Integrated Pharmacy PDF

Integrated Physical Pharmacy &
Pharmaceutics I
Belayneh K. Gelaw (B.pharm, Msc)

Addis Ababa University, College of Health Science
School of pharmacy
Department of pharmacology and clinical pharmacy
Belayneh.kefale@ambou.edu.et ,
bkefale5@gmail.com
02/03/2023 By Belayneh K. 1
UNIT ONE
Introduction to dosage forms
Objectives of the session
• At the end of the class, you will be able to:
 Define the term ‘dosage form”
 Describe the needs for dosage forms
 Differentiate different types of dosage forms
Introduction to dosage forms
 Dosage forms are physical forms by which drugs are
administered to patients.
 Drug substances are rarely administered alone, but rather
as a part of a formulation in combination with one or
more non-medicinal agents that serve varied and
specialized pharmaceutical functions.
 The non medicinal agents (excipients) provide varied
and specialized functions.
 It is the formulation additives that, amongst other things,
sweeten liquid dosage forms, improve the
compressibility of tablet, preserve creams from attack by
microorganisms, etc
Introduction to dosage forms……(cont’d)
 For the preparation of dosage forms different types of
excipients can be used. For example,
 For tablet production, fillers (diluents/bulking
agents), binders, disintegrants, glidants, lubricants,
coloring agents, flavoring agents, etc may be used.
 For preparation of oral solutions, solvent/vehicle,
solubilizers, preservatives, flavouring agents,
sweetening agents, coloring agents, etc may be used.
For preparation of ointments, base/vehicle,
preservatives, antioxidants, may be used
The need for dosage forms
 Direct clinical use of the active drug substances “as
they are” is rare due to a number of reasons:
• Drug handling can be difficult or impossible (e.g., low
mg and g doses)
• Accurate drug dosing can be difficult or impossible
• Drug administration can be impractical, unfeasible or
not according to the therapeutic aims.
• Some drugs can benefit from reducing the exposure to
the environmental factors ( oxygen, sunlight, moisture).
The need for dosage forms……(cont’d)
• Some drugs can be degraded at GIT (e.g., insulin
degrades in stomach when taken orally)
• Some drugs may cause local irritations or injury

when they are present at high concentrations at the
site of administration.
• Some drugs can have unpleasant organoleptic

properties (taste, smell, color)
General considerations in dosage form
design
 Before a drug substance is successfully formulated in
to a dosage form, many factors must be considered.
These can be broadly grouped in to three categories:
Physicochemical properties of the drug (drug
factors)
Pharmacokinetics of the drug
Disease and patient considerations
General considerations in dosage form design
……(cont’d)
 Physicochemical properties of the drug
• The physicochemical properties of the drug substance include:
Chemical structure, molecular weight, polarity
Solubility
Partition coefficient (affinity for non-polar & polar env’t )
Pka
Crystal properties (e.g., polymorphs, solvates, hydrates)
Stability
Organoleptic properties & others
……(cont’d)
 Pharmacokinetics of the drug
– Includes property of the drug when in contact with
living tissues or cells (e.g., membrane permeability,
metabolism, etc).
 Disease considerations
– Clinical indication (disease) to be treated & patient
factors like age, etc.
• High-quality and efficacious medicines will be
formulated and prepared only when all these factors are
considered and related to each other.
02/03/2023 By Belayneh K. 10
……(cont’d)
• Many drugs are formulated into several dosage forms of
varying strengths, each having selected pharmaceutical
characteristics suitable for a specific application.
• For example, through the use of different chemical
forms and formulation additives a range of effective
anti-inflammatory preparations of predinsolone are
available including tablets, enteric-coated tablets,
suspensions, injections, eye drops, ear drops and enema.
02/03/2023 By Belayneh K. 11
……(cont’d)
 The extremely low aqueous solubility of the base

prednisolone and acetate salt make these forms useful
in slowly absorbed intramuscular suspension
injection forms.
 Whereas the soluble sodium phosphate salt enables a
soluble tablet form, and solutions for eye and ear
drops, enema and intravenous injection to be
prepared.
02/03/2023 By Belayneh K. 12
……(cont’d)
 Paracetamol is also available in a range of dosage

forms and strengths to meet specific needs of the
user, including tablets, pediatric oral solution, oral
suspension and suppositories.
02/03/2023 By Belayneh K. 13
Classification of pharmaceutical dosage
forms according to physical forms
Dosage forms
Solid dosage Semi-solid Liquid dosage

dosage forms Gaseous DFs
forms forms
02/03/2023 By Belayneh K. 14
Solid dosage forms

  Liquid DFs
 Tablets Solutions
 Capsules  Suspensions
 powders
 Emulsions
 Pills

etc
etc
02/03/2023 By Belayneh K. 15

Semi-solid dosage forms 

Gaseous DFs
 Ointments Aerosols
 Creams  inhlations
 Pastes  etc
 Gels
 Jellies
02/03/2023 By Belayneh K. 16
Solid dosage forms
 Tablets
 Tablets are compressed solid dosage forms intended
for oral use.
 There are also some tablets for vaginal use.
 As well as the common tablets, there are many
different types of tablets designed for specific uses
e.g., dispersible, enteric-coated, modified release,
buccal, etc.
02/03/2023 By Belayneh K. 17
Solid dosage forms
 Capsules
 These are solid dosage forms in gelatin shell.
 There are two main types of capsules: Hard capsules
and soft capsules.
 Both types are available in a verity of sizes.
 They are useful for administering unpleasant (bad
test and odor) medicaments.
02/03/2023 By Belayneh K. 18
Solid dosage forms
 Hard capsules usually contain solid medicaments.
 They consist of a cylindrical body and cap, both with

hemispherical ends, and are usually made from
gelatin, plasticizer and water.
02/03/2023 By Belayneh K. 19
Solid dosage forms
 Soft capsules
 They may be spherical, ovoid, or cylindrical with
hemispheric ends.
 Are useful for incorporating solids, liquids and semi-
solids.
 In addition to the ingredients of hard capsule, they
contain excess plasticizers which provides flexibility.
02/03/2023 By Belayneh K. 20
Solid dosage forms
 Suppositories
 Suppositories are cylindrical and one or both ends
tappered, solid preparations for insertion into the
rectum where they melt, dissolve or disperse and exert a
local or systemic effect.
 They weigh 1 g (for children) or 2 g (for adults) or
occasionally 4 g.
02/03/2023 By Belayneh K. 21
Solid dosage forms
Pessaries
 Are suppositories for insertion into vagina.
 They are larger than suppositories (3-5 g) in weight.
 They are globular, oviform or cone shaped.
02/03/2023 By Belayneh K. 22
Solid dosage forms
 Powders
 The term 'powder' when used to describe a dosage
form describes a formulation in which a drug
powder has been mixed with other powdered
excipients to produce the final product.
02/03/2023 By Belayneh K. 23
Solid dosage forms
 Powders……
 The function of the added excipients depends upon
the intended use of the product.
 Colouring, flavouring and sweetening agents, may

be added to powders for oral use.
02/03/2023 By Belayneh K. 24
Solid dosage forms
Powders (oral)……
 Packed as both bulk and divided powders.
 Bulk powders usually contain non-potent active
ingredients such as antacids.
 Divided powders are used for more potent drugs
where accuracy of dosage is more important.
 In divided powders an individual dose is packed
separately, either in a sheet of paper or in a sachet.
02/03/2023 By Belayneh K. 25
Solid dosage forms
 Dusting powders
 These are finely divided powders for external use
(surface of the skin).
 Their main uses are as lubricants to prevent friction
between skin surfaces and for disinfection and
antisepsis in minor wounds.
02/03/2023 By Belayneh K. 26
Solid dosage forms
 Granules
 Granules as dosage forms consist of powder particles
that have been aggregated to form a larger particle,
which is usually 2-4 mm in diameter.
02/03/2023 By Belayneh K. 27
Solid dosage forms
 Granules…..
 Granules may be packed in individual sachets
containing a unit dose of medicament or may be
provided in bulk format where the dose is measured
using a 5 ml spoon.
 Some laxatives are among the drugs currently

presented as granules.
02/03/2023 By Belayneh K. 28
Solid Dosage Forms
Implants
 Implants are solid dosage forms which are inserted
under the skin by a small surgical incision.
 They are most commonly used for hormone
replacement therapy or as a contraceptive.
02/03/2023 By Belayneh K. 29
Solid dosage forms
Implants……….
 Release of drug from implants is generally slow and
long term therapy is achieved.
 In the case of contraceptive implants the effect

continues up to 3 years or above .
02/03/2023 By Belayneh K. 30
Solid dosage forms
 Lozenges (Troches)
 These are large tablets designed to be sucked and

remain in the mouth for up to 15 minutes.
02/03/2023 By Belayneh K. 31
Solid dosage forms
Lozenges (Troches)…….
 They do not contain a disintegrant and the active
ingredient is normally incorporated into a sugar base,
such as sucrose or glucose.
 The main use of lozenges is in the treatment of mouth

and throat infections ( e.g., clotrimazole lozenge).
02/03/2023 By Belayneh K. 32
Liquid dosage forms
 Solutions
 In solution DFs the drug is completely soluble in the
vehicle.
 For some solutions sterility is necessary, e.g.,
parentral preparations.
 Unsterile solutions are used orally or externally on
unbroken surfaces.
02/03/2023 By Belayneh K. 33
Liquid dosage forms
Suspensions
 Suspensions are liquid dosage forms where the active
ingredient is insoluble or very slightly soluble in the
vehicle.
 Suspensions are available for both oral and external

use.
02/03/2023 By Belayneh K. 34
Liquid dosage forms
Emulsions
 These are mixtures of two immiscible liquids, usually

oil and water and stabilized with emulsifying agent.
02/03/2023 By Belayneh K. 35
Liquid dosage forms
 Emulsions……….
 The oil, in a very fine state of subdivision, is

dispersed in water(O/W emulsion) or water dispersed
in oil (W/O emulsion) and the dispersion being
stabilized by the inclusion of an emulsifying agent.
02/03/2023 By Belayneh K. 36
Liquid dosage forms
 Syrups
 Syrups are liquid oral preparations in which the
vehicle is a concentrated aqueous solution of sucrose
or other sugar.
 Nowadays in syrups sucrose is being replaced by
sorbitol as the sweetening agent in many
preparations to give ‘sugar-free’ syrups to reduce the
risk of dental caries.
02/03/2023 By Belayneh K. 37
Liquid dosage forms
Enemas
 An enema is an aqueous solution which is
administered rectally.
 Many drugs are formulated as enemas and are used to

treat conditions such as constipation or ulcerative
colitis.
02/03/2023 By Belayneh K. 38
Liquid dosage forms
 Gargles
 Gargles are aqueous solutions used to treat infections
of the throat.
 They are often presented in concentrated form with
instructions to the patient for dilution with warm
water before use.
 Gargles should not be swallowed but held in the
throat while exhaling through the liquid.
 After suitable time of period, usually a minute or so,
the patient should spit out the gargle.
02/03/2023 By Belayneh K. 39
Liquid dosage forms
 Irrigations
 Are solutions of medicaments used to treat infections
of the bladder, vagina and less often, the nose.
 They are administered via a thin, soft, rubber or

plastic tube known as a catheter (for bladder), a
vulcanite or plastic pipe (for vagina) or a specially
designed glass irrigator (for nose).
02/03/2023 By Belayneh K. 40
Liquid dosage forms
 Linctuses
 Linctuses are viscous, oral preparations that are
usually prescribed for the relief of cough.
 They are simple solutions or admixtures containing a
high proportion of syrup and, sometimes, glycerin
which, as well as sweet taste, have a demulcent effect
on the mucus membrane of the throat.
02/03/2023 By Belayneh K. 41
Liquid dosage forms
 Linctuses….
 The viscous nature of the preparation coats the throat
& helps to alleviate the irritation which is causing the
problem.
 Previously many linctuses contained a level of

sucrose; however, many have been reformulated as
‘sugar-free’ products to reduce the risk of dental
caries.
02/03/2023 By Belayneh K. 42
Liquid dosage forms
 Elixers
 Elixirs are, sweetened, flavored, hydroalcoholic
solutions intended for oral use.
 The vehicle generally contains a high proportion of
sucrose or, increasingly nowadays, a ‘sugar free’
vehicle such as sorbitol solution which is less likely
to cause dental carries.
02/03/2023 By Belayneh K. 43
Liquid dosage forms
 Elixers…..
 Non medicated elixirs are employed as vehicles and
medicated elixirs are used for the therapeutic effect of
the medicinal substances they contain.
 The therapeutic action of drugs present as elixirs

varies widely and includes antihistamines, antibiotics
and decongestants.
02/03/2023 By Belayneh K. 44
Liquid dosage forms
 Liniments
 Are liquids for external use.
 They may be alcoholic or oily solutions or emulsions.
 They are used to alleviate discomfort of muscle
strains and injuries.
 Because of some of the rubefacient (increase blood
flow in the applied area) nature of some of the
ingredients, some sportsmen use them prior to starting
sporting activity in an attempt to avoid any muscle
damage.
02/03/2023 By Belayneh K. 45
Liquid dosage forms
 Liniments….
 Examples of active ingredients found in liniments are
turpentine oil and methyl salicylate.
 Liniments must not be applied to broken skin.
02/03/2023 By Belayneh K. 46
Liquid dosage forms
 Lotions
 Lotions are liquid preparations, usually containing
suspended insoluble material and applied externally.
 They are different from liniments by being aqueous,
rather than oleaginous or alcoholic in nature.
 They are either dabbed on the skin or applied on a
suitable dressing and covered with water-proof
material to reduce evaporation.
 They have a variety of uses which include antiseptic,
parasiticidal and soothing.
02/03/2023 By Belayneh K. 47
Liquid dosage forms
Mouthwashes
 These are similar to gargles but are used specifically
to treat conditions of the mouth.
 Mouth washes are less concentrated than gargles.
 The active ingredients are usually antiseptics.
02/03/2023 By Belayneh K. 48
Liquid dosage forms
 Nasal drops
 These are isotonic solutions used to treat conditions
of the nose.
 Locally acting decongestants are commonly
presented as nose drops.
 The container includes a dropper device to allow the
patient to deliver the appropriate dose into the
affected nostril(s).
02/03/2023 By Belayneh K. 49
Liquid dosage forms
 Ear drops
 These are used topically to treat verity of ear
problems.
 The drug, or mixture of drugs, is presented as a
solution or suspension in a suitable vehicle such as
water, glycerol, propylene glycol or alcohol.
 The drops are inserted into the ear, using dropper.
 Some vehicles, such as alcohol, may cause a degree
of stinging when applied to the ear.
02/03/2023 By Belayneh K. 50
Semi-solid dosage forms
 Ointments
 Ointments are semi-solid preparations for application
to the skin or mucous membrane.
 The base usually contains the medicament in solution

or suspension form.
02/03/2023 By Belayneh K. 51
 Creams
 Creams are semi-solid emulsions for external use.
 There are two kinds: aqueous and oily creams in
which the emulsions are oil-in-water(O/W) and
water- in-oil (W/O), respectively.
 The (O/W) type is relatively non greasy.
 Creams are very popular form of external
preparations.
02/03/2023 By Belayneh K. 52
Pastes…..
• Pastes are ointment like preparations intended
for external application to the skin.
• They differ from ointments primarily in that they
generally contain a larger proportion of solid
materials and as a consequence are thicker and stiffer
than ointments.
• Pastes often are used in the treatment of oozing
lesions, where they act to absorb serous secretions.
02/03/2023 By Belayneh K. 53
Gels
 Gels are semisolid organic or inorganic colloids rich
in liquid.
 They consist of hydrated large molecules or granules of
the dispersed phase intimately associated with the
dispersion medium.
 They are usually transparent or translucent and have a
verity of uses.
 There are medicated and non medicated gels.
 Medicated gels are often used for topical or on mucus
membrane.
02/03/2023 By Belayneh K. 54
 Jellies
 Are a class of gels containing high proportion of

liquid, usually water.
02/03/2023 By Belayneh K. 55
Gaseous dosage forms
Aerosols
 These consists of pressurized packs which contain
the drug in solution or suspension and a suitable
propellent (gas).
02/03/2023 By Belayneh K. 56
Gaseous dosage forms
Aerosols….
 They are used to apply drug in the respiratory tract
( e.g., asthma) and skin (e.g., muscle sprains and
injuries).
 These devices are fitted with metering valve which

allows a known dose of drug to be delivered each
time the device is fired.
02/03/2023 By Belayneh K. 57
Aerosol dosage forms
Insufflations
 Insufflations are medicated dusting powders that are
blown by insufflator ( a device similar to atomizer)
into regions such as the nose, throat, body cavities
and the ear to which it would be difficult to apply the
powder directly.
02/03/2023 By Belayneh K. 58
Introduction to Pharmaceutical
Ingredients
(Definition, importance)
Objectives
 At the end of this session, you will be able to:
 define pharmaceutical ingredients
 mention types of excipients used in liquid and
semi solid and solid dosage forms
02/03/2023 By Belayneh K. 60
Introduction to Pharmaceutical Ingredients
• Drug substances are rarely administered alone rather

they are given as part of a formulation in combination
with one or more non- medicinal agents that serve
varied & specialized pharmaceutical functions.
• Some excipients are added to specific dosage forms

while others are common to most dosage forms.
02/03/2023 By Belayneh K. 61
Introduction to Pharmaceutical Ingredients………cont’d
 Generally, the pharmaceutical ingredients may be

categorized in to two:
1. Active pharmaceutical ingredient (API)- having
pharmacologic effect and
2. Inactive pharmaceutical ingredients (Additives or

excipients) – ‘have no pharmacologic effect’.
02/03/2023 By Belayneh K. 62
Introduction to Pharmaceutical Ingredients ………cont’d
 Pharmaceutical solvents
 Used to dissolve API in preparation of a
solution.
 Pharmaceutical solvents may be aqueous or

non aqueous.
02/03/2023 By Belayneh K. 63
………cont’d
 Pharmaceutical solvents
 Pharmaceutical solvents may be categorized as
water-miscible and water-immiscible.
1. Water miscible solvents include: ethanol, aromatic
water, glycerol, propylene glycol, isopropyl alcohol,
dimethyl sulfoxide, etc.
2. Water immiscible solvents – for example, e.g. almond
oil, castor oil, arachis oil, olive oil, diethyl ether, liquid
paraffin, isopropyl myristate, etc
02/03/2023 By Belayneh K. 64
………cont’d
Preservatives
 Are substances used in liquid & semisolid
preparations to prevent growth of microorganisms.
 Antioxidants
 Antioxidants are substances used to prevent
deterioration of preparations by oxidation.
 These substances, which are easily oxidizable, act by
possessing lower oxidation potential than the active
ingredients.
02/03/2023 By Belayneh K. 65
………cont’d
 Buffers
 Are used to resist change in pH upon dilution or
addition of acid or alkali.
 Chemically they are combinations of weak acid and
salt of the weak acid or weak base and salt of the
weak base.
 Viscosity inducing agents
 Used in suspensions to deter sedimentation, in
ophthalmic solutions to enhance contact time (e.g.
methyl cellulose), to thicken topical creams, etc.
02/03/2023 By Belayneh K. 66
Introduction to Pharmaceutical
Ingredients ………cont’d
 Surfactants (surface active agents)
 Are substances having a tendency to accumulate at the
boundary between two immiscible phases (oil and
aqueous phases) because of their amphiphatic nature.
 May be used as wetting agents in suspensions and
emulsifiers in emulsions.
 Coloring agents
 Substances that impart color to preparations attempting
to enhance the appearance of the preparations or to
increase their acceptability to the patient.
02/03/2023 By Belayneh K. 67
Introduction to pharmaceutical ingredients
………cont’d
Flavors
 Flavorants are used to impose a pleasant flavor to oral
preparations.
 Sweetening agents
 Used to impart sweetness to a preparation e.g.
sucrose, glucose, sorbitol, saccharin sodium, manitol,
glycerin, dextrose, aspartame
02/03/2023 By Belayneh K. 68
………cont’d
Ointment, cream & paste bases

 They are semisolid vehicles for medicated ointments.
 May be prepared from petrolatum, hard paraffin,
mineral oil, wool fat, etc.
02/03/2023 By Belayneh K. 69
Excipients for solid dosage forms
Diluents (or fillers)

• Diluents are fillers used to increase the bulk volume
of a tablet or capsule (5-80%)
– Increase the mass of the tablets and capsule that contain
a low concentration of therapeutic agent
• Minimum tablet weight is typically ~50mg
• Actual API doses can be as low as ~20μg, e.G. For oral steroids
– Thereby render the manufacturing process more reliable and
reproducible
• Diluents must exhibit good compression properties and be
inexpensive, compatible, inert and resistant to microbial growth.
Eg . microcrystalline cellulose they should also be inexpensive and have Good bulk powder flow
02/03/2023 Belayneh Kefale 70

Classification of diluents
• Natural diluents
– Starch (old)
– Soya bean powder (newly introduced)
• Organic diluents
– Lactose
•  lactose mono hydrate
• anhydrous lactose
• spray dried lactose
– sucrose, mannitol, sorbitol, micro crystalline cellulose (MCC)
• Inorganic diluents
– Dibasic calcium phosphate anhydrate (dihydrate)
– Tribasic calcium phosphate
• The inorganic diluents do not exhibit binding properties when
they are used in direct compression and wet granulation

• Most of the excipients are dehydrates, i.e. contain
certain amount of bound water, this bound water is
important during
– granulation process,
– it reduces the hygroscopic nature of the
formulation and
– makes the formulation stable.

