap in between the two rollers.
Basically, it is the two rollers that increase material density, forming a ribbon.
Step 3:
At this stage, the machine will mill the ribbon or briquettes to a required shape and size. This section
of the machine has a sieve that allows only the right size of granules to pass through.
Advantages:
Below are some of the main advantages of roller compaction in dry granulation process:
 It simplifies the dry granulation process; unlike slugging, roller compaction is simple and
eliminates the difficulty in material processing.
 Cost saving; roller compactors require less material and energy to operate
 Being a fully automated system, it requires less manpower and energy to operate.
 It is an accurate dry granulation process that helps to control weight and density of the granules.
As a result, it is easier to produce consistent and accurate granule density.
 Granulates from roller compactors form capsules and tablet that disintegrate easily.
 There is no need for solvent or aqueous granulation process.
 It allows for continuous granulation of materials
 A perfect equipment for processing hygroscopic materials
 Improves process cycle time
 Guarantees a shorter material processing time
 Facilitates powder flow
 Roller compactor machines save on dry granulation processing space while maximizing the
production
 Disadvantages:
 Possible loss in tensile strength; at times, when you use granules from roller compactor
machines to make tablets, they tend to have inferior tensile strength. So, you need to improve
the tensile strength by choosing appropriate excipients.
 There is a possibility of less product yield; this is due to the non-compacted powder as high
amount of fine powder remain. To eliminate this, the design of roller compactor machine should
be such that it allows the fine powder back into the system for compression.
Wet granulation
Granulating fluid
E.g; water +Organic solvent
Granulating fluid + binder =solution is formed
Ingredients
 Drug + diluents
 Binder +granulating fluid
 Gladiant
 Lubricant
 disintegrant
steps
mixing of all ingredient for content uniformity
↓
Binder + solution is added
↓
Screening to obtain desired particle size
Drying through tray dryer
Screening
Pregelatinized starch
 hydrated from starch for excellent sticky property
 stability properties for moisture sensitivity
 MC→ MICROCRYSTALLINE CELLULOISE
 HPMC→ HYDROXY PROPYL METHLY CELLULOSE
 Sustained release agents at very low ratews
 Use as binder
 Added gladient before and after granulation added lubricant decreases the friction aur
increases the flow property
Steps of wet granulation
 Mixing drug+ lubricant
 Add binder to the solution to make powder wet
 Screening 6 to 12 sieves
 After screening granular size are formed
 Drying
 Sieving 14 to 20 number
Mechanism of granule formation
Three steps
Nucleation
 Individual particle→ convert into nucleus
 In between two particle→ liquid bond or bridge
 Pendular stage →max liquid is evaporated or particle arrange into the 3D structure
 WITH INTERPARTICULAR SPACE AND BIND THE PARTICLE
TRANSITION
Single nucleus (binder+ingredient) --> may grow
Two nucleus -->combine --> increase granule size (decrease liquid on surface) --> then dry
3) Ball growth :
Done with nucleus
Spheronizer : equipment that rotates the liquid

Advantages : excellent cohesiveness  due to binder with the help of liquid
3) Particle distribution :
Graph – x axix particle size distribution – y axis percentage distribution
Up and down curve with gradual increase and gradual decrease.
Normal graph – starts from the top of y axis decreases slowly towards x-axis.
4)Wet granulation
Hydrophilic drug is equally distributed throughout the dosage form.
Disadvantages :
Migration of soluble dyes  when water evaporates  with it all the soluble component moves
with water.
Dyes are used in liquid form
Some materials resist the formulation of granules for example light density material.
Wet Granulation Equipments :

1)Shear Granulator :
Mechanical agitation by paddle of large size
Mixing bowl
Mix powder+binder  agitated converted in to granules
Mixing arms  move at a side way  when it runs the particles along the wall of the container
move with it.
Dead spot  minor mechanical stirrer are use known as planetary mixer also called orbitary mixer.
Binder liquid +powder  and machine is started
Dry power  mix  add liquid binder  wet mixing (massing)
High aptitude of the mixing arm is high,from its axis again high shear force
Mechanical degradation :
Stage 3 granules began to degrade  starts degradation  because binder material,unmixed
poweder and converted material are all in one container.
2) Oscillating Granulator :
No paddles
Oscillator/roller just rolls
It is use in sieving done after drying
Just for sizing
Damp mass/ moist mass (goes to oscillator  convert to small particles)
Gral Mixer :
Type of planetary mixer
Only milling is done
Use for sizing
Chopper  use for sizing reduce particle size
Large blade size causes good mixing of powder
Little ford Lodige Mixer :

Dead spots  contain minor blades (high speed mixer)
Mostly planetary mixer is use for wet granulation for content uniformity.
Dry slate prior to granulation  liquid bridge ad solid , pendular state (for higher mixing) increase
liquid or binder - funicular - suspension  liquid
1) Nuclei formed in nucleation helps in granular growth
2) Nuclei surface expose to moisture  dry particle may attach to its surface
Fluidized Bed Dryer :

Grinding,drying,mixing
Filter system (removes extra moisture)
Blow hot air
Heater
Slurry (granulating liquid) sprayed  tiny droplets  touch to dry powder
Extra moisture on granules removed by hot air

Particles from cyclone  get suspended in air  granulating liquid added  convert dry
powder into granules
Spray Dryer:
Use liquid feed  cyclone formation by hot air  increase residual time for material  to
remove moisture.
POLYMER
When monomers combined to each other they form polymers.
Mode of release
1-sustained
2-control
3-immediate
Release of drug is defined by which type of polymer is used.
For example.... Sugar is used in immediate release not suitable fir extended release.
Properties of polymers
Polymers should be stable i.e polystyrene
Non toxic
BIO compatible
Have Pharmaceutical properties
Characteristics of polymers
1-safety profile should be clear.
2- pharmaceutical property e.g jelling, stiffing.
3-stability
4- polymers should be:
Bioerosion
BIOcompatible
5-Pharmaceutical properties
Sugar, sweeting agent, solublize, bulking agent.
Chemistry of polymers
Capability to exist in polymeric or condensed form.
1-Polymers may be Oligopolymer that are low degree of polymerization.
2-And polymer may be high degree polymers.
Range range of monomers
200-2000 (number of monomers)
Examples
1-Polymers should not in case of tablet (solid dosage form).
2-In case of suppositories polymers should melt at specific body temperature.
3-They have ability to bear aby physical shake or shock.
4-In pre oral route polymer is going ti residue fir 12-24 hours in the body.
5- in iv the polymers should be stored in organs and stays larger than pre oral route.
6-ideal properties of polymers various from
-:one dosage from to other.
-:one route of administration to other.
7-coating polymer have good mechanical properties of a coating layer. (i.e hardness and softness).
8-Nontoxic
9 - easy to fabricat i.e
-:polymerization
:- to formulate
:- non toxic enzymes should be used for preparation of polymers..
Criteria for polymer selection
1-Easily soluble and recoverable.
2-Molecular weight must be suitable to control the chain length.
E.g grades 200, 600, 800, 1000, 2000, 4000, 8000.
Grade 8000 have the slowest release property.
3- chain length increases the release property decrease.
4- polymers control the release :
:- ability to form bind to produce a conjugate with drug.
:- should have property to hold the drug in its structure to form sustained release.
Mechanism of polymer release
Diffusion:
:- Polymers does not degrade in the dosage form and the body cavity.
:- maintain integrity.
:- drug release depot.
:- in solublized form.
:- drug release maintaining the polymer intact.
Swelling
Polymer imbibe water from surrounding then change volume or size in polymer that cause increase
in size leads to release drug and water from it.
Degradation
Polymer in contact with body cavity e.g human git and water start rushing into dosage form that's
leads to degradation of polymer.
In result: polymer break down in to monomers.
And polymer may soluble in dosage form.
Example: polysaccharides
Classification
Source :
:- which reference or source a polymer was procured.
Special theory
Delivery of small or specific amount of drug to or required at specific body place.
Example: vaccine
:- 5mg of drug for beta receptor.
Generations
There are four generations of DDS.
First Generation
Simplest dosage form
Conventional method of DDS
Examples: Decoction, infusion, tablets, pills, trouches.
5th(fifth) Generation is genetical engineering.
Advantages:
1-Content uniformity
2- active ingredients
3- decreased chance of toxicity.
Disadvantages
No selectivity or specificity.
POLYMERS AND THEIR

CLASSIFICATION IN MODIFIED
DRUG DELIEVERY SYSTEM
Definition
polymers are constructed from pieces (monomers) that can be easily connected into long chains
(polymer) the process of formation of polymers from respective monomers is called polymerization.
Characteristics of polymers:
 Polymers with a high degree of polymerization are called 'high polymers’’ and those with low
degree of polymerization are called oligopolymers (short chain polymers or oligomers).
 Polymers do not exhibit strength for n < 30 strength of most of the polymers is Obtained at n
around 500
 The useful range of n is from 200 to 2000.
Classification:
 Source
 Type of chain/functionalization
 Structure
 Composition
 Mode of polymerization
 Molecular force
Classification Based on Source:
 Natural Polymers: These polymers are found in plants and animals.
Examples are proteins, cellulose, starch, resins and rubber
2.Semi-synthetic Polymers: Cellulose derivatives as cellulose acetate (rayon)zcellulose nitrate etc.
3. Synthetic Polymers: A variety of synthetic polymers as plastic (polythene), synthetic fibres (nylon
6,6) and synthetic rubbers (Buna-S) are examples of man-made polymers
Organic polymers:
A polymer whose backbone chain is essentially made of carbon atoms is termed as organic polymer
The atoms attached to the side valencies of the backbone carbon atoms are hydrogen, oxygen,
nitrogen etc.
Exampleis synthetic polymers are organic .
Inorganic Polymers:
A polymer chain backbone contains no carbon atom is called inorganic polymers
Glass and silicone rubber are examples of it.
 Linear Polymers: These polymers consist of long and straight chains. The examples are high
density polythene, PVC, etc. Linear polymers are commonly soft, often rubbery substances, and
often likely to soften (or melt) on heating and to dissolve in certain solvent.
 Branched Polymers: These polymers contain linear chains hav：rf> some branches, e.g.，low
density polythene
 Cross-linked Polymers: These are usually formed from bi functional and tri-functional
monomers and contain strong covalent bonds between various linear polymer chains, e.g.
vulcanized rubber, urea-formaldehyde resins, etc. Cross linked polymers are hard and do not
melt, soften or dissolve in most cases
Classification Based on Composition of Polymers:
 Homopolymer
A polymer resulting from the polymerization of a single monomer, a polymer consisting substantially
of a single type of repeating unit
 Copolymer:
When two different types of monomers are joined in the same polymer chain, the polymer 'S called
a copolymer.
Copolymerization A heteropolvmer or copolymer is a polymer derived from two (or more*
monomeric species as opposed to a homopolymer where only one monomer used ,Th.s s a method
used to chemically synthesize a copolymer. Examples are Nitrile rubber, styrene acrylonitrile,
styrene-isoprene styrene (SIS) and ethylene vinyl acetate
Alternating copolymer: When the two monomers are arranged m an a'tern.King fasr a" Random
copolymer: The two monomers may NOT following any order.
Block copolymer: all of one type of monomers are grouped together, and all of the other arc
grouped together.
Graft copolymer： A block copolymer can be thought of as two homopolymers joined together at
the ends
Branched copolymers： One kind of monomers in their main cham and another kma o*
monomers in their side chains
Classification Based on Mode of Polymerisation:
Two sub groups:
 Addition
 Condensation Polymers
 Addition Polymers: The addition polymers are formed by the repeated addition of monomer
molecules possessing double or triple bonds, e g., the formation of polythene from ethene and
polypropene from propene However, the addition polymers formed by the polvmerisation of a
single monomeric species are known as homopolymer, e.g., polythene The polymers made by
addition polymerisation from two different monomers are termed as copolymers, e g., Buna-S
，Buna N，etc
 Condensation Polymers: The condensation polymers are formed by repeated condensation
reaction between two different b> functional groups.e.g. polyesters,polyamides
Classification Based on Molecular Forces:
The mechanical properties of polymers arc governed by mtermolecular forces, e g , van der Waals
forces and hydrogen bonds, present in the polymer, these forces also bind the polymer chains.
Under this category, the polymers are classified into the following groups on the basis of
magnitude of intermolecular forces present in them.
they are
 Elastomers
 Fibers
(lii) Liquid resins
(Iv) Plastics (a) thermoplastic (b) thermosetting plastic
Biodegradable and non-biodegradable polymers

Biodegradable Polymers comprised of monomers linked to one another through functional groups
and have unstable links in the backbone,broken down into biologically acceptable molecules that are
metabolizedand removed from tne body
e g collagen,poy glycolic acid etc.
Non-Biodcgradable polymers:
• Most polymers are non-biodegradable because they consist of long chains of hydrogen and carbon
atoms.
polymers down.
e g： poly vinyl chloride,polyethylene etc
Polymer degradation
Change in the properties-tensile,colour,shape,etc of a polymer or polymer based product under the
influence ofone or more environment factors such as heat,light or chemicals.
 Bioerosion may be restricted to refer to physical processes that result in weight loss of a
polymer device.
 Biorosion is of two types:
 1. Bulk erosion
 2. Surface erosion
Processes of erosion:
l.BULK EROSION:
Degradation takes place through the whole of the sample.Incoming of water is faster than the rateof
degradation.e.g:PLA (Polylactic acid)& PGA(Polyglycolic acid)
2.SURFACE EROSION:
Sample is eroded from the surface.mass loss is faster than incoming of water into bulk.e.g.
polyanhydrides & polyorthoesters.
Classification of biodegradable polymers
 Synthetic biodegradable polymers:
Aliphatic polyesters , poly anhydrides, poly amino acids etc.
 Natural biodegradable polymers:
Albumin ，collagen, dextran gelatin，pectin，starch etc
FACTORS EFFECTING BIODEGRADATION OF
POLYMERS:
 Morphological factors:
Shape & size,variation of diffusion coefficient and mechanical stresses.
 Chemical factors:
chemical structure and composition,presence of ionic group and configuration structurezmolecular
weight and presence of low molecular compounds.
 Physical factors:
FACTORS EFFECTING BIODEGRADATION OF
POLYMERS:
 Morphological factors:
Shape & size,variation of diffusion coefficient and mechanical stresses.
 Chemical factors:
chemical structure and composition,presence of ionic group and configuration structurezmolecular
weight and presence of low molecular compounds.
 Physical factors:
Advantages of biodegradable polymers:
 Localized delievery of drug

 Sustained delievery of drug
 Stabilization of drug
 Decrease in dosing frequency
 Reduce side effects
 Improved patient compliance
 Contollable degradation rate
Applications of biodegradable polymers
 Polymer system for gene therapy.
 Biodegradable polymer for ocular,tissue
engineering,vascular,orthopedic,skin adhesive &surgical glues.
 Biodegradable drug system for therapeutic agents such as anti tumor,anti psychotic agents,anti
inflammatory agents.
 Polymeric materials are used in and on soil to improve aeration, and promote plant growth and
health.
 Many biomaterials ,heart valve replacements and blood vessels made of polymers like dacron
and teflon etc.
: LE QF (jptYMER PHARMACEUTICTVDRUG
timVERY*
■ Immediate release dosage forms
• Tablets
Polymers have been used (or many years as excipients In conventional immediate release oral
dosage forms, either to aid m the manufacturine process or to protect the drug from degradation
upon storage. Microcrystalline cellulose is often used as an alternative to carbohydrates as diluents
in tablet formulations of highly potent low-dose drugs Starch and cellulose are used as disintegrants
in tablet formulations, which swell on contact with water, resulting in the tablet “bursting,"
increasing the exposed surface area of the drug and improving the dissolution characteristics of a
formulation. Polymers including polyvinyl pyrrolidone and hydroxypropyl methylcellulose (HPMC)
also find uses as tinders that aid the formation of granules that improve the flow and compaction
properties of tablet formulations prior to tableting. Occasionally, dosage forms must be coated with
a *non- functionar polymeric film coating in order to protect a druR from degradation, mask the
taste of an unpalatable drug or excipients, or improve the visual elegance of the foimulation without
affecting the drug release rate
• Capsules
Capsules are used as an alternative to tablets, for poorly compressible materials, to mask the bitter
taste of certain drugs, or sometimes to increase bioavailability. Many of the polymeric excipients
used to "bulk out* capsule fills are the same as those used in immediate-release tablets. Gelatine
has been used almost exclusively as a shell material for hard (two-piece) and soft (one-piece)
capsules. HPMC has recently been developed and accepted as an alternative material for the
manufacture of hard (two-piece) capsules.
■ Modified-release dosage forms
It is now generally accepted that for many therapeutic agents drug delivery using immediate release
dosage forms results in suboptimal therapy and/or systemic side effects. Pharmaceutical scientists
have attempted to overcome the limitations of conventional oral dosage forms by developing
modified release dosage forms
The therapeutic effect of drug that have a short biological half life may be enhanced by formulating
them as extended or sustained release dosage forms. Extended and sustained release dosage forms
prolong the time that systemic drug levels are within the therapeutic range and thus reduce the
number of doses the patient must take to maintain a therapeutic effect thereby Increasing
compliance. The most commonly used water-soluble polymers for extended release application are
the ammonia ethacrylate copolymers (Eudragit RS RL) ， cellulose derivatives ethylcellulose.
cellulose acetate. and polyvinyl derivative, polyvinyl acetate Eudragit RS RL differ in the proportion
of quaternary ammonium groups, rendering Eudragit RS less permeable to water, whereas ethyl
cellulose is available in a number of different grades of different viscosity, with higher viscosity
grades forming stronger and more durable films.
• Gastro retentive Dosage Forms
Gastro retentive dosage forms offer an alternative strategy for achieving extended release profile, in
which the formulation will remain in the stomach for prolonged periods, releasing the drug in situ,
which will then dissolve in the liquid contents and slowly pass into the small intestine Unlike a
conventional extended release dosage form, which gradually releases the drug during transit along
the gastrointestinal tract, such a delivery system would overcome the problems of drug that are
absorbed preferentially from specific sites within the gastrointestinal tract (for example, many drug
are absorbed poorly from the distal gut. where an extended release dosage form may spend the
majority of its time) producing nonuniform plasma time profile delivery systems donot relay on
polymer present, to achieve gastroretention mucoadhesive and low density polymers have been
evaluated. with little success so far, for their ability to extend gastric residence time by bonding to
the mucus lining of the stomach and floating on top of the gastric contents respectively.
Polymers for Drug Delivery in Tissue Engineering:

Several strateg.es have been developed in order to regenerate functional tissue, the majority
which Involve the use of polymer scaffolds specifically to direct tissue growth. The cell
transplantation method is one of the most commonly used in cartilage and bone formation. Polymer
matrices both natural and synthetic can play a vital role in the delivery of protein growth factors and
cytokines to aid angiogenesis and reconstruction procedures These molecules are essential to tissue
growth as they control a number of vital cellular processes including proliferation and
differentiation. It has been shown by careful selection of the polymer and the processing method ,
controlled release matrices incorporating proteins and growth factors that induce and enhance
tissue growth can be produced. The future use of gene therapy as a way of regenerating tissue is an
exciting area,and despite still being in its infancy ,it may yet provide a solution to the challenge of
delivery drugs and proteins more effectively in all areas of medicines.
Poly(lactic-co-glycolic acid) Mircrosphere:
The term microsphere refers to a small sphere with a porous inner matrix and variable surface
from smooth and porous irregular and nonporous. The drug when encapsulated is it dispersed
throughout the inner matrix. The size range of microspheres is typically 1 to 500 um In diameter.Poly
(lactic-co-glycolic acid) Microspheres Have increasingly become the focus of research Effort in the
scientific community And pharmaceutical industry. There application as Drug delivery vehicles has
risen In line with the expanding biotechnology sector and the promise of new drugs discovered in
the wake of human Genome project and proteomics.
Polymeric nano particles as drug carriers;

Certain chemical entities are either Rapidly degraded and/or metabolised after
Administration(Peptides, proteins, and nucleic acids) this is the reason the idea that
nanotechnologies may be employed To modify or even to control the drug distribution of the tissue.
, Cellular, Or sub cellular levels has emerged. Among the technology is utilised for drug targeting are
polymer based nano particles, which have been developed since the early 1980s , When progress in
polymer chemistry materials. Nano particles may be defined as being <1um Colloidal systems
generally composed of polymers. Thus,Nano particle are colloidal systems With a size 7 to 70 times
smaller than the red cells. They may be administered intravenously without any risk or embolisation.
Depending on the method used in the preparation of nano particles, Either nanospheres Or nano
capsules can be obtained. Nano spheres Are matrix system in which the drug is dispersed Within the
polymer throughout the practical. On the contrary, nano capsules are vesicular systems, which are
formed by a drug containing liquid core ( aqueous or lipophilic) Surrounded by a Single polymeric
membrane.
Polymeric Miscelles as Pharmaceutical carrier :

Polymeric miscelles Demonstrate many addictive properties as pharmaceutical carriers. They are
stable both invivo and invitro , Can be loaded with a Wide variety of poorly Soluble pharmaceutical
agents, Effectively accumulate in pathological body areas With compromised Vasculature
(infarcts,tumors) And can be targeted by attaching various specific ligands To their surface
Polymeric Vesicles
p0lymeric vesicles may be fabricated from a variety of macromolecular amphiphile architectures,
which include： block copolymers, random graft copolymers, and polymers bearing hydrophobic
low-molecular-weight pendant or terminal groups. These tough particles, which reside in the
nanometre and micrometer size domains, may be used for drug targeting, the preparation of
responsive release systems, and other drug delivery applications.
Polymer Drug Conjugates

Current research in the field of polymer anticancer drug conjugates is directed towards the
identification of the mechanism of action of free and polymer-bound drugs at tne cellular and
subcellular levels. Newer applications for polymer-drug conjugates are also being explored21.
Inflammatory diseases are characterized by an increase in the vascular permeability (similar to
tumors). Though there may be lesser amounts of retention as the lymphatics are not blocked, there
may be a therapeutic advantage offered by the conjugation of drugs to polymer backbones. These
represent new and exciting avenues of research for polymeric drug delivery scientists.
Polymers Used for the Delivery of Genes in Gene Therapy
A number of polymers by virtue of possessing a cationic charge at physiological pH have been found
to be suitable candidates for the transfer of genes across the various biological barriers outlined in
the preceding text. An ideal gene delivery system has to be able to shuttle the gene safely to the
nuclei of its target tissue with the travelling gene having limited encounters with degradative
influences.
influences.
PERS IN PHARMACEUTICAL APPLICATIONS22 2
POLYMERS IN PHARMACEUTICAL APPLICATIONS
Water-Soluble Synthetic Polymers
 Poly (acrylic acid) Cosmetic, pharmaceuticals, immobilization of cationic drugs, base for Carbopol
polymers.
 Poly (ethylene oxide) Coagulant, flocculent, very high molecular-weight up to a few millions,
swelling agent,
 Poly (ethylene glycol) Mw <10,000; liquid (Mw <1000) and wax (Mw >1000), plasticizer, base for
suppositories.
 Poly (vinyl pyrrolidone) Used to make betadine (iodine complex of PVP) with less toxicity than
iodine, plasma repiacement, tablet granulation.
 Poly (vinyl alcohol) Water-soluble packaging, tablet binder, tablet coating.
Cellulose-Based Polymers
» Ethyl cellulose Insoluble but dispersible in water, aqueous coating system for sustained release
applications.
Carboxymethyl cellulose super disintegrant,emulsion stabilizer.
 Hydroxyethyl and hydroxypropyl celluloses Soluble in water and in alcohol for tablet coating.
 Hydroxypropyl methyl cellulose Binder for tablet matrix and tablet coating, gelatin alternative
as capsule material.
 Cellulose acetate phthalate enteric coating.
Hydrocolloids
 Alginic acid Oral and topical pharmaceutical products; thickening and suspending agent in a
variety of pastes, creams, and gels, as well as a stabilizing agent for oil-in-water emulsions;
binder and disintegrants.
 Carrageenan Modified release, viscosifier.
 Chitosan Cosmetics and controlled drug delivery applications, mucoadhesive dosage forms,
rapid release dosage forms.
applications,mucoadhesive dosage forms rapid dosage forms.
Water insoluble biodegradable Polymers

• (Lactide-co-glycolide) polymers microparticle-nanoparticle for protein delivery.
Starch Polymers
 Starch Glidant, a diluent in tablets and capsules a disintegrant in tablets and capsules, a
tablet binder.
 Sodium starch glycolate super disintegrant for tablets and capsules in oral delivery.
Plastic and Rubbers
 Polyurethane Transdermal patch backing, blood pump, artificial heart, and vascubr grafts,
foam in biomedical and industrial products.
 Polyisobutylene Pressure sensitive adhesives for transdermal delivery.
 Polycyanoacrylate Biodegradable tissue adhesives in surgery, a drug carrier in nano- and
microparticles.
 Poly (vinyl acetate) Binder for chewing gum.
 Poly (vinyl chloride) Blood bag, ar.d tubing.
 Polyethylene transdermal patch backing for drug in adhesive design, wrap, packaging,
containers.
 Poly (methyl methacrylate) Hard contact lenses.