Binders
• Binders are predominantly (but not exclusively)
polymeric components used to hold API and excipient in
a cohesive mix
• They are employed in the production of tablets by the
wet granulation method of manufacture.
– Give adherence to powder mixtures → necessary
mechanical strength (5-25 %)
• In this role, binders are either added as a solution or as
a solid into the powder mix (following which the
granulating fluid, typically water, is added)

Classification of binders
• According to their solubility

– Insoluble in water eg starch mucilage
– Soluble in water eg. HPMC
– Soluble in water and ethanol eg. Polyvinylpyrrolidone (Povidone)
• According to their chemical source
– Saccharides and their derivatives
• Disaccharides: sucrose, lactose
• Polysaccharides and their derivatives
– Starch, MCC, HPMC
– Natural gum: acacia, tragacanth
– Protein: gelatin
– Synthetic polymers: polyvinylpyrrolidone(PVP), polyethylene
glycol(PEG)

Disintegrants
• Disintegrants are employed in tablet formulations to
facilitate the breakdown of the tablet into granules upon
entry into the stomach (15 minutes) (5-20 %)
• If the formulated tablet is hydrophobic and/or it has been
manufactured using a high compression force, the rate of
water uptake into will decrease, and hence disintegration
of, the tablet will be unacceptably low.

Mode of action:
 Increase the porosity and wettability of the compressed tablet
matrix
 Water uptake rupturing the intra-particle cohesive forces
that hold the tablet together → disintegration
 starch, MCC, sodium starch glycolate. Sodium starch
glycolate is the sodium salt of the carboxymethyl ether of
starch and is employed at 5% w/w as a disintegrant within
tablet formulations.
 Operate by swelling in the presence of aqueous fluids
Water uptake → swelling →physical rupture →widened the
channels for penetration of water → disintegration
• Example: sodium starch glycolate, crospovidone,
croscarmellose sodium

Lubricants
• These are used to reduce friction between powders and metal
surfaces during tablet manufacture
• During compression lubricants act at the interface between the
face of the die and the surface of the tablet
• Lubricants tend to be hydrophobic, so their levels (typically 0.3 –
2%) need to be optimized
– Under-lubricated blends tend to flow poorly and show
compression sticking problems
– Over-lubricated blends can adversely affect tablet hardness
and dissolution rate
– Example: Magnesium stearate

Glidants
• Glidants act to enhance the flow properties of the powders

within the hopper and into the tablet die in the tablet press (0.1-2
%)
• By reducing the friction between the powders/granules due to
the ability of the particles of the glidants to locate within the
spaces between the particles/granules
Glidant particles to be small
Arrange at the surface of the particles/granules
• Example: Colloidal silicon dioxide (traditionally, talc was used)

Routes of drug administration
Objectives
• At the end of the session, you will be able to:
 Define routes of drug administration
 Differentiate different routes of drug
administration
 Mention advantages and disadvantage of each
route of drug administration
 Describe dosage forms suitable for each route of
administration
02/03/2023 By Belayneh K. 80
 Route of drug administration is the way through

which the dosage form is administered into the body
for treatment of various diseases and disorders.
• For a drug to bring its beneficial effect it has to be
administered into the body by convenient route.
 Routes of drug administration can be divided into
 Enteral, parenteral, topical, respiratory route
and miscellaneous routes.
02/03/2023 By Belayneh K. 81
 Enteral routes are routes related with GIT and

include:
Oral
Sublingual
Buccal
Rectal
02/03/2023 By Belayneh K.
82
Routes of drug administration….cont’d
 Parentral route of drug administration include:

Intravenous
Subcutaneous
Intramuscular
Intraspinal
Intrarterial
Intrapretonial
 Topical route
 Respiratory route
02/03/2023 By Belayneh K. 83
Oral route
 In this route the dosage form is placed in the mouth
and then swallowed.
 It is also called per oral (p.o.)
 This is the most commonly used route for drug
administration.
 The most popular dosage forms are tables, capsules,
solutions, suspensions & emulsions.
 The oral route can produce either a systemic or a
local effect.
 For a systemic effect the drug, formulated in either a
solid or a liquid form, is absorbed from the GIT.
02/03/2023 By Belayneh K. 84
Oral route…..Cont’d
 Advantages
From a patient point of view it is the simplest,
convenient (self-administration of drug can be
carried out) and if used properly, it is also the
safest route.
02/03/2023 By Belayneh K. 85
 Disadvantages
The onset of drug action is relatively slow
Unpleasant test of some drugs can be felt
Irritation of gastric mucosa by some drugs
Absorption from the GIT may be irregular (e.g.,
some foods delay absorption of drugs)
 Drug solubility may be altered by the presence of
other substances in the GIT( e.g., calcium forms
complex with tetracycline)
02/03/2023 By Belayneh K. 86
 Disadvantages…….
 It is an unsuitable route of administration in
unconscious or vomiting patients.
Gastric emptying is very variable and can be
influenced by factors such as food, drugs, disease
state and posture.
Not only does it affect the onset of action, but if it
is extended it may cause a drug to be inactivated
by gastric juice owing to prolonged contact.
02/03/2023 By Belayneh K. 87
 Disadvantages…….
 Some drugs are destroyed by enzymes and other
secretions found in the GIT (e.g., insulin &
penicillin become inactivated by the action of
stomach acid)
Because of the blood supply from the GIT passes
through the liver via the hepatic portal system, it is
subject to hepatic metabolism before it enters the
systemic circulation.
This is called first pass or presystemic metabolism. e.g.,
lidocaine
02/03/2023 By Belayneh K. 88
Buccal route
 In the buccal route the dosage form is positioned
beside the mucus membrane lining the checks.
 A drug is administered by these route by being
formulated as a tablet or spray and is absorbed from
the buccal cavity.
 The dosage form is kept in the buccal cavity where it
disintegrates and absorption occurs in the mouth.
 Water is not used for taking the dosage form.
02/03/2023 By Belayneh K. 89
Buccal route……….(cont’d)
 The highly vascular nature of the tongue and buccal

cavity, and the presence of saliva which can facilitate
the dissolution of the drug, make this a highly
effective and useful route for drug administration.
02/03/2023 By Belayneh K. 90
 Advantages
There is a relatively quick onset of action( due to
rapid absorption of drugs)
Drugs can be administered to unconscious patients
No deactivation of drug by gastric fluid
 Drugs are absorbed into the systemic
circulation, there by avoiding the “first-pass”
effect.
02/03/2023 By Belayneh K. 91
 Disadvantage
 Unpleasant test of some drugs can be felt
 It is useful for small dose drugs
 Inconvenient
02/03/2023 By Belayneh K. 92
Sublingual route
 In the sublingulal route the dosage form is placed on
the floor of the mouth (palate) or under the tongue.
 Formulations which have been specifically designed
for sublingual delivery include chewing gums, fast-
dissolving tablets and mucoadhesive patches.
 Example of sublingual tablet is nitroglycerine tablets.
02/03/2023 By Belayneh K. 93
Sublingual route……(cont’d)
Advantages
There is a relatively quick onset of action( due to
rapid absorption of drugs)
Drugs can be administered to unconscious
patients
 No deactivation of drug by gastric fluid
Drugs are absorbed into the systemic circulation,
there by avoiding the “first-pass” effect
02/03/2023 By Belayneh K. 94
Sublingual route……(cont’d)
Disadvantages
Unpleasant test of some drugs can be felt
 It is useful for small dose drugs &
Inconvenient
02/03/2023 By Belayneh K. 95
Rectal route
02/03/2023 By Belayneh K. 96
Rectal route………(cont’d)
 In the rectal administration dosage form is placed in
the rectum of the patient from where the drug is
released to give a local effect or it may be absorbed to
give systemic effect.
 For administration by this route, drugs are formulated

as liquids, solid DFs and semi-solids.
02/03/2023 By Belayneh K. 97
 The rectum is supplied by three veins, namely the
middle and inferior(lower) rectal veins which drain
directly into the systemic circulation and the upper
rectal vein which drains into the portal system which
flows into the liver,
This means that, depending on the position within
the rectum, only some of the drug absorbed from
the rectum will be subject to the first pass effect.
 Bioavailability, therefore may be less than 100%
but may be better than obtained from other parts of
the GIT.
02/03/2023 By Belayneh K. 98
Rectal route………(Cont’d )
 The amount of fluid present in the rectum is small,
estimated at approximately 3 ml.
This affect the rate of dissolution of drug released
from DFs.
However, there is also muscular movement which
spreads the drug over a large area and promote
drug absorption.
02/03/2023 By Belayneh K. 99
Rectal route………Cont’d
 Advantages
 To provide a local effect for the treatment of
infection and inflammation, e.g. hemorrhoids',
proctitis.
 To promote evacuation of the bowel to relieve

constipation or to cleanse the bowel prior to surgery.
02/03/2023 By Belayneh K. 100

Rectal route………Cont’d
 To provide systemic drug absorption in situations
where oral drug absorption is not recommended.
Examples of such applications include:
 Patients who are unconscious, e.g. in intensive
care or who are postoperative.
 Patients who are vomiting, e.g. gastrointestinal

infection, migraine
02/03/2023 By Belayneh K. 101

 Advantages……..
 To administer gastroirritant drugs, particularly in
chronic usage (e.g. non-steroidal anti-
inflammatory agents(NSAIDs)).
 Drugs that are prone to degradation in the stomach
Drugs that are erratically absorbed from the upper
gastrointestinal tract
 Administration of drugs that are extensively first-
pass metabolized.
02/03/2023 By Belayneh K. 102

Rectal route………(Cont’d )
Disadvantages
Uncomfortable
Specialist advice is required concerning the
administration of dosage forms
 The absorption of therapeutic agents from the
rectum is slow and prone to large intrasubject and
intersubject variability.
Rectal administration of therapeutic agents may
result in the development of local side effects, in
particular proctitis.
02/03/2023 By Belayneh K. 103
Vaginal route
 By this route, dosage forms are administered in the

vaginal cavity.
 For administration, drugs may be formulated as

Pessaries, tablets, solutions, sprays, creams,
ointments and foams.
02/03/2023 By Belayneh K. 104

Vaginal route……(cont’d)
 Most often this route is used for a local effect (used to

treat vaginal infections and vaginitis).
 However, drugs absorbed from the vagina are not

subject to the first pass effect and systemic
bioavailability better than the oral route.
02/03/2023 By Belayneh K. 105

Vaginal route……..cont’d
 Advantages
Possibility of self-administration,
 High vascularization,
 Relatively low enzymatic activity (e.g.,trypsin and
chymotrypsin are absent)
Bypass hepatic first pass-effect,
Increased permeability for some drugs when
comparing to the oral or other routes.
02/03/2023 By Belayneh K. 106

Vaginal route……..cont’d
 Disadvantages
Social taboo
Removal of dosage form after administration
Only few drugs are administered by this route
Variability in drug absorption related with
menstrual cycle, menopause and pregnancy
Influence with sexual intercourse
Gender specificity
02/03/2023 By Belayneh K. 107

Parentral route
 This is the term used to describe drug administration by
injection.
 Within this general term there are variety of different

routes. The main ones are:
 Intravenous route (IV)
 Intramuscular route (IM)
 Subcutaneous route (SC)
02/03/2023 By Belayneh K. 108

02/03/2023 By Belayneh K. 109
Parentral route……Cont’d
 Intravenous route (IV ), where drugs are injected

directly into the vein.
 It is the surest way of introducing drug into systemic

circulation.
 Permit rapid onset of action (no absorption of drug ).
 Large volume of pharmaceutical preparations can be
administered than other routes.
02/03/2023 By Belayneh K. 110

Intramuscular route (IM)
 Drugs are injected into muscle from where they are
absorbed due to the perfusion of the muscle by
blood.
 Usually injected at deltoid and gluteus muscle

 This method can be used to produce a fairly fast
onset of action when the drug is formulated as an
aqueous solution.
02/03/2023 By Belayneh K. 111

 Intramuscular route (IM)
 A slower and more prolonged action will occur when
the drug is presented as a suspension or in non
aqueous vehicle such as ethylene glycol or peanut
oil.
 As the vehicle diffuses out of the muscle, the
drug precipitates at the site of injection.
The drug then dissolves slowly, providing a
sustained release over extended period of time.
02/03/2023 By Belayneh K. 112

 E.g., haloperidole decanoate whose slow diffusion

from the muscle produce an extended neuroleptic
effect.
 Usually produce a faster effect than oral

administration.
 The volume to be injected is < 10 ml.
02/03/2023 By Belayneh K. 113

 The rate of absorption depends on the site of

injection and physiological factor at the site of
injection.
 High blood flow at the site of injection

increase drug absorption
02/03/2023 By Belayneh K. 114

 Subcutaneous route (SC), where drugs are injected

into the subcutaneous fat layer of the skin.
 This is the easiest and least painful type of

injection to administer.
 It is used for administering aqueous solution and

specialized preparations
02/03/2023 By Belayneh K. 115

 It requires absorption.
 Volume of preparations to be injected is smaller

than in IV and IM routes ( usually not more than 2
ml).
 Absorption of drug from the site of injection for

both IM and SC can be increased by massaging,
heating and adding an enzyme hyaluronidase
02/03/2023 By Belayneh K. 116

 The rate of absorption from IM and SC routes can
be reduced by epinephrine.
 Minute amount of epinephrine are some times

administered combined with drug to restrict its
area of action.
 Epinephrine acts as local vasoconstrictor and

decrease removal of drug such as lidocaine from
the site of administration.
02/03/2023 By Belayneh K. 117
Parenteral route……Cont’d
 Advantages of parenteral route:

 Useful to administer drugs in emergency
conditions.
When patients are unconscious.
In case when drugs are inactivated or poorly

absorbed following oral administration.
02/03/2023 By Belayneh K. 118

Parenteral route……Cont’d
 Disadvantages of parenteral route:

 Irreversible
 Injected drugs cannot be recalled by strategies
such as emesis or binding to activated charcoal.
Painful and inconvenient
02/03/2023 By Belayneh K. 119

Respiratory route
 Drugs are administered usually by inhalation

through the nose or mouth to produce either local
or systemic effects.
 Drugs are delivered as aerosol or very fine solid

particle form.
02/03/2023 By Belayneh K. 120

Respiratory route…….cont’d
 This route is used predominantly for local

administration to treat respiratory conditions such
as asthma.
 A major benefit of the respiratory route is that the

drug dose required to produce the desired effect is
much smaller than for the oral route, with a
consequent reduction in side-effects.
02/03/2023 By Belayneh K. 121

Respiratory route…….cont’d
 This route is being increasingly recognized as a useful

means for administering therapeutic agents
emerging from biotechnology requiring systemic
distribution & targeted delivery, such as peptides &
proteins.
 Because of the high blood flow to the lungs and their

large surface area, drug absorption by this route is
extremely rapid .
02/03/2023 By Belayneh K. 122

Topical route
 Drugs are applied topically mainly for local action.
 Application of drugs to surfaces such as the eye, ear

& nose are also regarded as topical administration.
 Drugs applied to the skin for local effect include:

antiseptics, anti fungals, anti- inflammatory agents ,
skin emollients, protective agents, etc.
02/03/2023 By Belayneh K. 123

Introduction to intermolecular
force of interaction
Intermolecular Forces
• Forces binding atoms in a molecule are due to
chemical bonding.
• The energy required to break a bond is called
the bond-energy.
– E.g. the average bond-energy for O-H bonds in
water is 463 kJ/mol. On average, 463 kJ is required
to break 6.023x1023 O-H bonds, or 926 kJ to
convert 1.0 mole of water into 1.0 mol of O and
2.0 mol of H atoms.
02/03/2023 By Belayneh K. 125

02/03/2023 By Belayneh K. 126
Intermolecular binding forces
• Attractive forces between atoms are

responsible for the formation of molecules.
• Attractive forces between molecules are
responsible for the state of substances, that is,
solid, liquid, or gas.
• Intermolecular forces are attractive forces
between molecules that occur when there is a
variation in the electron distribution in a
molecule.
02/03/2023 By Belayneh K. 127
• Intermolecular forces (IMFs) are forces of
attraction or repulsion which act between
neighboring particles (atoms, molecules, or
ions).
• They are weak compared to the intramolecular
forces, the forces which keep a molecule
together.
02/03/2023 By Belayneh K. 128

Intermolecular binding forces (cont’d)
• Intermolecular forces are weaker than the

weakest covalent bonds.
• Intermolecular forces arise when a partially

negative charge on a molecule is attracted to a
partially positive charge on another molecule.
02/03/2023 By Belayneh K. 129

The strengths of intermolecular forces are
generally weaker than either ionic or covalent
bonds
16 kJ/mol (to separate molecules)
 + -
+ -
431 kJ/mol (to break bond)
02/03/2023 By Belayneh K. 130

Types of attractive intermolecular forces
 van der Waals forces
Dipole - dipole attractions (Keesom forces )
Dipole - induced dipole attractions (Debye forces)
Induced dipole - induced dipole attractions (London
forces or dispersion forces)
 Hydrogen bonding
 Ion – dipole and ion – induced dipole forces
 Ion - ion interaction
02/03/2023 By Belayneh K. 131

Dipole - Dipole attractions
 Dipole – dipole attractions occur between the
dipoles of two polar molecules and are caused by
the permanent, uneven distribution of electrons,
which is caused by the electro negativity differences
of atoms in the molecule.
 These attractions are stronger than London forces
because the dipoles of polar molecules is permanent.
+ - + -
HCl ---- HCl
dipole-dipole attraction
02/03/2023 By Belayneh K. 132
Dipole - induced dipole attractions
 This a type of attraction that occurs between a

polar molecule and non polar molecule.
 The non polar molecule temporarily become
polarized.
02/03/2023 By Belayneh K. 133

Induced dipole - induced dipole attractions
 A force in which non polar molecules induce

instantaneous polarity in one another.
 “electrons are shifted to overload one side of an
atom or molecule”.
02/03/2023 By Belayneh K. 134

Ion - dipole and Ion - induced dipole forces
 In addition to the dipolar interactions other attractions

occur between polar or non polar molecules and ions.
 These types of interactions account in part for the
solubility of ionic crystalline substances in water.
 The cation, for example, attracts the relatively negative
oxygen atom of water and the anion attracts the
hydrogen atoms of the dipolar water molecules.
 Ion-induced dipole forces are presumably involved in
the formation of the iodide complex,
I2 + k+I- = K+I-3
 This reaction accounts for the solubility of iodine in a
solution of potassium iodide.
02/03/2023 By Belayneh K. 135
Ion-dipole interactions
(e.g., a salt dissolved in water)
cation
Polar molecule
anion
02/03/2023 By Belayneh K. 136

Ion – Ion interactions
 Ion – ion interactions are normally viewed from

the stand point of attractive forces: a cation on
one compound will interact with an anion on
another compound, giving rise to an
intermolecular association.
 Ion-ion interactions may be intermolecular
(e.g.,a hydrochloride salt of a drug) or
intramolecular ( e.g., a salt-bridge interaction
between counter ions in proteins)
02/03/2023 By Belayneh K. 137

Hydrogen Bonds/hydrogen bridge
 A hydrogen bond is the attractive force between the
hydrogen attached to an electronegative atom of one
molecule and an electronegative atom of a different
molecule.
 Usually the electronegative atom is oxygen, nitrogen, or
fluorine.
 It is the strongest type of dipole-dipole attractions
where the most electronegative atoms such as O, N
and F are involved.
 For example, hydrogen bond exists in ice and in

liquid water; it accounts for many of the unusual
properties of water including
02/03/2023 By Belayneh K. its high dielectric 138
Hydrogen Bonds/hydrogen bridge
02/03/2023 By Belayneh K. 139

Hydrogen bond………….Cont’d
 Roughly one sixth of the hydrogen bonds of ice are
broken when water passes into the liquid state and
essentially all the bridges are destroyed when it
vaporizes.
 Hydrogen bonds can also exist between alcohol
molecules, carboxylic acids, aldehydes, esters and
polypeptides.
 It will be noticed that intra- as well as intermolecular
hydrogen bonds may occur (as in salicylic acid).
02/03/2023 By Belayneh K. 140

02/03/2023 By Belayneh K. 141
Phase equilibria and the phase
rule
Phase equilibria and The phase rule
 Phase is a homogeneous, physically distinct portion
of a system that is separated from other portions of
the system by bounding surfaces.
 The three primary phases (solid, liquid, and gaseous)
of matter are defined individually under different
conditions, but in most systems we encounter phases
in coexistence.
 For example, a glass of ice water on a hot summer
day comprises three coexisting phases: ice(solid),
water (liquid), and vapour (gaseous).
02/03/2023 By Belayneh K. 143
The phase rule
 A system containing water and its vapor is a 2- phase
system.
 J. Willard Gibbs formulated the phase rule, which is a
relationship for determining the least number of
intensive variables (independent variables that do not
depend on the size of the phase, e.g., temperature,
pressure, density, and concentration) that can be
changed without changing the equilibrium state of the
system, or alternatively, the least number required to
define the state of the system.
02/03/2023 By Belayneh K. 144

The phase rule (cont’d)
 This critical number is called F, the number of
degrees of freedom of the system, and the rule is
expressed as follows:
F = C-P+2
Where, C is the number of components and P is the
number of phases present.

 The degree of freedom is the least number of
intensive variables that must be fixed/known to
describe the system completely.
 Although a large number of intensive properties are
associated with any system,
02/03/2023 it is not necessary to
By Belayneh K. 145
 An equilibrium mixture of ice, liquid water, and water

vapor is a three-phase system.
 The number of components is the smallest number
of constituents by which the composition of each
phase in the system at equilibrium can be expressed
in the form of a chemical formula or equation.
 The number of components in the equilibrium
mixture of ice, liquid water and water vapor is one
because the composition of all the three phases is
described by the chemical formula H2O.
02/03/2023 By Belayneh K. 146
Examples
1. A given mass of gas ,say, water vapor, confined to a
particular volume
F = 1-1+2 = 2
2. A system comprising a liquid, say, water in equilibrium
with its vapor
F = 1-2+2 = 1
3. Suppose we cool liquid water and its vapor until a third
phase/ice/ separates out
F = 1-3+2 = 0
02/03/2023 By Belayneh K. 147
 As the number of components increases, so do the

number of degree of freedom required to define the
system.
 The greater the number of phases in equilibrium,
however, the fewer are the degrees of freedom.
02/03/2023 By Belayneh K. 148

• Liquid water+vapor F=1-2+2=1
• ethyl alcohol+vapor F=1-2+2=1
• liquid water+liquid ethanol+vapor F=2-2+2=2
• liquid water+liquid benzyl alcohol+vapor
mixture  F=2-3+2=1  benzyl alcohol and
water form two separate liquid phases and one
vapor phase.
02/03/2023 By Belayneh K. 149

02/03/2023
02/03/2023 By Belayneh K. 151

One component systems
• The previous figure (phase diagram for water at moderate
pressures), the curve OA is known as the vapor pressure curve;
its upper limit is at the critical temperature, 374ºC for water,
and its lower end terminates at 0.0098ºC, called the triple point.
• Along the vapor pressure curve, vapor and liquid coexist in
equilibrium.
• Curve OC is the sublimation curve, and here vapor and solid
exist together in equilibrium.
• Curve OB is the melting point curve at which liquid and solid
are in equilibrium.
• The negative slope of OB shows that the freezing point of
water decreases with increasing external pressure.
02/03/2023
• If t1 is held constant, no matter how much the
pressure is raised, the system remains a gas.
• At t2 below the critical temperature and above the

triple point, water vapor is converted into liquid
water by an increase in pressure.
• At temperature below the triple point e.g. t3, an

increase in pressure on water in the vapor state
converts the vapor first to ice and then at higher
pressure into liquid water.
02/03/2023
 In any one of the three regions of phase diagram of

water, in which pure solid, liquid, or vapor exists and
p= 1, the phase rule gives
F = 1-1+2 = 2
Therefore, we must fix two conditions, namely
temperature and pressure, to specify or describe the
system completely.
 This statement means that if we were to record the
results of a scientific experiment involving a given
quantity of water, it would not be sufficient to state
that the water was kept at, say, 76 oC.
02/03/2023 By Belayneh K. 154
 The pressure would also have to be specified to define the
system completely.
 Conversely, it would not be sufficient to state that liquid
water was present at a certain pressure without also stating
the temperature.
 Along any three of the curves where two phases exist in
equilibrium, F = 1
 Hence, only one condition need be given to define the system.
 If we state that the system contains both liquid water and
water vapor in equilibrium at 100 oC, we need not specify
the pressure, for the vapor pressure can have no other value
than 760 mm Hg.
 At the triple point, where the three phases- Ice, liquid water,
and water vapor – are in equilibrium,
02/03/2023 By Belayneh K. we say F = 0. 155
Phase equilibria of two- component system
 A maximum of three degrees of freedom is possible in

a two-compartment system, for example, temperature,
pressure and concentration.
 Because in practice we are primarily concerned with
liquid and/or solid phases in the particular system under
examination, we frequently choose to disregard the
vapor phase and work under normal conditions of 1 atm
( 760 mm Hg) of pressure.
 In this manner we reduce the number of degrees of
freedom by one.
02/03/2023 By Belayneh K. 156
Phase equilibria of two- component system
(cont’d)
 In a two-component system, therefore, only two

variables (temperature and concentration) remain, and
we are able to portray the interaction of these variables
by the use of planer figures on a rectangular –
coordinate graph paper.
 Systems in which the vapor phase is ignored and only
solid and/or liquid phases are considered are termed
condensed systems.
 Condensed systems are most appropriate for solid and
liquid dosage forms.
02/03/2023 By Belayneh K. 157
Two- component systems containing
liquid phases
 We know from experience that water and ethyl alcohol
are miscible in all proportions, whereas water and
mercury are, for all practical purposes, completely
immiscible regardless of the relative amounts of each
present.
 Between these extremes lies a whole range of systems
that exhibit partial miscibility (or immiscibility).
 One of such system is phenol and water, and a portion of
the condensed phase diagram is plotted in the next slide
02/03/2023 By Belayneh K. 158

Two component systems containing liquid phases
• Miscible systems such as water and ethanol.
• Immiscible systems such as water and mercury.
• Partial miscibility (or immiscibility) such as phenol

and water.
• Critical solution temperature: The maximum

temperature at which the two – phase region exists.
02/03/2023
• Phenol and water.
– These liquids are partially miscible in each other.
– At certain ratios the liquids are completely miscible
and at others they are immiscible.
– The 2 degrees of freedom of this mixture are
temperature and concentration (condensed system).
– The maximum temperature that these two liquids can
exist in a 2 phase system is 66.8°C.
– This is called the critical solution temperature or the
upper consolute temperature.
– In this system above 66.8°C all combinations of
phenol and water will be completely miscible and
will be one phase.
02/03/2023
Phenol – water systems
02/03/2023 By Belayneh K. 161

liquid phases
 The curve gbhci shows the limits of temperature and
concentration within which two liquid phases exist in
equilibrium.
 The region outside this curve contains systems having
but one liquid phase.
 Starting at the point a, equivalent to a system
containing 100% water (i.e., pure water) at 50 oC,
adding known increments of phenol to a fixed weight of
water, the whole being maintained at 50 oC, will result in
the formation of a single phase until the point b is
reached, at which a minute amount of second phase
appears.
02/03/2023 By Belayneh K. 162
Two- component systems containing liquid phases
(cont’d)
 The concentration of phenol and water at which this
occurs is 11% by weight of phenol in water.
 Analysis of the second phase, which separates out on the
bottom, shows it to contain 63% by weight of phenol in
water.
 The phenol-rich phase is denoted by the point c on the
phase diagram.
 As we prepare mixtures containing increasing quantities
of phenol, that is, as we proceed the diagram from point
b to point C, we form systems in which the amount of
phenol rich phase(B) continually increases
02/03/2023 By Belayneh K. 163
liquid phases (cont’d)
 At the same time the amount of water-rich phase (A)
decreases.
 Once the total concentration of phenol exceeds 63%
at 50 oC, a single phenol-rich liquid phase is formed.
 The maximum temperature at which the two-phase
region exists is termed the critical solution, or upper
consolute temperature.
 In the case of phenol water system, this is 66.8 oC.
 All combinations of phenol and water above this
temperature are completely miscible and yield one-
phase liquid systems.
02/03/2023 By Belayneh K. 164
 The line bc drawn across the region containing two
phases is termed a tie line; it is always parallel to the
base line in two component systems.
 All systems prepared on a tie line, at equilibrium, will
separate into phases of constant composition.
 This phases are termed conjugate phases.
 For example, any system represented by a point on the
line bc at 50 oc separate to give pair of conjugate
phases whose compositions are b and c
 However, the relative amounts of the two layer of
phases vary.
02/03/2023 By Belayneh K. 165
 Thus, if we prepare a system containing 24% by weight
of phenol and 76% by weight of water (point d), at
equilibrium we have two liquid phases present in the
tube.
 The upper one, (A) has a composition of 11% of
phenol in water (point b on the diagram), where as the
lower layer, B contains 63% phenol (point C on the
diagram)
 In terms of relative weights of the two phases, there
will be more of the water-rich phase A than the
phenol- rich phase B at point d.
02/03/2023 By Belayneh K. 166
 Thus:
 Example. Suppose that we mixed 24 g of phenol with 76 g of

water, warmed the mixture to 50 oC and allowed it to reach
equilibrium at this temperature. On separation of the two
phases, calculate
i. Weight of phase A
ii. Weight of phase B
iii. Weight of phenol and weight of water in phase A,
iv. Weight of phenol and weight of water in phase B
02/03/2023 By Belayneh K. 167
Example
• At 50°C, the concentrations of phenol in the
water-rich phase and the phenol-rich phase
are 11 and 63% w/w (phenol/water),
respectively. Then a total of 120 g of a 35:65
w/w (phenol/water) is mixed. Calculate the
amount of the phenol-rich and water-rich
phases.
02/03/2023 By Belayneh K. 168

• Upper consolute temperature: All combinations above this

temperature are completely miscible (one phase).
• Lower consolute temperature: below which the components are

miscible in all proportions.
02/03/2023
Applications of phase diagram
 The phase diagram is used in practice to formulate
systems containing more than one component where
it may be advantageous to achieve a single phase
product.
 For example, the handling of solid phenol, a necrotic
agent, is facilitated in pharmacy if a solution of phenol
with water is formulated
 A number of solutions containing different
concentrations of phenol are official in several
pharmacopeias.
02/03/2023 By Belayneh K. 170

Applications of phase diagram (cont’d)
 Unless freezing point of phenol-water mixture is

sufficiently low, however, some solidifications may
occur at low ambient temperature.
 This will lead inaccuracies in dispensing as well as loss
of convenience.
 Mulley determined the relevant portion of phenol-
water phase diagram and suggested that the most
convenient formulation of a single liquid phase
solution was about 76% w/w.
02/03/2023 By Belayneh K. 171

Applications of phase diagram (cont’d)
 This mixture has a freezing point of about 3.5 oC

compared with liquified phenol, USP, which contains
90% w/w of phenol and freezes at about 17 oC.
 It is not possible, therefore, to use the official
preparation much below 20 oC.
 The formulation proposed by Mulley from consideration
of phenol-water phase diagram is therefore is to be
preferred.
02/03/2023 By Belayneh K. 172

Three component systems (ternary system)
 For three component systems at constant
temperature and pressure, the composition can be
expressed in terms of the coordinates of an
equilateral triangle.
02/03/2023 By Belayneh K. 173

Three component systems………….
 In figure each corner of the triangle represents a
pure component, i.e. 100% A, 100% B and 100% C.
 Each side represents a binary mixture and the
interior represents all ternary compositions.
 A line parallel to one side of the triangle represents a
constant percentage of one component. For e.g., DE
represents 20% A with varying amounts of B and C.
Similarly, line FG represents all mixtures containing
50% of B.
 These lines intersect at K which must be 20% of A,
50% of B, and therefore 30% of C.
02/03/2023 By Belayneh K. 174

Three component systems…………
 In the formulation of pharmaceutical

solutions containing two immiscible
liquids plus a mutually soluble liquid (co-
solvent or blending agent) the triangular
diagram provides a convenient means of
expressing the data.
02/03/2023 By Belayneh K. 175

Interfacial Phenomena
Interfacial phenomena
 Interfacial phenomena in pharmacy and medicine are

significant factors that affect emulsion formation and
stability, the dispersion of insoluble particles in
liquids to form suspensions, adsorption of drugs onto
solid adjuncts in dosage forms, and penetration of
molecules through biological membranes.
 Interface is the boundary between two phases.
 Surface is an interface between liquid and gas or
solid and gas.
02/03/2023 By Belayneh K. 177

Surface/interfacial tension
 In the bulk portion of each phase, molecules are

attracted to each other equally in all directions, such
that no resultant forces are acting on any one
molecule.
 At the boundary between phases, however,
molecules, are acted upon unequally because they
are in contact with other molecules exhibiting
different forces of attraction.
 Thus, molecules situated at the interface experience
interaction forces dissimilar to those experienced in
the bulk phase.
02/03/2023 By Belayneh K. 178
Surface/interfacial tension (cont’d)
02/03/2023 By Belayneh K. 179

Intermolecular forces acting on a molecule
gas
liquid
а, б) – inside the volume of liquid

в) – in the surface layer
 In liquid systems such unbalanced forces can be

satisfied by spontaneous movement of molecules
from the interface to the bulk phase.
 This leaves fewer molecules per unit area at the

interface (greater intermolecular distance) and
reduces the actual contact area between dissimilar
molecules.
02/03/2023 By Belayneh K. 181

 Any attempt to reverse this process by increasing the

area of contact between phases – that is, bringing
more molecules into the interface – causes the
interface to resist expansion and behave as though it is
under tension everywhere in a tangential direction.
 The force of this tension per unit length of interface
generally is called the interfacial tension/surface
tension.
 In the centimeter-gram-second (cgs) system, surface
tension is expressed in units of dynes per centimeter
(dyne/cm).
 In the SI system, interfacial tension is expressed in N/M
02/03/2023 By Belayneh K. 182
02/03/2023 By Belayneh K. 183
Surface free energy
 To move a molecule from the inner layers to the
surface, work needs to be done against the force of
tension.
 In other words, each molecule near the surface of
liquid possesses a certain excess of potential energy
as compared to the molecules in the bulk of the
liquid.
 The higher the surface of the liquid, the more
molecules have this excessive energy.
02/03/2023 By Belayneh K. 184

Surface free energy (cont’d)
 Therefore, if the surface of the liquid increases (e.g.,
when water is broken into a fine spray), the energy of
the liquid also increases.
 Because this energy is proportional to the size of free
surface, it is called surface free energy.
 Each molecule of the liquid, has a tendency to move
inside the liquid from the surface; therefore, the
liquid takes form with minimal free surface and with
minimal surface energy.
02/03/2023 By Belayneh K. 185

Surface free energy (cont’d)
 For example, liquid droplets tend to assume a
spherical shape because a sphere has the smallest
surface area per unit volume.
 The relationship between interfacial tension and
surface energy can be expressed by the following
equation.
• Where, ∆G is change in surface energy, ∆A is change in

surface area and ϒ is surface tension.
02/03/2023 By Belayneh K. 186

Involuntary surface phenomena
Cohesion is the interaction between
molecular inside one phase (homogeneous
system).
Adhesion is the interaction between
molecular inside of the different phases
Spreading
 If a small quantity of an immiscible liquid is placed on
a clean surface of a second liquid, it may spread to
cover the surface with a film or remain as a drop or
lens.
• Which of the two applies depends on the
achievement of a state of minimum free energy.
02/03/2023 By Belayneh K. 188

Spreading (cont’d)
 The ability of one liquid to spread over another

can be assessed in terms of the spreading
coefficient (S):
A positive or zero value of S is required

for spreading to occur.
02/03/2023 By Belayneh K. 189

Adsorption at liquid interfaces
 Certain molecules and ions, when dispersed in the

liquid, move of their own accord to the interface.
 Their concentration at the interface then exceeds
their concentration in the bulk of the liquid.
 Obviously, the surface free energy and surface
tension of the system are automatically reduced.
 Such a phenomenon, where the added molecules are
partitioned in favor of the interface, is termed
adsorption, or more correctly, positive adsorption.
02/03/2023 By Belayneh K. 190

Adsorption at liquid interfaces (cont’d)
 Other materials (e.g., inorganic electrolytes) are

partitioned in favor of the bulk, leading to negative
adsorption and a corresponding increase in surface
free energy and surface tension.
 Adsorption should not be confused with absorption.
 The former is solely a surface effect, whereas in
absorption, the liquid or gas being absorbed
penetrates into the capillary spaces of the absorbing
medium.
02/03/2023 By Belayneh K. 191

Sorption Processes
 Adsorption – the phenomenon of higher concentration of
molecular species on the surface of a solid than in the bulk
 Absorption is the process of arbitrary absorption of the

substance by volume
 Chemisorption - chemical interaction adsorbent with

adsorbate
 Adsorbent – an adsorptive material, such as
activated charcoal
 Adsorbate – an adsorbed substance
 The solid substance on the surface of which
adsorption occurs is known as adsorbent.
 The substances that get adsorbed on the solid
surface due to intermolecular attraction are
called adsorbate.
 The adsorbent may be a solid or a liquid and the
adsorbate may be a gas or a solute in some
solution.
Difference between Adsorption and Absorption
POSITIVE AND NEGATIVE ADSORPTION
Types of adsorption
Surface active agents (surfactants)
 Molecules and ions that are adsorbed at interfaces

are termed surface-active agents (surfactants).
 An alternative term is amphiphile, which suggests
that the molecule or ion has a certain affinity for
both polar and non polar solvents.
 Depending on the number and nature of the polar
and non polar groups present, the amphiphile may
be predominantly hydrophilic (water-loving),
lipophilic (oil-loving), or reasonably well balanced
between these two extremes.
02/03/2023 By Belayneh K. 197
Surface active agents (cont’d)
 For example, straight - chain alcohols, amines, and

organic acids are amphiphiles that change from
being predominantly hydrophilic to lipophilic as the
number of carbon atoms in the alkyl chain increased.
 If a molecule is too hydrophilic, it remains within the
body of aqueous phase and exerts no effect at the
interface.
 Likewise, if it is too lipophilic, it dissolves completely
in the oil phase and little appears at the interface.
02/03/2023 By Belayneh K. 198

The HLB System
 Griffin devised an arbitrary scale of values to serve as
a measure of the hydrophilic-lipophilic balance
(HLB) of surface active agents.
 The HLB scale is a numerical scale extending from 1
to approximately 50.
 The more hydrophilic surfactants have high HLB
numbers (in excess of 10).
 Whereas, surfactants with HLB numbers from 1 to 10
are considered to be lipophilic.
02/03/2023 By Belayneh K. 199

The HLB System (cont’d)
02/03/2023 By Belayneh K. 200

The HLB system and application (cont’d)
 The HLB of polyhydric alcohol fatty acid esters such as glyceryl

monostearate may be obtained from equation
 S is saponification value of the ester and

 A is acid value of the fatty acid
 S is the weight in mg of KOH required to saponify 1 g of
fat or oil
 A is the weight in mg of KOH required to react with 1 g of
fatty acid.
• Note this formula can also be used to determine HLB of
polysorbates and sorbitan esters
02/03/2023 By Belayneh K. 201
 For polysorbates (Tweens®) and sorbitan esters (Spans®)
 E is the percentage by weight of oxyethylene chains
 P is the percentage by weight of polyhydric alcohol

group (sorbitol or glycerol)
 This formula can be also used to determine HLB of
beeswax and lanolin derivative

 Polysorbates (Tweens)
02/03/2023 By Belayneh K. 202
 Calculation of HLB of a polysorbate

o For example, Polysorbate 20 has a molecular weight
of approximately 1300 and contains 20 oxyethylene
groups and two sorbitan rings.
HLB = (68 + 14)/ 5 = 16.4
02/03/2023 By Belayneh K. 203