 Poly (hydroxycthyl methacrylate) Soft contact lenses.
Characteristics of an ideal polymer
 it should be versatile and possess a wide range of mechanical, physical, chemical
properties.
 it should be non-toxic and have good mechanical strength and should be easily
administered.
 It should be inexpensive and easy to fabricate.
 It should be inert to host tissue and compatible with environment.
Criteria followed in polymer selection
 The polymer should be soluble and easy to synthesis.
 It should have finite molecular weight.
 It should be compatible with biological environm ent.
 It should be biodegradable.
 it should provide good drug polymer linkage.
General mechanism of drug release from polymer
There are three primary mechanisms by which active Can e released from a delivery system
namely
Diffusion
Diffusion occurs when a drug or other active agent passes through the polymer that forms the
controlled-release device Diffusion occurs when the drug passes from the polymer matrix into the
external environment. As the release continues its rate normally decreases with this type of system
since the active agent has a progressively longer distance to travel and therefore requires a longer
diffusion time to release. In these systems, the combinations of polymer matrices and bioactive
agents chosen must allow for the drug to diffuse through the pores or macromolecular structure of
the polymer upon introduction of the delivery system into the biological environment without
inducing any change in the polymer itself.
Degradation:
Biodegradable polymer degrades within the body as a result of natural biological processes,
eliminating the need to remove a drug delivery system after release of the active agent his been
completed. Most biodegradable polymers are designed to degrade as a result of hydrolysis of the
polymer chains into biologically acceptable and progressively smaller compounds. For some
degradable polymers, most notably the polyanhydrides and polyorthoesters, the degradation occurs
only at the surface of the polymer, resulting in a release rate that is proportional to the surface area
of the drug delivery system
Swelling
They are Initially dry and when placed in the body will absorb water or other body fluids and swell.
The swelling increases the aqueous solvent content within the ormulation as well as the polymer
mesh size, enabling the drug to diffuse through the swollen network into the external environment.
POLYMER IN PHARMACEUTICAL DRUG DELIVERY SYSTEM:
ROSIN:
Rosin a film-coating biopolymer and its derivatives have been extensively evaluated
pharmaceutically as film coating and microencapsulating materias to achieve sustained drug release.
They are also used in cosmetics,chewing gum and dental varnishes. Rosin has been used to prepare
spherical microcapsules by a method based on phase separation by solvent evaporation. Rosin
combination witth polyvinyl pyrrolidone and dibutyl phthalate (30 % w/w) produces smooth film
with improved elongation and tensile strength.
Chitin and Chitosan

Chitin a naturally abundant muco polysaccharide and consist of 2-acetamido-2- deoxy-b-D-glucose.
Chitin can be degraded by chitinase. Chitosan is a linear polysaccharide composed of randomly
distributed 3-(1- 4 - D-glucosamine (deacetylated unit) and N-acetyl-
Lack of positive charge means neutral and basic environments.
Zein
Zein an alcohol-soluble protein contained in the endosperm tissue of Zeamais, occurs as by product
of processing Zein has been employed as an edible coating for foods and pharmiceuticals for
decades . Zein is disintegrating synthetic and semi synthetic film coatings currently used for the
formulation of substrates that allow extrusion coating.
Collagen
Collagen st the most widely found protein in mammals and is the major provider of strength
to tissue it not only has been explored for use in various types of surgery. cosmetics and drug
delivery, but in bioprosthetic Implants and tissue engineering of multiple organs
Starches
It Is the principal form of carbohydrate reserve In green plants and especially present in Meeh md
underground organs. Starch occurs In the form of granules (swrch grains), the shape and size of
which are characteristic of the species, as is also the ratio of the content of the principal
constituents, amylose and amylopectin. A number of starches are recognized for pharmaceutical
use. These include maize (Zea mays), rice (Oryza sativa). wheat (Tritlcum aestivum), and potato
(olanum tuberosum). To deliver proteins or peptidic drugs orally, microcapsules containing a protein
and a proteinase inhibitor were prepared Starch/bovine serum albumin mixed-walled microcapsules
were prepared using interfacial cross-linking with terephthaloyl chlonde The microcapsules were
loaded with native or aminoprotected aprotinin by incorporating protease inhibitors in the aqueous
phase during the cross-linking process The protective effect of microcapsules with aprotinin for
bovine scrum albumin was revealed in vitro
Polycaprolactone
Polycaprolactone (PCL| Is biodegradable polyester with a low melting point of around 60
degree C and a glass transition temperature of about -60.C PCL is prepared by ring opening
polymerization of £-caprolactone using a catalyst such as stannous octanate The most common
use of polycaprolactone is in the manufacture of polyurethanes. Polycaprolactones imparts good
water, oil solvent and chlorine resistance to the polyurethane produced.
Polyorthoesters
These materials have gone through several generations of synthetic improvements to yield
materials that can yield materials that can be with few exceptions also biocompatible.
Cellulose
The polysaccharides of the plant cell wall consist mainly of cellulose, hemicelluloses and pectin
used in pharmaceutical applications such as filler In tablets, it is microcrystalline cellulose that
represents a novel and more useful cellulose powder. Microcrystalline cellulose is mainly used in
the pharmaceutical industry as a diluent/binder in tablets for both the granulation and direct
compression processes. Microcrystalline cellulose is partially depolymerised cellulose prepared by
treating high quality cellulose with hydrochloric acid to produce free flowing non-fibrous particles.
It was further found that the hydroxypropylmethylcellulose matrix systems have a stronger gel
structure than those made of Molecules polyethylene oxide, which may provide superior in vivo
performance in terms of matrix resistance to the destructive forces within the gastrointestinal
tract.14
Figure 2: Chemical structure of a) powdered cellulose (n =500) or microcrystalline Cellulose (n = 220)
and b) hydroxyl propyl methyl cellulose.
Pectin
Pectin is a family of complex polysaccharides present in the walls that surround growing and dividing
plant cells It is also present in the junctional zone between cells within secondary cell walls including
xylem and fiber cells in woody tissue. Pectin has been investigated as excipients In many different
types of dosage forms such as film coating of colon-specific drug delivery systems when mixed with
ethyl cellulose, microparticulate delivery systems for ophthalmic preparations and matrix
type transdermai patches. the composition of pectin can vary based on the botanical source, for
example pectin from citrus contains less neutral sugars and has a smaller molecular size compared
to pectin obtained from apples.
PTECH TESTS MCQs
1. Substance may exhibit an inherent odor characteristics of
a. anhydrous groups present
b. functional groups present
c. solubility
d. unsaturation
e. saturation
2. Most applicable technique used for characterizing the purity of a drug
substance include
a. TEM
b. TLC
C. SEM
d. DSC
e. TGA
3. andreasen pipette is used
to determine
a. flow property
b. purity
c. particle size
d. crystalinity
e. solubility
4. investigation of physico chemical properties of the new drug compound that
could affect drug performance and development of an efficacious
dosage form is known as
a. pharmacovigillance
b. preliminary parameters for advanced dosage forms
c. bioavailability
d. Preformulation studies
e. post formulation studies
5. powders having angle of repose 25-30 degree have flow property
a. passable
b. excellent
C. very poor
d. rejected
e. good
6. taste of a drug substance exhibited by
a. crystalline nature
b. amorphous nature
c. presence of certain functional groups
d. less solubility
e. high solubility
7. microscopic method for determination of particle size have size range of
a. 5-50 micrometer
b. 1-10 micrometer
c. 0.2-100 micrometer
d. 2-100 micrometer
e. 50-150 micrometer
8. Color is generally a function of a drug inherent chemical structure relating to

a certain level of
a. hydrous
b. saturation
c. solubility
d. anhydrous
e. unsaturation
9. Term moderately course for characterizing the particle size of a substance

have mesh size No.
a. 8
b. 20
c. 60
d. 40
e. 80
10. Cascade impaction is a technique used to determine
a. particle size
b. solubilization
C. solubility
d. purity
e. crystalinity
11. following is the technique of dry granulation
a.Low shear mixer
b. steam
c. pellitizer
d. slugging
e. moisture activated dry
12. following is the triphasic stage of agglomeration
a. droplet
b. interlocking
c. pendular
d. capillary
e. steaming
13. granulation is required for
a. dust production
b. enhance flow rate
c. nano particles
d. reduction of flow
e. cake formation
a. cake formation
b. nano particles
C. tablets
d. dust production
e. reduce flow rate
15. following is the technique of wet granulation
a. slugging
b. roller compactor
c. continuous fluid bed granulator
d. foam
e. thermal adhesion
16. pharmaceutical granules ranges between
a. 0.1-5 mm
b. 1-4 mm
c. 0.2-4 mm
d. 1-5 mm
e. 0.2-5 mm
17. granulation is a process where
a. small particles can not Identify
b. small particles can not gathered
c. small particles can not adhere
O d. small particles can identify
e. a compact mass produced
18. following is the technique of advanced granulation
a. roller compactor
b. extrusion
c. spheronization
d. thermal adhession
e. fluid bed granulator
19. granulation is a process where
a. original particles can not Identify
b. small particles can not adhere
c. small particles can not gathered
d. a compact mass
e. small particles are gathered
a. dust production
b. cake formation
c. increased uniformity of drug distribution
d. reduced uniformity of drug distribution
e. niosomes
21. microcapsules are designed to
a. formulate immediate release DDS
b. give unpalatable taste
C. gastric irritation
d. controlled release DDS
e. enhance odor of drug
22. microspheres are
a. liquid
b. solution
C. solid
d. disperssion
e. slurry
in texture
23. in process of microencapsulation following is essential
a. high temperature
b. stable emulsion
c. insufficiency of solvent for polymer with agitation
d. avoid agitation
e. sufficient solvent for polymer
24. according to nokhodch and farid the particle size range of microcapsules is
a. 500-5000 micrometer
b. 1-100 micrometer
c. 1 -1000 micrometer
d. 5-5000 micrometer
e. 5-500 micrometer
25. microcapsules are small particles having wall material of
a. suspending agents
b. polymer
C. emulsifiers
d. essential oils
e. drug
26. solvent evaporation technique fully developed at the end of
a. 1980
b. 1940
C. 1950
d. 1870
e. 1970
27. microencapsulated drugs can not be given in the form of
a. creams
b. capsules
C. niosomes
d. aerosoles
e. tablets
e. tablets
28.according to burgees and hickey particle particle size range of microcapsule

is
a. 1-1000 micrometer
29. microcapsules follow
a. matrices
b. drug polymer blend
c. embedded system
d. barrier system
e. matrix system
30. in microencapsulation process very small are coated
a. gas particles
b. solid and liqiud

a liquid droplets
d. solid, liquids and gases
e. slid particles
CHAPTER 1
• Phyto chemistry
2.Excipients:
• Pharmaceutics
• Dispensing
Chromatography:
• HPLC
• TLC
Spectroscopy:
• Transmittance
• Dispensing
• Dispensing

like
1
• Instrumentation
• Qc
Dosage form & Drug:

Drug:
1-Diagnose
2-Mitigate
3-Treat
4-Cure
5-Prevent
DOSAGE FORM:

2
administration
tissues

Two ways
1. chewing
Flowers e.g rose
Seeds e.g clove
Anther e.g sefron
2. Snuffing :
3. Inhaling:
4. Smoking:
Tobacco, chars

Luman
3
• No selectivity

Goals and Aims:

Bullets.

• Tablet
• Capsule
• Solution
• Elixirs
Advantages:
• Dose accuracy
• Selective
4
Disadvantages:
• Side effects
2nd Generation DDS:

Goals:
Bioavailability:
3rd Generation DDS:

Goals:
independent.
5
time.
4th Generation DDS:

the drug.
Drawbacks:
range.

nose.
• Drug/API
• Carrier
6

12:00 (Noon)
12:00 (Mid-night)

Classification:
➢ Biosensor
➢ Algorithm
➢ A pump
7
regulate it.
This system:
5th generation DDS:

8
CHAPTER 2
Classification:


Repeat action DDS:
pills.

9
CIRCADIAN RYTHMS
CIRCADIAN RYTHMS
Definition(By sir):
• Physical
• Mental
• Behavioral

Function Of SCN:
Graph 1:
10
11
Body clock Guide
Time Situation
12:00am Midnight
7:30am Melatonin
secretion stops
likely
12:00pm noon
time
5:00pm Greatest CV
efficiency of
muscle strength
6:00pm evening
6:30pm Highest Bp
9:00pm Melatonin
secretion starts
suppressed
12
needed):
13
CHRONOTHERAPEUTICS

14
Granulation
Ch. Sherjeel Adnan
CHEE 440 1
Objectives
 Granulation
 Why?
 Equipments
CHEE 440 2
Granulation
identified. or

CHEE 440 3
CHEE 440 4
Why granulation?
 Done to
CHEE 440 5
Wet
 Spray dryer
more common
 Wet
granulator
 Dry
 pelletizers
 Others/advance
CHEE 440 6
Dry Others/advance
 Foam
granulation process
CHEE 440 7
 Solid bridges
CHEE 440 8
Massing
particles
CHEE 440 9
CHEE 440 10
 Nucleation
 Transition
 Ball growth
o Coalescence
o Breakage
o Abrasion transfer
o Layering
CHEE 440 11
CHEE 440 12
Low shear/planetary
CHEE 440 13
Diosna
 Diosona
 Gral
CHEE 440 14
Collette gral
CHEE 440 15
 Fludized bed
 Spray drier
 Day nauta mixer
 Topo granulator
 CF granulator
CHEE 440 16
Fludized bed dryer
CHEE 440 17
CHEE 440 18
Spray dryer
CHEE 440 19
 Steps
o Dry mixing
o Wet massing
o Extrusion
o Spheronization
o Drying
o Screening
CHEE 440 20
CHEE 440 21
Spheronization
CHEE 440 22
Spheronizer
CHEE 440 23
CHEE 440 24
Rotogranulator
CHEE 440 25
 sluggers
CHEE 440 26
CHEE 440 27
Other /advance
 Melt
 Foam
CHEE 440 28
CHEE 440 29
your life.
always a pupil.
CHEE 440 30
CHEE 440 31
MICROENCAPSULATION
Ch. Sherjeel adnan

• Microencapsulation is defined as the application
of a thin coating to individual core materials that
• MICROENCAPSULATION is a process by
which very tiny droplets or particles of liquid or
solid material are surrounded or coated with a
• For solids, liquid and gases
Microcapsules
thickness. Generally the active substance
is called CORE & the coating is called
WALL MATERIAL.
membrane
Microspheres
• Microspheres are
defined as solid,
approximately
spherical particles
about 1-1000 µm
(Burgess and Hickey
• To make the formulation sustained or controlled
release.
• To mask the taste & odour of bitter drugs
• A mean of separating incompatible materials
• To protect the drug from environmental
conditions (light, moisture & oxidation)
• For converting liquid into free flowing powders
• To prevent the gastric irritation of certain drugs
• Water solubility or dispersability
pharmacological classes can be given in
the form of free flowing powders in hard &
soft gelatin capsules, tablets, suspensions,
rectal & vaginal suppositories, ointments,
creams, aerosols, plasters and dressings.
Determined by some formulation • Nature of polymer
• Drug
• The particle size requirement.
• The drug or the protein should
• Intended use
not be, adversely affected by • Duration of therapy
the process
• Reproducibility of the release
profile
• No stability problem.
• No toxic products associated
• Solvent evaporation (Emulsification-Evaporation)
• Polymerization techniques
• Bulk polymerization
• Suspension polymerization
• Emulsion polymerization
• Phase separation coacervation technique
• Spray drying and spray congealing
Solvent evaporation
• Fully developed at end of 1970
• Based on the evaporation of the internal phase of an emulsion
by agitation
microencapsulation by solvent
evaporation.
• Single emulsion solvent evaporation
• Multiple emulsion solvent evaporation
technique. (W/O/W)
• Water as nonsolvent to the polymer are in
general preferred.
• Extremely economical and negate the
• Suitable for the encapsulation of lipophilic
active principles
• Microencapsulation of hydrophilic active
principles by this process can pose
problems
Multiple emulsions: Water-in-oil-
in-water (w/o/w)
• For the efficient encapsulation of water-soluble
active principles
• Organic phase acts as a barrier between the two
• This process proves much more effective when
the water solubility of the medicine is high (>900
mg/ mL) and prevent partioning of drug into
organic phase
• Sometimes viscosity of primary emulsion is
oil (o/o)
• Continuous & discontinuous phase are oil and
• For drugs having high hydrophilicity and gives
highest yield
• For drugs/polymers that are degraded in
presence of water
• More expensive than aqueous methods
• Difficult to recycle oil phase
• Traces of oil possesses problems
• The process consists of bringing two reactants at the
• This is usually accomplished by emulsifying the liquid
containing first reactant (dispersed phase) into
continuous phase, which is initially devoid of second
reactant
• Additional continuous phase containing the second
reaction produces a continuous film of the polymer
around the drug.
• Microcapsules can be recovered by spray drying or
filtration
Procedures adopted for
interfacial polymerization
• Procedure for water immiscible liquid core
• Procedure for water miscible liquid core
• Procedure for solid core
Procedure for water
When the core material is lipophilic liquid,
the monomer is dissolved in the liquid
core. Usually isocyanate or acid chloride is
user as monomer. Then this solution is
disperesed in aqueous phase (containing
2nd monomer) this prpduces
poolymerization of monomers at the
interface & results in formation of the
capsule wall
liquid core
additional oil containing 2nd monomer is added
to W/O emulsion, polymer membrane is formed.
techniques

• Different solvents used
o CCl4
o Chloroform
o Methanol
o Water
• Different monomers used
phenol propane) polybasic acid halide (sebacoyl
chloride)
polymerization
• Enzymes
• Proteins
• Artificial cells
• Pharmaceuticals
• Adsorbants
• Hormones and antibiotics
• Pigments, oily liquids & polyelectrolytes
Coacervation Or phase
separation technology
A process in which aqueous colloidal
solution separate upon alteration of
thermodynamic condition of state into two
liquid phases, one rich in colloid i.e. the
coacervate & the other containing little
colloide.
core material form the embryonic capsule
& then appropriate gelling of coacervate
Core material
encapsulated by coacervation can be
solid, liquid, gas, liquid slurry, suspension
or emulsion and analgesics, antibiotics,
vitamins
Wall material
• The coating material can be selected from a variety of
characteristics.
• The amount of coating material used ranges from 3%-
• Both natural and synthetic colloids can be used,
coacervation
Following methods can be used for coacervation & the
choice of method depend upon the polymer and the set
of conditions which are being used;
• Temperature change
• Salt addition
• Nonsolvent addition
• Incompatible polymer addition
• polymer-polymer interaction
Temperature change

takes place in the form of immiscible liquid droplets, if
drug is present these droplets surround the core & form
microcapsules.
microencapsulation. Ethylcellulose is soluble in
cyclohexane elevated temp. but insoluble at room temp.
first of all ethylcellulose is dispersed in cyclohexane &
then mixture is heated to boiling point so that a
homogenous polymer solution is formed. Then core
material is added in the solution with continous stirring &
mixture is allowed to cool.
the coating.
Salt addition
Soluble inorganic salts can be added to aqueous solution
of water soluble polymers to cause phase separation. A
Nonsolvent addition
immiscible core.
Fro example;
addition of isopropyl ether (nonsolvent for polymer) ----
----- phase separation & microencapsulation of
suspended drug occur.
Incompatible polymer
interaction
addition.
polybutadiene which is soluble in toluene but
incompatible with ethyl cellulose. Thus causes demixing
of ethyl cellulose & phase separation occur.
whereas acacia possess a negative charge. Gelatin-
gelatin, gelatin-CMC are examples of other oppositely
chaeged polyelectrolyte used in microencapsulatio.
Coacervation method is divided into two
main groups
• Aqueous phase separation
• Organic phase separation
CHARACTERIZATION
• Recovery of formed microspheres
• Hydration of microspheres
• Drug loading
• Encapsulatipon efficiency
• Rheological properties
• Morphology (SEM,TEM)
• FTIR
• XRD
• TGA/DSC
• Drug release
• Drug release kinetics
Or
Simple Coacervation +
(gelatin in water)


solvent
O/W Emulsion
Cacervation water insoluble particles
Or
+
Particles
(accacia in water)
wash with water
W/O Emulsion
Organic Phase +
Or


Wash and dry
• Antibiotics; amoxicillin, ampicillin,
chloramphenicol
• Anti-inflammatory drugs; diclofenac
sodium, ibuprofen, naproxen, mefenamic
acid & flufenamic acid.
• Bronchodilators; theophylline & terbutaline
sulphate.
• Sulfa drugs; sulfadiazine, sulfamerizine &
sulfamethoxazole
• Diuretics; furosemide, chlorothiazide &
sulfonamide
• Urinary antiseptics; nitrofurantoin &
nalidixic acid
• Antiepileptic drugs; phenytoin sodium,
beclamide
• Antihypertensive; isosorbide mononitrate,
• Analgesics; acetyl salicylic acid
• Anticancers; mitomycin, bleomycin &

mercaptopurine.
• Tranquilizers; diazepam & oxazepam.
• Electrolyte replenisher; sodium chloride &
potassium chloride.
• Vitamins & metal salts; A, B1, B2, B6,
B12, C & D and mineral salts like Zinc
sulphate.
• Converting liquids into free flowing
• Recovery of formed • Hydration of
• Rheological studies
• Drug loading
• Encapsulation efficiency
• Polyhydroxybutyrate-
microspheres
DSC
• 5-FU microspheres
Drug release
Equation for drug release
kinetics
• Zero order release Qt  k 0 t
• First order log Qt  log Q0  k1 t
• Higuchi,s model Qt  k H t 1 / 2
 Qt  k HC t
1/ 3 1/ 3
• Hixson-Crowell Q0
• Korsmeyer-Peppas Mt
 k KP t n
M0
Application
microspheres
• Taste and odor masking
• Conversion of oils and other liquids to solids for ease of
handling
• Protection of drugs against the environment as moisture ,
pain of injection
• Delay of volatilization
• Separation of incompatible materials
• Improvement of flow properties of powders
• Safe handling of toxic substances
• Aid in dispersion of water insoluble substances in aqueous
media
• Production of sustained release, controlled release and
• Reducing dose dumping potential compared to large
• If you stand for a reason, be prepared to
stand alone like a tree and if you fall on
the ground , fall as seed that grows back
to fight again
• Whenever you get really attached to some

than any one else
Ch. Sherjeel Adnan
B.Sc. B-Pharmacy BZU
M.Phil (Pharmaceutics)IUB
Ph.d (Pharmaceutics)BZU
CONTENTS
• Introduction
• Organoleptic properties
• Purity
• Particle size, shape and surface area
• Solubilisation, Surfactants and its importance
• Temperature, pH, co-solvency, solid dispersion, β-
cyclodextrin drug-dispersion system
• Preformulation stability studies
• A consideration of physico-chemical characteristics of
new drug molecules with respect to different dosage
forms
Preformulation
• Preformulation is branch of Pharmaceutical science that
utilizes biopharmaceutical principles in the determination
of physicochemical properties of the drug substance.
• Prior to the development of any dosage form new drug ,
it is essential that certain fundamental physical &
chemical properties of drug powder are determined .
• This information may dictate many of subsequent event
& approaches in formulation development.
• This first learning phase is called as preformulation.
INTRODUCTION
DEFINITION:-
Investigation of physico-chemical properties of
the new drug compound that could affect drug
performance and development of an efficacious
dosage form”.
Preformulation commences when a newly

synthesized drug shows a sufficient
pharmacologic promise in animal model to
warrant evaluation in man.
Introduction
• The preformulation is the first step in the rational

development of a dosage form of a drug substance
alone and when combined with excipients.
• Objective :
To generate useful information to the formulator
to design an optimum drug delivery system.
Introduction
• Before embarking on a formal programme of
preformulation, scientist must consider the following
:
1. Available physicochemical data (including
chemical structure, different salt available).
2. Anticipated dose.
3. Supply situation and development schedule.
4. Availability of stability – indicating assay.
GOALS OF PREFORMULATION
• To establish the necessary physicochemical

parameters of new drug substances.
• To determine kinetic rate profile.
• To establish physical characteristics.
• To establish compatibility with common
excipients.
Preliminary Evaluation
a) Compound identity.
b) Formula and molecular weight.
c) Structure.
d) Therapeutic indications:
- Probable human dose.
- Desired dosage form(s)
- Bioavailability model
- Competitive products
Contd…
e) Potential hazards
f) Initial bulk lots:
- Lot number
- Crystallization solvent(s)
- Particle size range
- Melting point
- % volatiles
g) Analytical methods:
- HPLC assay
- TLC assay
- UV/ Visible spectroscopy
Contd…
ORGANOLEPTIC PROPERTIES
COLOR ODOUR TASTE
OFF-WHITE PUNGENT ACIDIC
CREAM-YELLOW SULFUROUS BITTER
SHINY FRUITY SWEET
AROMATIC TASTELESS
ODOURLESS TASTELESS
COLOR
• Color is generally a function of a drug’s inherent

chemical structure relating to a certain level of
unsaturation.
• Color intensity relates to the extent of conjugated

unsaturation as well as the presence of chromophores.
• Some compound may appear to have color although

structurally saturated.
ODOUR
• The substance may exhibit an inherent odor
characteristic of major functional groups present.
• Odor greatly affects the flavor of a preparation or
food stuff.
Taste:-
• If taste is considered as unpalatable, consideration is
to be given to the use of a less soluble chemical form
of the drug.
• The odour and taste may be suppressed by using

appropriate flavors and excipients or by coating the
final product.
PURITY
• Designed to estimate the levels of all known &
significant impurities & contaminates in the drug
substance under evaluation.
• Study performed in an analytical research &
development group.
• It is another parameter which allows for comparison
with subsequent batches.
• Occasionally, an impurity can affect stability.
e.g.
- Metal contamination
- Appearance
PURITY
• The techniques used for characterizing the purity of a
drug are the same as those used for other purpose in a
preformulation study.
• Thin layer chromatography is a wide ranging
applicability & is an excellent tool for characterizing
the purity.
• HPLC, paper chromatography & gas chromatography
are also useful.
• More quantitative information can be obtained by
using quantitative differential scanning colorimetry.
PARTICLE SIZE
• Particle size is characterized using these

terms :
i. Very coarse (#8)
ii. Coarse (#20)
iii. Moderately coarse (#40)
iv. Fine (#60)
v. Very fine (#80)
PARTICLE SIZE
• Particle size can influence variety of
important factors :
- Dissolution rate
- Suspendability
- Uniform distribution
- Penetrability
- Lack of grittiness
Methods to Determine Particle Size
• Sieving
• Microscopy
• Sedimentation rate method
• Light energy diffraction
• Laser holography
• Cascade impaction
1. Sieving method :
• Range : 50 – 150 µm
• Simple, inexpensive
• If powder is not dry, the apertures get clogged.
2. Microscopy :
• Range : 0.2 – 100 µm
• Particle size can be determined by the use of
calibrated grid background.
• Most direct method.
• Slow & tedious method.
3. Sedimentation method :
• Range : 1 - 200 µm
• Andreasen pipette is used.
• Particle size is calculated by stoke’s law :
18 η0 h
dst = (ρs -ρ0) gt
Where,
h = distance of fall in time, t
no = viscosity of the medium
ρs = density of the particles
ρ0 = density of the dispersion medium
g = acceleration due to gravity
4. Light energy diffraction :
• Range : 0.5 – 500 µm
• Particle size is determined by the reduction in light
reaching the sensor as the particle, dispersed in a liquid
or gas, passes through the sensing zone.
• Quick & fast.
5. Laser holography :
• Range : 1.4 – 100 µm
• A pulsed laser is fired through an aerosolized particle
spray & photographed in three dimensional with
holographic camera, allowing the particles to be
individually imaged & sized.
6. Cascade impaction :
• The principle that a particle driven by an
airstream will hit a surface in its path,
provide that its inertia is sufficient to
overcome the drug force that tends to keep in
it in airstream.
POWDER FLOW PROPERTIES
 Powder flow properties can be affected by change in particle
size, shape & density.
 The flow properties depends upon following-

1. Force of friction.
2. Cohesion between one particle to another.
 Fine particle posses poor flow by filling void spaces between

larger particles causing packing & densification of particles..
 By using glident we can alter the flow properties.

e.g. Starch, Talc.
Determination Of Powder Flow Properties
 By determining Angle Of Angle Of Type Of Flow

Repose. Repose
 A greater angle of repose ( In degree)
indicate poor flow.
Excellent
 It should be less than 30°. <25
& can be determined by
following equation. 25-30 Good
tan θ = h/r.
where, θ = angle of repose. 30-40 Passable
h=height of pile.
r= radius. >40 Very poor
 Measurement of free flowing powder by compressibility.

 Also known as Carr's index.
CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) X 100

TAPPED DENSITY
 It is simple, fast & popular method of predicting powder

flow characteristics.
Carr’s Index Type of flow

5-15 Excellent
12-16 Good
18-21 Fair To Passable
23-35 Poor
33-38 Very Poor
>40 Extremely Poor
PARTICLE SHAPE
Cont…
PARTICLE SHAPE
• Particle shape will influence the surface area, flow of
particles, packing & compaction properties of the
particles.
• A sphere has minimum surface area per unit volume.
• Therefore, these properties can be compared for
spheres & asymmetric particles, in order to decide the
shape.
• The following expression can be obtained:
Property Sphere particle
surface area πds2 αs x dp2
volume (1/6)πds3 αv x dp3
Cont…
Cont…
PARTICLE SHAPE
• Therefore,
surface area = πds2 = αs x dp 2
Volume = (1/6)πds3 = αv x dp3
• Solving for αs & αv by equating the appropriate properties
provides:
αs =
πd s
2 & αv = πds3
dp2 6 dp3
• When particle shape is spherical, the ds = dp

• Thus, αs = π = 3.124 & αv = π/6 = 0.524
• Therefore, Shape factor = αs = 3.124 =6
αv 0.524
SURFACE AREA
• Particle size & surface area are inversely
related to each other.
• Smaller the drug particle, greater the surface
area.
Specific surface is defined as the surface area

per unit weight (Sw) or unit volume (Sv) of the
material.
SURFACE AREA
 Estimation of Sv :
Sv = Surface area of the particles
Volume of particles
= n αs d
2
n αv d 3
= αs
αv d
• According to shape factor,
αs = 6
αv
• So, Sv = 6 / d.
SURFACE AREA
 Estimation of Sw:
Sw = Surface area = Surface area
Weight density x volume
= Sv
ρ
= 6
ρ.d
Methods for determining
surface area
1. Adsorption method :
• Particles with a large specific surface are good adsorbents
for the adsorption of gases & of solutes from solution.
• The volume of nitrogen gas, Vm, in cm3 that 1 g of the
powder can adsorb when the monolayer is complete is
more accurately given by using the BET equation, however,
which can be written as:
P = 1 + (b-1) . P
V(P0 – P) Vmb Vmb P0
Cont….
Cont….
surface area
• Where,
V = Volume of gas in cm3 adsorbed per gram of powder
at pressure P.
P = Pressure of the adsorbate, in mmHg.
Po= Saturation vapor pressure (monolayer)
Vm= Amount of vapor adsorbed per unit mass adsorbent,
when the surface is covered with monomolecular
layer
b = Constant that express the difference between the
heat of adsorption & heat of liquefaction of the
adsorbate (nitrogen).
Quantasorb QS – 16 instrument
P
V( P0 – P)
P/P0
Air permeability method :
HOWEVER SIZE REDUCTION
IS NOT REQUIRED IN FOLLOWING CASES
• WHEN DRUG IS UNSTABLE.
• DEGRADE IN SOLUTION FORM.
• PRODUCE UNDESIRABLE EFFECTS.
• WHEN SUSTAINED EFFECT IS DESIRED.

SOLUBILIZATION
“ Solubilization is defined as the spontaneous

passage of poorly water soluble solute
molecules into an aqueous solution of a soap
or detergent in which a thermodynamically
stable solution is formed ”.
SOLUBILIZATION
 It is the process by which apparent solubility of

an otherwise sparingly soluble substance is increased
by the presence of surfactant micelles .
 MICELLES: -
 The mechanism involves the property of

surface active agents to form colloidal aggregates
known as micelles .
SOLUBILIZATION
 When surfactants are added to the liquid at low
concentration they tend to orient at the air-liquid
interface .
 On further addition of surfactant the interface

becomes completely occupied and excess molecules
are forced into the bulk of liquid.
 At very high concentration surfactant molecules in

the bulk of liquid begin to form micelles and this
concentration is know as CRITICAL MICELLE
CONCENTRATION {CMC}
SOLUBILIZATION
 Solubilization is thought to occur by virtue of the
solute dissolving in or being adsorbed onto the
micelle.
 Thus the ability of surfactant solution to

dissolved or solubilize water insoluble materials
starts at the CMC and increase with increase in the
concentration of micelles.
 Solubilization of any material in any solvent

depends on proper selection of solubilising agents.
 The process of solubilization involves the breaking
of inter-ionic or intermolecular bonds in the solute,
the separation of the molecules of the solvent to
provide space in the solvent for the solute,
interaction between the solvent and the solute
molecule or ion.
Step 1: Holes opens in the solvent

Step2: Molecules of the solid breaks away from the
bulk
Step 3: The free solid molecule is intergraded into

the hole in the solvent
 The amount of substance that passes into
solution in order to establish equilibrium at
constant temperature and pressure to
produce a saturated solution.
 If solubility is <1mg/ml indicates need for salt
formation to improve solubility.
 If solubility is <1mg/ml in pH= 1 to 7,

preformulation study should be initiated.
 Solubility should ideally be measured at two

temperatures: 4°C and 37°C.
 4°C to ensure Physical stability.
 37°C to support Biopharmaceutical evaluation.

Description Parts of solvent required for
one part of solute
Very soluble <1

Freely soluble 1 - 10
Soluble 10 - 30
Sparingly soluble 30 - 100
Slightly soluble 100 - 1000
Very slightly soluble 1000 - 10,000
Insoluble > 10,000
SOLUBILITY ANALYSIS
 Preformulation solubility studies focus on drug

solvent system that could occur during the delivery of
drug candidate.
 For e.g. A drug for oral administration should be

examined for solubility in media having isotonic
chloride ion concentration and acidic pH.
SOLUBILITY ANALYSIS
 Analytic method that are particularly useful
for solubility measurement include HPLC, UV
spectroscopy, Fluorescence spectroscopy and
Gas chromatography.
 Reverse phase HPLC offer accurate and

efficient mean of collecting solubility data of
drug.
 Ionization constant (pKa)
Can be calculated by Henderson Hasselbach
equation-
For acidic drugs….pH= pKa+ log [ionized drug]

[unionized drug]
For basic drugs….pH= pKa+ log[unionized drug]

[ionized drug]
 pH Solubility Profile
 The solubility of acidic or basic drug will show
difference in solubility with changes in pH.
 pH solubility profile of a drug can be established

by running the equilibrium solubility experiment
within pH range of 3-4.
 Partition Coefficient
 It is the ratio of unionized drug distributed
between organic and aqueous phase at equilibrium.
P o/w = ( C oil / C water )equilibrium

 Effect Of Temperature
 The heat of solution Hs, represents the heat
released or absorbed when a mole of solute is
dissolved in large quantity of solvent.
 Endothermic reaction
 Exothermic reaction
Determination of solubility
 The following points should be considered
 The solvent & solute must be pure.
 A saturated solution must be obtained before any
solution is removed for analysis.
 The method of separating a sample of saturated
solution from undissolved solute must be
satisfactory.
 The method of analyzing solution must be reliable
 Temperature must be adequately controlled .
Solubility Determination Method
 Solubility is normally depends on temperature,

so temperature is recorded in each solubility
measurement.
 Plot of solubility against temperature is
commonly used for solubility determination.
 Two methods are available for determination
are as follow.
I. Analytical method
II. Synthetic method
Analytical method
 Temperature of equilibrium is fixed and

concentration of the solute in the saturated solution
is determined at equilibrium by a suitable
analytical procedure.
 In other words a saturated solution in the

presence of an excess of the undissolved solute is
prepared at an accurately known temperature.
This situation can be achieved by suitable contact
b/w solute and solvent.
Synthetic method
 In this method a weighed amount of solute is

placed in the vessel.
 While agitating the system at constant temperature
known amount of solvent is added gradually until
the solubility limit is reached.
 At equilibrium, temperature and content of the
system is recorded.
 This method is carried out at micro scale level by
examining the small amount of the system under
hot stage microscope.
General Method of Increasing
the Solubility
 Addition of co-solvent
 pH change method
 Reduction of particle size
 Temperature change method
 Hydotrophy
 Addition of Surfactant
 Dielectrical Constant
 Complexation
Addition Of Co-Solvent
• Weak Electrolyte :- Phenobarbitone

• Non polar :- Nitro Cellulose
 These are poorly soluble in given solvent.
 For such poorly soluble materials, to enhance
their solubility, the water miscible solvents are used
in which the drug has good solubility.
 This process of improving solubility is known as
co-solvency and the solvent used is known as co-
solvents.
e.g. Phenobarbitone is insoluble in water. A clear
solution is obtained by dissolving in mixture of
Alcohol, Glycerin, Propylene glycol.
e.g. Of Cosolvents:-
PG, glycerin, sorbitol, PEG, Glyceryl formal,
glycofurol, ethyl carbamate, ethyl lactate and
dimethyl acetamide.
pH change Method
 Weak base:- Alkaloids, Local Anaesthesia
 Weak acid:- Sulphonamides, Barbiturates
 In aqueous medium they dissociate poorly and

undissociated portion is insoluble.
e.g. Benzoic acid, Phenobarbitone
 So, solubility of the undissociated portion is
improved by pH control.
For weak acidic drug:- increase pH, solubility is
increase.
 For weak base drug:- decrease pH, increase
solubility.
Reduction Of Particle size
 Reduction in Particle size improve solubility of

drug.
 Basically reduction in particle size increase contact

surface area of the particle, there by ultimately it
increase rate of solubility of drug.
Temperature Change Method
 In endothermic reaction by increasing temperature

solubility is increase.
 In exothermic reaction by increasing temperature

solubility is decrease.
e.g. Methyl Cellulose when mixed with water and

temperature is raised, it becomes insoluble. To
dissolve it cold water is added.
Hydotrophy
The term Hydotrophy has been used to designate the

increase in solubility in water of various substances
due to the presences of large amount of additives.
e.g. Solubilization of Benzoic acid with Sodium

benzoate.
Addition of Surfactant
 Surfactants are molecules with well defined polar
and non-polar region that allow them to aggregate in
solution to form micelles. Non polar drugs can
partition into micelles and be solubilized.
e.g. Surfactant based solution of Taxol, that is

solubilized in 50% solution of Cremophor.
Dielectrical Constant
Dielectrical Constant is the effect that substances
has, when it acts as a solvent on the case with which it
separates oppositely charged atoms.
e.g. DEC of Water- 80

Kerosene- 2
Glycerine- 48
Benzene- 2.2
Complexation
 For the Complexation occur both drug and ligand
molecule should be able to donate or accept
electrons.
 The solubility of compound is the sum of solubility
of the compound and its complex.
e.g. HgI2 (Mercuric Iodide) is sparingly soluble in

water. Its solubility in water is increased by forming
complex with KI.
HgI2 +2KI K2HgI4 (water soluble)

Applications of solubilization
 Drugs with limited aqueous solubility can be

solubilized. These include oil-soluble vitamins,
steroid hormones and antimicrobial agents etc.
 Solubilization of orally administered drugs results

in an improved appearance and improves
unpleasant taste.
 Both oil-soluble and water-soluble compounds can

be combined in a single phase system as in case of
multivitamin preparations.
 Solubilization may lead to enhanced absorption
and increased biological activity.
 Improves the intestinal absorption of vitamin A.
 Drug absorption from ointment bases and

suppositories also increased.
 Liquid preparations with small quantity of

preservative can be prepared by solubilization.
 Aqueous concentrates of volatile oils can be
prepared by solubilization.
 Example: soaps used for solubilising phenolic

compounds for use as disinfectants- Lysol, Roxenol
etc.
 Barbiturates, anticoagulant, alkloidal drugs are

dissolved with polysorbate by solubilization.
SURFACTANT
 Surfactants:-
are wetting agents that lower the surface
tension of a liquid, allowing easier spreading,
and lower the interfacial tension between two
liquids.
 Classification
Some commonly encountered surfactants of
each type include:
1. Ionic 2. Non ionic
 Cationic
 Anionic
 Zwitterionic
IONIC
 Cationic Surfactants:-
 Quaternary ammonium salts are more preferred
because they are less affected by pH.
e.g. Cetyl Trimethyl Ammonium Bromide (CTAB)

Hexadecyl Trimethyl Ammonium Bromide, and other
Alkyltrimethyl Ammonium Salts, Cetylpyridinium
Chloride (cpc)
IONIC
Anionic Surfactants:-
 They are the most commonly used surfactants,
containing Carboxylate, Sulfonate, Sulfate ions.
e.g. Sodium Dodecyl Sulphate (SDS), Ammonium

Lauryl Sulphate and other alkyl sulfate salts, Sodium
Laureth Sulphate, also known as Sodium Lauryl
Ether Sulphate (SLES).
IONIC
 Zwitterionic:-
 When a single surfactant molecule exhibit both
anionic and cationic dissociations it is called
amphoteric or Zwitterionic.
The anion include carboxylates and phosphate
group and the cation include quaternary
ammonium group.
e.g. Dodecly Betamine

Dodecly Dimethylamine Oxide
NONIONIC
 These are most widely used because they are
free from non compatability, stability and
potential toxicity and classified as water soluble
and water insoluble non ionic surfactants.
e.g. Long chain fatty acids, fatty alcohols
 Water solubility of these agents is further

increased by addition of polyoxyethylene groups
through ether linkage with one of the alcohol
group.
e.g. spans
HLB SCALE
 Griffin in 1947 developed the system of the
hydrophilic-lipophilic balance [ HLB ] of surfactant.
 The higher the HLB of the an agent, the more
hydrophilic it is.
 Tween, polyoxyethylene derivative of the spans are
hydrophilic and have high HLB value (9.6-16.7)
 The lower the HLB of the agent, the more lipophilic
it is.
 The sorbitan ester are lipophilic and have low HLB
value (1.8-8.6)
HLB SCALE
0
Most antifoaming agents
3
W/O Emulsifying agents

6
9
Wetting and Spreading agents
12 O/W Emulsifying agents
15
Detergents and Solubilizing agents
18
HLB SCALE
• The HLB of non ionic surfactant whose only

hydrophilic portion is polyoxyethylene is calculated
using the formula
• HLB = E/5
Where, E = Percentage weight of ethylene oxide
Importance Of Surfactant
 Surfactants play an important role in many

practical applications and products, including:
• Detergents
• Fabric Softener
• Emulsifier
• Paints
• Adhesive
• Inks
• Soil remediation
• Wetting
• Ski Wax
• Snowboard Wax
• Foaming
• Defoaming
• Laxatives
• Agrochemical formulations
Herbicides
Insecticides
• Quantum dot coating
• Biocides (Sanitizers)
• Hair Conditioners (after shampoo)
• Spermicide (Nonoxynol 9)
Temperature, pH, Cosolvancy, Solid
dispersion
Effect of Temperature
• The solubility of a solute in a solvent is dependent on
temperature, nature of solute and nature of solvent.
• Heat of solution represents the heat released or

absorbed when a mole of solute is dissolved in a large
quantity of solvent.
• Most of the substances are endothermic, absorbing

heat in the process of dissolution.
• For this substances, an increase in temperature results
in an increase in solubility.
• Exothermic substances give off heat in the process of

dissolution. The solubility of such substances would
decrease with increase in temperature.
• Care should be taken as heat may destroy a drug or

cause other changes in the solution.
e.g. On excess heating the sucrose solution it can get

converted in to the invert sugar.
• Depending on the type of reactions weather it is

exothermic or endothermic heat is either released or
absorbed.
e.g. Mixture of chloroform and acetone. The heat

produced by the solute-solvent interaction is so much
greater than the heat necessary to separate the
molecules of acetone and chloroform, which can be
detected as a rise in temperature of the liquid.
• Applications:
• Pharmaceutical solutions must be administered
at or near room temperature. So, it is more
important factor for product storage than the
formulation.
• To increase the solubility of sparingly
soluble solute.
• To increase the stability by reducing the
moisture content.
Effect of pH
• Weak electrolytes undergo ionization and are more
soluble when in ionized form. The degree of ionization
depends on dissociation constant (pKa) and the pH of the
medium.
• Solubility is a function of pH, that is related to its pKa

which gives ratio of ionized and unionized forms of the
substance.
This can be shown as:
pH = pKa + log [ A- ]
[ HA ]
Effect of pH
• If the substance is brought outside its pKa, i.e. the pH
value where half the substance is ionized and half is
not, than solubility will be changed because we are
introducing new intermolecular forces, mainly ionic
attraction.
• e.g. –COOH has pKa value at pH around 4. If pH is

increased then –COOH is converted into –COO- .
This may interact with the H+ of water.
Effect of pH
• The effect of pH on solubility for weak electrolytes
can be described by:
pHp = pKa + log S –S0

S0
• Where,
pHp = pH below which the drug precipitates from
solution as the undissociated acid.
S = total solubility.
S0 = molar solubility of the undissociated acid.
Effect of pH
• It is to be ensured that pH change for one
single compound should not affect the other
requirements of product.
• e.g. the chemical stability of drug may depend

on pH, and this pH of optimum stability should
not coincide with the pH of other ingredients
specially colors, preservatives and flavors.
Cosolvancy
• To enhance the solubility of poorly soluble
materials, the water miscible solvents are used in
which the drug has good solubility. This process
of improving solubility is known as co-solvency.
• Solvents used to increase the solubility are

known as co-solvents.
Cosolvancy
• The mechanism for solubility enhancement by
co-solvency is not clearly understood. But it is
proposed that, solubility is increased may be
by reducing the interfacial tension between the
solvent and hydrophobic solutes and
decreasing dielectric constant of solvent.
Cosolvancy
• The commonly used and acceptable co-solvents in
formulation of aqueous liquids for oral solutions are
Ethanol, Sorbitol, Glycerin, Several members of PEG
series.
• For parenteral products, Dimethylacetamide is widely

used. But in case of oral liquids its application is
limited, because of its objectionable odour and taste.
Cosolvancy
• Some characteristics of co-solvent, which are used in
preparation:
1. It must be non-toxic. Non-irritating.
2. It should be able to solubilize the drug in
given solvent.
3. It should be able to cross the membrane.
• Apart from increasing solubility, they are also used to
improve the solubility of volatile constituents used to
impart a desirable flavour and odour to the product.
Solid – Dispersion System
• Definition :
Solid dispersion is defined as dispersion of one or

more active ingredients in an inert carrier or matrix at
solid state prepared by the melting, solvent or melting
solvent method.
Classification
(Based on Fast Release Mechanism)
• Simple Eutectic Mixtures
• Solid Solutions
• Glass Solutions and Glass Suspensions
• Amorphous precipitation of drug in crystalline
carrier
• Compounds or Complex formation between drug
and carrier
• Any combination among the above
A. Eutectic Mixtures
• When two or more substances are mixed
together they liquefy due to the lowering of
melting point than their individual melting
point. Such substances are called as eutectic
substances.
e.g. paracetamol-urea, griseofulvin-urea
• Simple binary phase
diagram showing eutectic
point E.
• The eutectic composition at
point E of substance A and
B represents the melting
point.
• TA and TB are melting point
of pure A and pure B.
• The following factors may contribute to faster
dissolution rate of drug dispersed in the eutectic
mixtures:-
1. Increase in drug solubility.
2. Solubilization effect by the carrier which
completely dissolves in a short time in diffusion
layer surrounding drug particles.
3. Absence of aggregation and agglomeration
between fine crystallites of pure hydrophobic
drug.
4. Excellent wettability and dispersibility
of a drug as the encircling soluble carrier
readily dissolves and causes water to
contact as wet drug particles.
5. Crystallization of drug in a metastable

form after solidification from fused solution,
which has high solubility.
• Eutectics are easy to prepare and economical
with no solvents involved. The method
however cannot be applied to:
- Drugs which fail to crystallize from
mixed melt.
- Thermolabile drugs.
- Carriers such as succinic acid that
decompose at melting point.
B. Solid Solutions
• It is made up of a solid solute dissolved in a solid
solvent. It is often called a “mixed crystal” because
the two components crystallize together in a
homogenous phase system.
• It is prepared by fusion method.
• A solid solution of poorly soluble drug in a rapidly

soluble carrier achieves a faster dissolution because
particle size of drug is reduced to molecular size.
Classification
• According to extent of miscibility :
1. Continuous (iso-morphous, unlimited,
complete) solid solution.
2. Discontinuous (limited, restricted,
incomplete) solid solution.
• According to crystalline structure of solid
solutions :
1. Substitutional solid solutions.
2. Interstitial solid solutions.
Classification
a) Continuous Solid Solutions :-
 The two components are miscible or soluble at
solid state in all proportions.
 No established solutions of this kind has been
shown to exhibit fast release dissolution properties.
 The faster dissolution rate would be obtained if the
drug is present as a minor compartment.
b) Discontinuous Solid Solutions :-

 There is only limited solubility of a solute in a solid
solvent in this group of solid solutions.
C. Glass Solutions and Glass
Suspensions
• A glass solution is a homogenous, glassy system in
which a solute is usually obtained by abrupt
quenching of the melt.
• Many compounds have been shown to be able to

form glasses readily upon cooling from liquid state.
• These compounds include sucrose, glucose, ethanol

and 3- methyl hexane.
Suspensions
• It is presumably due to their strong hydrogen bonding
which may prevent their crystallization.
• Polymers possessing linear, flexible chains can freeze
into a glass state to transparency and brittleness.
• The strength of chemical binding in a glass solution is
much less compared to that in a solid solution.
• Hence, dissolution rate of drugs in the glass solution
is faster than in solid solution.
• e.g. Glass solution of citric acid
D. Amorphous Precipitation
of Drug in Crystalline Carrier
• Instead of forming a simple eutectic mixture in which
both drug and the carrier crystallize simultaneously
from a solvent method of preparation, the drug may
also precipitate out in an amorphous form in
crystalline carrier.
• It has faster dissolution and absorption rates than

crystalline form.
• e.g. Amorphous novobicin has 10 fold higher
solubility than its crystalline form.
E. Compound or Complex
Formations
• Dissolution and absorption of a drug can occur from a
complex or a compound formed between the drug and
an inert soluble carrier.
• Complexation also implies that dissolution could be

retarded as observed with PEG 4000 - phenobarbital.
• However, the formation of a soluble complex with a

low association constant results in increased rates of
dissolution and absorption.
F. Combinations and
Miscellaneous Mechanisms
• A solid dispersion entirely belongs to any five groups
discussed so far, but it can also be made up of
combinations of different groups.
• These combinations increase the dissolution and

absorption rate.
• The griseofulvin dispersed at high concentrations in

PEG may exist as individual molecules and as micro-
crystalline particles.
Methods of Preparations
• Melting Method
• Solvent Method
• Melting - Solvent Method
• Hot Melt Extrusion Technique
1. Melting Method or
Fusion Method
• The physical mixture of a drug and water soluble
carrier is heated until it melts.
• The melt is then cooled and solidified rapidly in an
ice bath with vigorous stirring .
• The final solid mass is crushed, pulverized and
sieved.
• To facilitate faster solidification, the homogenous
melt is poured in the form of a thin layer onto
stainless steel plate and cooled by flowing air or
water on the opposite side of the plate.
1. Melting Method or Fusion Method
• Advantages :
• Simplicity of method.
• Supersaturation of a solute or a drug in a system can
often be obtained by quenching the melt rapidly from
high temperature.
• Disadvantage :
• Some drugs or carriers may decompose or evaporate
during fusion process at high temperatures .
e.g. succinic acid used as a carrier for griseofulvin is
quite volatile and may also partially decompose by
dehydration near its melting point.
2. Solvent Method
• They are prepared by dissolving a physical
mixture of two solid components in a common
solvent, followed by evaporation of the
solvent.
• The method is used to prepare solid

dispersions of griseofulvin-
polyvinylpyrrolidone, sulphathiazole - pvp.
2. Solvent Method
• Advantage :
- Thermal decomposition of drugs or carriers can be
prevented because of low temperature required for
the evaporation of organic solvents.
• Disadvantages :
- High cost of preparation.
- Difficulty in completely removing the solvent.
- Difficulty in producing crystal forms.
3. Melting Solvent Method
• It is prepared by first dissolving the drug in a
suitable solvent and then incorporating this solution
in a melt of PEG without removing the solvent.
• Advantages :
Same as above two methods
• Disadvantage :
From practical stand point, it is only limited to
drugs with a low therapeutic dose, e.g. below 50mg.
4. Hot Melt Extrusion Method
• In this method, a blend of active ingredients,
polymeric carrier and other processing aids like
plasticizers and antioxidants is heated and softened.
• This softened material is called as extrudate.
• When the extrudate is cooled at room temperature,

the polymeric thermal binder solidifies and bonds the
excipients together to form a matrix.
• Advantages :
- There are no concerns with solvent handling or
recovery after processing
- It is simple and continuous process for
preparation of tablets and granulations.
- The process is faster and there were fewer steps
than the wet granulation method.
- Can be used for formulating sustained
release granules.
e.g. Diltiazem granules.
Methods of Determination
of Solid Dispersion Systems
a) Cooling curve method
b) Thaw-melt method
c) Thermoscopic method
d) Differential thermal analysis (DTA)
e) Zone Melting Method
• X-Ray diffraction Method
• Microscopic method
• Spectroscopic method
• Thin layer chromatography
• Solubility determinations
A. Thermal Analysis
• It is used to study the physico-chemical
interactions of two or more components.
• Principle : Change in thermal energy as a
function of temperature.
a) Cooling curve method :
- The physical mixtures of various
compositions are heated until a
homogenous melt is obtained.
- The temperature of the mixture is then
recorded as function of time.
A. Thermal Analysis
b) Thaw-melt method :
- Here a sample of solidified mixture in a
capillary melting point tube is heated
gradually till the thaw point.
- The thaw point is referred to as crossing
solidus line.
- It is useful in differentiating between a
simple eutectic system and a limited
solution.
A. Thermal Analysis
c) Thermoscopic method :
- Polarized microscopy is used with hot
stage to study phase diagrams of binary
systems.
- The physical mixture is gradually
heated on a slide until it completely
liquefies.
- After cooling, the mixture is heated at rate
of 4 degree per minute.
- The thaw and melting points are
determined by visual observations.
A. Thermal Analysis
d) Differential thermal analysis (DTA) :
- An effective thermal method for studying
phase equilibria of either pure compound or
mixture.
- Different effects, associated with physical
or chemical changes are automatically
recorded as function of time or temperature as
the substance is heated in uniform rate.
- In addition; evaporation, sublimation,
polymorphic transition, desolvation can
be detected.
A. Thermal Analysis
e) Zone Melting Method :
- It is primarily used for ultra
purification of metal and inorganic and
organic metal.
B. X-Ray Diffraction Method
• In this method the intensity of x-ray diffraction or
reflection from a sample is measured as a function of
diffraction angles.
• Counter and film methods detect diffraction intensity.
• Counter method provides better resolution of
diffraction and relative intensity which can be easily
compared.
• This method is used to characterize physico-chemical
properties of Griseofulvin dispersed in PEG 4000 and
6000.
C. Microscopic Method
• It has been used to study polymorphism and
morphology of solid dispersion.
• The fine particles of crystallization in glass
PVP can be easily detected by polarizing
microscope.
• The resolution of electron microscope was
used to study dispersed particle size of iopanic
acid in PVP.
D. Spectroscopic Method
• In the UV study, the spectra of pure drug and
the dispersed drug are scanned.
• e.g. The spectrum of the dispersed beta –
carotene resembles that beta–carotene is
dissolved in organic solvents but do not
indicate the molecular dispersion of drug in
polymer.
E. Thin Layer Chromatography
• TLC characteristics of pure and dispersed
drugs are studied to test whether the drugs are
decomposed by process.
• A single spot with same ‘Rf ’value is expected

for both the pure and processed samples in thin
layer plate.
F. Solubility determinations
• Results from aqueous solubility studies of drug
in various concentrations of carrier would
indicate interactions between drug and carrier.
• Such studies indicated weak or insignificant
interactions between griseofulvin and PEG
6000.
• Increased rate of dissolution due to solubility
of the drug by carrier can be predicted by this
method.
Pharmaceutical Applications
• To obtain a homogenous distribution of small
amount of drugs at solid state.
• To stabilize unstable drugs.
• To dispense liquid or gaseous compounds.
• To formulate a faster release priming dose in a
sustained release dosage form.
• To formulate sustained release dosage or
prolonged release regimens of soluble drugs by
using poorly soluble or insoluble carriers.
β-cyclodextrin drug dispersion system,
techniques for studies of crystals,
polymorphism
β-cyclodextrin drug dispersion system
• The poorly dissolution of relatively insoluble drug

has for long been a problem in the formulation of
oral dosage form.
• This limits the aspect such as