 Alternatively, HLB value can be calculated by
02/03/2023 By Belayneh K. 204

Matching HLB values to application needs
• mixing unlike oils together
– use surfactants with HLB’s of 1 to 3
• making water-in-oil emulsions
• wetting powders into oils
• making self emulsifying oils
• making oil-in-water emulsions
– use surfactant blends with HLB’s of 8 to16
• making detergent solutions
• for solubilizing oils (micro-emulsifying) into water
– use surfactant blends with HLB’s of 13 to 18
Adsorption at solid interfaces
 The study of adsorption of gases on solids arises in
such diverse applications as the removal of
objectionable odors from rooms and foods, the
operation of gas masks, and the measurement of
the dimension of particles in a powder.
 The principles of solid-liquid adsorption are used in
decolorizing solutions, adsorption chromatography,
detergency, and wetting.
02/03/2023 By Belayneh K. 206

Adsorption at solid-gas interfaces
 The degree of adsorption of a gas by a solid depends
on the chemical nature of the adsorbent( the
material used to adsorb the gas) and the adsorbate
( the substance being adsorbed), the surface area of
the adsorbent, the temperature, and the partial
pressure of the adsorbed gas.
 The types of adsorption are generally recognized as
physical or van der Waals adsorption and chemical
adsorption or chemisorption.
02/03/2023 By Belayneh K. 207

Adsorption at solid-gas interfaces (cont’d)
 Physical adsorption, associated with van der Waal

forces, is reversible, the removal of the adsorbate
from the adsorbent is known as desorption.
 For example, physically adsorbed gas can be
desorbed from a solid by increasing temperature and
reducing the pressure.
 Chemisorption, in which the adsorbate is attached to
the adsorbent by primary chemical bonds, is
irreversible unless the bonds are broken.
02/03/2023 By Belayneh K. 208

 The relationship between the amount of gas
physically adsorbed on a solid and the equilibrium
pressure or concentration at constant temperature
yields an adsorption isotherm.
 The term isotherm refers to a plot at constant
temperature.
 The number of moles, grams, or milliliters, x, of gas
adsorbed on, m, grams of adsorbent at standard
temperature and pressure is plotted on the vertical
axis against the equilibrium pressure of the gas in
mmHg on the horizontal axis is shown on the next
slide
02/03/2023 By Belayneh K. 209
Type I isotherm
02/03/2023 By Belayneh K. 210

Adsorption isotherms
02/03/2023 By Belayneh K. 211

 Freundlich suggested a relationship, the Freundlich
isotherm,
where y is the mass of gas, x, adsorbed per unit

mass, m, of adsorbent, and K and n are constants
reflecting adsorption affinity and capacity.
 The equation is handled more conveniently when
written in logarithmic form
02/03/2023 By Belayneh K. 212

 Langmuir developed an equation based on the
theory that molecules or atoms of gas are adsorbed
on active sites of a solid to form a layer one molecule
thick (monolayer).
 The fraction of centers occupied by gas molecules at
pressure P is represented by θ, and fraction of sites
not occupied is 1- θ.
 The rate, r1 , of adsorption or condensation of gas
molecules on the surface is proportional to the
unoccupied spots, 1- θ, and to the pressure, P, or
 r1 = K1(1- θ)p …………………….1
02/03/2023 By Belayneh K. 213
(cont’d)
 The rate, r2 ,of evaporation(desorption) of molecules
bound on the surface is proportional to the fraction
of surface occupied, θ, or r2 = k2θ ………………………2
 At equilibrium, r1 = r2 or
K1(1- θ)p = k2θ ………………………3
 By rearrangement, we obtain
……………4
02/03/2023 By Belayneh K. 214

(cont’d)
 We can replace K1/k2 , by b and θ by y/ym , where y is
the mass of gas adsorbed per gram of adsorbent at
pressure p and at constant temperature and ym is the
mass of gas that 1 g of the adsorbent can adsorb
when the monolayer is complete.
 Inserting these terms into equation (4 ) produces the
formula
………….5 ( Langmuir isotherm)
02/03/2023 By Belayneh K. 215

(cont’d)
 By inversing equation (5), and multiplying through by
p, we can write this for plotting as
………………6
 A plot of p/y against p yield a straight line, and ym

and b can be obtained from the slope and intercept.
02/03/2023 By Belayneh K. 216

• For multilayer adsorption, Langmuir equation was
modified by Brunauer, Emmett and Teller (BET equation)
• Where
p is pressure of the adsorbate at which the mass, y, of
vapor per gram of adsorbent is adsorbed
po is vapor pressure when the adsorbent is saturated with
adsorbate vapor,
ym is the quantity of the vapor adsorbed per unit mass of
adsorbent when the surface is covered with
monomolecular layer
02/03/2023 By Belayneh K. 217

 b is a constant proportional to the difference

between the heat of adsorption of the gas in the first
layer and the latent heat of condensation of successive
layers
 The saturation vapor pressure po is obtained by

bringing excess adsorbate in contact with the
adsorbent.
02/03/2023 By Belayneh K. 218

Solubility and
Distribution
Phenomena
Introduction
• A fundamental understanding of factors

affecting solubility is important to the
pharmacist, not only because many drugs are
formulated as solution dosage forms, but also
because, regardless of dosage form a drug must
be in solution form to be biologically active.
• Thus an understanding of the forces
responsible for solubility and the rate of
dissolution are very important concepts in
pharmacy
02/03/2023 By Belayneh K. 221
Terminologies
 A solute is a substance which is being dissolved
 A solvent is a substance which dissolves the solute.
 Solubility is defined in quantitative terms as the
concentration of solute in a saturated solution at a
certain temperature and in a qualitative way, it can
be defined as the spontaneous interaction of two or
more substances to form homogenous molecular
dispersion.
02/03/2023 By Belayneh K. 222

Introduction
• A solution is a chemically and physically
homogenous mixture of two or more substances.
• The term solution generally denotes a homogenous
mixtures that is liquid, even though it is possible to
have homogenous mixtures that are solid or gases.
• Thus, it is possible to have solutions of solids in
liquids, liquid in liquids, gases in liquids, gases in
gases, and solids in solids.
• The first three of these are most important in
pharmacy
02/03/2023 By Belayneh K. 223
Solubility Expressions
• The solubility of a drug may be expressed in a
number of ways: for example, weight of
solute per weight of solvent, weight of solute
per volume of solvent, weight of solute per
volume of solution, and weight of solute per
weight of solution
• The US pharmacopeia & National formulary
lists the solubility of drugs as the number of
milliliters of solvent in which 1 gm of solute
will dissolve.
02/03/2023 By Belayneh K. 224
Table: Quantitative solubility expressions
Expression Symbol Definition
Molarity M,C Moles (gram molecular weight) of solute in 1 liter of solution
Normality N Gram equivalent weights of solute in 1 liter of solution

Molality m Moles of solute in 1000 gm of solvent
Mole fraction X,N Ratio of the moles of one constituent (e.g. the solute) of a
solution to the total moles of all constituents (solute &
solvent)
Mole percent Moles of one constituent in 100 moles of the solution; mole
percent is obtained by multiplying mole fraction by 100
Percent by weight %w/w Grams of solute in 100 gm of solution
Percent by volume %v/v Milliliters of solute in 100 ml of solution
Percent weight in %w/v Grams of solute in 100ml of solution

volume
Milligram percent
02/03/2023
milligrams of solute in 100ml of solution
By Belayneh K. 225
Table: Terms to approximate solubility expressions
Term Parts of solvent required for one part of

solute
Very soluble less than 1 part
Freely soluble 1 to 10 parts
Soluble 10 to 30 parts
Sparingly soluble 30 to 100parts
Slightly soluble 100 to 1000 parts
Very slightly soluble 1000 to 10,000 parts
Practically insoluble or more than 10,000 parts

insoluble
02/03/2023 By Belayneh K. 226
Solvent –Solute interactions
 On the basis of the force of interaction occurring in

solvents one may broadly classify solvents as one of
three types
 Polar solvent- those made up of strong dipolar
molecules having hydrogen bonding (e.g., water or
hydrogen peroxide)
 Semi polar solvents- those also made up of
strong dipolar molecules but that do not form
hydrogen bonds (e.g., acetone and pentyl alcohol)
 Non polar solvents- those made up of molecules
having a small or no dipolar character( benzene,
vegetable oil, or mineral oil)
02/03/2023 By Belayneh K. 227
 Polar solvents
 In brief, polar solvents such as water act as
solvents according to the following
mechanisms:
1) Owing to their high dielectric constant,
namely about 80 for water, polar solvents
reduce the force of attraction between
oppositely charged ions in crystals such as
sodium chloride.
02/03/2023 By Belayneh K. 228

2) Polar solvents break covalent bonds of potentially
strong electrolytes by acid-base reactions because
these solvents are amphiprotic.
 For example, hydrogen chloride dissolves in water and
functions as an acid
HCl + H2O  H3O+ + Cl-
 Polar solvents are capable of solvating molecules and
ions through dipole interaction forces, particularly
hydrogen bond formation, which leads to the
solubility of the compound (the solvent and solute
are capable of being coupled through hydrogen bond
formation).
02/03/2023 By Belayneh K. 229
Cont …
 The solubility of the low-molecular - weight alcohols
in water, for example, is attributed to the ability of
the alcohol molecules to become part of a water-
alcohol association complex.
 As the molecular weight of the alcohol increases, it
becomes progressively less polar and less able to
compete with water molecules for a place in the
lattice-like arrangement formed through hydrogen
bonding
02/03/2023 By Belayneh K. 230

Cont …
 When the number of carbon atoms in a
normal alcohol reaches five, its solubility in
water is reduced significantly.
 When the number of hydroxyl groups in the

alcohol is increased, its solubility in water
generally is increased greatly;
02/03/2023 By Belayneh K. 231

Cont …
 It is principally, if not entirely, for this reason
that such high molecular weight compounds
as sugars, gums, many glycosides, and
synthetic compounds such as the polyethylene
glycols are very soluble in water.
• Although nitrogen is less electronegative than
oxygen, and thus tends to form weaker
hydrogen bonds, amines are at least as soluble
as alcohols containing an equivalent chain
length.
02/03/2023 By Belayneh K. 232
Cont …
 The reason for this is that alcohols form two
hydrogen bonds with a net interaction of 12
kcal/mol. Primary amines can form three hydrogen
bonds; two amine protons are shared with the
oxygen of two water molecules, and the nitrogen
accepts one water proton
 The net interaction for primary amine is between 12
and 13 kcal/mol; hence, it show an equal or greater
solubility compared with corresponding alcohols.
02/03/2023 By Belayneh K. 233

Cont …
• When an ionic salt is dissolved (e.g., by water),
the process of solution involves separation of
the cations and anions of the salt with
attendant orientation of molecules of the
solvent about the ions.
• Such orientation of solvent molecules about
the ions of the solute – a process called
solvation (hydration, if the solvent is water),
whereby the dipoles of the solvent are
attracted to and held by the ions of the solute.
02/03/2023 By Belayneh K. 234
Cont …
• The solvent must also posses the ability
to keep the solvated, charged ions apart
with minimal energy.
Non polar solvents
• The solvent action of non polar liquids,
such as the hydrocarbons, differs from
that of polar substances.
02/03/2023 By Belayneh K. 235

Non polar solvents
• Non polar solvents are unable to
reduce the attraction between the ions
of strong and weak electrolytes
because of the solvents low dielectric
constants.
02/03/2023 By Belayneh K. 236

Non polar solvents
 Nor can the solvents break covalent bonds
and ionize weak electrolytes, because they
belong to the group known as aprotic
solvents, and they cannot form hydrogen
bridges with non-electrolytes.
 Hence, ionic and polar solutes are not soluble
or are only slightly soluble in non polar
solvents.
02/03/2023 By Belayneh K. 237

Cont …
 Non polar solvents can dissolve, in
general, other non polar substances in
which the bonds between molecules are
weak.
 The forces involved usually are of the
induced dipole-induced dipole type.
Such is the case when one hydrocarbon
is dissolved in another, or an oil or a fat is
dissolved in petroleum ether.
02/03/2023 By Belayneh K. 238
Cont …
 Sometimes it is observed that semipolar
substances, such as alcohol, will dissolve in a
nonpolar liquid, such as benzene.
 This apparent exception to the proceeding
generalization may be explained by the
assumption that the alcohol molecule induces a
temporary dipole in the benzene molecule which
forms an association complex with the solvent
molecules.
 A binding force of this kind is referred to as a
dipole-induced dipole force.
02/03/2023 By Belayneh K. 239
Semi polar solvents
• Semi polar solvents, such as ketones and alcohols, can
induce a certain degree of polarity in non polar solvent
molecules, so that, for example, benzene, which is
readily polarizable, becomes soluble in alcohol.
• In fact, semi polar compounds can act as intermediate
solvents to bring about miscibility of polar and non
polar liquids.
• Accordingly, acetone increases the solubility of ether in
water.
• Propylene glycol has been shown to increase the
mutual solubility of water and peppermint oil and of
water and benzyl benzoate.
02/03/2023 By Belayneh K. 240
Some useful generalizations about solubility
 The greater the structural similarity between solute

and solvent, the greater the solubility
( “Like dissolves like”)
 Organic compounds containing polar groups capable
of forming hydrogen bonds with water are soluble in
water, provided that the molecular weight of the
compound is not too great.
 The polar groups OH, CHO, COH, CHOH, CH2OH,
COOH, NO2, NH2, and SO3H tend to increase the
solubility of an organic compound in water.
02/03/2023 By Belayneh K. 241

Some useful generalizations about solubility
 Non polar or very weak polar groups, such as the
various hydrocarbon radicals, reduce solubility in
water; the greater the number of carbon atoms in
the radical, the greater the decrease in solubility.
 Introduction of halogen atoms into a molecule in
general tends to decrease solubility in water because
of an increased molecular weight without a
proportionate increase in polarity.
02/03/2023 By Belayneh K. 242

Some useful generalizations ……..
 The greater the number of polar groups contained
per molecule, the greater the solubility of a
compound in water; provided that the size of the rest
of the molecule is not altered; thus pyrogallol is
much more soluble in water than phenol.
 The relative positions of the groups in the molecule
also influence solubility; thus, in water resorcinol (m-
dihydroxybenzene) is more soluble than catechol(o-
dihydroxybenzene), and the latter is more soluble
than hydroquinone (p-dihydroxybenzene).
 Polymers and compounds of high molecular weight
can be poorly soluble.
02/03/2023 By Belayneh K. 243
Some useful generalizations ……..
 High melting points frequently are indicative of

low solubility for organic compounds.
 One reason for high melting points is the
association of molecules, and this cohesive forces
tends to prevent dispersion of the solute in the
solvent.
 The cis form of an isomer is more soluble than
trans form.
 Acids, especially strong acids, usually produce
water-soluble salts when reacted with nitrogen-
containing organic bases.
02/03/2023 By Belayneh K. 244
Solubility of gases in liquids
• Pharmaceutical solutions of gases include:

– hydrochloric acid,
– effervescent preparations containing carbon
dioxide that are dissolved & maintained in solution
under positive pressure.
– Aerosol products in which the propellant is either
carbon dioxide or nitrogen, some of which is
dissolved under pressure
 The solubility of a gas in a liquid is the concentration
of the dissolved gas when it is in equilibrium with
some of the pure gas above the solution.
02/03/2023 By Belayneh K. 245
Factors affecting the solubility of gases in
liquids
Effect of pressure
 The pressure of a gas above the solution is an
important consideration in gaseous solutions
because it changes the solubility of the dissolved gas
in equilibrium with it.
 The effect of the pressure on the solubility of a gas is
expressed by Henry’s law, which states that:
“in a very dilute solution at constant temperature,
the concentration of dissolved gas is proportional to
the partial pressure of the gas above the solution at
equilibrium”.
02/03/2023 By Belayneh K. 246
Cont …
The partial pressure of the gas is obtained by
subtracting the vapor pressure of the solvent from the
total pressure above the solution.
If C2 is the concentration of the dissolved gas in grams
per liter of solvent & p is the partial pressure in
millimeters of the undissolved gas above solution,
Henry’s relationship can be written as:
C2 = σp
In which σ is the inverse of the Henry’s Law constant,
k. it is sometimes referred to as the solubility
coefficient.
02/03/2023 247
Cont …
 Effect of temperature
• Temperature also has a marked influence on
the solubility of a gas in a liquid.
• As the temperature increases, the solubility of
most gases decreases owing to the greater
tendency of the gas to expand.
• Solutions of gases are potentially dangerous
when exposed to warm temperature because
of the libration and expansion of dissolved gas
which may cause the container to burst.
02/03/2023 By Belayneh K. 248
Cont …
Effect of temperature…..
 The pharmacist exercise caution in opening
containers of gaseous solutions in warm climates
& under other conditions of temperatures.
 A vessel containing a gaseous solution or a liquid
with a high vapor pressure such as ethyl nitrite,
and strong ammonia solution should be
immersed in ice or cold water for some time to
reduce the temperature & pressure of the gas
before opening the container.
02/03/2023 By Belayneh K. 249

Cont …
 Effect of adding salt
• Gases are often liberated from solutions in
which they are dissolved by the introduction
of an electrolyte such as sodium chloride &
sometimes by a non electrolyte such as
sucrose.
– This phenomenon is known as salting out.
• The salting out effect can be demonstrated
by adding a small amount of salt to a
“carbonated” solution.
02/03/2023 By Belayneh K. 250
Cont …
 Effect of adding salt………
• The resultant escape of gas is due to the
attraction of salt ions or the highly polar non
electrolyte for the water molecules which
reduces the density of the aqueous
environment adjacent to the gas molecules
and therefore, reduce the solubility of the
gas.
• Salting out effect can also occur in solutions
of liquids in liquids and solids in liquids.
02/03/2023 By Belayneh K. 251
Cont …
 Effect of chemical reaction

• Henry’s law applies strictly to gases that are
only slightly soluble in solution & that do not
react in any way in the solvent.
• Gases such as hydrogen chloride, ammonia &
carbon dioxide show deviations as a result of
chemical reaction between the gas & solvent,
usually with a resultant increase in solubility.
• Accordingly, hydrogen chloride is about
10,000 times more soluble in water than is
oxygen.
02/03/2023 By Belayneh K. 252
Solubility of liquids in liquids
 Frequently two or more liquids are mixed together
in the preparation of pharmaceutical solutions. For
example:
• Alcohol is added to water to form hydroalcoholic
solutions
• Volatile oils are mixed with water to form dilute
solutions known as aromatic waters
• Volatile oil are added to alcohol to yield spirits and
elixirs
• Various fixed oils are blended into lotions, sprays
and medicated oils.
02/03/2023 By Belayneh K. 253
Ideal and Real solutions
Ideal solutions
• An ideal solution is a solution in which:
– there is no change in the properties of the
components, other than dilution, when they are
mixed to form the solution.
– No heat is evolved or absorbed during the mixing
process, and
– the final volume of the solution represents and
additive property of the individual constituents.
Stated another way, no shrinkage or expansion
occurs when the substances are mixed.
02/03/2023 By Belayneh K. 254
Ideal and Real solutions
Ideal solutions
– Uniformity of intermolecular forces
– Irrespective of the volume of the solute and
solvent they are miscible to each other
– Obey Raoult’s law over the whole range of
composition
– Mixtures of benzene + toluene, n-hexane +
n-heptane and ethyl bromide + ethyl iodide
are commonly mentioned systems that
exhibit ideal behaviour
02/03/2023 By Belayneh K. 255
Raoult’s law
“In ideal solution, the partial vapor pressure of each

volatile constituent is equal to the vapor pressure of
the pure constituent multiplied by its mole fraction in
the solution”.
Thus, for two constituents A and B,
PA = PA0XA
PB = PB0XB
• Where PA and PB are the partial vapor pressures of
the constituents over the solution when the mole
fraction concentrations are XA and XB.
• The vapor pressures of the pure components are PA0
and PB0 respectively. By Belayneh K.
02/03/2023 256
Raoult’s law
 Total pressure is the sum of the pressures
of the two components
Example, Total pressure in a mixture of toluene

(b.p. = 110.6ºC) and benzene (b.p. = 80.1ºC)
equals sum of vapor pressures of components
02/03/2023 By Belayneh K. 257