 Absorption &
 Bioavailability
• Several approach have been followed in improving

the solubility of drug, one of them being
complexation using cyclodextrin.
• Cyclodextrin is cyclic structure oligomers of glucose

which are obtained from the starch digests of the
bacteria Bacillus macerans.
• The most abundant cyclodextrins available are

a-cyclodextrin - 6 glucose units
b-cyclodextrin - 7 glucose units
g-cyclodextrin - 8 glucose units
Chemistry of b-cyclodextrin
• Cyclodextrine molecule have cylindrical shape with
central axial cavity and resembles with shape of
truncated cone.
• The interior cavity is hydrophobic and the outside of

the molecule is hydrophilic.
Characteristics of β-cyclodextrin
• Glucose unit – 07
• Molecular wt. – 1135
• Solubility – 1.85g/100ml
o
• Cavity diameter – 6.4 A
• Diameter of outer periphery –
o
15.4 A
• Approx. vol. of cavity –
o 3
262 (A )
Method of preparation of b-cyclodextrin
complex
• Physical mixture method
• Kneading method
• Co-evaporation method
• Solid dispersion method
• Spray drying method
• Neutralization method
Physical mixture method
• Here the drug and b-cyclodextrin (1:2) are mixed

physically with spatula & then the pulverized powder
is passed through 100#.
• Eg. Diclofinac sodium

Kneading method
• Here the b-cyclodextrin is dissolved in small vol. of

water-methanol solution(6:4).
• To the above solution required drug is added in small
amount.
• The slurry is then kneaded for 45 min. & dried at
o
45 c.
• The dried mass is pulverized and sieved through
100#.
• Eg. Nimesulide , Omeprazole
Co-evaporation method
• In this method, aq. solution of b-cyclodextrin is added

to an alcoholic solution of drug.
• The
o
resulting mix. is stirred for 1 hr. & evaporated at
45 c until it is dried.

100#.
• Eg. Steroids & Diclofenac sodium

Solid dispersion method
• Here the drug & molar qty. of b-cyclodextrin is
dissolved in methanol.
o
• The solution is then evaporated in vacuum at 40 c
with rotatory evaporator.
• The powder is stored under vacuum in dessicator for

3 days & analysed.
• Eg. Rifampicin
Spray drying method
• In this, the drug & double molar of β-cyclodextrin are
• The solution was then spray dried under foll.

conditions –
Feed rate – 10 ml/min
o
Inlet temp. - 95 c
o
Outlet temp. - 65 c
Press. – 5 bar
3
Drying air – 35 m
Spray drying method
• The powder is then collected & stored under vacuum

in dessicator for 3 days & analysed.
• Eg. Naproxene
Neutralization method
• Here the drug & b-cyclodextrin are dissolved in 0.1N

HCl & then 0.1N NaOH is added to precipitate the
complex at pH-7.5.
• The ppt. is washed with distilled water.
• Then it is pulverized & sieved through 90# and stored

in dessicator over fused CaCl2.
• Eg. Ketoconazole
Applications
• To increase aq. solubility
• To increase dissolution rate of drug
• To improve bioavailability of drug
• To increase chemical/physical stability
• To decrease drug irritation
Crystallinity
• Crystal habit & internal structure of drug can affect

bulk & physicochemical property of molecule.
• Crystal habit is description of outer appearance of

crystal.
• Internal structure is molecular arrangement within the

solid.
Crystallinity
• Change with internal structure usually alters crystal

habit.
Eg. Conversion of sodium salt to its free acid form
produce both change in internal structure & crystal
habit.
Different shapes of crystals
• Cubic or isometric - not • Hexagonal - six-sided
always cube shaped. Also prisms. When you look at
find as octahedrons (eight the crystal on-end, the cross
faces) and dodecahedrons section is a hexagon.
(10 faces). • Trigonal - possess a single
• Tetragonal- similar to cubic 3-fold axis of rotation
crystals, but longer along instead of the 6-fold axis of
one axis than the other, the hexagonal division.
forming double pyramids • Triclinic - usually not
and prisms. symmetrical from one side
• Orthorhombic - like to the other, which can lead
tetragonal crystals except to some fairly strange
not square in cross section shapes.
(when viewing the crystal • Monoclinic - like skewed
on end), forming rhombic tetragonal crystals, often
prisms or dipyramids (two forming prisms and double
pyramids stuck together). pyramids.
• Depending on internal structure compounds is

classified as
1. Crystalline
2. Amorphous
• Crystalline compounds are characterized by
repetitious spacing of constituent atom or molecule in
three dimensional array.
• In amorphous form atom or molecule are randomly
placed.
• Solubility & dissolution rate are greater for

amorphous form then crystalline, as amorphous form
has higher thermodynamic energy.
Eg. Amorphous form of Novobiocin is well absorbed

whereas crystalline form results in poor absorption.
Polymorphism
• It is the ability of the compound to crystallize as more

than one distinct crystalline species with different
internal lattice.
• Different crystalline forms are called polymorphs.
• Polymorphs are of 2 types

1. Enatiotropic
2. Monotropic
Polymorphism
• The polymorph which can be changed from one form

into another by varying temp. or pressure is called as
Enantiotropic polymorph.
Eg. Sulfur.
• One polymorph which is unstable at all temp. &

pressure is called as Monotropic polymorph.
Eg. Glyceryl stearate.
Polymorphism
• Polymorph differ from each other with respect to

their physical property such as
Solubility
Melting point
Density
Hardness
Compression characteristic
Polymorphism
• During preformulation it is important to identify the

polymorph that is stable at room temp.
Eg. 1)Chloromphenicol exist in A,B & C forms,

of these B form is more stable & most
preferable.
2)Riboflavin has I,II & III forms, the III form
shows 20 times more water solubility than
form I.
Techniques for studies of
crystals
• Microscopy
• Hot stage microscopy
• X-ray diffraction
Microscopy
• Material with more than one refractive index are
anisotropic & appear bright with brilliant colors
against black polarized background.
• The color intensity depends upon crystal thickness.
• Isotropic material have single refractive index and

this substance do not transmit light with crossed
polarizing filter and appears black.
Microscopy
• Advantage :
By this method, we can study crystal morphology &
difference between polymorphic form.
• Disadvantage :
This require a well trained optical crystallographer, as
there are many possible crystal habit & their
appearance at different orientation.
Hot stage microscopy
• The polarizing microscope fitted with hot stage is
useful for investigating polymorphism, melting point
& transition temp.
• Disadvantage :
In this technique, the molecules can degrade during
the melting process.
• Diagrammatic • Results of hot stage
representation microscopy
Thermal analysis
• Differential scanning calorimetry (DSC) &
Differential thermal analysis are (DTA) are
particularly useful in the investigation of
polymorphism.
• It measures the heat loss or gain resulting from

physical or chemical changes within a sample as a
function of temp.
Thermal analysis
• For characterizing crystal forms , the heat of fusion
can be obtained from the area under DSC- curve for
melting endotherms.
• Similarly, heat of transition from one polymorph to

another may be calculated.
• A sharp symmetric melting endotherm can indicate

relative purity of molecule.
Thermal analysis
• A broad asymmetric curve indicates presence of
impurities.
• Disadvantage :
Degradation during thermal analysis may provide
misleading results.
X-ray diffraction
• Working :
When beam of nonhomogenous X-ray is allow to
pass through the crystal, X-ray beam is diffracted & it
is recorded by means of photographic plate.
• Diffraction is due to crystal which acts as 3

dimensional diffraction grating toward X-ray.
X-ray diffraction
X-ray diffraction
• Random orientation of crystal lattice in the powder
causes the X-ray to scatter in a reproducible pattern of
peak intensities.
• The diffraction pattern is characteristic of a specific

crystalline lattice for a given compound.
X-ray diffraction
• An amorphous form does not produce a pattern
mixture of different crystalline forms.
• Single – Crystal x-ray provide the most complete

information about the solid state.
Stability testing….
Why Stability?
• Provide a evidence on how the quality of a drug
substance or drug product varies with time under the
influence of a variety of environmental factors such
as….. temperature, Humidity and light.
• Establish a re-test period for the drug substance or a

shelf life for the drug product and recommended storage
conditions.
• Because physical, chemical or microbiological changes

might impact the efficiency and security of the final
product
Where and Why?
Stability Studies are preformed on ...
• Drug Substances (DS)  The unformulated drug
substance that may subsequently be formulated with
excipients to produce the dosage form.
• Drug Products (DP)  The dosage form in the final

immediate packaging intended for marketing…….
• controlled and documented determination of

acceptable changes of the drug substance or drug
product
What are changes?
• Physical changes
• Appearance
• Melting point
• Clarity and color of solution
• moisture
• Crystal modification (Polymorphism)
• Particle size
• Chemical changes
• Increase in Degradation
• Decrease of Assay
• Microbial changes
Forced degradation studies
• Acidic & Basic conditions.
• Dry heat exposure
• UV radiation exposure
• Influence of pH
• Influence of temperature
• Influence of ionic strength

Arrhenius Equation
• K = Se-Ha /RT
where..k = specific rate of degradation.
R = gas constant ( 1.987 calories degree -1mole)
T = absolute temperature.
S = frequency factor.
Logarithmically ,
ln k = -Ha/ RT + ln S
converting to log 10
Log k = -ΔHa/2.303 R .1/T + log S
log k = specific rate of degradation
S = constant
Arrhenius Equation
• Plot of log K v/s 1/T….yields a slope equal to -ΔHa/2.303 R ….. From which
heat of activation (ΔHa) can be calculated.
• Log k2/k1 = ΔHa/2.303 R . ( T2 – T1 )/ T2.T1
Mean Kinetic Temperature

ΔH/R
• Tk =
-ln ( e – DHRT1 + e -ΔH/R T2 +….+ e- ΔH/R Tn
n
Tk = Mean kinetic temp
H = Heat of activation (83.144 KJ/mole)
R = Universal gas constant (8.3144 . 10 1 – KJ/mole/degree )
T1 = average storage temp during first time period ( months)
T2 = average storage temp during second time period ( months)
Tn = average storage temp during nth time period ( months)
n = no of average temp recorded (min )
T = temp in o k ( degree kelvin )
Clasius – Clapeyron equation
• ln = P2 / P1 . ΔH V ( T2 – T1 ) / R ( T 2 _ T 1)
where…. P2 & P1 = vapour pressure at T1 & T 2

ΔH
=molar ( latent ) heat of evaporation
Relative humidity
Q =PD / PS . 100
RH is expressed in percentage ( %)
Q = Relative humidity
PD = partial pressure of unsaturated air
PS = saturation pressure
Chemical degradation studies
• Hydrolysis
• Oxidation
• Reduction
• Decarboxylation
• Photolysis
Stability studies at different stages
• Stress- and accelerated Testing with drug substances
• Stability on pre-formulation batches
• Stress testing on scale-up Batches
• Accelerated and long term testing for registration
• On-going Stability testing
• Follow-up Stabilities
Stability studies at different
stages
􀂄 Selection of samples
• API, excipient, batches
􀂄 Scope
• Appearance
• Appropriate physical-chemical parameter
• Assay / Degradation products
􀂄 Up to 3 month
Scope
• Determination of expire date
Scope • Determination of preliminary
• Solubility Profile specifications
• Hygroscopicity • Release of clinical batches
• Thermal stability • Monitoring of samples during the clinical
(Melting point, phases
Polymorphism) • Definition of storage conditions
• Chemical stability • Definition of Tests for registration
􀂄 1 Batch stability
􀂄 Up to 3 month 􀂄 Up to 36 month
Testing scope for Solid dosage
Tablet & Capsule
• Physical-chemical properties
– Appearance
– Elasticity
– Mean mass
– Moisture
– Hardness
– Disintegration
– Dissolution
• Chemical properties
– Assay
– Degradation
• Microbial properties
• Container closure system properties

– Functionality tests (e.g. extraction from blister)
Testing scope for Oral liquid
form
– pH
– Color & clarity of solution
– Viscosity
– Particle size distribution (for oral suspensions only)
– Assay
– Degradation products
– Degradation preservatives
– Content antioxidants

– Functionality tests
Testing scope for
LIQUID FORMS for inj. and
PARENTRAL
– pH
– Loss on weight
– Assay

Testing scope for
SEMI LIQUID FORMS
– Appearance, odor, homogenesity, consistency
– Loss on weight, Viscosity
– Content uniformity (within the container)
– Assay
– Degradation products & preservatives
– Content preservatives
– Degradation– Content antioxidants

Climatic Zones / Storage conditions
Climatic Zone Calculated data Derived data
Countries Temp. MKT humidity Temp humidity
°C °C % r.h. °C % r.h.
Climatic Zone I
"Temperate"
Japan, United Kingdom,
20 20 42 21 45
Northern Europe,
Canada, Russia, United
States
Climatic Zone II
"Mediterranean,
Subtropical" 26.4 22 52 25 60
Japan, United States,
Southern Europe
°C °C % r.h. °C % r.h.
Climatic Zone III

"Hot, dry"
Iran, Iraq, Sudan
26,4 27,9 35 30 35
Climatic Zone IV
"Hot, humid" 26,7 27,4 76
Brazil, Ghana, Indonesia,
30 70
Nicaragua,
Philippines
What or Who is ICH?
• ICH stands for International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for
Human use
• Objectives of ICH
• Harmonization of registration applications within the three
regions of the EU, Japan and the United States.
• ICH is a joint initiative involving both regulators and industry

as equal partners in the scientific and technical discussions of
the testing procedures which are required to ensure and assess
the safety,quality and efficacy of medicines.
What or Who is ICH?
There are Six Parties directly involved in the decision making process
• EU: European Commission - European Union
• EFPIA: European Federation of Pharmaceutical Industries and

Associations
• MHLW: Ministry of Health, Labor and Welfare, Japan
• JPMA: Japan Pharmaceutical Manufacturers Association

• FDA: US Food and Drug Administration
• PhRMA: Pharmaceutical Research and Manufacturers of America
• There are additionally observers installed to act as a link
with non-ICH countries and regions
• WHO
• The European Free Trade Area (EFTA),

represented by Swissmedic Switzerland
• Health Canada
٠Global guidelines
ICH Guidelines
• Quality Guidelines “Q” (chemical and pharmaceutical QA)
– details see next slide
• Safety Guidelines “S” (in vitro and in vivo pre-clinical studies)
– covering Carcinogenicity Testing, Genotoxicity Testing,
Toxicokinetics and Pharmacokinetics ….. etc.
• Efficacy Guidelines “E” (clinical studies in human subject)
– Covering clinical safety, Dose Response Studies, Good
Clinical Practices, Clinical evaluation …. etc.
• Multidisciplinary Guidelines “M”
– Covering Medical Terminology, Electronic Standards for
Transmission of Regulatory Information …… etc.
– Important for Stability !
» Guideline M4: The Common Technical Document (CTD)
ICH Q-Guidelines (Quality)
• Stability Testing in Climatic Zone I and II (Q1A)
• Photostability Testing (Q1B)
• Stability Testing for New Dosage Forms (Q1C)
• Bracketing and Matrixing Designs (Q1D)
• Evaluation of Stability Data (Q1E)
• Stability Testing in Climatic Zones III and IV
(Q1F)
• Validation of Analytical Procedures (Q2)
• Impurities (Q3)
• Biotechnological Products (Q5)
• Specifications (Q6)
Q1A(R2) Stability testing of
New Drug Substances & Products
(Q1F)
• Impurities (Q3)
Drug substances - General case
Minimum time period
Storage condition covered by data at
Study
submission
Long term 25°C ± 2°C / 60% ± 5% r.h or 12 months
30°C ± 2°C / 65% ± 5% r.h.
Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months
Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6 months
Drug substances - intended for storage in a Refrigerator

Study Storage condition Minimum time period
covered by data at
submission
Long term 5°C ± 3°C 12 months
Drug substances/Product- intended for storage in Freezer
covered by data at
submission
Long term -20°C ± 5°C 12 months
Drug products - General case

covered by data at
submission
Long term 25°C ± 2°C / 60% ± 5% r.h. or 12 months
30°C ± 2°C / 65% ± 5% r.h.

Drug products - packaged in Semi-permeable containers
covered by data at
submission
30°C ± 2°C / 35% ± 5% r.h.
Drug products - intended for storage in a Refrigerator

covered by data at
submission

CALCULATIONS FOR SHELF LIFE PREDICTION
. From the graph no : time period to have 90% potency for each temperature
namely 37°c, 45°c and 60°c were ascertained for Formulation F3 which are
depicted in the following table
Temperature under study Time required to have a 90%

potency (days) i.e.‘t’ 90%
37°C 262
45°C 192
60°C 95
‘t’ 90% values from the above table then convert into log ‘t’ 90% and their
coresponding temperature (t) into absolute temperature (‘T’). Then reciprocal of
absolute temperature 1/T was calculated at each temperature.
CALCULATIONS FOR SHELF LIFE
PREDICTION
AT 37°C
‘t’ 90% = 262
log ‘t’ 90% = 2.41
T = ‘t’+273
= 37+273
T =310 1/T=1/310=3.225*10-3
AT 45°C
‘t’ 90% = 192
log ‘t’ 90% = 2.28
T = ‘t’ +273
= 45+273
T =318 1/T=1/318=3.144*10-3
At 60°C
1/T=1/333=3.00*10-3
TABLE DEPICTING ‘t’ 90% ,1/T AND LOG ‘t’
90% VALUES FOR FORMULATION F3 AT 37°C,
45°C AND 60°C
Temperature ‘t’ 90% (days) 1/T Log ‘t’ 90%
under study
37°C 262 3.225*10-3 2.41
45°C 192 3.14*10-3 2.28
60°C 95 3.000*10-3 1.97

90% VALUES FOR FORMULATION F3 AT 37°C,
45°C AND 60°C
• At 30°C(Room Temperature)
T = ‘t’ +273
= 30+273
T = 303 1/T=1/303=3.30*10-3
Depicts a plot between log t 90% and 1/T10-3 Formulation F3 at 37°C ,

45°C,60 °C. The straight line so obtained was extra plotted to 1/T value at
30°C & the corresponding log ‘t’ at 30°C on y axis was noted down. It was
found to be 2.69.
Now log’ t’ 90% at 30°C = 2.69
‘t’ 90°C at 30°C = 490 days.
Therefore shelf life of formulation F3 in years = 490/365 = 1.342 years or =
1.3 years.
REFERENCES
1. Ansel’s pharmaceutical Dosage forms & Drug delivery
systems, 8th edition by Loyd V. Allen, Nicholas G.popovich,
Howard C. Ansel, publised by B.I.Publication pvt. Ltd.,
page no:- 187-193,42 & 43,126-133.
2. Pharmaceutical preformulation by J.T.Cartensen published

by technomic publishing Co., page no:- 1-6, 211-212.
3. Textbook of physical pharmaceutics by C.V.S.

Subrahmanyam, published by Vallabh prakashan, page no:-
182-208, 222-226.
REFERENCES
4. The theory & practice of industrial pharmacy by
Leon Lachman, Herbert A. Lieberman, Joseph L.
kenig, 3rd edition, published by Varghese Publishing
house, page no:- 171-184.
5. Martin’s Physical pharmacy & Pharmaceutical

science, 5th edition by Patrick J. Sinco, Published by
Lippincott williams & wilkins, page no:- 547-550.
6. Pharmaceutical dosage forms : Tablet volume1,

edited by Herbert A. Lieberman & Leon Lachman,
published by Marcel dekker, page no:- 1-10.
Thank You
E-mail: m.zaman2157@gmail.com
334 Theory and Practice of Contemporary Pharmaceutics
a. Reservoir Devices ..........................................................................................346

b. Methods for Developing Reservoir Devices .................................................348
i. Coated Beads or Pellets .........................................................................348
ii. Microencapsulation ................................................................................348
c. Matrix Devices...............................................................................................349
i. Dissolved Drug ......................................................................................349
ii. Dispersed Drug ......................................................................................350
iii. Porous Matrix.........................................................................................351
iv. Hydrophilic Matrix ................................................................................351
4. Dissolution Controlled Systems ..........................................................................352
a. Matrix Dissolution .........................................................................................352
b. Encapsulated Dissolution Controlled System ...............................................353
5. Dissolution and Diffusion Controlled Systems...................................................353
F. Introduction to the Pharmacokinetics of Oral Controlled-Release Dosage
Forms .........................................................................................................................354
G. Elements of Regulatory Assessment of Controlled Release Products .....................357
III. Conclusion..........................................................................................................................358
Tutorial ...............................................................................................................................358
Answers ..............................................................................................................................359
Cases...................................................................................................................................360
References ......................................................................................................................................365
Learning Objectives
After studying this chapter the student will be able to:
• Describe the advances in drug delivery systems

• Describe various terms associated with modified release dosage forms
• Discuss advantages and disadvantages of controlled release dosage forms
• Describe the various factors affecting the design of controlled release dosage forms
• Classify oral controlled-release dosage forms with commercial examples for each class
• Describe the mechanisms of release and the equations for modeling the release of
bioactive agents from each class of controlled oral dosage form
• Solve some numerical problems associated with the design of oral controlled-release
dosage forms
• Describe the type of formulation science that forms the basis of the design of some
commercially available oral controlled-release dosage forms
I. INTRODUCTION
A. DEVELOPMENTS IN PHARMACEUTICAL DOSAGE FORM DESIGN
A drug is rarely administered to human being as a pure chemical compound. What is given is a
drug product containing the drug. When a drug is prepared in a form suitable for administration,
it is called a dosage form or a drug product or, in a modern term, a delivery system. Almost anything
done to the dosage form may alter the availability (the rate and the amount) of the drug delivered
to the desired place in the body. The following discussion of developments in pharmaceutical dosage
form design is intended to provide an overview of the progress that has been made in the efforts
to improve upon the delivery of bioactive agents (drugs). The divisions into various generations
Oral Controlled Release Solid Dosage Forms 335
serve only to point out the transition from one major form of delivery to another based on advances
in physical, chemical, and biological sciences. Some of the newer drug delivery systems will be
handled in clinics by current pharmacy students.
Historically, humans developed primitive ways of introducing drugs into the body:
• Chewing leaves and roots of medicinal plants