Raoult’s law…….
• In ideal solution, when liquid A is mixed with

liquid B, the vapor pressure of A is reduced by
dilution with B in a manner depending on the
mole fractions of A and B present in the final
solution.
• This will diminish the escaping tendency of
each constituent, leading to a reduction in the
rate of escape of the molecules of A and B
from the surface of the liquid.
02/03/2023 By Belayneh K. 258

Cont …
Real (Non ideal) solutions
• Ideality in solutions assumes complete uniformity of
attractive forces.
• Many examples of solution pairs are known, however, in
which the “cohesive” attraction of A for A exceeds the
“adhesive” attraction existing between A and B may be
greater than those between A and A or B and B.
• Such mixtures are real or non ideal; that is, they do not
adhere to Raoult’s law throughout the entire range of
composition.
• Two types of deviation from Raoult’s law are Recognized,
negative and positive deviation.
02/03/2023 By Belayneh K. 259
Cont …
Negative Deviation
• Like ideal gas law, Raoult’s Law works for an ideal
solution
• Occurs when the “adhesive” attractions between
molecules of different species exceed the
“cohesive” attractions between like molecules,
the vapor pressure of the solution is less than
that expected from Raoult’s ideal solution law.
• If the deviation is sufficiently great, the total
vapor pressure curve shows a minimum.
02/03/2023 By Belayneh K. 260

Cont …
Negative Deviation
• The dilution of constituent A by addition of B normally
could be expected to reduce the partial vapour
pressure of A; this is the simple dilution effect
embodied in Raoult’s law.
• In the case of liquid pairs that show negative deviation
from the law, however, the addition of B to A tends to
reduce the vapor pressure of A to a greater extent
than can be accounted for by the simple dilution
effect,
– e.g. chloroform and acetone solution.
02/03/2023 By Belayneh K. 261

Cont …
Positive deviation
• When the interaction between A and B
molecules is less than between molecules of
the pure constituents, the presence of B
molecules reduces the interaction of the A
molecules, and A molecules correspondingly
reduce the B-B interaction.
• Accordingly, the dissimilarity of polarities or
internal pressures of the constituents results in
a greater escaping tendency of both the A and
the B molecules.
02/03/2023 By Belayneh K. 262
Cont …
Positive deviation
• The partial vapor pressure of the constituents is
greater than that expected from Raoult’s law, and
the system is said to exhibit positive deviation.
• The total vapor pressure often shows a maximum at
one particular composition if the deviation is
sufficiently large.
• Liquid pairs that demonstrate positive deviation are
– benzene and ethyl alcohol,
– carbon disulfide and acetone, and
– chloroform and ethyl alcohol.
02/03/2023 By Belayneh K. 263
Cont …
• Liquid –liquid systems can be divided into

two categories according to the solubility
of the substances in one another
– Complete miscibility and,
– Partial miscibility.
• The term miscibility refers to the mutual
solubilities of the components in liquid-
liquid systems.
02/03/2023 By Belayneh K. 264
Cont …
• Two liquids are considered "immiscible" or

unmixable if shaking equal volumes of the
liquids together results in a meniscus visible
between two layers of liquid.
• If the liquids are completely immiscible, the
volumes of the liquid layers are the same as
the volumes of liquids originally added to the
mixture.
02/03/2023 By Belayneh K. 265

Cont …
Complete Miscibility
• Polar and semi polar solvents, such as water
and alcohol, glycerin and alcohol, and alcohol
and acetone, are said to be completely
miscible because they mix in all proportions.
• Non polar solvents such as benzene and CCl4
are also completely miscible.
• Completely miscible liquid mixtures in general
create no solubility problems for the
pharmacist and need not be considered
further.
02/03/2023 By Belayneh K. 266
Cont …
 Partial Miscibility
• The mutual solubility’s of partially miscible liquids
are influenced by concentration & temperature.
• In a system such as phenol & water, the mutual
solubilities of the two conjugate phases increase
with temperature until, at the critical solution
temperature (or upper consolute temperature), the
compositions become identical.
• At this temperature, a homogeneous or single
phase system is formed.
02/03/2023 By Belayneh K. 267

Cont …
• In the case of some liquid pairs, the

solubility can increase as the
temperature is lowered, and the system
will exhibit a lower critical solution
temperature, below which the two
members are soluble in all proportions
and above which two separate layers
form.
02/03/2023 By Belayneh K. 268

Lower critical temperature
02/03/2023 By Belayneh K. 269

Cont …
 Another type, involving a few mixtures

such as nicotine and water, shows both
an upper and lower critical temperature
with an intermediate temperature region
in which the two liquids are only partially
miscible.
02/03/2023 By Belayneh K. 270

Upper and lower critical temperature
02/03/2023 By Belayneh K. 271

Cont …
 A final type exhibits no critical solution

temperature; the pair ethyl ether and water,
for example, has neither an upper nor a lower
critical temperature and shows partial
miscibility over the entire temperature range
at which the mixture exists.
02/03/2023 By Belayneh K. 272

Solubility of solid in liquid
 Solubility and heat of solution
 When a solute (Solute A) dissolves in some solvent,
two steps may be considered as occurring: the solid
absorbs energy to become liquid and then the liquid
dissolves.
A(solid)  A (liquid)  A(solution)
 For the overall dissolution, the equilibrium existing
between solute molecules in the solid and solute
molecules in solution may be treated as an
equilibrium.
 Thus, for Solute A in equilibrium with its solution,
A(solid)  A(solution)
02/03/2023 By Belayneh K. 273
Solubility and heat of solution
 Using the Law of mass action, an equilibrium
constant for this system can be defined and
may be written as:
where alpha denotes the activity of the solute

in each phase. Because the activity of solute is
defined as unity, Keq= α(solution)
02/03/2023 By Belayneh K. 274

 Because the activity of a compound in dilute
solution is approximated by its concentration,
and because this concentration is saturated
solubility, Ks, the Van’t Hoff equation may be
used, which defines the relationship between an
equilibrium constant (here, solubility) and
absolute temperature.
02/03/2023 By Belayneh K. 275

 Where dlogKs/dT is the change of logKs with
a unit change of absolute temperature, T;
is a constant that, in this situation is the heat of
solution for the over all process (solid liquid
solution); R is gas constant, 1.99 cal/mol/deg
where j is constant
02/03/2023 By Belayneh K. 276

 A more useful form of the above equation is
where Ks1, is the saturation solubility at absolute

temperature T1, and Ks2 is the solubility at
temperature T2
 Through the use of this equation, if and the
solubility at one temperature are known, the
solubility at any other temperature can be
calculated
02/03/2023 By Belayneh K. 277
 As evident from this equation
the solubility of a solid in a liquid depends
on temperature.
 In the process of solution, if heat is
absorbed (as evidenced by reduction in
temperature), is by convention positive
and the solubility of the solute will
increase with increasing temperature.
02/03/2023 By Belayneh K. 278

Solubility of solid in liquid……Cont’d
 If the solute gives off heat during the process
of solution (as evidenced by an increase in
temperature), by convention, is negative
and solubility decreases with an increase in
temperature.
 When heat is neither absorbed nor given off,
the solubility is not affected by variation of
temperature.
02/03/2023 By Belayneh K. 279

Solubility of strong and slightly soluble electrolytes
 Strong electrolytes are soluble in polar

solvents
 But many important drugs belong to the
class of weak acids and bases
 They react with strong acids and bases
and, within definite ranges of pH, exist as
ions that are ordinarily soluble in water
02/03/2023 By Belayneh K. 280

Solubility of strong and slightly soluble
electrolytes
 Although carboxylic acids containing more
than five carbons are relatively insoluble in
water, they react with dilute sodium
hydroxide, carbonates, and bicarbonates to
form soluble salts.
The fatty acids containing more than 10
carbon atoms form soluble soaps with the
alkali metals and insoluble soaps with other
metal ions.
02/03/2023 By Belayneh K. 281

electrolytes
 They are soluble in solvents having low dielectric
constant; for example, oleic acid( C17H33COOH) is
insoluble in water but is soluble in alcohol and ether
 Hydroxy acids, such as tartaric acid and citric acids,
are quite soluble in water because they are solvated
through their hydroxyl groups
 Aromatic acids react with dilute alkalies to form
water soluble salts, but they can be precipitated as
the free acids if stronger acidic substances are
added to the solution
02/03/2023 By Belayneh K. 282

electrolytes
 Phenol is weakly acidic and only slightly
soluble in water but is quite soluble in dilute
sodium hydroxide solution
C6H5OH + NaOH  C6H5O- + Na+ + H2O
Many organic compounds containing a basic
nitrogen atom in the molecule are important in
pharmacy.
These include the alkaloids, sympatomimetic
amines, antihistamines, local anesthetics and
others.
02/03/2023 By Belayneh K. 283
electrolytes
 Most of these weak electrolytes are not soluble
in water but soluble in dilute solutions of acids;
such compounds as atropine sulfate and
tetracycline hydrochloride are formed by
reacting the basic compounds with acids.
Addition of alkali to a solution of the salt of
these cpds precipitates the free base from
solution if the solubility of the base in water is
low.
02/03/2023 By Belayneh K. 284

Solubility of weak electrolytes (calculating the
solubility as influenced by PH)
 It becomes evident that the solubility of weak
electrolytes is strongly influenced by the pH of the
solution.
 For example, a 1% solution of phenobarbital sodium
is soluble at pH values high in the alkaline range.
The soluble ionic form is converted into molecular
phenobarbital as the pH is lowered, and below 9.3,
the drug begins to precipitate from solution at room
temperature.
 On the other hand, alkaloidal salts such as atropine
sulphate begin to precipitate as the pH is elevated .
02/03/2023 By Belayneh K. 285
Solubility of weak electrolytes (calculating
the solubility as influenced by PH)
 To ensure a clear homogenous solution and
maximum therapeutic effectiveness, the
preparations should be adjusted to an optimum
pH
 The pH below which the salt of a weak acid,
sodium phenobarbital, for example, begins to
precipitate from aqueous solution is readily
calculated in the following manner.
02/03/2023 By Belayneh K. 286

 Representing the free acidic form of

phenobarbital as HP and the soluble ionized
form as P- we write the equilibra in a
saturated solution of this slightly soluble
weak electrolye as
HPsolid  HPso l ….………………….1
HPsol + H20  H3O+ + P- ……………2
02/03/2023 By Belayneh K. 287

 Because the concentration of the unionized
form in solution, HPso l, is essentially
constant, the equilibrium constant for the
solution equilibrum, is
So = [HP]sol …………………3
where So is molar or intrinsic solubility.

The constant for the acid-base equilibrium is,
02/03/2023 By Belayneh K. 288
………………4
or
…………………5
 The total solubility, S, of phenobarbital consists of

the concentration of the undissociated acid, [HP],
and that of the conjugate base or ionized form,
[P-]:
02/03/2023
S= [HP] + [P -
] By…………………6
Belayneh K. 289
 Substituting So for [HP] from equation 3 and
the expression from equation 5 for [P-] yields
……………….7
………………8
02/03/2023 By Belayneh K. 290

 When the electrolyte is weak and does not dissociate
appreciably, the solubility of the acid in water or
acidic solution is S = [HP], which, for phenobarbital
is approximately 0.005 mol/lit, in other words, 0.12%
 The solubility equation can be written in logarithmic
form, beginning with equation 7. By rearrangement,
we obtain
log (S-So) = log Ka +log So – log[H3O+]
02/03/2023 By Belayneh K. 291

and finally
pHp is the pH below which the drug separates

from solution as the undissociated acid.
02/03/2023 By Belayneh K. 292

Solubility of weak electrolytes (calculating the
solubility as influenced by PH)
 An analogous derivation can be carried out to
obtain the equation for the solubility of a weak
base as a function of the pH of a solution. The
expression is
Where S is the concentration of the drug initially

added as the salt and So is molar solubility of the
free base in water.
 Here pHp is the pH above which the drug begin to
precipitate from solution as the free base
02/03/2023 By Belayneh K. 293
The influence of solvents on the solubility
of drugs
 Frequently, a solute is more soluble in a mixture
of solvents than in one solvent alone.
 This phenomenon is known as cosolvency .
 The solvents that in combination increase the
solubility of solute are called cosolvents.
 Approximately, 1 g of phenobarbital is soluble in
1000 ml of water, 10 ml of alcohol, in 40 ml of
chloroform, and 15 ml of ether at 25 oC
02/03/2023 By Belayneh K. 294

Solubility of solid in liquid……Cont’d
 Figure below shows the solubility of phenobarbital
in a mixture of water, alcohol and glycerin at 25 oC
 For example, at 22% alcohol, 40% glycerin, and the
remainder water (38% ), 1.5% w/v of phenobarbial
is dissolved.
02/03/2023 By Belayneh K. 295

Influence of surfactants
 Surfactants (surface-active agents) are molecules
characterized by having two distinct regions in their
chemical structure; these are termed hydrophilic
‘water-liking’) and hydrophobic (‘water-hating’)
regions.
 The existence of two such moieties in a molecule is
referred to as amphipathy and the molecules are
consequently often referred to as amphipathic
molecules.
02/03/2023 By Belayneh K. 296

Influence of surfactants (cont’d)
 The hydrophobic portions are usually saturated or
unsaturated hydrocarbon chains or, less commonly,
heterocyclic or aromatic ring systems.
 The hydrophilic regions can be anionic, cationic,
zwitterionic, or nonionic.
 Surface-active agents reduce interfacial tension
existing between insoluble solid and the liquid;
thereby facilitate solubilization process.
02/03/2023 By Belayneh K. 297

Influence of solid state (polymorphs,
amorphous, solvates)
 Polymorphs are crystalline substances that exist in
more than one crystalline forms with different space
lattice arrangements.
 Solvates are crystalline solids which contain liquid
molecules in their structure.
 If the solvent of crystalization is water the crystal is
called as hydrate.
 If the crystallization conditions are changed in any
way, it is possible that the molecules may start to
form crystals with a different packing pattern from
that which occurred when the original conditions were used.
02/03/2023 By Belayneh K. 298
Influence of solid state (cont’d)
 The change in conditions could be a different

solvent, or a change in the stirring, or different
impurities being present.
 Polymorphs show differences in solubility,
melting point, density, crystal shape, optical,
electrical properties and vapour pressure.
 In general there is a correlation between the
melting point of the different polymorphs and
solubility.
 Polymorphs with high melting points have low
solubility
02/03/2023 By Belayneh K. 299
Influence of solid state (cont’d)
 Hydrates often have very different properties

from the anhydrous form, in the same way as
two different polymorphs have different
properties from each other.
 With hydrates it is possible for the hydrate form
to have either a higher or a lower solubility than
the anhydrous form.
02/03/2023 By Belayneh K. 300

Distribution of solutes between immiscible solvents
 If an excess of liquid or solid is added to a mixture

of two immiscible liquids, it will distribute it self
between the two phases so that each become
saturated.
 If the substance is added to the immiscible solvents
in an amount insufficient to saturate the solution, it
will still become distributed between the two layers
in a definite concentration ratio.
02/03/2023 By Belayneh K. 301

Distribution of solutes (cont’d)
 If C1 and C2 are the equilibrium concentrations of

the substance in Solvent1 and Solvent2 , respectively,
the equilibrium expression becomes:
……………………….(1)
 The equilibrium constant, K, is known as the
distribution ratio, distribution coefficient, or
partition coefficient.
 Equation 1 is known as distribution law
02/03/2023 By Belayneh K. 302

Distribution of solutes (cont’d)
 Knowledge of partition is important to the

pharmacist because the principle is involved in
several areas of current pharmaceutical interest.
 These include preservation of oil-water system,

drug action at receptor site, the absorption and
distribution of drugs throughout the body.
02/03/2023 By Belayneh K. 303

Packaging & storage of
pharmaceuticals
02/03/2023 By Belayneh K. 304

Objectives
• At the end of the this session you will know
about:
• What is packaging ?
• Functions of packaging
• Importance of packaging
• Primary and secondary packaging
materials
• Types of glasses
02/03/2023 By Belayneh K. 305
Introduction
What is packaging ?
• Packaging is defined as the collection of
different components which surround the
pharmaceutical product from the time of
production until its use.
• Pharmaceutical formulations must be
contained, protected & labeled from the time
of manufacture until the patient uses them.
02/03/2023 By Belayneh K. 306
Introduction
• Throughout this period the container must maintain

the quality, safety, and stability of the medicine &
protect the product against physical, climatic, chemical
& biological hazards.
• To promote good patient compliance, containers most

be user friendly & in the selection of a container which
is used to pack a pharmaceutical formulation, cost &
the need for both child resistant closures & temper
evident seals should be taken into consideration.
02/03/2023 By Belayneh K. 307
Introduction
Importance of packaging
• Protect against all adverse external influences
that can alter the properties of the product.
• Protect against biological contamination.
• Protect against physical damage.
• Carry the correct information and
identification of the product.
• Tamper evident /Child resistance
02/03/2023 By Belayneh K. 308
Introduction
 Functions of packaging
 Containment
– Not to leak, nor allow diffusion and permeation
– Strong enough to hold the contents during handling
 Protection
– Light
– Moisture
– Oxygen
– Biological contamination
– Mechanical damage
– Counterfeiting
02/03/2023 By Belayneh K. 309

Introduction
 Additional qualities required
• It must preserve the physical properties of all dosage
forms and protect them against damage or breakage.
• It must not alter the identity of the product.
• It must preserve the characteristics properties of the
product to comply specifications.
• It must protect product against undesirable or
adulterating chemical, biological or physical entities.
02/03/2023 By Belayneh K. 310

Primary & secondary packaging
• Primary packaging materials are in direct contact with the
product.
– This also applies to the closure which is also part of primary pack.
• Secondary packages are additional packaging materials that
improve the appearance of the product & include outer
wrappers or labels that do not make direct contact with the
product.
• Secondary packages can also supply information about the
product & its use.
• They should provide evidence of tampering with the
medicine.
02/03/2023 By Belayneh K. 311

The following terms are used to describe containers
• Single dose containers: hold the medicine intended for

single use (glass ampoules).
• Multidose containers: hold a quantity of the material
that will be used as two or more doses (Multiple dose
vial, plastic tablet bottle).
• Because of the risk of contamination of injectable
preparations, USP requires all multiple dose injectables
must contain antimicrobial preservatives
02/03/2023 By Belayneh K. 312

The following terms are used to describe containers
• Well closed containers: protect the product

from contamination with unwanted foreign
materials & from loss of contents during using
period.
• Airtight containers: impermeable to solids,

liquids & gases during storage & use and
remain airtight after use.
02/03/2023 By Belayneh K. 313

Cont …
• Sealed containers: such as glass ampoules are
closed by fusion of the container material.
• Tamper-evident containers: closed containers fitted
with a device that irreversibly indicates if the
container has been opened.
• Light resistance containers: protect the contents
from the effect of radiation at a wavelength b/n 290
& 450 nm.
• Child resistant containers (CRCs): designed to
prevent children accessing the potentially hazardous
product.
02/03/2023 By Belayneh K. 314
The selection of packaging for pharmaceutical
product is dependent on the following factors:
• The nature of the product itself: its chemical activity,
sensitivity to moisture & oxygen, compatibility with
packaging materials
• The type of patient: is it to be used by an elderly or
arthritic patient or by a child?
• The dosage form
• Method of administering the medication
• Required shelf life
• Product use, such as for dispensing or for an- over - the
counter product.
02/03/2023 By Belayneh K. 315
Packaging materials
I. Glass
• It is the preferred packaging material for many
pharmaceutical products.
• It is composed principally of silicon dioxide, with
varying amount of other oxides such as sodium,
potassium, calcium, magnesium, aluminum,
boron and iron.
02/03/2023 By Belayneh K. 316

Glass
• The basic structural network of glass is
formed by the silicon dioxide tetrahedron.
• Boric oxide will enter into this structure,
but most other oxides do not.
• The latter are only loosely bound, are
present in the network interstices, and are
relatively free to migrate
02/03/2023 By Belayneh K. 317

Packaging materials……
• The migratory oxides may be leached into a solution in
contact with the glass, particularly during the increased
reactivity of thermal (heat) sterilization.
Glasses have several advantages:
• It is inert to most medicinal products
• It is impervious to air and moisture
• It allows easy inspection of the container contents
• It can be colored to protect contents from light
• It is easy to clean & sterilize by heat
• It is available in variously shaped containers.
02/03/2023 By Belayneh K. 318

The disadvantages of glass:
–It is fragile: glass fragments can be released into
the product during transport or contaminants
can penetrate the product by way of cracks in
the container.
–Certain types of glass release alkali into the
container contents
–It is expensive when compared to the price of
plastic
–It is heavy resulting in increased transport costs
02/03/2023 By Belayneh K. 319

Types of glass containers
 The United States Pharmacopeia (USP) classifies
glass containers as Type I, II, III and NP
according to the amount of alkali released from
glass when attacked by ( or in intimate contact
with water under specified conditions)
02/03/2023 By Belayneh K. 320

Type I
• Also known as neutral or borosilicate glass
• Composed principally of silicon dioxide (~81%) and
boric oxide(~13%), with low levels of the non-network
forming oxides (e.g., sodium and aluminum oxides)
• Possesses a hydrolytic resistance
• The most inert type of pharmaceutical glass(low leach
ability) with the lowest coefficient of thermal
expansion.
• As a result, it is unlikely to crack on exposure to rapid
temperature changes.
02/03/2023 By Belayneh K. 321
• Suitable for packing all pharmaceutical

preparations, however it is expensive & this
restricts its application.
• Widely used as glass ampoules & vials to

package fluids for injection.
• In addition, it is used to package solutions that
could dissolve basic oxides in the glass.
02/03/2023 By Belayneh K. 322

Type II glass
• Made of soda - lime- silica glass with a high

hydrolytic resistance due to surface treatment of
the glass.
• Soda-lime-silica implies made up of sodium
oxide, limestone (Cao) and silica
• The sodium oxide makes the material easy to
process and mould while the calcium oxide
produces a degree of chemical resistance
02/03/2023 By Belayneh K. 323

Type II glass, a soda –lime treated glass
• Type II and Type III glasses are composed

of relatively high proportions of sodium
oxide(~14%) and calcium oxide (~8%)
• While there is no one standard
formulation for glass among
manufacturers of these USP categories,
Type II glass usually has a lower
concentration of migratory oxides than
Type III.
02/03/2023 By Belayneh K. 324
Type III glass
 It is a soda-lime glass
 Usually will be suitable principally for
anhydrous liquids or dry substances
02/03/2023 By Belayneh K. 325

Type II and III glasses
• Both types melt at lower temperature, are
easier to mold into varies shapes and have a
higher thermal coefficient of expansion.
• It is thus easier to produce and consequently
cheaper.
• Type II glass may be suitable, for example, for a

solution that is buffered, or is not reactive with
glass
02/03/2023 By Belayneh K. 326
NP glass type
• It is a soda-lime glass
 Type NP release the highest amount
of alkali
• Must not be used to package
parenteral products but it is suitable
for packaging solid & semisolid
formulations.
02/03/2023 By Belayneh K. 327
• Bottles: these are commonly used in the
dispensary as either amber medical bottles or
ribbed (fluted) oval bottles (50-500ml)
• Dropper bottles: for ear & nasal use
• Jars: For powder & semisolid preparations (15-
500ml)
• Glass ampoules: for parenteral solutions
intended for single use
• Multiple dose vials: for parenteral formulations
that will be used or more than one occasion
02/03/2023 By Belayneh K. 328
Dropper bottles Jars
02/03/2023 By Belayneh K. 329

Glass ampoules Multiple dose vials
02/03/2023 By Belayneh K. 330

 Preparations that are light sensitive must be
protected by placing them in amber glass
container or by enclosing flint glass containers in
opaque carton labeled to remain on the
container during the period of use.
• It should be noted that the amber color of the
glass is imparted by the incorporation of
potentially leachable heavy metals, mostly iron
and manganese, which may act as catalysts for
oxidative degradation reactions.
02/03/2023 By Belayneh K. 331
II. Plastics
• Chemically plastics are synthetic polymers
of high molecular weight
• In more recent times, plastic has been
developed for the packaging of parenteral
products including infusion fluids & small
volume injections.
• Plastics are classified into two groups
according to their behavior when heated.
These are thermoplastics and thermosets
02/03/2023 By Belayneh K. 332
II. Plastics
Thermoplastic types
• On heating, these soften to a viscous fluid
which hardens again on cooling
• Their hardness when cold is influenced by

the degree of cross-linkage or
intermolecular attraction between the
long-chain molecules.
02/03/2023 By Belayneh K. 333

II. Plastics
Thermosetting types
 When heated, these may become flexible
but they do not become fluid; usually their
shape is retained right up to the
temperature of decomposition.
 Because of a high degree of cross-linking

they are usually hard and brittle at room
temperature.
02/03/2023 By Belayneh K. 334
The advantages of plastics for packaging
• Release few particles into the product

• Are flexible & not easily broken
• Are of low density & thus light in weight
• Can be heat sealed
• Are easily moulded into various shapes
• Are suitable for use as container, closure, & as
secondary packaging
• Are cheap
02/03/2023 By Belayneh K. 335

The disadvantages of plastics are that:
• They are not as chemically inert as type I glass

• Some plastics undergo stress cracking & distortion from
contact with some chemicals
• Some plastics are heat sensitive
• They are not as impermeable to gas & vapor as glass
• They may possess an electrostatic charge which will
attract particles
• Additives in the plastic are easily leached into the product
• Substances such as the active drug & preservatives may
be taken from the product.
02/03/2023 By Belayneh K. 336
Additives used in plastic containers include:
Plastic pharmaceutical containers are made of at

least one polymer together with additives such as:
– Plasticizers
– Resins
– Stabilizers
– Lubricants
– Antistatic agents
– Mould - release agents
02/03/2023 By Belayneh K. 337

Additives used in plastic containers
 Lubricants
 Lubricants are used to assist processing of plastic during
the molding or extrusion operation, facilitating flow in
contact with metal surfaces (e.g., zinc stearate)
 Stabilizers
 Stabilizers are used to retard or prevent degradation of
the polymer by heat and light during manufacturing as
well as to improve its ageing characterstics
 Antioxidants
 Are special type of stabilizer used to retard oxidation, by
inhibiting formation of free radicals.
02/03/2023 By Belayneh K. 338
Additives used in plastic containers include:
 Plasticizers
 Are used to achieve softness, flexibility and melt flow
during processing
 Antistatic agents
 Are used to prevent the buildup of static charge on the
plastic surface
 Slipping agents
 Are used primarily to polyethylene and polypropylene
to reduce coefficient of friction of the material
 Dyes and pigments are added to impart color
02/03/2023 By Belayneh K. 339
Metals
 Materials used for various pharmaceutical
packaging include aluminum and tinplate.
• Tinplate is a steel composite material that uses a

steel core coated with tin.
• Aluminum and tinplate cans need to be coated or

painted with an organic lining to separate the
product from bare metal.
02/03/2023 By Belayneh K. 340
Metals……………cont’d
 General properties
 Metal is strong, opaque, and impermeable to
moisture, gases, odors, light, bacteria, etc.
 Metal is resistant to high and low temperatures
 Metal is malleable and ductile
Disadvantage
 Metal is not inert and can be attacked by acids
and alkalis.
 It will corrode unless coated or lacqured.
02/03/2023 By Belayneh K. 341
Paper and paperboard
 Paper and paperboard are composed of cellulose
obtained by the mechanical or semi-chemical
treatment of vegetable fibers(pulp) derived from
various sources like wood, hemp, cotton, etc.
• Paper is always treated, coated, laminated or
impregnated with materials such as waxes, resins or
lacquers when used as primary packaging to improve
functional and protective properties.
02/03/2023 By Belayneh K. 342

Paper and paperboard…….cont’d
• Wood usually consists of 50% cellulose fibers,
30% lignin, 16% carbohydrates, and 4% others,
such as proteins, resins, and fats
• Having all the properties combined,

paperboard is thicker than paper and in
multiple layers with high weight per unit
area.
02/03/2023 By Belayneh K. 343
Paper and paperboard…….cont’d
 Paper and paperboard products are non toxic, low cost,
and from a natural renewable source.
 These cellulose products have good rigidity and
strength, but properties change according to moisture
content (fibers expand or contract).
 They are readily printable by virtually all processes.
 The finished products are generally opaque but can be
translucent.
02/03/2023 By Belayneh K. 344

Closures
• Any closure system should provide an effective

seal to retain the container contents & exclude
external contaminants.
• Child- Resistant Containers (CRCs) commonly
consist of a glass or plastic vial or bottle with a
specially designed closure.
• The CRCs closures in common use with dispensed
medicines are the snap-safe® alignment closure
and the push down & turn Clic-loc® closure.
02/03/2023 By Belayneh K. 345
Closures (cont’d)
• The Clic-loc® closure are based on the assumption

that young children are unable to coordinate two
separate and dissimilar actions; that is, applying
pressure and rotating the closure top.
02/03/2023 By Belayneh K. 346

child resistant & tamper-evident closures
02/03/2023 By Belayneh K. 347

Closures (cont’d)
• In recent years greater awareness of the

vulnerability of products has led to the
development of tamper-evident closures.
• The closures indicate if unlawful access to

the container contents has occurred & are
currently available in various designs
suitable for different containers & closures.
02/03/2023 By Belayneh K. 348
Collapsible tubes
• These are used to contain viscous and liquid

based topical products.
• With this package, the tube remains collapsed
as the product is removed.
• They usually are constructed of metal or metal-
lined LDPE
02/03/2023 By Belayneh K. 349

Collapsible tubes (cont’d)
• Metal tubes are airtight, light-proof and

impermeable and offer superior protection
• Plastic tubes are light-weight, leak-proof,
and relatively non breakable.
• In contrast to collapsible metal tubes that
flatten as the product is removed, plastic
tubes retain their original shape after
squeezing.
02/03/2023 By Belayneh K. 350

Unit Dose Packaging
• This term usually means that a single item
such as a tablet or capsule or a specific
dose is enclosed within its own disposable
packaging.
• The most commonly used methods for unit-
dose packaging are:
blister packs &
strip packs
02/03/2023 By Belayneh K. 351
Blister packs
• These are used for packaging unit doses of
tablets and capsules and can act as an aid for
patient compliance.
• The medication is placed in a compartment in a
base material made of paper, paperboard,
plastic or metal foil or a combination of these.
02/03/2023 By Belayneh K. 352

Blister packs (cont’d)
• The blister is generally composed of a thermo

formed plastic such as PVC.
• Perforations in this material allow individual
sections of the package to be broken off.
• Blister packs are rigid unlike strip packs that
are flexible.
02/03/2023 By Belayneh K. 353

Strip packaging
• With strip packaging, two webs of material
sandwich various types of medicine such as
tablets, capsules, suppositories or pessaries.
• Each of these dosage forms is contained within
its own compartment.
• Aluminum foil is commonly used to manufacture
strip packs & provides a good barrier against
moisture penetration.
02/03/2023 By Belayneh K. 354

Labeling pharmaceutical dosage forms
• The label on dispensed medicines has two main
functions.
– To uniquely identify the contents of the container
– To ensure that patients have clear & concise
information which will enable them to take or use
their medicine in the most effective &
appropriate way.
• It should be noted that provision of an adequate
label does not remove the need to counsel the
patient.
02/03/2023 By Belayneh K. 355
Labeling pharmaceutical dosage forms
The label of a pharmaceutical product must be in the right place and
contain the right information. The following need to be taken into
consideration:
Appearance
• Correct position
• Clean
• Secure
Information should be:
•Legible
•Concise
•Adequate
•Intelligible
•Accurate
02/03/2023 By Belayneh K. 356
Information given on the label
• Name and strength of the preparation: The official name

(Pharmacopoeial name) of the dosage form should be mentioned
 For example: “ Simple Ointment BP”
• Quantitative particulars
 Quantitative particulars are not required if the product is
official
• Product-specific cautions (or additional labelling requirements)
E.g., ‘shake the bottle before use’
• Directions for use
 interpretation of Latin abbreviations where necessary e.g.
‘Apply as directed’
02/03/2023 By Belayneh K. 357
Information given on the label (cont’d)
 Additional information:
 the name and address of the manufacturer or
pharmacy and the words
‘Keep out of the reach of children’
 Manufactured date
 Expiry date
 Batch number
02/03/2023 By Belayneh K. 358

Storage & stability of Pharmaceuticals
• Medicines do not keep indefinitely. Some can be
kept for only a short time. There are many reasons
why this is the case.
• In 1984, Rhodes listed six general causes for the
limited time for which medicines can be kept.
These are:-
– Loss of drug (such as hydrolysis or oxidation)
– Loss of vehicle (such as evaporation of water or other
volatile ingredient)
– Loss of uniformity (such as caking of a suspension or
creaming of an emulsion)
02/03/2023 By Belayneh K. 359
Storage & stability of Pharmaceuticals (cont’d)
– Change in bioavailability (particularly with tablets

where ageing can reduce availability), change of
appearance (such as color changes)
– Appearance of toxic or irritant products (as a result of
chemical change)
• There is a need to specify storage conditions and
shelf life to ensure effective stock control and pay
attention to the packaging used in dispensing.
• It is also useful to be able to offer advice to a
patient where a medicine has been kept at a
correct temperature.
02/03/2023 By Belayneh K. 360
Storage conditions
• These include phrases like ‘protect from moisture’,
‘protect from light’, etc, which are described as
being non mandatory. Thus they are recommended
rather than being required.
• With commercial products, the manufacturer will
specify any special storage requirements on the
packaging.
• Some products require storage at low temperature.
• A refrigerator should be between 2 & 80C.

• A cool place is between 8 & 150C.
02/03/2023 By Belayneh K. 361
Storage conditions (cont’d)
• Patients must be given adequate information
about the storage of their medicines.
• The label should state the storage conditions

required & be backed up by a verbal reminder,
especially where it is out of the normal.
• It should also be remembered that there are legal

storage requirements in the pharmacy, such as a
lockable cabinet for controlled drugs.
02/03/2023 By Belayneh K. 362
Pharmaceutical solutions
Introduction
 A solution is a homogenous mixture that is prepared
by dissolving a solid, liquid, ogroup of preparations r
gas in another liquid and represents a in which the
molecules of the solute or dissolved substance are
dispersed among those of the solvent.
 Most solutions are unsaturated with the solute, in

other words, the concentration of the solute in the
solution is below its solubility limit.
02/03/2023 By Belayneh K. 364

Introduction (cont’d)
 The strengths of pharmaceutical solutions are usually
expressed in %strength, although for very dilute
preparations ratio strength are sometimes used.
 Solutions may be classified on the basis of physical or
chemical properties, method of preparation, use,
physical state, number of ingredients and particle size.
 For the pharmacist, solutions are more defined by site
of administration and composition than by
physicochemical definitions.
02/03/2023 By Belayneh K. 365

 For instance, pharmaceutical solutions may be

classified as an oral solution, otic solution,
ophthalmic solution or topical solution.
02/03/2023 By Belayneh K. 366

Solutions can be formulated for different routes of
administration
Orally: Syrups, elixirs, drop
In mouth and throat: Mouth washes, gargles, throat
sprays
In body cavities: Douches, enemas, ear drops, nasal
spray
On body Surfaces: Collodions, lotions
Parenterals: small and large volume IV fluids, …
2/3/23 By Belayneh K. Department of Pharmacy 367
 Advantages of solution dosage forms:
 Easier to swallow than solids
 Particularly acceptable for pediatric and
geriatrics
 Therapeutic response of the drug is fast from
solutions than solid dosage forms
 Uniform (even) dosing is possible
 Minimized irritation effect of some drugs( e.g.,
aspirin, KCl)
Solution dilutes immediately with gastric fluid
02/03/2023 By Belayneh K. 368

 Disadvantages of solution dosage forms:

 Bulky and inconvenient to transport and store
 The stability of ingredients in aqueous solution is
often poorer than if formulated as a tablet or
capsule, (particularly if they are susceptible to
hydrolysis)
 May support microbial growth and hence require
incorporation of preservatives
 Bad test of drugs can be felt
02/03/2023 By Belayneh K. 369

Terms of solution
 A saturated solution: a solution that contains the
maximum amount of a solute that will dissolve in a given
solvent, at a specific temperature.
 An unsaturated solution: A solution that contains less
solute than the capacity of solvent to dissolve.
 A supersaturated solution: A solution that contains
more solute than is present in a saturated solution.

Formulation of solutions
 Solution formulations contain several ingredients in
addition to drugs such as:
 Solvents
 Buffers
 Density modifiers
 Isotonicity modifiers
 Viscosity enhancement
 Preservatives
 Reducing agents and antioxidants
 Sweetening agents
 Flavors' and perfumes, colures
02/03/2023 By Belayneh K. 371

Solvents
 Aqueous solutions
 Water is the solvent most widely used as a vehicle for
pharmaceutical products, because of its physiological
compatibility and lack of toxicity.
 Types of pharmaceutical water
 Potable water
• Is drinking water, drawn freshly from a main supply
• It should be palatable and safe for drinking
• Its chemical composition may include mineral impurities
which could react with drugs, e.g., the presence of calcium
carbonate in hard water
02/03/2023 By Belayneh K. 372

Solvents (cont’d)
 Purified water
 Freshly boiled & cooled potable water, normally
prepared by the distillation or deionization of
potable water or by the process of reverse osmosis.
• Distilled water is purified water that has been
prepared by distillation.
 Water for preparations
 Is potable or freshly boiled and cooled purified water,
which can be used in oral or external preparations
which are not intended to be sterile.
02/03/2023 By Belayneh K. 373
Solvents (cont’d)
 The boiling removes dissolved oxygen and carbon

dioxide from solution in the water.
 Water for injection (WFI)

 Pyrogen-free distilled water, sterilized immediately
after collection and used for parentral products.
 The European pharmacopoeia permits distillation as
the process for producing WFI.
02/03/2023 By Belayneh K. 374

Solvents (cont’d)
 Aromatic water
 Are near-saturated aqueous solution of volatile oils or
other aromatic or volatile substances, and are often
used as a vehicle in oral solutions.
 Although water is very widely used for inclusion in

pharmaceutical preparations, it may not be possible to
ensure complete solution of all ingredients at all
normal storage temperatures.
02/03/2023 By Belayneh K. 375

Solvents (cont’d)
 The solubility of a weak electrolyte or non-polar

compound in water can often be improved by
altering the polarity of the solvent.
 This can be achieved by the addition of another
solvent that is both miscible with water and in which
the compound is also soluble.
 Vehicles used in combination to increase the
solubility of a drug are called cosolvents.
02/03/2023 By Belayneh K. 376

Solvents (cont’d)
 The choice of suitable co solvents is somewhat

limited for pharmaceutical use because of possible
toxicity and irritancy, particularly if required for oral
or parenteral use.
 Ideally, suitable blends should possess values of
dielectric constant between 25 and 80.
 The most widely used system that will cover this
range is a water/ethanol blend.
 Other suitable solvents for use with water include
glycerol, propylene glycol and isopropyle alcohol
02/03/2023 By Belayneh K. 377

Solvents (cont’d)
 Non-aqueous solutions
 If it is not possible to ensure complete solution of the
ingredients at all storage temperatures, or if the drug
is unstable in aqueous systems it may be necessary
to use an alternative, non-aqueous solvent.
 It is essential that, in choosing a suitable solvent, its
toxicity, irritancy and sensitizing potential are taken
into account, as well as its flammability, cost,
stability and compatibility with other excipients.
02/03/2023 By Belayneh K. 378

Solvents (cont’d)
 Fixed oils of vegetable origin
• These are non-volatile oils that consist mainly of fatty
acid esters of glycerol.
• For example, almond oil, arachis oil, olive oil, sesame
oil, maize oil, cottonseed oil, soya oil and castor oil
 Alcohols
 Ethyl alcohol is the most widely used solvent in this class
 Ethanol as solvent is next in importance to water
02/03/2023 By Belayneh K. 379

Solvents (cont’d)
 Ethanol is widely used for its miscibility with water and
its ability to dissolve many water insoluble ingredients
including drug substances, flavors, and antimicrobial
preservatives.
 Ethanol is rarely used for internal preparations but is
useful solvent for external preparations.
 An advantage of ethanol is that growth of
microorganisms does not occur in solutions containing
alcohol in reasonable concentration (> 15%).
02/03/2023 By Belayneh K. 380

Solvents (cont’d)
• In OTC products the USP limits ethanol content

limit of 0.5% for children under 6 years old.
• Products intended for children 6 to 12 years of
age, the recommended limit is 5%.
• For products recommended for children over
12 years of age and for adults, the
recommended limit is 10%.
02/03/2023 By Belayneh K. 381

Solvents (cont’d)
 Glycerin
• Is an excellent solvent, although its range is not as
extensive as that of water or alcohol.
• In higher concentrations (above 20%) it has
preservative action.
• It is viscous and miscible both with water and alcohol
• It dissolves fixed alkalis, salts, vegetable acids,
pepsin, tannin, and some active principles of plants,
gums, soluble carbohydrates, and starch
• It may be added as a stabilizer and sweetener in
internal preparations.
02/03/2023 By Belayneh K. 382