• Inhaling soot from the burning of medicinal substances
• Primitive extracts from plants and animals
• Treatment of asthma by smoking medicinal cigarettes as recently as 1950s
These primitive approaches to the delivery of drugs lacked consistency, uniformity, and specificity.
1. The First Generation Drug Delivery Systems
The first generation drug delivery systems (pharmaceutical dosage forms) appeared toward the end
of the nineteenth century and in the twentieth century, and they have consistency and uniformity.
These drug delivery systems (conventional dosage forms) include tablets, capsules, elixirs, syrups,
suspensions, emulsions, and solutions and topical administration of ointments, lotions and creams,
suppositories or injection of suspensions and solutions. Though these conventional drug delivery
systems are still with us, the need for more efficient drug delivery systems was realized with time.
The aims of the anticipated drug delivery systems were to deliver the minimum amount of drug
necessary to the site of action to produce the desired therapeutic response (spatial placement of
the drug) and to deliver the drug at an optimal rate to maximize the beneficial response and to
minimize unwanted side effects (temporal delivery of the drug).
2. The Second Generation Drug Delivery Systems
With advances in biopharmaceutics, pharmacokinetics, and human physiology and their applications
to drug formulation and development, various modifications in drug molecules and dosage forms
were introduced. These second generation drug delivery systems (dosage forms) represent attempts
to improve upon conventional dosage forms. These dosage forms were supposed to protect drugs
against hostile conditions along the gastrointestinal tract, prolong their action if necessary, and
improve bioavailability. The materials of formulation include polymers, waxes, plastics, and oils.
They are described by various terms such as repeat action, prolonged action, and timed release.
These drug products were introduced in the 1950s. In the second generation drug delivery systems,
repetitive, intermittent dosing of a drug occurs from one or more immediate release units incorpo-
rated into a single dosage form (e.g., enteric coated tablets). Though these drug delivery systems
provide some degree of control, it is not complete. More often than not, the release of the drug is
subject to the environmental conditions at the site of administration or drug release, and the drug
products do not generally permit a long-term drug release. Further, they do not produce a uniform
blood–drug concentration as a function of time.
3. The Third Generation Drug Delivery Systems
In the middle to late 1960s, the term controlled drug delivery was introduced to describe a new
concept of dosage form design. Controlled drug delivery refers to the precise control of the rate at
which a drug dosage is released from a delivery system, ideally in a constant or near constant
manner over a long period of time. In order to permit an accurate, reproducible, and predictable
drug therapy, the third generation drug delivery systems (controlled drug delivery systems) were
designed to provide drug release that is dependent on the properties of the device and the physic-
ochemical characteristic of the drug and the delivery system and independent of the environmental
factors existing at the site of administration (i.e., pH of fluids and the presence of enzymes in the body).
The third generation drug delivery system moved beyond extension of the blood level within
the therapeutic range, which is characteristic of the second generation drug delivery systems, to
controlled drug release such that a constant blood drug level can be maintained for a long period
of time. The design of the third generation drug delivery systems that revolves around the zero-
order approach is based on the assumption that optimal clinical outcomes may be achieved by
maintaining a constant drug plasma concentration and that the relationship between plasma drug
concentration and therapeutic effect of a drug is invariant with time. This is the era of time when
drug formulation scientists believe that the most desirable situation is that “the flatter the plasma
drug concentration vs. time curve the better”.
Based on the type of mechanism that triggers and eventually controls the release of drug
incorporated into the system, the controlled-release drug-delivery systems are classified as osmot-
ically controlled systems, swelling-controlled systems, magnetically controlled systems, chemically
controlled systems, electrically controlled systems, and diffusion-controlled systems. The design
of the vast majority of the third generation drug delivery systems involves the use of polymers. As
there is an element of diffusion of drug molecules in most of the systems, polymers serve as
permeable barriers that the drug must cross before reaching the body fluids. Polymers are partic-
ularly suitable for this purpose because their properties can be manipulated easily and diffusion
rates of drug molecules through polymers are orders of magnitude less than the diffusion rates of
the same molecules through water.
4. The Fourth Generation Drug Delivery Systems
Third generation drug delivery systems have no control over the fate of the drug once it enters the
body. With the advent of highly potent drugs such as peptides, proteins, and low molecular weight
anticancer drugs with narrow therapeutic indices, efforts were geared toward drug delivery systems
that could exercise control on the time of availability and the localization of the drug in the body.
Various drug delivery systems belong to this generation: targetable, modulated, pulsatile and self-
regulated, or feedback controlled drug delivery systems.
a. Drug Targeting or Site-Specific Drug Delivery
This mode of delivery involves specific delivery of the active compound (drug) to its site of action
and keeping it there until it is inactivated or detoxified. Drug targeting increases the therapeutic
potential and reduces side effects of the drug. Targeted (site-specific) delivery systems by the
parenteral route are, at present, in different stages of development, and most of them consist of the
following components: an active moiety for the therapeutic effect, a carrier for protection and
changing the disposition of the drug, and a homing device for selection of the assigned target (site-
specificity). The systems are suitable for anticancer drugs and highly potent recombinant peptides
and proteins in which site-specific delivery is needed to reduce side effects (particularly the paracrine
and autocrine acting proteins). The occurrence of severe side effects with cytokines such as tumor
necrosis factor and interleukin-2 limits their therapeutic potential. This problem can be circum-
vented by the delivery of these proteins at the proper site, rate, and dose. This problem also exists
for anticancer drugs. Gastrointestinal targeting of peptide and protein drugs to a suitable site for
absorption is also being investigated.
Commercial targetable drug products have reached the clinic in the field of immunotherapy. It
is believed that new immunotherapies, such as monoclonal antibodies, antisense compounds,
vaccines, and angiogenesis inhibitors, will revolutionize cancer treatment in the near future. Mono-
clonal antibodies bind to specific targets on cancer cells, then destroy the cells or mark them for
destruction by the immune system. The specificity of the drugs is such that they do not destroy
healthy cells; they have fewer side effects than traditional chemotherapies, and they can reduce the
relapse rate among chemotherapy patients. Examples of monoclonal antibodies already approved
by the Food and Drug Administration (FDA) are Rituxan (rituximab, made by Genentech) for
B-cell non-Hodgkin’s lymphoma, Herceptin (transtuzumab, made by Genentech) for breast cancer,
Mylotarg (gemtuzumab ozoganmicin, made by Wyeth) for acute myeloid leukemia, and Campath
(alemtuzumab, made by Millenium) for chronic lymphocytic leukemia. Zevalin (90Y-ibritumomab
tiuxetan, made by IDEC Pharmaceuticals) is a radioimmunotherapeutic agent that aims to combine
the targeting power of monoclonal antibodies with the cancer-killing ability of radiation. It has
been approved by the FDA.
Cancer vaccines have the potential to prevent or delay cancer recurrence by destroying residual
cells following first-line therapy. Some of them have been approved in Australia and Canada, and
some are in advanced clinical development in the U.S. Antisense compounds are complimentary
small fragments of RNA. They bind to specific sequences of mRNA target sites and prevent
translation and thereby inhibit the production of disease-causing proteins. ISIS’Vitraven has been
approved by FDA for the treatment of cytomegalovirus in AIDS patients. The angiogenesis inhib-
itors block the development of new blood vessels that supply nutrients and blood to tumors. They
can shrink tumors and prevent them from growing. None has made it to the clinic.
b. Pulsatile or Modulated Drug Delivery Systems
Twenty-four-hour ambulatory blood pressure monitoring has revealed a marked circadian rhythm
in hypertensive patients. Receptor down-regulation has been observed with a long-term delivery
of nitrates and hormones. Consequently, pulsatile drug delivery has been suggested as the best
mode of delivery for certain drugs so that their delivery should mirror the physiological release
profiles of endogenous peptides and proteins or human physiological needs. Efforts in this direction
resulted in a new body of knowledge called chronotherapeutics, which is the integration of chro-
nobiology, the science of biologic rhythm (i.e., the predictable cyclic variability of human biologic
functions), physiology, and therapeutics.
c. Self-Regulated or Feedback-Controlled Drug Delivery Systems
The long-term complications of diabetes, such as cardiovascular and neuropathic problems, have
been associated with the poor control over glucose levels that result from conventional therapy.
This consideration has been an impetus for the development of self-regulated or feedback-controlled
drug delivery systems. The types that are being investigated can be classified as follows:
• Closed loop systems that involve biosensor-pump combinations: The major requirement
is that there should be a known relationship between plasma level and pharmacological
effect. The components of the system are (a) a biosensor that determines the plasma
level of the drug, (b) an algorithm to calculate the required input rate for the delivery
system, and (c) a pump system capable of administering the drug at the required rate
over a prolonged period of time.
• Closed loop systems that involve delivery by self-regulating systems: Drug release is
controlled as a consequence of response to stimuli in the body. Efforts are directed toward
insulin release in response to glucose concentration. The progress on the development
of these self-regulating systems can be found in most text books on pharmaceutical
biotechnology.
• Closed loop systems based on microencapsulated secretory cells: Reports have shown
that clinical data obtained on human secretory islet of Langerhans cells encapsulated in
alginate-based microspheres for restoring insulin production in a biofeedback fashion
are very encouraging. Polymers are used to protect the secretory cells from the body’s
microenvironment.
5. The Fifth Generation Drug Delivery Systems

Gene therapy, intended to treat the cause of a disease rather than the symptoms, is essentially the
redesign of cells by introducing therapeutic genes into genetically disabled cells to deliver therapeutic
agents made by the gene. There are two methods of inserting genetic material into cells: viral and
nonviral gene transfer methods. Such systems are in various phases of drug development.
II. CONTROLLED RELEASE ORAL DRUG DELIVERY SYSTEMS:

SOLID DOSAGE FORMS
A. VARIOUS TERMS ASSOCIATED WITH MODIFIED RELEASE DOSAGE FORMS
Modified release dosage forms are drug products designed to alter the time and rate of release of the
bioactive agent (drug substance). They can achieve certain therapeutic or convenience objectives that
conventional dosage forms cannot offer. Modified release dosage forms can be classified as follows:
Delayed (sustained) release dosage forms: In delayed-release dosage forms, repetitive,
intermittent dosings of a drug occur from one or more immediate-release units incorporated
into a single dosage form. Examples of types of delayed-release dosage forms are:
Repeat-action (release of two doses successively)
Prolonged action (initial dose plus a replenishment)
Enteric coated tablets (timed release is achieved by a polymer barrier coating)
Modified enteric coated tablets (additional drug is applied over the enteric coat and is
released in the stomach, while the remainder is released further down the GI tract)
Controlled release dosage forms: This system releases the bioactive agent (drug) over an
extended period of time. It avoids the undesirable sawtooth characteristics of the plasma
concentration vs. time profiles of the conventional drug products. The dosage form can
control the rate of release of the incorporated bioactive agents and maintaining constant
drug concentrations at the biophase: target tissue or cells. The nature of the controlled
release dosage form is such that the release is determined by the design of the system and
the physicochemical properties of the drug and is independent of the external factors or
the microenvironment in which the dosage form is placed. The design of controlled release
dosage forms is based on the philosophy that optimum biological response occurs when
the level and the time of availability of the drug to the target tissue are optimized. Since
release-rate control complements drug molecular structure in determining both the selectivity
and duration of action, it is believed that controlled-release drug-delivery systems permit
more accurate, effective, reproducible, and predictable drug administration. Figure 11.1
shows a hypothetical serum drug concentration vs. time curves of various oral dosage forms.
Targeted dosage forms: Two types of targeted dosage forms are commonly described: site-
specific targeting and receptor targeting. In site-specific targeting, drug release is at the
diseased organ or site of absorption, while in receptor targeting, drug release is at the receptor
for the drug action.
All the dosage forms described above can be grouped under the generalized term controlled
drug delivery. Controlled drug delivery is now a generalized term that encompasses any system
that is capable of spatial placement and temporal delivery of a drug. In spatial placement, the drug
is targeted to a specific organ or tissue (this includes targeted dosage forms); in temporal delivery,
the rate of drug delivery to the target tissue is controlled (this includes the delayed and controlled
release dosage forms as well as pulsatile or modulated drug delivery systems because the rate of
delivery is controlled based on human physiological need).
B. RATIONALE FOR THE DEVELOPMENT OF A DRUG AS A CONTROLLED RELEASE

DOSAGE FORM
• Controlled release drug delivery systems increase efficacy by maintaining constant
plasma drug level in the therapeutic window range for an extended period of time.
• Controlled release drug delivery systems reduce dosing frequency and eliminate drug
accumulation in the body, thereby minimizing untoward effects.
• Controlled drug delivery increases patient compliance.
• The cost of treatment for chronic diseases may be reduced.
Toxic Range
Zero-Order Release Therapeutic Range

Arbitrary
Plasma Concentration
Therapeutic
Sustained Release Range
Immediate Release
Subtherapeutic Range
Time
FIGURE 11.1 Hypothetical serum drug concentration vs. time curves of various oral dosage forms. (From
Jantzen, G. M., and Robinson, J. R., Sustained and controlled release drug delivery systems, in Modern
Pharmaceutics, 3rd ed., Banker, G. S. and Rhodes, C. T., Eds., Marcel Dekker, New York, 1996, p. 575, with
permission.)
C. DISADVANTAGES OF CONTROLLED RELEASE DOSAGE FORMS

It is important to consider some of the drawbacks of using controlled release dosage forms,
especially as an aid in drug product evaluation and selection.
• Dose dumping can result from the failure of controlled release dosage forms. Dose
dumping has been defined as either the release of more than the usual fraction of drug
or as the release of drug at a greater rate than the customary amount of drug per dosing
interval, such that potentially adverse plasma levels may be reached. Controlled release
dosage forms are particularly prone to dose dumping if not properly designed and
fabricated because they usually contain the equivalent of two or more drug doses present
in a conventional dosage form. This problem is exemplified by delayed and enteric coated
dosage forms: If poorly formulated, the enteric coating may be dissolved in the stomach,
resulting in premature release of the drug with the concomitant irritation of gastric mucosa.
Moreover, if the coating is poorly done, the enteric coating may not dissolve at the proper
site along the gastrointestinal tract. Thus, the drug may not be available for absorption.
• Should the patient suffer from an adverse drug reaction or become accidentally intoxi-
cated, the removal of the drug from the system may be difficult, if not impossible, for
controlled release dosage forms.
• Orally administered controlled release dosage forms may yield erratic or variable drug
absorption owing to interactions with the contents of gastrointestinal tract and changes
in gastrointestinal motility. The result is drug ineffectiveness.
D. BIOLOGICAL AND PHYSICOCHEMICAL CONSIDERATIONS IN THE DESIGN

OF CONTROLLED RELEASE DOSAGE FORMS
1. Physicochemical Factors
a. Dose Size
Generally, 0.5 to 1.0 g is considered to be the maximum amount for a single dose of a conventional
dosage form. For drugs requiring large doses (>500 mg) in conventional dosage forms, the size of
Pharmaceutical technology
1. Microcapsules are designed to

a) Formulate immediate release DDS
b) Enhance odor of drug
c) Controlled release of drug
d) Give unpalatable taste
e) Gastric irritation
2. Microspheres are__________ in texture

a) Liquid
b) Solid
c) Solution
d) Dispersion
e) Slurry
3. Microcapsules are small particles having wall material of
a) Polymer
b) Drug
c) Emulsifiers
d) Suspending agent
e) Essential oils
4. In process of microencapsulation following is essential

a) Stable emulsion
b) Insufficiency of solvent for polymer with agitation
c) Avoid agitation
d) Sufficient solvent for polymer
e) High temperature
5. According to burgees and hickey particle size range of microcapsules is

a) 500-5000 micrometer
b) 1-100 micrometer
c) 1-10000micrometer
d) 5-5000 micrometer
e) 5-500 micrometer
6. In microencapsulation process very small ________________are coated
a) Solid and liquid
b) Solid particles
c) Gas particles
d) Liquid droplets
e) Solid liquid and gases
7. Solvent evaporation technique fully developed at the end of

a) 1940
b) 1950
c) 1970
d) 1870
e) 1980
8. Microcapsules follow
a) Barrier system
b) Matrix system
c) Embedded system
d) Drug polymer
e) Materices
9. Microencapsulated drugs cannot be given in the form of

a) Capsules
b) Creams
c) Niosomers
d) Aerosoles
e) Tablets
10. According to nokhodach and farid the particle size range of microcapsules
is
a) 500-5000 micrometer
b) 1-100 micrometer
c) 1-10000micrometer
d) 5-5000 micrometer
e) 5-500 micrometer
11. Granulation is required for
a) Cake formation
b) Reduced uniformity of drug distribution
c) Niosomes
d) Dust production
e) Increased uniformity of drug distribution
12. Granulation is process where

a) Small particles cannot adhere
b) Small particles cannot identify
c) Small particles cannot gathered
d) Small particles can identify
e) Compact mass Produced
13. Granulation is requires for
a) Tablets
b) Dust production
c) Nano particles
d) Cake formation
e) Reduce flow rate
14. Following is the technique for advanced granulations.
a) Spheronization
b) Roller compactor
c) Extrusion
d) Fluid
e) Thermal adhession
15. Following is the technique of wet granulation.
a) Foam
b) Continuous fluid bed granulation
c) Rolloer compactor
d) Thermal adhession
16. Following is the technique of dry granulation.
a) Steam
b) Slugging
c) Pelletizer
d) Moisture activated dry
e) Low shear mixture
17. Granulation is process where

a) Small particles cannot adhere
b) Small particles cannot identify
c) Small particles cannot gathered
d) Small particles are Gathered
e) Compact mass Produced
18. Following is the tripphasic stage of agglomeration
a) Capillary
b) Droplet
c) Steaming
d) Pendular
e) Interlocking
19. Pharmaceutical granules range between.
a) 1-5mm
b) 0-1.5mm
c) 1-4mm
d) 0-2.5mm
e) 0.2-4mm
20. Microscopic method for determination of particle size have size range of.
a) 5-50 micrometer
b) 1-10 micrometer
c) 0.2-100 micrometer
d) 2-100 micrometer
e) 50-150 micrometer
21. Substance may exhibit an inherent odor characteristics of ________
a) Functional group present
b) Saturation
c) Unsaturation
d) Anhydrous
e) Solubility
22. Cascade impaction is technique used to determine.
a) Particle size
b) Solubilization
c) Solubility
d) Purity
e) Crystallinity
23. Term moderately course for characterizing the particle size of a substance
have mesh size no.
a) 8
b) 20
c) 60
d) 40
e) 80
24. Color is generally a function of a drug inherent chemical structure relating to
a certain level of no.
a) Hydrous
b) Saturation
c) Solubility
d) Anhydrous
e) Unsaturation
25. Powder having angle of repose 25-30 degree have ________flow property
a) Good
b) Passable
c) Very poor
d) Rejected
e) Good
26. Investigation of physiochemical properties of the new drug composed
that could affect drug performance and development of an efficacious
dosage form is known as
a) Post formulation study
b) Pharmacovigilance
c) Bioavailability
d) Performulation studies
27. Taste of a drug substance exhibited by ___________
a) Crystalline nature
b) Amorphous nature
c) Presence of certain functional group
d) Less solubility
e) High solubility
28. Andreason pipette is used to determine.
a) Purity
b) Crystalline
c) Flow property
d) Particle size
e) Solubility
29. Most applicable technique used for characterizing the purity of drug
substance include.
a) SEM
b) TLC
c) DSC
d) TEM
e) TGA
30. Granulation is required for
a) Nano particles
b) Enhance flow rate
c) Cake formation
d) Dust production
e) Reduction of flow
CHAPTER 1
• Phyto chemistry
2.Excipients:
• Pharmaceutics
• Dispensing
Chromatography:
• HPLC
• TLC
Spectroscopy:
• Transmittance
• Dispensing
• Dispensing

like
1
• Instrumentation
• Qc
Dosage form & Drug:

Drug:
1-Diagnose
2-Mitigate
3-Treat
4-Cure
5-Prevent
DOSAGE FORM:

2
administration
tissues

Two ways
1. chewing
Flowers e.g rose
Seeds e.g clove
Anther e.g sefron
2. Snuffing :
3. Inhaling:
4. Smoking:
Tobacco, chars

Luman
3
• No selectivity

Goals and Aims:

Bullets.

• Tablet
• Capsule
• Solution
• Elixirs
Advantages:
• Dose accuracy
• Selective
4
Disadvantages:
• Side effects
2nd Generation DDS:

Goals:
Bioavailability:
3rd Generation DDS:

Goals:
independent.
5
time.
4th Generation DDS:

the drug.
Drawbacks:
range.

nose.
• Drug/API
• Carrier
6

12:00 (Noon)
12:00 (Mid-night)

Classification:
➢ Biosensor
➢ Algorithm
➢ A pump
7
regulate it.
This system:
5th generation DDS:

8
CHAPTER 2
Classification:


Repeat action DDS:
pills.

9
CIRCADIAN RYTHMS
CIRCADIAN RYTHMS
Definition(By sir):
• Physical
• Mental
• Behavioral

Function Of SCN:
Graph 1:
10
11
Body clock Guide
Time Situation
12:00am Midnight
7:30am Melatonin
secretion stops
likely
12:00pm noon
time
5:00pm Greatest CV
efficiency of
muscle strength
6:00pm evening
6:30pm Highest Bp
9:00pm Melatonin
secretion starts
suppressed
12
needed):
13
CHRONOTHERAPEUTICS

14
Ch. Sherjeel Adnan
B.Sc. B-Pharmacy BZU
M.Phil (Pharmaceutics)IUB
Ph.d (Pharmaceutics)BZU
CONTENTS
• Introduction
• Organoleptic properties
• Purity
• Particle size, shape and surface area
• Solubilisation, Surfactants and its importance
• Temperature, pH, co-solvency, solid dispersion, β-
cyclodextrin drug-dispersion system
• Preformulation stability studies
• A consideration of physico-chemical characteristics of
new drug molecules with respect to different dosage
forms
Preformulation
• Preformulation is branch of Pharmaceutical science that
utilizes biopharmaceutical principles in the determination
of physicochemical properties of the drug substance.
• Prior to the development of any dosage form new drug ,
it is essential that certain fundamental physical &
chemical properties of drug powder are determined .
• This information may dictate many of subsequent event
& approaches in formulation development.
• This first learning phase is called as preformulation.
INTRODUCTION
DEFINITION:-
Investigation of physico-chemical properties
of the new drug compound that could affect
drug performance and development of an
efficacious dosage form”.
Preformulation commences when a newly

synthesized drug shows a sufficient
pharmacologic promise in animal model to
warrant evaluation in man.
Introduction
• The preformulation is the first step in the rational

development of a dosage form of a drug substance
alone and when combined with excipients.
• Objective :
To generate useful information to the formulator
to design an optimum drug delivery system.
Introduction
• Before embarking on a formal programme of
preformulation, scientist must consider the following
:
1. Available physicochemical data (including
chemical structure, different salt available).
2. Anticipated dose.
3. Supply situation and development schedule.
4. Availability of stability – indicating assay.
GOALS OF PREFORMULATION
• To establish the necessary physicochemical

parameters of new drug substances.
• To determine kinetic rate profile.
• To establish physical characteristics.
• To establish compatibility with common
excipients.
a) Compound identity.
b) Formula and molecular weight.
c) Structure.
d) Therapeutic indications:
- Probable human dose.
- Desired dosage form(s)
- Bioavailability model
- Competitive products
Contd…
e) Potential hazards
f) Initial bulk lots:
- Lot number
- Crystallization solvent(s)
- Particle size range
- Melting point
- % volatiles
g) Analytical methods:
- HPLC assay
- TLC assay
- UV/ Visible spectroscopy
Contd…
ORGANOLEPTIC PROPERTIES
COLOR ODOUR TASTE
OFF-WHITE PUNGENT ACIDIC
CREAM-YELLOW SULFUROUS BITTER
SHINY FRUITY SWEET
AROMATIC TASTELESS
ODOURLESS TASTELESS
COLOR
• Color is generally a function of a drug’s inherent

chemical structure relating to a certain level of
unsaturation.
• Color intensity relates to the extent of conjugated

unsaturation as well as the presence of chromophores.
• Some compound may appear to have color although

structurally saturated.
ODOUR
• The substance may exhibit an inherent odor
characteristic of major functional groups present.
• Odor greatly affects the flavor of a preparation or
food stuff.
Taste:-
• If taste is considered as unpalatable, consideration is
to be given to the use of a less soluble chemical form
of the drug.
• The odour and taste may be suppressed by using

appropriate flavors and excipients or by coating the
final product.
PURITY
• Designed to estimate the levels of all known &
significant impurities & contaminates in the drug
substance under evaluation.
• Study performed in an analytical research &
development group.
• It is another parameter which allows for comparison
with subsequent batches.
• Occasionally, an impurity can affect stability.
e.g.
- Metal contamination
- Appearance
PURITY
• The techniques used for characterizing the purity of a
drug are the same as those used for other purpose in a
preformulation study.
• Thin layer chromatography is a wide ranging
applicability & is an excellent tool for characterizing
the purity.
• HPLC, paper chromatography & gas chromatography
are also useful.
• More quantitative information can be obtained by
using quantitative differential scanning colorimetry.
PARTICLE SIZE
• Particle size is characterized using these

terms :
i. Very coarse (#8)
ii. Coarse (#20)
iii. Moderately coarse (#40)
iv. Fine (#60)
v. Very fine (#80)
PARTICLE SIZE
• Particle size can influence variety of
important factors :
- Dissolution rate
- Suspendability
- Uniform distribution
- Penetrability
- Lack of grittiness
• Sieving
• Microscopy
• Sedimentation rate method
• Light energy diffraction
• Laser holography
• Cascade impaction
1. Sieving method :
• Range : 50 – 150 µm
• Simple, inexpensive
• If powder is not dry, the apertures get clogged.
2. Microscopy :
• Range : 0.2 – 100 µm
• Particle size can be determined by the use of
calibrated grid background.
• Most direct method.
• Slow & tedious method.
3. Sedimentation method :
• Range : 1 - 200 µm
• Andreasen pipette is used.
• Particle size is calculated by stoke’s law :
18 η0 h
dst = (ρs -ρ0) gt
Where,
h = distance of fall in time, t
no = viscosity of the medium
ρs = density of the particles
ρ0 = density of the dispersion medium
g = acceleration due to gravity
4. Light energy diffraction :
• Range : 0.5 – 500 µm
• Particle size is determined by the reduction in light
reaching the sensor as the particle, dispersed in a liquid
or gas, passes through the sensing zone.
• Quick & fast.
5. Laser holography :
• Range : 1.4 – 100 µm
• A pulsed laser is fired through an aerosolized particle
spray & photographed in three dimensional with
holographic camera, allowing the particles to be
individually imaged & sized.
6. Cascade impaction :
• The principle that a particle driven by an
airstream will hit a surface in its path,
provide that its inertia is sufficient to
overcome the drug force that tends to keep in
it in airstream.
POWDER FLOW PROPERTIES
 Powder flow properties can be affected by change in particle
size, shape & density.
 The flow properties depends upon following-

1. Force of friction.
2. Cohesion between one particle to another.
 Fine particle posses poor flow by filling void spaces between

larger particles causing packing & densification of particles..
 By using glident we can alter the flow properties.

e.g. Starch, Talc.
 By determining Angle Of Angle Of Type Of Flow

Repose. Repose
 A greater angle of repose ( In degree)
indicate poor flow.
Excellent
 It should be less than 30°. <25
& can be determined by
following equation. 25-30 Good
tan θ = h/r.
where, θ = angle of repose. 30-40 Passable
h=height of pile.
r= radius. >40 Very poor
 Measurement of free flowing powder by

compressibility.
 Also known as Carr's index.
CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) X 100

TAPPED DENSITY
 It is simple, fast & popular method of predicting powder

flow characteristics.
Carr’s Index Type of flow

5-15 Excellent
12-16 Good
18-21 Fair To Passable
23-35 Poor
33-38 Very Poor
>40 Extremely Poor
PARTICLE SHAPE
Cont…
PARTICLE SHAPE
• Particle shape will influence the surface area, flow of
particles, packing & compaction properties of the
particles.
• A sphere has minimum surface area per unit volume.
• Therefore, these properties can be compared for
spheres & asymmetric particles, in order to decide the
shape.
• The following expression can be obtained:
Property Sphere particle
surface area πds2 αs x dp2
volume (1/6)πds3 α v x d p3
Cont…
Cont…
PARTICLE SHAPE
• Therefore,
surface area = πds2 = α s x dp 2
Volume = (1/6)πds3 = αv x dp3
• Solving for αs & αv by equating the appropriate properties
provides:
πd 2 & αv = πds3
αs = s
dp2 6 dp3
• When particle shape is spherical, the ds = dp

• Thus, αs = π = 3.124 & αv = π/6 = 0.524
• Therefore, Shape factor = αs = 3.124 =6
αv 0.524
SURFACE AREA
• Particle size & surface area are inversely
related to each other.
• Smaller the drug particle, greater the surface
area.
Specific surface is defined as the surface area

per unit weight (Sw) or unit volume (Sv) of the
material.
SURFACE AREA
 Estimation of Sv :
Sv = Surface area of the particles
Volume of particles
= n αs d
2
n αv d3
= αs
αv d
• According to shape factor,
αs = 6
αv
• So, Sv = 6 / d.
SURFACE AREA
 Estimation of Sw:
Sw = Surface area = Surface area
Weight density x volume
= Sv
ρ
= 6
ρ.d
surface area
1. Adsorption method :
• Particles with a large specific surface are good
adsorbents for the adsorption of gases & of solutes
from solution.
• The volume of nitrogen gas, Vm, in cm3 that 1 g of the
powder can adsorb when the monolayer is complete is
more accurately given by using the BET equation,
however, which can be written as:
P = 1 + (b-1) . P
V(P0 – P) Vmb Vmb P0
Cont….
Cont….
surface area
• Where,
V = Volume of gas in cm3 adsorbed per gram of powder
at pressure P.
P = Pressure of the adsorbate, in mmHg.
Po= Saturation vapor pressure (monolayer)
Vm= Amount of vapor adsorbed per unit mass adsorbent,
when the surface is covered with monomolecular
layer
b = Constant that express the difference between the
heat of adsorption & heat of liquefaction of the
adsorbate (nitrogen).
Quantasorb QS – 16 instrument
P
V( P0 – P)
P/P0
Air permeability method :
HOWEVER SIZE REDUCTION
IS NOT REQUIRED IN FOLLOWING CASES
• WHEN DRUG IS UNSTABLE.
• DEGRADE IN SOLUTION FORM.
• PRODUCE UNDESIRABLE EFFECTS.
• WHEN SUSTAINED EFFECT IS DESIRED.