Solvents (cont’d)
 Propylene glycol
 Which has been used widely as a substitute for
glycerin, is miscible with water, acetone, or
chloroform in all proportions
 Less viscous liquid and a better solvent than glycerin.
 It is soluble in ether and will dissolve many essential
oils but immiscible with fixed oils.
 It is claimed to be as effective as ethanol in its power
of inhibiting mold growth and fermentation.
 Propylene glycol act as preservative in the range of
15% to 30%.
02/03/2023 By Belayneh K. 383
Solvents (cont’d)
 Isopropyl alcohol
 Possesses solvent properties similar to those of
ethanol and is used instead of ethanol in a number of
pharmaceutical manufacturing operations.
 It has the advantage in that the commonly available
product contains not over 1% water, whereas
ethanol contains about 5% water, often a
disadvantage
 It is used in some liniment and lotion preparations
 It should not be taken internally
02/03/2023 By Belayneh K. 384

Solvents (cont’d)
 Dimethylsulphoxide (DMSO)
 This is a highly polar compound and is thought to aid
the penetration of drugs through the skin.
 Although used mainly as a solvent for veterinary
drugs, it is used as a carrier for idoxuridine, an
antiviral agent, for application to human skin.
 Ethyl ether
 This material is widely used for the extraction of
crude drugs, but because of its own therapeutic
activity it is not used for the preparation of
formulations for internal use.
 It is, however, used as a cosolvent with alcohol in
some collodions. By Belayneh K. 385
Solvents (cont’d)
 Liquid paraffin (mineral oil, liquid petrolatum)

 Often used as a solvent for the topical application of
drugs in emulsion formulations.
 Miscellaneous solvents
 Isopropyl myristate and isopropyl palmitate (in
cosmotics)
 Dimethylformamide and dimethylacetamide (in
veterinary formulations)
 Xylene( in ear drops)
 Kerosene (in insecticide formulations)
02/03/2023 By Belayneh K. 386

Buffers
 Resist any change in pH when an acid or an alkali be
added.
 The choice of suitable buffer depends on the pH and
buffering capacity required.
 Most pharmaceutically acceptable buffering systems
are based on carbonates, citrates, gluconates,
lactates, phosphates or tartrates.
 Borates can be used for external application, but not
to mucous membranes or to abraded skin.
02/03/2023 By Belayneh K. 387

Buffers (cont’d)
1. Lactic acid 1.
2. Gluconic acid 2.
3. Sodium Citrate 3.
4. Tartaric acid 4.
02/03/2023 By Belayneh K. 388
Buffers (cont’d)
 As the pH of most body fluids is 7.4, products such as
injections, eye drops and nasal drops should, in
theory, be buffered at this value to avoid irritation.
 Many body fluids themselves, however, have a
buffering capacity and, when formulating low volume
intravenous injections or eye drops, a wide pH range
can be tolerated.
 This is potentially useful should a compromise be
necessary when choosing a pH that is physiologically
acceptable for a drug whose optimum stability,
solubility and absorption may depend on different
pHs.
02/03/2023 By Belayneh K. 389
Isotonicity modifiers
 Solutions for injection, for application to mucous
membranes, and large-volume solutions for
ophthalmic use must be made iso-osmotic with
tissue fluid to avoid pain and irritation.
 The most widely used isotonicity modifiers are
dextrose and sodium chloride.
 Isotonicity adjustments can only be made after the
addition of all other ingredients, because each
ingredient will contribute to the overall osmotic
pressure of a solution.
02/03/2023 By Belayneh K. 390

Viscosity enhancers
 Low viscous solutions will not remain in place on the
skin or eyes for any significant time.
 To counteract this effect, low concentrations of
gelling agents can be used to increase the apparent
viscosity of the product.
 For example, polyvinyl pyrolidone (povidone),
hydroxyethylcellulose, carbomer, etc.
02/03/2023 By Belayneh K. 391

Preservatives
• Substances used in liquid & semisolid preparations to
prevent growth of microorganisms.
• liquid & semisolid preparations which provide excellent
growth media for microbes are most aqueous
preparations, especially syrups, emulsions, suspensions
& among semisolid preparations are creams
• Certain hydroalcoholic & most alcoholic preparations
may not require the addition of a chemical preservative
when the alcoholic content is sufficient to prevent
microbial growth.
• In general, an alcohol content of 15% by weight in acid
solutions and 18% by weight in alkaline solutions is
sufficient to prevent microbial
02/03/2023 By Belayneh K.
growth. 392
Preservative (cont’d )
• Most alcohol containing preparations such as
elixirs, spirits, and tinctures are self-preserving
and will not require preservation.
• Syrups can be preserved by the maintenance
of a high concentration of sucrose as part of
the formulation (sucrose kills microorganisms
by its osmotic effect).
02/03/2023 By Belayneh K. 393

Preservatives (cont’d)
Examples of preservatives:
Acids (e.g., Benzoic acid, boric acid);
Alcohol (e.g., chlorobutanol);
Esters (e.g., methylparabens, ethylparaben,
propylparaben, buthylparaben)
Quaternary ammonium compounds (e.g.,
benzalkonium chloride)
 Phenols & chlorinated phenolic compounds
 Mercurials ( e.g., thiomersal)
02/03/2023 By Belayneh K. 394

Preservatives (cont’d)
 When choosing a suitable preservative it must
be ensured that:
 adsorption of the preservative onto the
container from the product does not occur,
 its efficiency is not impaired by the pH of the
solution or by interactions with other
ingredients.
02/03/2023 By Belayneh K. 395

Density modifiers
 Density adjustment or modification is
important in formulating spinal anesthetics.
 Solutions of lower density than cerebrospinal
fluid will tend to rise after injection and those
of higher density will fall.
 The most widely used material for density
modification is dextrose.
02/03/2023 By Belayneh K. 396

Antioxidants
 The decomposition of pharmaceutical products by
oxidation can be controlled by antioxidants.
 Vitamins, essential oils, and almost all fats and oils
can be oxidized.
 Antioxidants: Ascorbic acid, Ascorbyl palmitate,
Butylated hydroxyanisole (BHA), Butylated
hydroxyltoluene (BHT), sodium metabisulfite
(Na2S2O5) etc.
02/03/2023 By Belayneh K. 397

Sweetening agents
• There is often a correlation between the chemical structure
of a compound and its taste.
• Low molecular weight salts tend to taste salty whereas
higher molecular weight salts tend toward bitterness.
• Nitrogen containing compounds, such as the alkaloids, tend
to be quite bitter.
• Organic compounds containing hydroxyl groups tend to
become increasingly sweet as the number of OH groups
increase.
• Organic esters, alcohols, and aldehydes are known for their
pleasant taste and cool sensation produced by their
volatility
02/03/2023 By Belayneh K. 398

Sweetening agents (cont’d)
 Used to impart sweetness to a preparation.
 Sucrose is traditionally the most widely used
sweetening agent.
 Mask the tastes of both salty and bitter drugs
 A soothing effect on the membranes of the throat
 Disadvantage: Cariogenic(tooth decay)

 Polyhydric alcohols: sorbitol, mannitol and
glycerol (lesser extent) are incorporated in
preparations for diabetic use
02/03/2023 By Belayneh K. 399
 Others less widely used sweeteners include:
maltilol, lactilol, isomalt, fructose and xylitol.
• Treacle, honey and liquorice are now very rarely
used:
 Some applications in extemporaneously
prepared formulations.
 Artificial sweeteners
 Can be used in conjunction with sugars and alcohols
or by their own for patients who must restrict their
sugar intake.
02/03/2023 By Belayneh K. 400
 They are also termed intense sweeteners because,
weight for weight, they are hundreds and even
thousands of times sweeter than sucrose.
• Only about six artificial sweeteners are permitted for
oral use within the European Union.
• The most widely used being the sodium saccharin and
calcium saccharin.
• Less widely used are aspartame (E951), which is a
compound of L-aspartic acid and L-phenylalanine,
acesulfame potassium (E950), thaumatin (E957),
sodium cyclamate (E952) and neohesperidine DCE959).
02/03/2023 By Belayneh K. 401
Flavours and perfumes
 The simple use of sweetening agents may not
be sufficient to render palatable a product
containing a drug with a particularly
unpleasant taste.
 In many cases, therefore, a flavouring agent
can be included.
 This is particularly useful in pediatric
formulation to ensure patient compliance.
02/03/2023 By Belayneh K. 402

Types of flavoring agents
• Natural flavor: Anise oil, cinnamon oil, cocoa,
menthol, orange oil, peppermint oil, vanillin
• Artificial flavor: Any substance used to impart
flavor that is not derived from a spice or
natural source
• Spice: Any aromatic vegetable substance in
whole, broken or ground form except
substances traditionally regarded as foods
such as onion, garlic or celery.
02/03/2023 By Belayneh K. 403
02/03/2023 By Belayneh K. 404
Coloring agents
 After choosing a suitable flavor, it is often
useful to include a colour associated with that
flavour in order to:
 Improve product attractiveness and
 Enable easy product identification
 Types of coloring agents: natural and artificial.
 Natural:
 Example, Carotenoids, chlorophylls, saffron, red
beetroot extract, caramel & cochineal, iron oxide
02/03/2023 By Belayneh K. 405

Coloring agents
 Saffron Caramel
 cochineal
02/03/2023 By Belayneh K. 406

Coloring agents (cont’d)
 Artificial coloring agents:
Amaranth ( also known as FD and C Red Number
2)
Coal tar dyes
sodium salts of sulphonic acids
02/03/2023 By Belayneh K. 407

Injectables (sterile products)
• Are sterile solutions for injection into the body
• These are subdivided into:
– Small volume parenteral fluids
– Large volume parenteral fluids
• Small volume parenterals are sterile, pyrogen
free injectable products.
• They are packed in volumes up to 100 mL.
• Small volume parenterals are packed as:
– Single dose ampoules
– Multiple dose vials
02/03/2023 By Belayneh K. 408

General method of preparation
• Most solutions are prepared by simply mixing of
the solutes with the solvent.
• For both small and large scale manufacture of
solutions the only equipment necessary is suitable
mixing vessels, a means of agitation & a filtration
system to ensure clarity of the final solution.
• During preparation, the solute is simply added to
the solvent in a mixing vessel & stirring is
continued until dissolution is complete.
02/03/2023 By Belayneh K. 409

02/03/2023 By Belayneh K. 410
Cont…
• If the solute is more soluble at elevated
temperature, it may be advantageous to apply
heat to the vessel particularly if the
dissolution rate is normally slow.
• Size reduction of solid materials to increase
their surface area also speed up the process of
solution.
02/03/2023 By Belayneh K. 411

Methods to speed up dissolution of the
solute
– Applying heat
– Reducing the particle size of the solute
– Using a solubilizing agent
– Subjecting the ingredients to vigorous
agitation
02/03/2023 By Belayneh K. 412

Pharmaceutical suspensions
Quiz
02/03/2023 By Belayneh K. 414

Disperse system
• Liquid preparations containing
undissolved or immiscible drug
distributed throughout a vehicle.
• In these preparations, the substance

distributed is referred to as the
dispersed phase, and the vehicle is
termed the dispersing phase or
dispersion medium.

Dispersion system consist of
(1)- particulate matter (dispersed phase)
(2)- continuous medium (dispersion medium)
Classification of dispersed systems (based on particle
size)
1 Molecular < 1 nm Oxygen molecules,
dispersion glucose solution
2 Colloidal 1nm- 0.5 Natural polymers

dispersion µm
3 Coarse > 0.5 µm Suspension and
dispersion emulsion

What is suspension dosage form?
 A pharmaceutical suspension is a coarse dispersion
in which insoluble solid particles are dispersed in a
liquid medium.
 Suspensions are a class of disperse systems in which
finely divided drug particles are distributed
uniformly throughout a vehicle in which the drug
exhibits a minimum degree of solubility.
• The finely divided solids (disperse phase) are also
called internal phase or discontinuous phase
• The vehicle (dispersion medium) is also called
continuous phase or external phase .
02/03/2023 By Belayneh K. 417
• According to the particle size of the dispersed
phase, suspensions are divided into:
 Coarse suspension: which is a dispersion of particles
with a mean diameter greater than 1 µm.
 Colloidal suspension is a dispersion of particles with
a mean diameter less than 1 µm.
• A suspension containing particles between 1 nm
to 0.5 µm in size is called colloidal suspension.
• When the particle size is between 1 to 100 µm,
the suspension is called coarse suspension.
02/03/2023 By Belayneh K. 418

• Most of the pharmaceutical suspensions are
coarse suspension.
• Majority of the marketed suspensions are
available as dry powders that must be
reconstituted before administration but
occasionally some products in the market are
ready-to-use.
• The first products are not very stable once
reconstituted; must be used within 7 to 10
days.
02/03/2023 By Belayneh K. 419

• The particles of the dispersed phase vary widely in
size, from large visible particles to colloidal
dimensions.
• Most pharmaceutical suspensions consist of an
aqueous dispersion medium, although organic or
oily liquids are also used in some instances.
• When the particles constituting the internal phase
of the suspension are therapeutically active, the
suspension is known as pharmaceutical suspension
02/03/2023 By Belayneh K. 420

Introduction.....cont’d
 Based on the intended route of drug delivery,
pharmaceutical suspensions can be broadly classified
as:
 Parenteral suspensions (e.g., antidiarrheal susps
(I.M.); anticancer susps (I.V.)
 Topical suspensions ( e.g.,lotions)
 Oral suspensions ( e.g., oral antacid susps, oral
antibacterial susps)
02/03/2023 By Belayneh K. 421

Pharmaceutical application of suspensions
Why suspensions?
Against solid dosage forms:
• If patient has a difficulty of swallowing solid dosage
forms (a need for oral liquid dosage form).
• Faster rate of dissolution and oral absorption than
solid dosage forms, yet slower than solutions.
• Bulky insoluble powders as kaolin or chalk are
better formulated as suspensions so that they are
easier to take.

Against solutions:
• Drugs that have very low solubility are usefully formulated as
suspensions.
• Drugs that have an unpleasant taste in their soluble forms (e.g.,
chloramphenicol (soluble) vs. chloramphenicol palmitate
(insoluble )).
• Prolongation of effect (e.g. I.M and S.C. suspensions).
Stability and instability issues:
 Insoluble forms of drugs may prolong the action of a drug by
preventing rapid degradation of the drug in the presence of water
(e.g., Oxytetracycline hydrochloride (soluble, hydrolyses rapidly) vs
oxytetracycline calcium salt (insoluble, stable).
 Non-aqueous suspensions (tetracycline hydrochloride in coconut oil)
 Reconstitution (ampicillin suspension).

Properties of a good pharmaceutical suspension
• There is ready redispersion of any sediment which

accumulates on storage.
• After gentle shaking, the medicament stays in
suspension long enough for a dose to be accurately
measured.
• The suspension is pourable.
• Particles in suspension are small and relatively
uniform in size, so that the product is free from a
gritty texture.

• The dispersed particles should not settle readily and the
settle should redispersed immediately on shacking.
• Ideally, the particles in a suspension should not
sediment at any time during the storage period.
• Unfortunately, the present technology does not allow us
to prepare such a suspension.
• Since one cannot completely avoid the sedimentation of
particles, it is desirable that the particles should settle
slowly.
• The easy redispersion of sedimented particles in a
suspension is important for the uniformity of dose.

• The particle should not form a cake on settling
• The viscosity should be such that the preparation
can be easily poured.
• A highly viscous suspension would make pouring
difficult.
• It should be chemically and physically stable
• It should be palatable (orally)
• It should be free from gritting particles (external
use)

Examples of Pharmaceutical Suspensions:
Antacid oral suspensions
Antibacterial oral suspension
Dry powders for oral suspension (antibiotic)
Analgesic oral suspension
Anthelmentic oral suspension
Anticonvulsant oral suspension
Antifungal oral suspension


What are the pharmaceutical applications of
suspensions?
 For people who have difficulty of swallowing
solid dosage forms ( e.g., pediatrics and
geriatrics).
If a drug is insoluble or poorly soluble in
conventional, safe vehicles (e.g., water, syrup,
hydroalcoholic mixtures, water and glycerin
blends) to provide the desired dose in 5 to 15
mL volumes.
02/03/2023 By Belayneh K. 428
 Drugs that have unpleasant test in their soluble form
can be made into insoluble derivatives, and
formulated as a suspension.
 For example, chloramphenicol (soluble) has bitter test but
chloramphenicol palmitate (slightly soluble) does not.
 paracetamol suspension (more palatable)
 Suspension form of a drug can be used to increase
stability of a drug
 e.g., Oxytetracycline hydrochloride tablet
(soluble in aqueous solution) hydrolyses rapidly
 Oxytetracycline calcium (insoluble) is stable in
suspension
02/03/2023 By Belayneh K. 429
 Drugs which degrade in aqueous solution may
be suspended in a non-aqueous liquids.
for example, tetracycline hydrochloride is suspended
in a fractionated coconut oil for ophthalmic use.
phenoxymethypencillin/ coconut oil
 Suspensions are also used to prolong the release
of drug (e.g., Suspensions in the form of
intramuscular or subcutaneous injections).
02/03/2023 By Belayneh K. 430

To mask the taste:
Examples are paracetamol suspension (more palatable) and
chloramphenicol palmitate.
Some materials are needed to be present as finely
divided forms to increase the surface area.
For example, Mg carbonate and Mg trisilcate are used to
adsorb some toxins
Suspension can be used topical applications:
An example is calamine lotion Bp  after evaporation of
dispersing media; the active agent will be left as light deposit
Can be used for parentral administration 
intramuscular (i.m.) to control rate of absorption

7. In vaccines Absorbed antigen

Aluminum hydroxide

e.g. Diphtheria and Tetanus vaccines
8. X-ray contrast media: an example is oral and rectal
administration of propyliodone
9. In aerosol  suspension of active agents in mixture of
propellants.

 The disadvantages of pharmaceutical suspensions:
 Pharmaceutical suspensions are thermodynamically
unstable
 The formulation of aesthetic suspension is difficult
 Suspension formulations may be bulky and therefore
difficult for a patient to carry.
 Pharmaceutical suspensions require to be shaked
before use
 Accuracy of dose is likely to be less than with
equivalent solution dosage form
02/03/2023 By Belayneh K. 433

Interfacial properties of suspended particles
 Because suspensions are dispersions of poorly
soluble solids in liquids, the process of
dispersions creates a tremendous increase in
interfacial area between the dispersed
particles and the dispersion medium.
 When considering the interfacial properties of
dispersed particles, two factors must be taken
into account, regardless of whether the
dispersed phase is solid or liquid.
02/03/2023 By Belayneh K. 434
Interfacial properties of suspended
particles…….(cont’d)
 The first relates to an increase in the free
energy of the surface as the particle size is
reduced and the specific surface increased.
 The second deals with the presence of

electrical charge on the surface of dispersed
particles.
02/03/2023 By Belayneh K. 435

Surface free energy
 When solid and liquid materials are reduced in size, they
tend to agglomerate or stick together.
 This clumping, which can occur either in an air or liquid
medium, is an attempt by the particles to reduce the
excess free energy of the system.
 The increase in surface free energy (∆G) is related to
the increase in surface area produced when the mean
particle size is reduced.
 The smaller ∆G is, the more thermodynamically stable is

the suspension of particles.
02/03/2023 By Belayneh K. 436
Electrical properties of suspended particles
 Suspensions contain uncharged particles suspended in
uncharged medium.
 But suspended particles frequently acquire charge
(either a positive or negative).
 Suspended particles acquire charge by two ways:
1. Selective adsorption of a particular ionic species
 It can be from an ion added to the solution (e.g.,
electrolytes added as flocculating agent) or
 Hydroxyl ion from dissociated water (vehicle)
02/03/2023 By Belayneh K. 437

Electrical properties of suspended
particles………..(cont’d)
2. Ionization of groups (such as COOH and NH2)
that may be situated at the surface of particles.
The degree of ionization is a function of pKa
of the molecule and the pH of the
surrounding solution.
02/03/2023 By Belayneh K. 438

Electric double layer
Electric double layer: It is a layer of ions that
appears on the surface of particles due to
adsorbed ions.
02/03/2023 By Belayneh K. 439

Electric double layer………..(cont’d)
 Electric double layer has two layers. The stern layer and
diffuse layer.
 Stern layer is a tightly bound layer which contains solvent and
the counter-ions
o Contains more co-ions than counter-ions, hence
determines the potential at the shear plane
 Diffuse layer
o A layer surrounding the stern layer
o contains more counter-ions than co-ions
o The ions in this layer are relatively mobile
o Electric neutrality occurs where the mobile diffuse layer
ends
02/03/2023 By Belayneh K. 440

 Potential-determining ions (co-ions)
 The ions which are selectively adsorbed on the
surface of particle
 Provides its charge to the particle on which it is
adsorbed
 Counter-ions (gegenions)
Are ions attracted by co-ions on to the surface of the
particle.
They have charge opposite to that of the potential-
determining ions.
02/03/2023 By Belayneh K. 441
02/03/2023 By Belayneh K. 442
 Beyond the diffuse layer the concentration of co- and
counter-ions are equal (i.e., electric neutrality)
 Despite the presence of unequal distribution of charges
in the double layer, the suspension is electrically
neutral.
 Electric potential between the actual or true surface of
the particle and the electro neutral region is referred to
as the surface or electrothermodynamic or Nernst
potential (E)
 Nernst potential is determined by potential
determining ions .
02/03/2023 By Belayneh K. 443
 The potential difference between the shear plane and
the electroneutral region is known as the electrokinetic
or zeta (ζ ) potential.
 Zeta potential governs the degree of repulsion between
adjacent, similarly charged solid dispersed particles.
 If Zeta potential is below a certain value, van der Waals
force, overcome the forces of repulsion and the particles
attach together to form floccules.
 This phenomenon is known as flocculation
02/03/2023 By Belayneh K. 444

Deflocculation and flocculation:
• Deflocculation of particles is obtained when the zeta
potential is higher than the critical value and the
repulsive forces supersede the attractive forces.
• The addition of a small amount of electrolyte reduces
the zeta potential.
• When this zeta potential goes below the critical value,
the attractive forces supersede the repulsive forces and
flocculation occurs.
• Deflocculated suspension: the dispersed solid particles
remain separate and settle slowly.
• However, the sediment that eventually forms is hard to
redisperse and is described as a 'cake' or clay.
Flocculation
 The natural tendency of particles towards aggregation
will determine the properties of a suspension.
 Whether or not a suspension is flocculated or
deflocculated depends on the relative magnitude of
repulsive/attractive forces between particles.
• Flocculated suspension, individual particles aggregate
into clumps or floccules in suspension.
• Because these flocs are larger than individual particles,
sedimentation is more rapid, but the sediment is loose
and easily redispersible.