SOLUBILIZATION
“ Solubilization is defined as the spontaneous

passage of poorly water soluble solute
molecules into an aqueous solution of a soap
or detergent in which a thermodynamically
stable solution is formed ”.
SOLUBILIZATION
 It is the process by which apparent solubility of

an otherwise sparingly soluble substance is increased
by the presence of surfactant micelles .
 MICELLES: -
 The mechanism involves the property of

surface active agents to form colloidal aggregates
known as micelles .
SOLUBILIZATION
 When surfactants are added to the liquid at low
concentration they tend to orient at the air-liquid
interface .
 On further addition of surfactant the interface

becomes completely occupied and excess molecules
are forced into the bulk of liquid.
 At very high concentration surfactant molecules in

the bulk of liquid begin to form micelles and this
concentration is know as CRITICAL MICELLE
CONCENTRATION {CMC}
SOLUBILIZATION
 Solubilization is thought to occur by virtue of the
solute dissolving in or being adsorbed onto the
micelle.
 Thus the ability of surfactant solution to

dissolved or solubilize water insoluble materials
starts at the CMC and increase with increase in the
concentration of micelles.
 Solubilization of any material in any solvent

depends on proper selection of solubilising agents.
 The process of solubilization involves the breaking
of inter-ionic or intermolecular bonds in the solute,
the separation of the molecules of the solvent to
provide space in the solvent for the solute,
interaction between the solvent and the solute
molecule or ion.
Step 1: Holes opens in the solvent

Step2: Molecules of the solid breaks away from the
bulk
Step 3: The free solid molecule is intergraded into

the hole in the solvent
 The amount of substance that passes into
solution in order to establish equilibrium at
constant temperature and pressure to
produce a saturated solution.
 If solubility is <1mg/ml indicates need for salt
formation to improve solubility.
 If solubility is <1mg/ml in pH= 1 to 7,

preformulation study should be initiated.
 Solubility should ideally be measured at two

temperatures: 4°C and 37°C.
 4°C to ensure Physical stability.
 37°C to support Biopharmaceutical evaluation.

Description Parts of solvent required
for one part of solute
Very soluble <1

Freely soluble 1 - 10
Soluble 10 - 30
Sparingly soluble 30 - 100
Slightly soluble 100 - 1000
Very slightly
1000 - 10,000
soluble
Insoluble > 10,000
SOLUBILITY ANALYSIS
 Preformulation solubility studies focus on drug

solvent system that could occur during the delivery of
drug candidate.
 For e.g. A drug for oral administration should be

examined for solubility in media having isotonic
chloride ion concentration and acidic pH.
SOLUBILITY ANALYSIS
 Analytic method that are particularly useful
for solubility measurement include HPLC, UV
spectroscopy, Fluorescence spectroscopy and
Gas chromatography.
 Reverse phase HPLC offer accurate and

efficient mean of collecting solubility data of
drug.
 Ionization constant (pKa)
Can be calculated by Henderson Hasselbach
equation-
For acidic drugs….pH= pKa+ log [ionized drug]

[unionized drug]
For basic drugs….pH= pKa+ log[unionized drug]

[ionized drug]
 pH Solubility Profile
 The solubility of acidic or basic drug will show
difference in solubility with changes in pH.
 pH solubility profile of a drug can be established

by running the equilibrium solubility experiment
within pH range of 3-4.
 Partition Coefficient
 It is the ratio of unionized drug distributed
between organic and aqueous phase at equilibrium.
P o/w = ( C oil / C water )equilibrium

 Effect Of Temperature
 The heat of solution Hs, represents the heat
released or absorbed when a mole of solute is
dissolved in large quantity of solvent.
 Endothermic reaction
 Exothermic reaction
Determination of solubility
 The following points should be considered
 The solvent & solute must be pure.
 A saturated solution must be obtained before any
solution is removed for analysis.
 The method of separating a sample of saturated
solution from undissolved solute must be
satisfactory.
 The method of analyzing solution must be reliable
 Temperature must be adequately controlled .
Solubility Determination Method
 Solubility is normally depends on temperature,

so temperature is recorded in each solubility
measurement.
 Plot of solubility against temperature is
commonly used for solubility determination.
 Two methods are available for determination
are as follow.
I. Analytical method
II. Synthetic method
Analytical method
 Temperature of equilibrium is fixed and

concentration of the solute in the saturated solution
is determined at equilibrium by a suitable
analytical procedure.
 In other words a saturated solution in the

presence of an excess of the undissolved solute is
prepared at an accurately known temperature.
This situation can be achieved by suitable contact
b/w solute and solvent.
Synthetic method
 In this method a weighed amount of solute is

placed in the vessel.
 While agitating the system at constant temperature
known amount of solvent is added gradually until
the solubility limit is reached.
 At equilibrium, temperature and content of the
system is recorded.
 This method is carried out at micro scale level by
examining the small amount of the system under
hot stage microscope.
General Method of Increasing
the Solubility
 Addition of co-solvent
 pH change method
 Reduction of particle size
 Temperature change method
 Hydotrophy
 Addition of Surfactant
 Dielectrical Constant
 Complexation
• Weak Electrolyte :- Phenobarbitone

• Non polar :- Nitro Cellulose
 These are poorly soluble in given solvent.
 For such poorly soluble materials, to enhance
their solubility, the water miscible solvents are used
in which the drug has good solubility.
 This process of improving solubility is known as
co-solvency and the solvent used is known as co-
solvents.
e.g. Phenobarbitone is insoluble in water. A clear
solution is obtained by dissolving in mixture of
Alcohol, Glycerin, Propylene glycol.
e.g. Of Cosolvents:-
PG, glycerin, sorbitol, PEG, Glyceryl formal,
glycofurol, ethyl carbamate, ethyl lactate and
dimethyl acetamide.
pH change Method
 Weak base:- Alkaloids, Local Anaesthesia
 Weak acid:- Sulphonamides, Barbiturates
 In aqueous medium they dissociate poorly and

undissociated portion is insoluble.
e.g. Benzoic acid, Phenobarbitone
 So, solubility of the undissociated portion is
improved by pH control.
For weak acidic drug:- increase pH, solubility is
increase.
 For weak base drug:- decrease pH, increase
solubility.
Reduction Of Particle size
 Reduction in Particle size improve solubility of

drug.
 Basically reduction in particle size increase contact

surface area of the particle, there by ultimately it
increase rate of solubility of drug.
Temperature Change Method
 In endothermic reaction by increasing temperature

solubility is increase.
 In exothermic reaction by increasing temperature

solubility is decrease.
e.g. Methyl Cellulose when mixed with water and

temperature is raised, it becomes insoluble. To
dissolve it cold water is added.
Hydotrophy
The term Hydotrophy has been used to designate the

increase in solubility in water of various substances
due to the presences of large amount of additives.
e.g. Solubilization of Benzoic acid with Sodium

benzoate.
Addition of Surfactant
 Surfactants are molecules with well defined polar
and non-polar region that allow them to aggregate in
solution to form micelles. Non polar drugs can
partition into micelles and be solubilized.
e.g. Surfactant based solution of Taxol, that is

solubilized in 50% solution of Cremophor.
Dielectrical Constant
Dielectrical Constant is the effect that substances
has, when it acts as a solvent on the case with which it
separates oppositely charged atoms.
e.g. DEC of Water- 80

Kerosene- 2
Glycerine- 48
Benzene- 2.2
Complexation
 For the Complexation occur both drug and ligand
molecule should be able to donate or accept
electrons.
 The solubility of compound is the sum of solubility
of the compound and its complex.
e.g. HgI2 (Mercuric Iodide) is sparingly soluble in

water. Its solubility in water is increased by forming
complex with KI.
HgI2 +2KI K2HgI4 (water soluble)

 Drugs with limited aqueous solubility can be

solubilized. These include oil-soluble vitamins,
steroid hormones and antimicrobial agents etc.
 Solubilization of orally administered drugs results

in an improved appearance and improves
unpleasant taste.
 Both oil-soluble and water-soluble compounds can

be combined in a single phase system as in case of
multivitamin preparations.
 Solubilization may lead to enhanced absorption

and increased biological activity.
 Improves the intestinal absorption of vitamin A.
 Drug absorption from ointment bases and

suppositories also increased.
 Liquid preparations with small quantity of

preservative can be prepared by solubilization.
 Aqueous concentrates of volatile oils can be
prepared by solubilization.
 Example: soaps used for solubilising phenolic

compounds for use as disinfectants- Lysol, Roxenol
etc.
 Barbiturates, anticoagulant, alkloidal drugs are

dissolved with polysorbate by solubilization.
SURFACTANT
 Surfactants:-
are wetting agents that lower the surface
tension of a liquid, allowing easier spreading,
and lower the interfacial tension between two
liquids.
 Classification
Some commonly encountered surfactants of
each type include:
1. Ionic 2. Non ionic
 Cationic
 Anionic
 Zwitterionic
IONIC
 Cationic Surfactants:-
 Quaternary ammonium salts are more preferred
because they are less affected by pH.
e.g. Cetyl Trimethyl Ammonium Bromide (CTAB)

Hexadecyl Trimethyl Ammonium Bromide, and other
Alkyltrimethyl Ammonium Salts, Cetylpyridinium
Chloride (cpc)
IONIC
Anionic Surfactants:-
 They are the most commonly used surfactants,
containing Carboxylate, Sulfonate, Sulfate ions.
e.g. Sodium Dodecyl Sulphate (SDS), Ammonium

Lauryl Sulphate and other alkyl sulfate salts, Sodium
Laureth Sulphate, also known as Sodium Lauryl
Ether Sulphate (SLES).
IONIC
 Zwitterionic:-
 When a single surfactant molecule exhibit both
anionic and cationic dissociations it is called
amphoteric or Zwitterionic.
The anion include carboxylates and phosphate
group and the cation include quaternary
ammonium group.
e.g. Dodecly Betamine

Dodecly Dimethylamine Oxide
NONIONIC
 These are most widely used because they are
free from non compatability, stability and
potential toxicity and classified as water soluble
and water insoluble non ionic surfactants.
e.g. Long chain fatty acids, fatty alcohols
 Water solubility of these agents is further

increased by addition of polyoxyethylene groups
through ether linkage with one of the alcohol
group.
e.g. spans
HLB SCALE
 Griffin in 1947 developed the system of the
hydrophilic-lipophilic balance [ HLB ] of surfactant.
 The higher the HLB of the an agent, the more
hydrophilic it is.
 Tween, polyoxyethylene derivative of the spans are
hydrophilic and have high HLB value (9.6-16.7)
 The lower the HLB of the agent, the more lipophilic
it is.
 The sorbitan ester are lipophilic and have low HLB
value (1.8-8.6)
HLB SCALE
0
Most antifoaming agents
3
W/O Emulsifying agents

6
9
Wetting and Spreading agents
12 O/W Emulsifying agents
15
Detergents and Solubilizing agents
18
HLB SCALE
• The HLB of non ionic surfactant whose only

hydrophilic portion is polyoxyethylene is calculated
using the formula
• HLB = E/5
Where, E = Percentage weight of ethylene oxide
 Surfactants play an important role in many

practical applications and products, including:
• Detergents
• Fabric Softener
• Emulsifier
• Paints
• Adhesive
• Inks
• Soil remediation
• Wetting
• Ski Wax
• Snowboard Wax
• Foaming
• Defoaming
• Laxatives
• Agrochemical formulations
Herbicides
Insecticides
• Quantum dot coating
• Biocides (Sanitizers)
• Hair Conditioners (after shampoo)
• Spermicide (Nonoxynol 9)
Temperature, pH, Cosolvancy, Solid
dispersion
• The solubility of a solute in a solvent is dependent on
temperature, nature of solute and nature of solvent.
• Heat of solution represents the heat released or

absorbed when a mole of solute is dissolved in a large
quantity of solvent.
• Most of the substances are endothermic, absorbing

heat in the process of dissolution.
• For this substances, an increase in temperature results
in an increase in solubility.
• Exothermic substances give off heat in the process of

dissolution. The solubility of such substances would
decrease with increase in temperature.
• Care should be taken as heat may destroy a drug or

cause other changes in the solution.
e.g. On excess heating the sucrose solution it can get

converted in to the invert sugar.
• Depending on the type of reactions weather it is

exothermic or endothermic heat is either released or
absorbed.
e.g. Mixture of chloroform and acetone. The heat

produced by the solute-solvent interaction is so much
greater than the heat necessary to separate the
molecules of acetone and chloroform, which can be
detected as a rise in temperature of the liquid.
• Applications:
• Pharmaceutical solutions must be administered
at or near room temperature. So, it is more
important factor for product storage than the
formulation.
• To increase the solubility of sparingly
soluble solute.
• To increase the stability by reducing the
moisture content.
Effect of pH
• Weak electrolytes undergo ionization and are more
soluble when in ionized form. The degree of ionization
depends on dissociation constant (pKa) and the pH of the
medium.
• Solubility is a function of pH, that is related to its pKa

which gives ratio of ionized and unionized forms of the
substance.
This can be shown as:
pH = pKa + log [ A- ]
[ HA ]
Effect of pH
• If the substance is brought outside its pKa, i.e. the pH
value where half the substance is ionized and half is
not, than solubility will be changed because we are
introducing new intermolecular forces, mainly ionic
attraction.
• e.g. –COOH has pKa value at pH around 4. If pH is

increased then –COOH is converted into –COO- .
This may interact with the H+ of water.
Effect of pH
• The effect of pH on solubility for weak electrolytes
can be described by:
pHp = pKa + log S –S0

S0
• Where,
pHp = pH below which the drug precipitates from
solution as the undissociated acid.
S = total solubility.
S0 = molar solubility of the undissociated acid.
Effect of pH
• It is to be ensured that pH change for one
single compound should not affect the other
requirements of product.
• e.g. the chemical stability of drug may depend

on pH, and this pH of optimum stability should
not coincide with the pH of other ingredients
specially colors, preservatives and flavors.
Cosolvancy
• To enhance the solubility of poorly soluble
materials, the water miscible solvents are used in
which the drug has good solubility. This process
of improving solubility is known as co-solvency.
• Solvents used to increase the solubility are

known as co-solvents.
Cosolvancy
• The mechanism for solubility enhancement by
co-solvency is not clearly understood. But it is
proposed that, solubility is increased may be
by reducing the interfacial tension between the
solvent and hydrophobic solutes and
decreasing dielectric constant of solvent.
Cosolvancy
• The commonly used and acceptable co-solvents in
formulation of aqueous liquids for oral solutions are
Ethanol, Sorbitol, Glycerin, Several members of PEG
series.
• For parenteral products, Dimethylacetamide is widely

used. But in case of oral liquids its application is
limited, because of its objectionable odour and taste.
Cosolvancy
• Some characteristics of co-solvent, which are used in
preparation:
1. It must be non-toxic. Non-irritating.
2. It should be able to solubilize the drug in
given solvent.
3. It should be able to cross the membrane.
• Apart from increasing solubility, they are also used to
improve the solubility of volatile constituents used to
impart a desirable flavour and odour to the product.
Solid – Dispersion System
• Definition :
Solid dispersion is defined as dispersion of one or

more active ingredients in an inert carrier or matrix at
solid state prepared by the melting, solvent or melting
solvent method.
Classification
(Based on Fast Release Mechanism)
• Simple Eutectic Mixtures
• Solid Solutions
• Glass Solutions and Glass Suspensions
• Amorphous precipitation of drug in crystalline
carrier
• Compounds or Complex formation between drug
and carrier
• Any combination among the above
• When two or more substances are mixed
together they liquefy due to the lowering of
melting point than their individual melting
point. Such substances are called as eutectic
substances.
e.g. paracetamol-urea, griseofulvin-urea
• Simple binary phase
diagram showing eutectic
point E.
• The eutectic composition at
point E of substance A and
B represents the melting
point.
• TA and TB are melting
point of pure A and pure B.
• The following factors may contribute to faster
dissolution rate of drug dispersed in the eutectic
mixtures:-
1. Increase in drug solubility.
2. Solubilization effect by the carrier which
completely dissolves in a short time in diffusion
layer surrounding drug particles.
3. Absence of aggregation and agglomeration
between fine crystallites of pure hydrophobic
drug.
4. Excellent wettability and dispersibility
of a drug as the encircling soluble carrier
readily dissolves and causes water to
contact as wet drug particles.
5. Crystallization of drug in a metastable

form after solidification from fused solution,
which has high solubility.
• Eutectics are easy to prepare and economical
with no solvents involved. The method
however cannot be applied to:
- Drugs which fail to crystallize from
mixed melt.
- Thermolabile drugs.
- Carriers such as succinic acid that
decompose at melting point.
B. Solid Solutions
• It is made up of a solid solute dissolved in a solid
solvent. It is often called a “mixed crystal” because
the two components crystallize together in a
homogenous phase system.
• It is prepared by fusion method.
• A solid solution of poorly soluble drug in a rapidly

soluble carrier achieves a faster dissolution because
particle size of drug is reduced to molecular size.
Classification
• According to extent of miscibility :
1. Continuous (iso-morphous, unlimited,
complete) solid solution.
2. Discontinuous (limited, restricted,
incomplete) solid solution.
• According to crystalline structure of solid
solutions :
1. Substitutional solid solutions.
2. Interstitial solid solutions.
Classification
a) Continuous Solid Solutions :-
 The two components are miscible or soluble at
solid state in all proportions.
 No established solutions of this kind has been
shown to exhibit fast release dissolution properties.
 The faster dissolution rate would be obtained if the
drug is present as a minor compartment.
b) Discontinuous Solid Solutions :-

 There is only limited solubility of a solute in a solid
solvent in this group of solid solutions.
Suspensions
• A glass solution is a homogenous, glassy system in
which a solute is usually obtained by abrupt
quenching of the melt.
• Many compounds have been shown to be able to

form glasses readily upon cooling from liquid state.
• These compounds include sucrose, glucose, ethanol

and 3- methyl hexane.
Suspensions
• It is presumably due to their strong hydrogen bonding
which may prevent their crystallization.
• Polymers possessing linear, flexible chains can freeze
into a glass state to transparency and brittleness.
• The strength of chemical binding in a glass solution is
much less compared to that in a solid solution.
• Hence, dissolution rate of drugs in the glass solution
is faster than in solid solution.
• e.g. Glass solution of citric acid
D. Amorphous Precipitation
of Drug in Crystalline Carrier
• Instead of forming a simple eutectic mixture in which
both drug and the carrier crystallize simultaneously
from a solvent method of preparation, the drug may
also precipitate out in an amorphous form in
crystalline carrier.
• It has faster dissolution and absorption rates than

crystalline form.
• e.g. Amorphous novobicin has 10 fold higher
solubility than its crystalline form.
E. Compound or Complex
Formations
• Dissolution and absorption of a drug can occur from a
complex or a compound formed between the drug and
an inert soluble carrier.
• Complexation also implies that dissolution could be

retarded as observed with PEG 4000 - phenobarbital.
• However, the formation of a soluble complex with a

low association constant results in increased rates of
dissolution and absorption.
F. Combinations and
Miscellaneous Mechanisms
• A solid dispersion entirely belongs to any five groups
discussed so far, but it can also be made up of
combinations of different groups.
• These combinations increase the dissolution and

absorption rate.
• The griseofulvin dispersed at high concentrations in

PEG may exist as individual molecules and as micro-
crystalline particles.
Methods of Preparations
• Melting Method
• Solvent Method
• Melting - Solvent Method
• Hot Melt Extrusion Technique
1. Melting Method or
Fusion Method
• The physical mixture of a drug and water soluble
carrier is heated until it melts.
• The melt is then cooled and solidified rapidly in an
ice bath with vigorous stirring .
• The final solid mass is crushed, pulverized and
sieved.
• To facilitate faster solidification, the homogenous
melt is poured in the form of a thin layer onto
stainless steel plate and cooled by flowing air or
water on the opposite side of the plate.
1. Melting Method or Fusion Method
• Advantages :
• Simplicity of method.
• Supersaturation of a solute or a drug in a system can
often be obtained by quenching the melt rapidly from
high temperature.
• Disadvantage :
• Some drugs or carriers may decompose or evaporate
during fusion process at high temperatures .
e.g. succinic acid used as a carrier for griseofulvin is
quite volatile and may also partially decompose by
dehydration near its melting point.
2. Solvent Method
• They are prepared by dissolving a physical
mixture of two solid components in a common
solvent, followed by evaporation of the
solvent.
• The method is used to prepare solid

dispersions of griseofulvin-
polyvinylpyrrolidone, sulphathiazole - pvp.
2. Solvent Method
• Advantage :
- Thermal decomposition of drugs or carriers can be
prevented because of low temperature required for
the evaporation of organic solvents.
• Disadvantages :
- High cost of preparation.
- Difficulty in completely removing the solvent.
- Difficulty in producing crystal forms.
3. Melting Solvent Method
• It is prepared by first dissolving the drug in a
suitable solvent and then incorporating this solution
in a melt of PEG without removing the solvent.
• Advantages :
Same as above two methods
• Disadvantage :
From practical stand point, it is only limited to
drugs with a low therapeutic dose, e.g. below 50mg.
• In this method, a blend of active ingredients,
polymeric carrier and other processing aids like
plasticizers and antioxidants is heated and softened.
• This softened material is called as extrudate.
• When the extrudate is cooled at room temperature,

the polymeric thermal binder solidifies and bonds the
excipients together to form a matrix.
• Advantages :
- There are no concerns with solvent handling or
recovery after processing
- It is simple and continuous process for
preparation of tablets and granulations.
- The process is faster and there were fewer steps
than the wet granulation method.
- Can be used for formulating sustained
release granules.
e.g. Diltiazem granules.
a) Cooling curve method
b) Thaw-melt method
c) Thermoscopic method
d) Differential thermal analysis (DTA)
e) Zone Melting Method
• X-Ray diffraction Method
• Microscopic method
• Spectroscopic method
• Thin layer chromatography
• Solubility determinations
A. Thermal Analysis
• It is used to study the physico-chemical
interactions of two or more components.
• Principle : Change in thermal energy as a
function of temperature.
a) Cooling curve method :
- The physical mixtures of various
compositions are heated until a
homogenous melt is obtained.
- The temperature of the mixture is then
recorded as function of time.
A. Thermal Analysis
b) Thaw-melt method :
- Here a sample of solidified mixture in a
capillary melting point tube is heated
gradually till the thaw point.
- The thaw point is referred to as crossing
solidus line.
- It is useful in differentiating between a
simple eutectic system and a limited
solution.
A. Thermal Analysis
c) Thermoscopic method :
- Polarized microscopy is used with hot
stage to study phase diagrams of binary
systems.
- The physical mixture is gradually
heated on a slide until it completely
liquefies.
- After cooling, the mixture is heated at rate
of 4 degree per minute.
- The thaw and melting points are
determined by visual observations.
A. Thermal Analysis
d) Differential thermal analysis (DTA) :
- An effective thermal method for studying
phase equilibria of either pure compound or
mixture.
- Different effects, associated with physical
or chemical changes are automatically
recorded as function of time or temperature as
the substance is heated in uniform rate.
- In addition; evaporation, sublimation,
polymorphic transition, desolvation can
be detected.
A. Thermal Analysis
e) Zone Melting Method :
- It is primarily used for ultra
purification of metal and inorganic and
organic metal.
B. X-Ray Diffraction Method
• In this method the intensity of x-ray diffraction or
reflection from a sample is measured as a function of
diffraction angles.
• Counter and film methods detect diffraction intensity.
• Counter method provides better resolution of
diffraction and relative intensity which can be easily
compared.
• This method is used to characterize physico-chemical
properties of Griseofulvin dispersed in PEG 4000 and
6000.
C. Microscopic Method
• It has been used to study polymorphism and
morphology of solid dispersion.
• The fine particles of crystallization in glass
PVP can be easily detected by polarizing
microscope.
• The resolution of electron microscope was
used to study dispersed particle size of iopanic
acid in PVP.
D. Spectroscopic Method
• In the UV study, the spectra of pure drug and
the dispersed drug are scanned.
• e.g. The spectrum of the dispersed beta –
carotene resembles that beta–carotene is
dissolved in organic solvents but do not
indicate the molecular dispersion of drug in
polymer.
E. Thin Layer Chromatography
• TLC characteristics of pure and dispersed
drugs are studied to test whether the drugs are
decomposed by process.
• A single spot with same ‘Rf ’value is expected

for both the pure and processed samples in thin
layer plate.
F. Solubility determinations
• Results from aqueous solubility studies of drug
in various concentrations of carrier would
indicate interactions between drug and carrier.
• Such studies indicated weak or insignificant
interactions between griseofulvin and PEG
6000.
• Increased rate of dissolution due to solubility
of the drug by carrier can be predicted by this
method.
Pharmaceutical Applications
• To obtain a homogenous distribution of small
amount of drugs at solid state.
• To stabilize unstable drugs.
• To dispense liquid or gaseous compounds.
• To formulate a faster release priming dose in a
sustained release dosage form.
• To formulate sustained release dosage or
prolonged release regimens of soluble drugs by
using poorly soluble or insoluble carriers.
β-cyclodextrin drug dispersion system,
techniques for studies of crystals,
polymorphism
• The poorly dissolution of relatively insoluble drug

has for long been a problem in the formulation of
oral dosage form.
• This limits the aspect such as

 Absorption &
 Bioavailability
• Several approach have been followed in improving

the solubility of drug, one of them being
complexation using cyclodextrin.
• Cyclodextrin is cyclic structure oligomers of glucose

which are obtained from the starch digests of the
bacteria Bacillus macerans.
• The most abundant cyclodextrins available are

a-cyclodextrin - 6 glucose units
b-cyclodextrin - 7 glucose units
g-cyclodextrin - 8 glucose units
Chemistry of b-cyclodextrin
• Cyclodextrine molecule have cylindrical shape with
central axial cavity and resembles with shape of
truncated cone.
• The interior cavity is hydrophobic and the outside of

the molecule is hydrophilic.
Characteristics of β-cyclodextrin
• Glucose unit – 07
• Molecular wt. – 1135
• Solubility – 1.85g/100ml
o
• Cavity diameter – 6.4 A
• Diameter of outer periphery –
o
15.4 A
• Approx. vol. of cavity –
o 3
262 (A )
Method of preparation of b-cyclodextrin
complex
• Physical mixture method
• Kneading method
• Co-evaporation method
• Solid dispersion method
• Spray drying method
• Neutralization method
Physical mixture method
• Here the drug and b-cyclodextrin (1:2) are mixed

physically with spatula & then the pulverized powder
is passed through 100#.
• Eg. Diclofinac sodium

Kneading method
• Here the b-cyclodextrin is dissolved in small vol. of

water-methanol solution(6:4).
• To the above solution required drug is added in small
amount.
• The slurry is then kneaded for 45 min. & dried at
o
45 c.
100#.
• Eg. Nimesulide , Omeprazole
Co-evaporation method
• In this method, aq. solution of b-cyclodextrin is added

to an alcoholic solution of drug.
• The
o
resulting mix. is stirred for 1 hr. & evaporated at
45 c until it is dried.

100#.
• Eg. Steroids & Diclofenac sodium

Solid dispersion method
• Here the drug & molar qty. of b-cyclodextrin is
o
• The solution is then evaporated in vacuum at 40 c
with rotatory evaporator.
• The powder is stored under vacuum in dessicator for

3 days & analysed.
• Eg. Rifampicin
Spray drying method
• In this, the drug & double molar of β-cyclodextrin are
• The solution was then spray dried under foll.

conditions –
Feed rate – 10 ml/min
o
Inlet temp. - 95 c
o
Outlet temp. - 65 c
Press. – 5 bar
3
Drying air – 35 m
Spray drying method
• The powder is then collected & stored under vacuum

in dessicator for 3 days & analysed.
• Eg. Naproxene
Neutralization method
• Here the drug & b-cyclodextrin are dissolved in 0.1N

HCl & then 0.1N NaOH is added to precipitate the
complex at pH-7.5.
• The ppt. is washed with distilled water.
• Then it is pulverized & sieved through 90# and stored

in dessicator over fused CaCl2.
• Eg. Ketoconazole
Applications
• To increase aq. solubility
• To increase dissolution rate of drug
• To improve bioavailability of drug
• To increase chemical/physical stability
• To decrease drug irritation
Crystallinity
• Crystal habit & internal structure of drug can affect

bulk & physicochemical property of molecule.
• Crystal habit is description of outer appearance of

crystal.
• Internal structure is molecular arrangement within the

solid.
Crystallinity
• Change with internal structure usually alters crystal

habit.
Eg. Conversion of sodium salt to its free acid form
produce both change in internal structure & crystal
habit.
• Cubic or isometric - not • Hexagonal - six-sided
always cube shaped. Also prisms. When you look at
find as octahedrons (eight the crystal on-end, the cross
faces) and dodecahedrons section is a hexagon.
(10 faces). • Trigonal - possess a single
• Tetragonal- similar to cubic 3-fold axis of rotation
crystals, but longer along instead of the 6-fold axis of
one axis than the other, the hexagonal division.
forming double pyramids • Triclinic - usually not
and prisms. symmetrical from one side
• Orthorhombic - like to the other, which can lead
tetragonal crystals except to some fairly strange
not square in cross section shapes.
(when viewing the crystal • Monoclinic - like skewed
on end), forming rhombic tetragonal crystals, often
prisms or dipyramids (two forming prisms and double
pyramids stuck together). pyramids.
• Depending on internal structure compounds is

classified as
1. Crystalline
2. Amorphous
• Crystalline compounds are characterized by
repetitious spacing of constituent atom or molecule in
three dimensional array.
• In amorphous form atom or molecule are randomly
placed.
• Solubility & dissolution rate are greater for

amorphous form then crystalline, as amorphous form
has higher thermodynamic energy.
Eg. Amorphous form of Novobiocin is well absorbed

whereas crystalline form results in poor absorption.
Polymorphism
• It is the ability of the compound to crystallize as more

than one distinct crystalline species with different
internal lattice.
• Different crystalline forms are called polymorphs.
• Polymorphs are of 2 types

1. Enatiotropic
2. Monotropic
Polymorphism
• The polymorph which can be changed from one form

into another by varying temp. or pressure is called as
Enantiotropic polymorph.
Eg. Sulfur.
• One polymorph which is unstable at all temp. &

pressure is called as Monotropic polymorph.
Eg. Glyceryl stearate.
Polymorphism
• Polymorph differ from each other with respect to

their physical property such as
Solubility
Melting point
Density
Hardness
Compression characteristic
Polymorphism
• During preformulation it is important to identify the

polymorph that is stable at room temp.
Eg. 1)Chloromphenicol exist in A,B & C forms,

of these B form is more stable & most
preferable.
2)Riboflavin has I,II & III forms, the III form
shows 20 times more water solubility than
form I.
Techniques for studies of
crystals
• Microscopy
• Hot stage microscopy
• X-ray diffraction
Microscopy
• Material with more than one refractive index are
anisotropic & appear bright with brilliant colors
against black polarized background.
• The color intensity depends upon crystal thickness.
• Isotropic material have single refractive index and

this substance do not transmit light with crossed
polarizing filter and appears black.
Microscopy
• Advantage :
By this method, we can study crystal morphology &
difference between polymorphic form.
• Disadvantage :
This require a well trained optical crystallographer, as
there are many possible crystal habit & their
appearance at different orientation.
• The polarizing microscope fitted with hot stage is
useful for investigating polymorphism, melting point
& transition temp.
• Disadvantage :
In this technique, the molecules can degrade during
the melting process.
• Diagrammatic • Results of hot stage
representation microscopy
Thermal analysis
• Differential scanning calorimetry (DSC) &
Differential thermal analysis are (DTA) are
particularly useful in the investigation of
polymorphism.
• It measures the heat loss or gain resulting from

physical or chemical changes within a sample as a
function of temp.
Thermal analysis
• For characterizing crystal forms , the heat of fusion
can be obtained from the area under DSC- curve for
melting endotherms.
• Similarly, heat of transition from one polymorph to

another may be calculated.
• A sharp symmetric melting endotherm can indicate

relative purity of molecule.
Thermal analysis
• A broad asymmetric curve indicates presence of
impurities.
• Disadvantage :
Degradation during thermal analysis may provide
misleading results.
X-ray diffraction
• Working :
When beam of nonhomogenous X-ray is allow to
pass through the crystal, X-ray beam is diffracted & it
is recorded by means of photographic plate.
• Diffraction is due to crystal which acts as 3

dimensional diffraction grating toward X-ray.
X-ray diffraction
X-ray diffraction
• Random orientation of crystal lattice in the powder
causes the X-ray to scatter in a reproducible pattern of
peak intensities.
• The diffraction pattern is characteristic of a specific

crystalline lattice for a given compound.
X-ray diffraction
• An amorphous form does not produce a pattern
mixture of different crystalline forms.
• Single – Crystal x-ray provide the most complete

information about the solid state.
Stability testing….
Why Stability?
• Provide a evidence on how the quality of a drug
substance or drug product varies with time under the
influence of a variety of environmental factors such
as….. temperature, Humidity and light.
• Establish a re-test period for the drug substance or a

shelf life for the drug product and recommended storage
conditions.
• Because physical, chemical or microbiological changes

might impact the efficiency and security of the final
product
Where and Why?
Stability Studies are preformed on ...
• Drug Substances (DS)  The unformulated drug
substance that may subsequently be formulated with
excipients to produce the dosage form.
• Drug Products (DP)  The dosage form in the final

immediate packaging intended for marketing…….
• controlled and documented determination of

acceptable changes of the drug substance or drug
product
What are changes?
• Physical changes
• Appearance
• Melting point
• Clarity and color of solution
• moisture
• Crystal modification (Polymorphism)
• Particle size
• Chemical changes
• Increase in Degradation
• Decrease of Assay
• Microbial changes
Forced degradation studies
• Acidic & Basic conditions.
• Dry heat exposure
• UV radiation exposure
• Influence of pH
• Influence of temperature
• Influence of ionic strength

Arrhenius Equation
• K = Se-Ha /RT
where..k = specific rate of degradation.
R = gas constant ( 1.987 calories degree -1mole)
T = absolute temperature.
S = frequency factor.
Logarithmically ,
ln k = -Ha/ RT + ln S
converting to log 10
Log k = -ΔHa/2.303 R .1/T + log S
log k = specific rate of degradation
S = constant
Arrhenius Equation
• Plot of log K v/s 1/T….yields a slope equal to -ΔHa/2.303 R …..
From which heat of activation (ΔHa) can be calculated.
• Log k2/k1 = ΔHa/2.303 R . ( T2 – T1 )/ T2.T1

ΔH/R
• Tk =
-ln ( e – DHRT1 + e -ΔH/R T2 +….+ e- ΔH/R Tn
n
Tk = Mean kinetic temp
H = Heat of activation (83.144 KJ/mole)
R = Universal gas constant (8.3144 . 10 1 – KJ/mole/degree )
T1 = average storage temp during first time period ( months)
T2 = average storage temp during second time period ( months)
Tn = average storage temp during nth time period ( months)
n = no of average temp recorded (min )
T = temp in o k ( degree kelvin )
Clasius – Clapeyron equation
• ln = P2 / P1 . ΔH V ( T2 – T1 ) / R ( T 2 _ T 1)
where…. P2 & P1 = vapour pressure at T1 & T 2

ΔH =molar ( latent ) heat of evaporation
Relative humidity
Q =PD / PS . 100
RH is expressed in percentage ( %)
Q = Relative humidity
PD = partial pressure of unsaturated air
PS = saturation pressure
Chemical degradation studies
• Hydrolysis
• Oxidation
• Reduction
• Decarboxylation
• Photolysis
stages
• Stress- and accelerated Testing with drug substances
• Stability on pre-formulation batches
• Stress testing on scale-up Batches
• Accelerated and long term testing for registration
• On-going Stability testing
• Follow-up Stabilities
stages
Selection of samples
• API, excipient, batches
Scope
• Appearance
• Appropriate physical-chemical parameter
• Assay / Degradation products
Up to 3 month
Scope
• Determination of expire date
Scope • Determination of preliminary
• Solubility Profile specifications
• Hygroscopicity • Release of clinical batches
• Thermal stability • Monitoring of samples during the clinical
(Melting point, phases
Polymorphism) • Definition of storage conditions
• Chemical stability • Definition of Tests for registration
1 Batch stability
Up to 3 month Up to 36 month
Testing scope for Solid dosage
Tablet & Capsule
– Appearance
– Elasticity
– Mean mass
– Moisture
– Hardness
– Disintegration
– Dissolution
– Assay
– Degradation

– Functionality tests (e.g. extraction from blister)
Testing scope for Oral liquid
form
– pH
– Viscosity
– Particle size distribution (for oral suspensions only)
– Assay

Testing scope for
LIQUID FORMS for inj. and
PARENTRAL
– pH
– Loss on weight
– Assay

Testing scope for
SEMI LIQUID FORMS
– Appearance, odor, homogenesity, consistency
– Loss on weight, Viscosity
– Content uniformity (within the container)
– Assay
– Degradation products & preservatives
– Content preservatives
– Degradation– Content antioxidants

°C °C % r.h. °C % r.h.
Climatic Zone I
"Temperate"
Japan, United Kingdom,
20 20 42 21 45
Northern Europe,
Canada, Russia, United
States
Climatic Zone II
"Mediterranean,
Subtropical" 26.4 22 52 25 60
Japan, United States,
Southern Europe
°C °C % r.h. °C % r.h.
Climatic Zone III

"Hot, dry"
Iran, Iraq, Sudan
26,4 27,9 35 30 35
Climatic Zone IV
"Hot, humid" 26,7 27,4 76
Brazil, Ghana, Indonesia,
30 70
Nicaragua,
Philippines
What or Who is ICH?
• ICH stands for International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for
Human use
• Objectives of ICH
• Harmonization of registration applications within the three
regions of the EU, Japan and the United States.
• ICH is a joint initiative involving both regulators and industry

as equal partners in the scientific and technical discussions of
the testing procedures which are required to ensure and assess
the safety,quality and efficacy of medicines.
What or Who is ICH?
There are Six Parties directly involved in the decision making
process
• EU: European Commission - European Union
• EFPIA: European Federation of Pharmaceutical Industries and

Associations
• MHLW: Ministry of Health, Labor and Welfare, Japan
• JPMA: Japan Pharmaceutical Manufacturers Association

• FDA: US Food and Drug Administration
• PhRMA: Pharmaceutical Research and Manufacturers of America
• There are additionally observers installed to act as a
link with non-ICH countries and regions
• WHO
• The European Free Trade Area (EFTA),

represented by Swissmedic Switzerland
• Health Canada
٠Global guidelines
ICH Guidelines
• Quality Guidelines “Q” (chemical and pharmaceutical QA)
– details see next slide
• Safety Guidelines “S” (in vitro and in vivo pre-clinical studies)
– covering Carcinogenicity Testing, Genotoxicity Testing,
Toxicokinetics and Pharmacokinetics ….. etc.
• Efficacy Guidelines “E” (clinical studies in human subject)
– Covering clinical safety, Dose Response Studies, Good
Clinical Practices, Clinical evaluation …. etc.
• Multidisciplinary Guidelines “M”
– Covering Medical Terminology, Electronic Standards for
Transmission of Regulatory Information …… etc.
– Important for Stability !
» Guideline M4: The Common Technical Document (CTD)
ICH Q-Guidelines (Quality)
(Q1F)
• Impurities (Q3)
Q1A(R2) Stability testing of
New Drug Substances & Products
(Q1F)
• Impurities (Q3)
Drug substances - General case
Minimum time period
Storage condition covered by data at
Study
submission
Long term 25°C ± 2°C / 60% ± 5% r.h or 12 months
30°C ± 2°C / 65% ± 5% r.h.
Drug substances - intended for storage in a Refrigerator

covered by data at
submission
Drug substances/Product- intended for storage in Freezer
covered by data at
submission
Long term -20°C ± 5°C 12 months
Drug products - General case

covered by data at
submission
30°C ± 2°C / 65% ± 5% r.h.

Drug products - packaged in Semi-permeable containers
covered by data at
submission
30°C ± 2°C / 35% ± 5% r.h.
Drug products - intended for storage in a Refrigerator

covered by data at
submission

CALCULATIONS FOR SHELF LIFE PREDICTION
. From the graph no : time period to have 90% potency for each temperature
namely 37°c, 45°c and 60°c were ascertained for Formulation F3 which are
depicted in the following table
Temperature under study Time required to have a 90%

potency (days) i.e.‘t’ 90%
37°C 262
45°C 192
60°C 95
‘t’ 90% values from the above table then convert into log ‘t’ 90% and their
coresponding temperature (t) into absolute temperature (‘T’). Then reciprocal of
absolute temperature 1/T was calculated at each temperature.
CALCULATIONS FOR SHELF LIFE
PREDICTION
AT 37°C
‘t’ 90% = 262
log ‘t’ 90% = 2.41
T = ‘t’+273
= 37+273
T =310 1/T=1/310=3.225*10-3
AT 45°C
‘t’ 90% = 192
log ‘t’ 90% = 2.28
T = ‘t’ +273
= 45+273
T =318 1/T=1/318=3.144*10-3
At 60°C
1/T=1/333=3.00*10-3
90% VALUES FOR FORMULATION F3 AT
37°C, 45°C AND 60°C
Temperature ‘t’ 90% (days) 1/T Log ‘t’ 90%
under study
37°C 262 3.225*10-3 2.41
45°C 192 3.14*10-3 2.28
60°C 95 3.000*10-3 1.97

90% VALUES FOR FORMULATION F3 AT
37°C, 45°C AND 60°C
• At 30°C(Room Temperature)
T = ‘t’ +273
= 30+273
T = 303 1/T=1/303=3.30*10-3
Depicts a plot between log t 90% and 1/T10-3 Formulation F3 at 37°C

, 45°C,60 °C. The straight line so obtained was extra plotted to 1/T
value at 30°C & the corresponding log ‘t’ at 30°C on y axis was
noted down. It was found to be 2.69.
Now log’ t’ 90% at 30°C = 2.69
‘t’ 90°C at 30°C = 490 days.
Therefore shelf life of formulation F3 in years = 490/365 = 1.342
years or = 1.3 years.
REFERENCES
1. Ansel’s pharmaceutical Dosage forms & Drug delivery
systems, 8th edition by Loyd V. Allen, Nicholas G.popovich,
Howard C. Ansel, publised by B.I.Publication pvt. Ltd.,
page no:- 187-193,42 & 43,126-133.
2. Pharmaceutical preformulation by J.T.Cartensen published

by technomic publishing Co., page no:- 1-6, 211-212.
3. Textbook of physical pharmaceutics by C.V.S.

Subrahmanyam, published by Vallabh prakashan, page no:-
182-208, 222-226.
REFERENCES
4. The theory & practice of industrial pharmacy by
Leon Lachman, Herbert A. Lieberman, Joseph L.
kenig, 3rd edition, published by Varghese
Publishing house, page no:- 171-184.
5. Martin’s Physical pharmacy & Pharmaceutical

science, 5th edition by Patrick J. Sinco, Published by
Lippincott williams & wilkins, page no:- 547-550.
6. Pharmaceutical dosage forms : Tablet volume1,

edited by Herbert A. Lieberman & Leon Lachman,
published by Marcel dekker, page no:- 1-10.
Thank You
E-mail: m.zaman2157@gmail.com
Ch. Sherjeel Adnan
CHEE 440 1
Objectives
 Granulation
 Why?
 Equipments
CHEE 440 2
Granulation
identified. or

CHEE 440 3
CHEE 440 4
Why granulation?
 Done to
CHEE 440 5
Wet
 Spray dryer
more common
 Wet
granulator
 Dry
 pelletizers
 Others/advance
CHEE 440 6
Dry Others/advance
 Foam
granulation process
CHEE 440 7
 Solid bridges
CHEE 440 8
Massing
particles
CHEE 440 9
CHEE 440 10
 Nucleation
 Transition
 Ball growth
o Coalescence
o Breakage
o Abrasion transfer
o Layering
CHEE 440 11
CHEE 440 12
Low shear/planetary
CHEE 440 13
Diosna
 Diosona
 Gral
CHEE 440 14
Collette gral
CHEE 440 15
 Fludized bed
 Spray drier
 Day nauta mixer
 Topo granulator
 CF granulator
CHEE 440 16
Fludized bed dryer
CHEE 440 17
CHEE 440 18
Spray dryer
CHEE 440 19
 Steps
o Dry mixing
o Wet massing
o Extrusion
o Spheronization
o Drying
o Screening
CHEE 440 20
CHEE 440 21
Spheronization
CHEE 440 22
Spheronizer
CHEE 440 23
CHEE 440 24
Rotogranulator
CHEE 440 25
 sluggers
CHEE 440 26
CHEE 440 27
Other /advance
 Melt
 Foam
CHEE 440 28
CHEE 440 29
your life.
always a pupil.
CHEE 440 30
CHEE 440 31
MICROENCAPSULATION
Ch. Sherjeel adnan
► Microencapsulation is defined as the application of
a thin coating to individual core materials that
► MICROENCAPSULATION is a process by which
very tiny droplets or particles of liquid or solid
material are surrounded or coated with a
► For solids, liquid and gases
Microcapsules
thickness. Generally the active substance is
called CORE & the coating is called WALL
MATERIAL.
membrane
Microspheres
► Microspheres are
defined as solid,
approximately
spherical particles
about 1-1000 µm
(Burgess and Hickey
► To make the formulation sustained or controlled
release.
► To mask the taste & odour of bitter drugs
► A mean of separating incompatible materials
► To protect the drug from environmental conditions
(light, moisture & oxidation)
► For converting liquid into free flowing powders
► To prevent the gastric irritation of certain drugs
► Water solubility or dispersability
pharmacological classes can be given in the
form of free flowing powders in hard & soft
gelatin capsules, tablets, suspensions, rectal
& vaginal suppositories, ointments, creams,
aerosols, plasters and dressings.
Determined by some formulation ► Nature of polymer
► Drug
► The particle size requirement.
► Intended use
► The drug or the protein
should not be, adversely ► Duration of therapy
affected by the process
► Reproducibility of the release
profile
► No stability problem.
► No toxic products associated
► Solvent evaporation (Emulsification-Evaporation)
► Polymerization techniques
► Bulkpolymerization
► Suspension polymerization
► Emulsion polymerization
► Phase separation coacervation technique
► Spray drying and spray congealing
Solvent evaporation
► Fully developed at end of 1970
► Based on the evaporation of the internal phase of an emulsion
by agitation
microencapsulation by solvent evaporation.
► Single emulsion solvent evaporation
► Multiple emulsion solvent evaporation
technique. (W/O/W)
► Water as nonsolvent to the polymer are in
general preferred.
► Extremely economical and negate the
► Suitable for the encapsulation of lipophilic
active principles
► Microencapsulation of hydrophilic active
principles by this process can pose problems
Multiple emulsions: Water-in-
oil-in-water (w/o/w)
► For the efficient encapsulation of water-soluble
active principles
► Organic phase acts as a barrier between the two
► This process proves much more effective when the
water solubility of the medicine is high (>900 mg/
mL) and prevent partioning of drug into organic
phase
► Sometimes viscosity of primary emulsion is
oil (o/o)
► Continuous & discontinuous phase are oil and
► For drugs having high hydrophilicity and gives
highest yield
► For drugs/polymers that are degraded in presence
of water
► More expensive than aqueous methods
► Difficult to recycle oil phase
► Traces of oil possesses problems
► The process consists of bringing two reactants at the
► This is usually accomplished by emulsifying the liquid
containing first reactant (dispersed phase) into continuous
phase, which is initially devoid of second reactant
► Additional continuous phase containing the second
reaction produces a continuous film of the polymer around
the drug.
► Microcapsules can be recovered by spray drying or
filtration
Procedures adopted for interfacial
polymerization
► Procedure for water immiscible liquid core
► Procedure for water miscible liquid core
► Procedure for solid core
Procedure for water
When the core material is lipophilic liquid, the
monomer is dissolved in the liquid core.
Usually isocyanate or acid chloride is user as
monomer. Then this solution is disperesed
in aqueous phase (containing 2nd monomer)
this prpduces poolymerization of monomers
at the interface & results in formation of the
capsule wall
liquid core
additional oil containing 2nd monomer is added to
W/O emulsion, polymer membrane is formed.
techniques

► Different solvents used
o CCl4
o Chloroform
o Methanol
o Water
► Different monomers used
phenol propane) polybasic acid halide (sebacoyl chloride)
polymerization
► Enzymes
► Proteins
► Artificial cells
► Pharmaceuticals
► Adsorbants
► Hormones and antibiotics
► Pigments, oily liquids & polyelectrolytes
Coacervation Or phase separation
technology
A process in which aqueous colloidal solution
separate upon alteration of thermodynamic
condition of state into two liquid phases,
one rich in colloid i.e. the coacervate & the
other containing little colloide.
core material form the embryonic capsule &
then appropriate gelling of coacervate
Core material
encapsulated by coacervation can be solid,
liquid, gas, liquid slurry, suspension or
emulsion and analgesics, antibiotics,
vitamins
Wall material
► The coating material can be selected from a variety of
characteristics.
► The amount of coating material used ranges from 3%-
► Both natural and synthetic colloids can be used,
coacervation
Following methods can be used for coacervation & the choice
of method depend upon the polymer and the set of
conditions which are being used;
► Temperature change
► Salt addition
► Nonsolvent addition
► Incompatible polymer addition
► polymer-polymer interaction
Temperature change

takes place in the form of immiscible liquid droplets, if drug
is present these droplets surround the core & form
microcapsules.
microencapsulation. Ethylcellulose is soluble in cyclohexane
elevated temp. but insoluble at room temp. first of all
ethylcellulose is dispersed in cyclohexane & then mixture is
heated to boiling point so that a homogenous polymer
solution is formed. Then core material is added in the
solution with continous stirring & mixture is allowed to
cool.
the coating.
Salt addition
Soluble inorganic salts can be added to aqueous solution of
water soluble polymers to cause phase separation. A
Nonsolvent addition
immiscible core.
Fro example;
addition of isopropyl ether (nonsolvent for polymer) -----
---- phase separation & microencapsulation of suspended
drug occur.
Incompatible polymer interaction
addition.
polybutadiene which is soluble in toluene but incompatible
with ethyl cellulose. Thus causes demixing of ethyl
cellulose & phase separation occur.
whereas acacia possess a negative charge. Gelatin-gelatin,
gelatin-CMC are examples of other oppositely chaeged
polyelectrolyte used in microencapsulatio.
Coacervation method is divided into two main
groups
► Aqueous phase separation
► Organic phase separation
CHARACTERIZATION
► Recovery of formed microspheres
► Hydration of microspheres
► Drug loading
► Encapsulatipon efficiency
► Rheological properties
► Morphology (SEM,TEM)
► FTIR
► XRD
► TGA/DSC
► Drug release
► Drug release kinetics
Or
Simple CoaCervation +
(gelatin in water)


solvent
O/W Emulsion
CaCervation water insoluble particles
Or
+
Particles
(accacia in water)
wash with water
W/O Emulsion
organiC phaSe +
Or


Wash and dry
► Antibiotics;amoxicillin, ampicillin,
chloramphenicol
► Anti-inflammatory drugs; diclofenac sodium,
ibuprofen, naproxen, mefenamic acid &
flufenamic acid.
► Bronchodilators; theophylline & terbutaline
sulphate.
► Sulfa drugs; sulfadiazine, sulfamerizine &
sulfamethoxazole
► Diuretics; furosemide, chlorothiazide &
sulfonamide
► Urinary antiseptics; nitrofurantoin & nalidixic
acid
► Antiepileptic drugs; phenytoin sodium,
beclamide
► Antihypertensive;isosorbide mononitrate,
► Analgesics; acetyl salicylic acid
► Anticancers; mitomycin, bleomycin &

mercaptopurine.
► Tranquilizers; diazepam & oxazepam.
► Electrolyte replenisher; sodium chloride &
potassium chloride.
► Vitamins & metal salts; A, B1, B2, B6, B12,
C & D and mineral salts like Zinc sulphate.
► Converting liquids into free flowing
► Recovery of formed ► Hydrationof
► Rheological studies
► Drug loading
► Encapsulation efficiency
► Polyhydroxybutyrate-
microspheres
DSC
► 5-FU microspheres
Drug release
Equation for drug release kinetics
• Zero order release Qt  k0 t
• First order logQt  logQ0  k1 t
• Higuchi,s model Qt  k H t 1/ 2
1/ 3 1/ 3
• Hixson-Crowell Q0  Qt  k HC t
• Korsmeyer-Peppas M t
 k KP t n
M 0
Application
microspheres
► Taste and odor masking
► Conversion of oils and other liquids to solids for ease of
handling
► Protection of drugs against the environment as moisture ,
pain of injection
► Delay of volatilization
► Separation of incompatible materials
► Improvement of flow properties of powders
► Safe handling of toxic substances
► Aid in dispersion of water insoluble substances in aqueous
media
► Production of sustained release, controlled release and
► Reducing dose dumping potential compared to large
► If you stand for a reason, be prepared to
stand alone like a tree and if you fall on the
ground , fall as seed that grows back to
fight again
► Whenever you get really attached to some

than any one else
APPARATUS ,PROCESS AND PRODCT VARIABLES INFLUCING FLUIDIZED- BED GRANULATION
APPARATUS PARAMETERS PROCESS PARAMETERS PRODUCT PARAMETERS
AIR DISTRIBUTION PLATE BED LOAD TYPE OF BINDER
SHAPE OF GRANULATED BODY FLUIDIZING AIR FLOW RATE QUALITY OF BINDER
NOZZLE HEIGHT FLUIDIZING AIR TEMPERATURE BINDER SOLVENT
POSITIVE OR NEGATIVE FLUIDIZING AIR HUMIDITY CONCENTRATION OF

PRESSURE OPERATION GRANUALTING SOLUTION
SCALE-UP ATOMIZATION TEMPERATURE OF
GRANULATION SOLUTION
NOZZLE TYPE STARING MATERIAL
SPRAY ANGLE FLUIDIZATION
SPRAYING REGIME PODWER HYDROPHOBIOITY
LIQUID FLOW RATE
ATOMIZING AIR FLOW RATE
ATOMIZING AIR PRESSURE
DROPLET SIZE
a. Reservoir Devices ..........................................................................................346

b. Methods for Developing Reservoir Devices .................................................348
i. Coated Beads or Pellets .........................................................................348
ii. Microencapsulation ................................................................................348
c. Matrix Devices...............................................................................................349
i. Dissolved Drug ......................................................................................349
ii. Dispersed Drug ......................................................................................350
iii. Porous Matrix.........................................................................................351
iv. Hydrophilic Matrix ................................................................................351
4. Dissolution Controlled Systems ..........................................................................352
a. Matrix Dissolution .........................................................................................352
b. Encapsulated Dissolution Controlled System ...............................................353
5. Dissolution and Diffusion Controlled Systems...................................................353
F. Introduction to the Pharmacokinetics of Oral Controlled-Release Dosage
Forms .........................................................................................................................354
G. Elements of Regulatory Assessment of Controlled Release Products .....................357
III. Conclusion..........................................................................................................................358
Tutorial ...............................................................................................................................358
Answers ..............................................................................................................................359
Cases...................................................................................................................................360
References ......................................................................................................................................365
Learning Objectives
After studying this chapter the student will be able to:
• Describe the advances in drug delivery systems

• Describe various terms associated with modified release dosage forms
• Discuss advantages and disadvantages of controlled release dosage forms
• Describe the various factors affecting the design of controlled release dosage forms
• Classify oral controlled-release dosage forms with commercial examples for each class
• Describe the mechanisms of release and the equations for modeling the release of
bioactive agents from each class of controlled oral dosage form
• Solve some numerical problems associated with the design of oral controlled-release
dosage forms
• Describe the type of formulation science that forms the basis of the design of some
commercially available oral controlled-release dosage forms
I. INTRODUCTION
A. DEVELOPMENTS IN PHARMACEUTICAL DOSAGE FORM DESIGN
A drug is rarely administered to human being as a pure chemical compound. What is given is a
drug product containing the drug. When a drug is prepared in a form suitable for administration,
it is called a dosage form or a drug product or, in a modern term, a delivery system. Almost anything
done to the dosage form may alter the availability (the rate and the amount) of the drug delivered
to the desired place in the body. The following discussion of developments in pharmaceutical dosage
form design is intended to provide an overview of the progress that has been made in the efforts
to improve upon the delivery of bioactive agents (drugs). The divisions into various generations
serve only to point out the transition from one major form of delivery to another based on advances
in physical, chemical, and biological sciences. Some of the newer drug delivery systems will be
handled in clinics by current pharmacy students.
Historically, humans developed primitive ways of introducing drugs into the body:
• Chewing leaves and roots of medicinal plants

• Inhaling soot from the burning of medicinal substances
• Primitive extracts from plants and animals
• Treatment of asthma by smoking medicinal cigarettes as recently as 1950s
These primitive approaches to the delivery of drugs lacked consistency, uniformity, and specificity.
1. The First Generation Drug Delivery Systems
The first generation drug delivery systems (pharmaceutical dosage forms) appeared toward the end
of the nineteenth century and in the twentieth century, and they have consistency and uniformity.
These drug delivery systems (conventional dosage forms) include tablets, capsules, elixirs, syrups,
suspensions, emulsions, and solutions and topical administration of ointments, lotions and creams,
suppositories or injection of suspensions and solutions. Though these conventional drug delivery
systems are still with us, the need for more efficient drug delivery systems was realized with time.
The aims of the anticipated drug delivery systems were to deliver the minimum amount of drug
necessary to the site of action to produce the desired therapeutic response (spatial placement of
the drug) and to deliver the drug at an optimal rate to maximize the beneficial response and to
minimize unwanted side effects (temporal delivery of the drug).
2. The Second Generation Drug Delivery Systems
With advances in biopharmaceutics, pharmacokinetics, and human physiology and their applications
to drug formulation and development, various modifications in drug molecules and dosage forms
were introduced. These second generation drug delivery systems (dosage forms) represent attempts
to improve upon conventional dosage forms. These dosage forms were supposed to protect drugs
against hostile conditions along the gastrointestinal tract, prolong their action if necessary, and
improve bioavailability. The materials of formulation include polymers, waxes, plastics, and oils.
They are described by various terms such as repeat action, prolonged action, and timed release.
These drug products were introduced in the 1950s. In the second generation drug delivery systems,
repetitive, intermittent dosing of a drug occurs from one or more immediate release units incorpo-
rated into a single dosage form (e.g., enteric coated tablets). Though these drug delivery systems
provide some degree of control, it is not complete. More often than not, the release of the drug is
subject to the environmental conditions at the site of administration or drug release, and the drug
products do not generally permit a long-term drug release. Further, they do not produce a uniform
blood–drug concentration as a function of time.
3. The Third Generation Drug Delivery Systems
In the middle to late 1960s, the term controlled drug delivery was introduced to describe a new
concept of dosage form design. Controlled drug delivery refers to the precise control of the rate at
which a drug dosage is released from a delivery system, ideally in a constant or near constant
manner over a long period of time. In order to permit an accurate, reproducible, and predictable
drug therapy, the third generation drug delivery systems (controlled drug delivery systems) were
designed to provide drug release that is dependent on the properties of the device and the physic-
ochemical characteristic of the drug and the delivery system and independent of the environmental
factors existing at the site of administration (i.e., pH of fluids and the presence of enzymes in the body).
The third generation drug delivery system moved beyond extension of the blood level within
the therapeutic range, which is characteristic of the second generation drug delivery systems, to
controlled drug release such that a constant blood drug level can be maintained for a long period
of time. The design of the third generation drug delivery systems that revolves around the zero-
order approach is based on the assumption that optimal clinical outcomes may be achieved by
maintaining a constant drug plasma concentration and that the relationship between plasma drug
concentration and therapeutic effect of a drug is invariant with time. This is the era of time when
drug formulation scientists believe that the most desirable situation is that “the flatter the plasma
drug concentration vs. time curve the better”.
Based on the type of mechanism that triggers and eventually controls the release of drug
incorporated into the system, the controlled-release drug-delivery systems are classified as osmot-
ically controlled systems, swelling-controlled systems, magnetically controlled systems, chemically
controlled systems, electrically controlled systems, and diffusion-controlled systems. The design
of the vast majority of the third generation drug delivery systems involves the use of polymers. As
there is an element of diffusion of drug molecules in most of the systems, polymers serve as
permeable barriers that the drug must cross before reaching the body fluids. Polymers are partic-
ularly suitable for this purpose because their properties can be manipulated easily and diffusion
rates of drug molecules through polymers are orders of magnitude less than the diffusion rates of
the same molecules through water.
4. The Fourth Generation Drug Delivery Systems
Third generation drug delivery systems have no control over the fate of the drug once it enters the
body. With the advent of highly potent drugs such as peptides, proteins, and low molecular weight
anticancer drugs with narrow therapeutic indices, efforts were geared toward drug delivery systems
that could exercise control on the time of availability and the localization of the drug in the body.
Various drug delivery systems belong to this generation: targetable, modulated, pulsatile and self-
regulated, or feedback controlled drug delivery systems.
a. Drug Targeting or Site-Specific Drug Delivery
This mode of delivery involves specific delivery of the active compound (drug) to its site of action
and keeping it there until it is inactivated or detoxified. Drug targeting increases the therapeutic
potential and reduces side effects of the drug. Targeted (site-specific) delivery systems by the
parenteral route are, at present, in different stages of development, and most of them consist of the
following components: an active moiety for the therapeutic effect, a carrier for protection and
changing the disposition of the drug, and a homing device for selection of the assigned target (site-
specificity). The systems are suitable for anticancer drugs and highly potent recombinant peptides
and proteins in which site-specific delivery is needed to reduce side effects (particularly the paracrine
and autocrine acting proteins). The occurrence of severe side effects with cytokines such as tumor
necrosis factor and interleukin-2 limits their therapeutic potential. This problem can be circum-
vented by the delivery of these proteins at the proper site, rate, and dose. This problem also exists
for anticancer drugs. Gastrointestinal targeting of peptide and protein drugs to a suitable site for
absorption is also being investigated.
Commercial targetable drug products have reached the clinic in the field of immunotherapy. It
is believed that new immunotherapies, such as monoclonal antibodies, antisense compounds,
vaccines, and angiogenesis inhibitors, will revolutionize cancer treatment in the near future. Mono-
clonal antibodies bind to specific targets on cancer cells, then destroy the cells or mark them for
destruction by the immune system. The specificity of the drugs is such that they do not destroy
healthy cells; they have fewer side effects than traditional chemotherapies, and they can reduce the
relapse rate among chemotherapy patients. Examples of monoclonal antibodies already approved
by the Food and Drug Administration (FDA) are Rituxan (rituximab, made by Genentech) for
B-cell non-Hodgkin’s lymphoma, Herceptin (transtuzumab, made by Genentech) for breast cancer,
Mylotarg (gemtuzumab ozoganmicin, made by Wyeth) for acute myeloid leukemia, and Campath
(alemtuzumab, made by Millenium) for chronic lymphocytic leukemia. Zevalin (90Y-ibritumomab
tiuxetan, made by IDEC Pharmaceuticals) is a radioimmunotherapeutic agent that aims to combine
the targeting power of monoclonal antibodies with the cancer-killing ability of radiation. It has
been approved by the FDA.
Cancer vaccines have the potential to prevent or delay cancer recurrence by destroying residual
cells following first-line therapy. Some of them have been approved in Australia and Canada, and
some are in advanced clinical development in the U.S. Antisense compounds are complimentary
small fragments of RNA. They bind to specific sequences of mRNA target sites and prevent
translation and thereby inhibit the production of disease-causing proteins. ISIS’Vitraven has been
approved by FDA for the treatment of cytomegalovirus in AIDS patients. The angiogenesis inhib-
itors block the development of new blood vessels that supply nutrients and blood to tumors. They
can shrink tumors and prevent them from growing. None has made it to the clinic.
b. Pulsatile or Modulated Drug Delivery Systems
Twenty-four-hour ambulatory blood pressure monitoring has revealed a marked circadian rhythm
in hypertensive patients. Receptor down-regulation has been observed with a long-term delivery
of nitrates and hormones. Consequently, pulsatile drug delivery has been suggested as the best
mode of delivery for certain drugs so that their delivery should mirror the physiological release
profiles of endogenous peptides and proteins or human physiological needs. Efforts in this direction
resulted in a new body of knowledge called chronotherapeutics, which is the integration of chro-
nobiology, the science of biologic rhythm (i.e., the predictable cyclic variability of human biologic
functions), physiology, and therapeutics.
c. Self-Regulated or Feedback-Controlled Drug Delivery Systems
The long-term complications of diabetes, such as cardiovascular and neuropathic problems, have
been associated with the poor control over glucose levels that result from conventional therapy.
This consideration has been an impetus for the development of self-regulated or feedback-controlled
drug delivery systems. The types that are being investigated can be classified as follows:
• Closed loop systems that involve biosensor-pump combinations: The major requirement
is that there should be a known relationship between plasma level and pharmacological
effect. The components of the system are (a) a biosensor that determines the plasma
level of the drug, (b) an algorithm to calculate the required input rate for the delivery
system, and (c) a pump system capable of administering the drug at the required rate
over a prolonged period of time.
• Closed loop systems that involve delivery by self-regulating systems: Drug release is
controlled as a consequence of response to stimuli in the body. Efforts are directed toward
insulin release in response to glucose concentration. The progress on the development
of these self-regulating systems can be found in most text books on pharmaceutical
biotechnology.
• Closed loop systems based on microencapsulated secretory cells: Reports have shown
that clinical data obtained on human secretory islet of Langerhans cells encapsulated in
alginate-based microspheres for restoring insulin production in a biofeedback fashion
are very encouraging. Polymers are used to protect the secretory cells from the body’s
microenvironment.
5. The Fifth Generation Drug Delivery Systems

Gene therapy, intended to treat the cause of a disease rather than the symptoms, is essentially the
redesign of cells by introducing therapeutic genes into genetically disabled cells to deliver therapeutic
agents made by the gene. There are two methods of inserting genetic material into cells: viral and
nonviral gene transfer methods. Such systems are in various phases of drug development.
II. CONTROLLED RELEASE ORAL DRUG DELIVERY SYSTEMS:

SOLID DOSAGE FORMS
A. VARIOUS TERMS ASSOCIATED WITH MODIFIED RELEASE DOSAGE FORMS
Modified release dosage forms are drug products designed to alter the time and rate of release of the
bioactive agent (drug substance). They can achieve certain therapeutic or convenience objectives that
conventional dosage forms cannot offer. Modified release dosage forms can be classified as follows:
Delayed (sustained) release dosage forms: In delayed-release dosage forms, repetitive,
intermittent dosings of a drug occur from one or more immediate-release units incorporated
into a single dosage form. Examples of types of delayed-release dosage forms are:
Repeat-action (release of two doses successively)
Prolonged action (initial dose plus a replenishment)
Enteric coated tablets (timed release is achieved by a polymer barrier coating)
Modified enteric coated tablets (additional drug is applied over the enteric coat and is
released in the stomach, while the remainder is released further down the GI tract)
Controlled release dosage forms: This system releases the bioactive agent (drug) over an
extended period of time. It avoids the undesirable sawtooth characteristics of the plasma
concentration vs. time profiles of the conventional drug products. The dosage form can
control the rate of release of the incorporated bioactive agents and maintaining constant
drug concentrations at the biophase: target tissue or cells. The nature of the controlled
release dosage form is such that the release is determined by the design of the system and
the physicochemical properties of the drug and is independent of the external factors or
the microenvironment in which the dosage form is placed. The design of controlled release
dosage forms is based on the philosophy that optimum biological response occurs when
the level and the time of availability of the drug to the target tissue are optimized. Since
release-rate control complements drug molecular structure in determining both the selectivity
and duration of action, it is believed that controlled-release drug-delivery systems permit
more accurate, effective, reproducible, and predictable drug administration. Figure 11.1
shows a hypothetical serum drug concentration vs. time curves of various oral dosage forms.
Targeted dosage forms: Two types of targeted dosage forms are commonly described: site-
specific targeting and receptor targeting. In site-specific targeting, drug release is at the
diseased organ or site of absorption, while in receptor targeting, drug release is at the receptor
for the drug action.
All the dosage forms described above can be grouped under the generalized term controlled
drug delivery. Controlled drug delivery is now a generalized term that encompasses any system
that is capable of spatial placement and temporal delivery of a drug. In spatial placement, the drug
is targeted to a specific organ or tissue (this includes targeted dosage forms); in temporal delivery,
the rate of drug delivery to the target tissue is controlled (this includes the delayed and controlled
release dosage forms as well as pulsatile or modulated drug delivery systems because the rate of
delivery is controlled based on human physiological need).
B. RATIONALE FOR THE DEVELOPMENT OF A DRUG AS A CONTROLLED RELEASE

DOSAGE FORM
• Controlled release drug delivery systems increase efficacy by maintaining constant
plasma drug level in the therapeutic window range for an extended period of time.
• Controlled release drug delivery systems reduce dosing frequency and eliminate drug
accumulation in the body, thereby minimizing untoward effects.
• Controlled drug delivery increases patient compliance.
• The cost of treatment for chronic diseases may be reduced.
Toxic Range
Zero-Order Release Therapeutic Range

Arbitrary
Plasma Concentration
Therapeutic
Sustained Release Range
Immediate Release
Subtherapeutic Range
Time
FIGURE 11.1 Hypothetical serum drug concentration vs. time curves of various oral dosage forms. (From
Jantzen, G. M., and Robinson, J. R., Sustained and controlled release drug delivery systems, in Modern
Pharmaceutics, 3rd ed., Banker, G. S. and Rhodes, C. T., Eds., Marcel Dekker, New York, 1996, p. 575, with
permission.)
C. DISADVANTAGES OF CONTROLLED RELEASE DOSAGE FORMS

It is important to consider some of the drawbacks of using controlled release dosage forms,
especially as an aid in drug product evaluation and selection.
• Dose dumping can result from the failure of controlled release dosage forms. Dose
dumping has been defined as either the release of more than the usual fraction of drug
or as the release of drug at a greater rate than the customary amount of drug per dosing
interval, such that potentially adverse plasma levels may be reached. Controlled release
dosage forms are particularly prone to dose dumping if not properly designed and
fabricated because they usually contain the equivalent of two or more drug doses present
in a conventional dosage form. This problem is exemplified by delayed and enteric coated
dosage forms: If poorly formulated, the enteric coating may be dissolved in the stomach,
resulting in premature release of the drug with the concomitant irritation of gastric mucosa.
Moreover, if the coating is poorly done, the enteric coating may not dissolve at the proper
site along the gastrointestinal tract. Thus, the drug may not be available for absorption.
• Should the patient suffer from an adverse drug reaction or become accidentally intoxi-
cated, the removal of the drug from the system may be difficult, if not impossible, for
controlled release dosage forms.
• Orally administered controlled release dosage forms may yield erratic or variable drug
absorption owing to interactions with the contents of gastrointestinal tract and changes
in gastrointestinal motility. The result is drug ineffectiveness.
D. BIOLOGICAL AND PHYSICOCHEMICAL CONSIDERATIONS IN THE DESIGN

OF CONTROLLED RELEASE DOSAGE FORMS
1. Physicochemical Factors
a. Dose Size
Generally, 0.5 to 1.0 g is considered to be the maximum amount for a single dose of a conventional
dosage form. For drugs requiring large doses (>500 mg) in conventional dosage forms, the size of
Table 25.1 apparatus, process and product variables influencing fluidized-bed granulation
Apparatus parameters Process parameter Product parameter
• Air distribution plate • Bed load • Type of binder
• Shape of granulator body • Fluidizing air flow rate • Binder solvent
• Nozzle height • Fluidizing air temperature • Concentration of
• Positive or negative • Fluidizing air humidity granulating solution
pressure operation • Atomization • Temperature of granulation
• Scale-up 1. Nozzle type solution
2. Spray angle • Starting material
3. Spraying regime 1. Fluidization
4. Liquid flow rate 2. Power hydrophobicity
5. Atomizing air flow rate
6. Atomizing air pressure
7. Droplet size
Microencapsulation technologies
• Solvent evaporation
• Thermal gelation
• Gelation
• Interfacial polycondensation
• Polymerization
• Spray drying
• Fluidized bed
• Droplet freezing
• Droplet gelation
• Extrusion
• Supercritical fluid
• Coacervation
DESCRIPTIVE SOLUBILITIES (I.P.)
Description Parts of solvent required for one part of solute

Very soluble <1
Freely soluble 1-10
Soluble 10-30
Sparingly soluble 30-100
Slightly soluble 100-1000
Very slightly soluble 1000-10000
insoluble >10000
Bonding Mechanisms in Wet Massing
Spraying solution → powder → wetting and absorbing → solidified → solid bridge → final granules
Extrusion/spheronization (pg 244)
• Screw-feed extruders
• Gravity-feed extruders
Spheronization (pg 247)
Cylinder → Cylinder with rounded edges → dumbbell → ellipsoid → sphere
Spheronization time---------------- >
EMULSIONS
Water (Drug solution) + Oil-phase (methylene chloride + polymer)
↓ (emulsification)
(Water-in-oil) + (emulsifying agent + polymer)
↓ (Vortexing)
EMULSION (Water-in-oil-in-water)
↓ (Evaporation)
Suspension (microspheres + drug in water)
APPLICATION MARKETS OF MICROENCAPSULATION
• Veterinary
• Household and personal care
• Biotech
• Pharmaceuticals
• Chemical industry
• Agriculture
• Waste treatment
• Textile
• Photography
• Graphics and printing
• Electronics
• Feed
• Food
• Medicine
Spheronization
The
powder
The wet
mix The plastic
(standard extrudate sphere Coated
mass
mixer) (spheronizer (coater sphere
(extruder)
) /dyer)
Extended product → breaking up → spheronising→pellets

Water
polymer
Emulsifying agent : gelatin polyvinyl alcohol
solvents : choloroform or methylene
, tweens
chloride
Ph adjustment or presaturation of the
other suitable organic solvents may be
aqueos medium
added to alter solubility of the core of
polymer
Drug
materiall
Dispersed oil phase Continues water phase
Mixing and mechanical agitation
Formation of o/w
emulsion
Complete evaporation
At atmosphere pressure vaccum,
of solvent
heating or a combination of of
condition
Collection of microcapsules
Filtration
configuration
Washing and
drying
Water
polymer Other vegetable oil may be used
solvents : acetonitrile Emulsifying agent oil soluble eg. spans
small amount of other organic

solvents may be added
Drug
materiall
Dispersed water phase Continues oil phase
heated 55 C heated to 55 C
Mixing and mechanical agitation
Formation of o/o
emulsion
Complete evaporation
At atmosphere pressure vaccum,
of solvent
heating or a combination of of
condition
Collection of microcapsules
Filtration
configuration
Washing and drying

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MCQs 10.

The cross linking of the Polymers in hydrogels is designed to

21. Glycolic acid and polyethylene are biodegradable polymers

37:- A biodegradable can be delivered in dosage form to oral

40:- Polyethylene is composed of repeating units of ethene

67:- Strict compliance in terms of flow property is not required O False

O a. condensed polymers True

81:- Segregation of "granules" is a term that explains the true

104:- The initial step of formulating granules through wet and

➢ We can conclude that Pharmaceutical Technology include multiple disciplines

Dosage form & Drug:

40 Dosage Form Names:

1. Linimints 15. Solution 28. Emulsion

Evolution In dosage form/Drug delivery or Transition periods of dosage form

5. Soots/ sooting/ soots (Particals in smoke):

To overcome these drawbacks go to modern ways

Derived from word space defined as delivery of smallest required amount of

1. 1st generation Drug delivery system:

In late 19th century it was introduced;

2nd Generation DDS:

3rd Generation DDS:

4th Generation DDS:

4th generation drug delivery system further classify into 3 classes:

Melanin secretion more exposure to sun more melanin secreted

(Melatonin secretion stops) 7:30 am

9:00 pm(Melatonin secretion start)

3. Bio responsive /self-regulated /feedback drug delivery system :

2. Close loop system with which releases drug by self-regulating mechanism:

5th generation DDS:

1.Delayed release DDS:

2. Extended release DDS:

3. Targeted release DDS:

That follows a 24-hours cycle

Plasma cortisol (nmol/L):

Graph 2: Alertness level: Dim light, physical repair, psychological repair

Factors effecting circadian rhythm

The study of circadian rhythm is called chronobiology.

Dosage form (ii) seuffina .  snoffing powder in nos tril

magic bullet 3rd Generation DDS

Bioresponsive DDs 2:- extended release DDS

ii:- in this system we use sensitive polymers these polymers are

 Pharmaceutical granules ranges between 0.2 and 4.0 mm

 Interfacial forces in mobile liquid films within granules

 Attractive forces between solid particles

 Form-Closed Bonds or Interlocking Bonds

Solid cores are encapsulated by vinyl monomers that

By temp. change, phase separation of dissolved polymer

Gel colloid by pouring Then add 20% w/w Na2SO4

Treat filtered material with Filter and wash particles with

Cooling of microcapsules to Phase separation Then addition of non solvent

Then further treatment with

► Analgesics; acetyl salicylic acid

► Anticancers; mitomycin, bleomycin &

► Whenever you get really attached to some

Doxorubicin (Doxarubicin) = cause cardiotoxicity so shifted to nyosomal (noisome ) dosage

GASTRO-RETENTIVE DRUG DELIVERY SYSTEM: (GRDD)

This complex formation is called solid dispersion technique.