• Excess flocculation may prevent 'pourability'
due to its effect on rheological properties.
• The ideal is to use either a deflocculated
system with a sufficiently high viscosity to
prevent sedimentation, or controlled
flocculation with a suitable combination of rate
of sedimentation, type of sediment and
pourability.

Non-flocculated
Flocculated
• Particles forms loose • Particles exist as separate
aggregates and form a entities
network like structure • Rate of sedimentation is slow
• Rate of sedimentation is high • Sediment is slowly formed
• Sediment is rapidly formed • Sediment is very closely
• Sediment is loosely packed packed and a hard cake is
and doesn’t form a hard cake formed
• Sediment is easy to redisperse • Sediment is difficult to
• Suspension is not pleasing in redisperse
appearance • Suspension is pleasing in
• The floccules stick to the sides appearance
of the bottle. • They don’t stick to the sides
of the bottle
Flocculation/deflocculation of suspensions
 The forces at the surface of particles affect the degree
of flocculation in suspension.
 Forces of attraction are of the London-van der Waals
type.
 The repulsive forces arise from the interaction of the
electric double layers surrounding each particle.
02/03/2023 By Belayneh K. 449

Flocculation/deflocculation of
suspensions..................(cont’d)
 If the attractive force predominates repulsive force
there is formation of flocs which rapidly settle on the
bottom of containers, the suppernatant separates
from floccules and the suspension appears unsightly.
02/03/2023 By Belayneh K. 450

Flocculation/deflocculation of
suspensions................(cont’d)
 On the other hand, if the repulsive force predominates
attractive force there exists deflocculated particles.
 Deflocculated particles settle slowly. However, they form
hard cake at the bottom of container.
 Disadvantages of deflocculation is formation of a hard cake
upon storage
02/03/2023 By Belayneh K. 451

Sedimentation in suspensions
 The rate at which particles in a suspension
sediment is related to size and density of
suspended particles and density and
viscosity of the dispersion medium.
 Stoke’s law
 Velocity of sedimentation (sedimentation
rate) of a uniform collection of spherical
particles is governed by Stoke’s law.
02/03/2023 By Belayneh K. 452

Sedimentation in suspensions..............(cont’d)
or
v is the terminal velocity (sedimentation rate) in

cm/sec; d is the diameter of the particle in cm;
ρs is the density (g/cm3) of the dispersed
phase; ρo is the densities (g/cm3) of dispersion
medium; g is acceleration due to gravity (980.7
cm/sec2 ); ηo is viscosity of the dispersion
medium in poises (g/cm.sec).
02/03/2023 By Belayneh K. 453
Limitations of Stoke’s law
 The lower limit of particles obeying Stoke’s
equation is about 0.5 µm.
 This is because Brownian movement becomes
significant and tends to offset sedimentation.
 To settle particles with diameter less than 0.5

µm, stronger force must be applied.
 This is accomplished by the use of the
ultracentrifuge, which can produce a force 1
million times that of gravity.
02/03/2023 By Belayneh K. 454
Limitations of Stoke’s law…….(cont’d)
 In centrifuge, the acceleration of gravity is
replaced by where ω is angular velocity
and x is the distance of the particle from the
center of the rotation.
02/03/2023 By Belayneh K. 455

Limitations of Stoke’s law…….(cont’d)
 Stoke’s law holds only if the downward
motion of the particles is not sufficiently rapid
to cause turbulence.
 Valid for dilute pharmaceutical suspensions
containing not more than 2.0% w/v of
dispersed phase.
In dilute suspensions, the particles do not
interfere with one another during
sedimentation, and free settling occurs.
02/03/2023 By Belayneh K. 456
Quantitative expression of sedimentation and flocculation
Sedimentation volume (F) =

Vu = final or ultimate volume of sediment
Vo = total volume of suspension
02/03/2023 By Belayneh K. 457

Quantitative expression of sedimentation and
flocculation……(cont’d)
 F=0.75 means 75% of the total volume of the
suspension is occupied by loose, porous flocs forming
the sediment.
 When F= 1(ideal suspension):
 no sediment is apparent
 the susp. is aesthetically pleasing( no visible
clear supernatant)
 Limitation of F: no reference for comparison
02/03/2023 By Belayneh K. 458

Quantitative expression of sedimentation and
flocculation……(cont’d)
The degree of flocculation (β)
 A better parameter for comparing flocculated systems
 An expression of the increased sediment volume resulting from
flocculation
For example, 𝛃 = 5 implies vol. of sediment in the

flocculated system is five times greater than in the
deflocculated state. By Belayneh K.
02/03/2023 459
• It should be noted that the deflocculated
suspensions should be avoided because of the
formation of irreversible solid hard cake.
• Although flocculated suspensions sediment faster

and form a clear supernatant, these are easy to
redisperse

Quiz
02/03/2023 By Belayneh K. 461

Quiz for Section B
1. __true___Most pharmaceutical solutions are
unsaturated with solute.
2. _false____ Most solutions intended for
parenteral administration contain flavorants and
colorants to make the medication more attractive
and palatable.
3. Most commonly Simple syrup can be prepared by:
A. Percolation
B. Agitation
C. Heating
D. Stirring
E. All the answer is "c"
02/03/2023 By Belayneh K. 462

4. Type of liquid dosage form which contain
higher concentration of alcohol
A. Elixir
B. Spirits
C. Tincture
D. Liniments
E. All the answer is"B"
5. One is not the advantage of solutions
F. Easier to swallow
G. Bulky
H. More quickly effective than tablets and capsules
I. Homogenous the answer is "B"
02/03/2023 By Belayneh K. 463
Formulation of suspensions
 There is a direct similarity between the types
of excipients used for the formulation of
suspensions and solutions for oral
administration.
 The difference between these two categories
of formulations is the inclusion of excipients to
physically stabilize suspensions.
 The formulation of suspension possessing
optimal physical stability depends on whether
the particles in suspension are to be flocculated
or to remain deflocculated.
02/03/2023 By Belayneh K. 464
The desirable properties of p”cal suspensions
• The product must remain sufficiently homogenous for at
least the period between shaking the container and
removing the required amount.
• If any sediment formed, it must be easily resuspended by
moderate agitation of the container.
• The flow properties of the suspension should enable the
formulation to be easily removed from the container and
transferred to the site of application.
• Suspended particles should be small and uniformly sized
in order to give a smooth, elegant product, free from a
gritty texture.
02/03/2023 By Belayneh K. 465

Formulation of suspensions
 The three major concerns associated with
formulation of pharmaceutical suspensions are:
Ensuring adequate dispersion of the particles in the
vehicle.
Minimizing settling of the dispersed particles.
Preventing caking of these particles when a sediment
forms.
02/03/2023 By Belayneh K. 466

Formulation of suspension
1. Control particle size. On a small scale, this can
be done using a mortar and pestle, to grind
down ingredients to a fine powder.
2. Use a thickening agent to increase viscosity of
vehicle by using suspending or viscosity-
increasing agents.
3. Use a wetting agent.

Method of preparation
• The preparation of suspension includes three
methods:
1. use of controlled flocculation and
2. use of structured vehicle
3. combination of both of the two pervious methods.
• The following is the general guidelines to
suspension formulation:

02/03/2023 By Belayneh K. 469
Structured vehicle
• Structured vehicles also called thickening or suspending
agents.
• They are aqueous solutions of natural and synthetic gums.
• These are used to increase the viscosity of the suspension.
• Methyl cellulose, carboxymethyl cellulose, sodium
carboxymethyl cellulose, acacia, gelatin and tragacanth are
the most commonly used structured vehicle in the
pharmaceutical suspensions.
• These are non-toxic, pharmacologically inert, and
compatible with a wide range of active and inactive
ingredients.

• These structured vehicles entrapped the particle
and reduces the sedimentation of particles.
• Although, these structured vehicles reduces the
sedimentation of particles, not necessarily
completely eliminate the particle settling.
• Thus, the use of deflocculated particles in a
structure vehicle may form solid hard cake upon
long storage.
• The risk of caking may be eliminated by forming
flocculated particles in a structured vehicle.

• Note that too high viscosity isn’t desirable and it
causes difficulty in pouring and administration.
• Also, it may affect drug absorption since they
adsorb on the surface of particle and suppress
the dissolution rate.
• Structured vehicles are pseudoplastic or plastic
in their rheological behaviors

• According to the Stoke's equation, the velocity of
sedimentation of particles in a suspension can be
reduced by decreasing the particle size and also by
minimizing the difference between the densities of
the particles and the vehicle.
• Since the density of the particles is constant for a
particular substance and cannot be changed, the
changing of the density of the vehicle close to the
density of the particle would minimize the difference
between the densities of the particles and the
vehicle.

• The density of the vehicle of a suspension can be
increased by adding the following substances either
alone or in combination: polyethylene glycol,
polyvinyl pyrolidone, glycerin, sorbitol, and sugar.
• The viscosity of the vehicle also affects the velocity of
sedimentation.
• It decreases as the viscosity of the vehicle increases.
• The viscosity and density of any vehicle are related to
each other, so any attempt to change one of these
parameters will also change the other one.

Formulation of suspensions.....(cont’d)
 Particle size control
 Small particle size is desirable:
 To reduce the rate of sedimentation
 To have smooth textured products
 Particles with diameter > 5 µm have gritty
texture
 To reduce irritation if instilled into eyes
02/03/2023 By Belayneh K. 475

Small particle size is desirable:
 To avoid blockage of capillary vessels
 To avoid blockage of hypodermic
needles.
 Particles over 25 µm diameter can block
hypodermic needles.
02/03/2023 By Belayneh K. 476

 Dispersion of drug particles
 A pharmaceutical suspension should be:
 Smooth,
Uniformly distributed,
Easily flowing (pouring or spreading)
Dispersion of particles possible with
minimum extent of agitation.
02/03/2023 By Belayneh K. 477

Suspending agent
• Suspending agents increase the viscosity of the
vehicle, thereby slowing down sedimentation.
• Most agents can form thixotropic gels which are
semisolid on standing, but flow readily after shaking.
• Care must be taken when selecting a suspending
agent for oral preparations.
• Suspending agents can be divided into five broad
categories: natural polysaccharides, semi-synthetic
polysaccharides, clays, synthetic thickeners and
miscellaneous compounds.

Natural polysaccharides
• The main problem with these agents is their natural
variability between batches and microbial
contamination.
• These materials should not be used externally as
they leave a sticky feel on the skin.
• They include tragacanth, acacia gum, starch, agar,
gum, carrageenan and sodium alginate.

• Tragacanth:
 Is a widely used suspending agent and is less viscous at pH
4-7.5.
 As a rule: 0.2g tragacanth powder is added per 100 mL
suspension or 2g compound tragacanth powder per 100 mL
suspension.
 Compound Tragacanth Powder BP 1980 contains
tragacanth, acacia, starch and sucrose and so is easier to
use.
 Tragacanth powder requires to be dispersed with the
insoluble powders before water is added to prevent
clumping .

Semi-synthetic polysaccharides
• These are derived from the naturally occurring
polysaccharide cellulose.
Examples include
 Methylcellulose (Cologel ®, Celacol®)
 Hydroxyethylcellulose (Natrosol 250®)
 Sodium carboxymethylcellulose (Carmellose
sodium®)
 Microcrystalline cellulose (Avicel®).

Clays
• These are naturally occurring inorganic materials
which are mainly hydrated silicates.
• Examples include bentonite and magnesium
aluminium silicate (Veegum®).

Synthetic thickeners:
• These were introduced to overcome the variable
quality of natural products.
• Examples include:
 Carbomer (Carboxyvinyl polymer, Carbopol®),
 Colloidal silicon dioxide (Aerosil®, Cab-o-sil®)
 Polyvinyl alcohol (PVA).
Miscellaneous thickeners:
• Gelatin used as a suspending agent and a viscosity
increasing agent

The use of wetting agents
 Some powders may not be wetted easily by
water due to either the surface is hydrophobic
or due to entraped air.
 Formation of large porous clamps within the liquid
or
 Clamps of powder remain on the surface of the
liquid or attached to container.
02/03/2023 By Belayneh K. 484

The use of wetting agents
 Insoluble therapeutic agents should be sufficiently
wetted to be homogeneously distributed in the
formulation.
 This enables correct dose removal by the patient

when required.
 Poorly wetted drugs become aggregated and do

not disperse sufficiently.
02/03/2023 By Belayneh K. 485

Types of wetting agents
 Surface-active agents (surfactants)
 Hydrophilic polymers
 Natural polymers (eg, acacia, tragacanth,
xanthan gum, sodium alginate)
Cellulose derivatives (methylcellulose,
sodium carboxymethylcellulose)
 Clays (e.g., bentonite, veegum)
 Solvents (ethyl alcohol, glycerol, propylene
glycol)
02/03/2023 By Belayneh K. 486
Surface-active agents (surfactants)
 For a powder to be wetted by the dispersion

medium, there should be a decrease in the
interfacial tension
 Surfactants not only reduce the interfacial
tension between liquid and vapor (γ L/v )but also
adsorb on the surface of the powder thereby
reducing (γS/V )
 Reduction of the contact angle which finally gives
improved dispersibility
02/03/2023 By Belayneh K. 487

Surface-active agents (surfactants)……(cont’d)
 Surfactants are the mostly widely used
wetting agents.
 Surfactants possessing HLB value between
7 and 9 are suitable as wetting agents.
 Adsorption of hydrocarbon chain on the
hydrophobic particles surface and polar
groups project into the aqueous medium
which leads to fall in interfacial tension
between solid and liquid finally wetting of
powder and enhanced dispersion occurs.
02/03/2023 By Belayneh K. 488
Hydrophilic polymers
• These materials include
• NATURAL POLYMERS( e.g., acacia, tragacanth,
sodium alginate, xanthan gum), and
• CELLULOSE DERIVATIVES and CLAYS ( e.g.,
bentonite, veegum)
• They can be also used as suspending agents
(thickening agents)
• They form a protective film by coating the solid
hydrophobic particles with a multimolecular
layer and as the result provide hydrophilic
character to the solid and result in wetting.
02/03/2023 By Belayneh K. 489
Solvents
 Includes solvents such as ethyl alcohol,
isopropyl alcohol, glycerin, and propylene
glycol.
 They are miscible with water.
 Penetrate the loose agglomerates of

powder and displace the air from the pores
of the individual particles and thereby
result in wetting.
02/03/2023 By Belayneh K. 490
Incorporation of structured vehicles
 Used to minimize sedimentation
 Structured vehicles are aqueous solutions of
hydrocolloids (hydrophilic polymers).
 Some are negatively charged in aqueous
solutions.
 For example, methylcellulose,
carbooxymethylcellulose, bentonite, carbomer.
 They Entrap deflocculated particles and as
the result minimize settling of particles.
02/03/2023 By Belayneh K. 491
The use of flocculating agents
Electrolytes
 Are the most widely used flocculating agents.
 Act by reducing the electrical forces of
repulsion between particles and thereby
reduce zeta potential and as result aid
formation of loose flocs.
 The ability of an electrolyte to flocculate
particles depends on the valiancy of the ion.
 valiancy of ions   Flocculating power
Calcium ions are more powerful than sodium or
potassium ions.
02/03/2023 By Belayneh K. 492
The use of flocculating agents……(cont’d)
 Trivalent ions are more powerful flocculating ions
than divalent ions.
 Trivalent ions are less commonly used because of
their toxicity.
The most widely used electrolytes include the
sodium salts of acetates, phosphates and citrates
 If anionic hydrophilic polymers are included in
the formulation they may be precipitated by the
presence of trivalent ions.
02/03/2023 By Belayneh K. 493

The use of flocculating agents……(cont’d)
 Excessive addition of electrolyte may lead to
deflocculated system due to charge reversal that
occurs on each particle.
02/03/2023 By Belayneh K. 494

The use of flocculating agents…….(cont’d)
Surfactants
 Both ionic and nonionic surfactants can be used.
 Ionic surfactants neutralize the charge on
particles and thereby reduce zeta potential and
then flocculation occurs.
 Nonionic surfactants have long chemical
structure which adsorb onto more than one
particle which results in formation of loose
flocculated structure.
02/03/2023 By Belayneh K. 495
Polymeric flocculating agents
 Many pharmaceutically useful polymers
contain polar functional groups that are
separated by a hydrocarbon backbone.
 Polymers act as bridges on the surfaces of
different particles and cause flocculation
 Ionizable polymers also reduce zeta
potential
 The flocculating action of polymers is highly
concentration dependant.
02/03/2023 By Belayneh K. 496

Flocculation in structured vehicles
Disadvantages of controlled flocculation:
The suspension can appear unsightly if the
sedimentation volume (F) is not close or equal to
1.
 Hence, in practice, a suspending agent is
frequently added to retard sedimentation of the
flocs.
 Materials such as carbooxymethylcellulose,
methylcellulose, veegum, tragacanth and
bentonite have been employed alone or in
combination.
02/03/2023 By Belayneh K. 497
Flocculation in structured vehicles…….(cont’d)
 Care must be taken when using anionic polymers
as structured vehicles when electrolytes are
used as flocculating agents.
 There will be an incompatibility with a positively
charged flocculating agent or ion as it is used to
flocculate a negatively charged particle.
 In the presence of such a material, the
negatively charged suspending agent may
coagulate and lose its suspendability.
 GELATIN (a +vely charged protein, at low pH )
can be used to reverse the charge on the
negatively charged particle to positive.
02/03/2023 By Belayneh K. 498
Flocculation in structured vehicles…….(cont’d)
 Flocculation in this case will be accomplished

with a negatively charged electrolyte ( e.g.,
citrate or phosphate ions) and will be
compatible with the negatively charged
suspending polymers.
02/03/2023 By Belayneh K. 499

Preparation of suspensions
 Diffusible solids
 Some insoluble powders are light and easily
wettable; hence, they readily mix with water
and, on shaking, diffuse evenly through the
liquid for long enough to ensure even
distribution in each dose. Such substances are
known as diffusible or dispersible solids.
 Example, calcium carbonate, light kaolin, light
magnesium carbonate, magnesium trisilicate
02/03/2023 By Belayneh K. 500

Preparation of suspensions (cont’d)
 Indiffusible solids
 Indiffusible solids will not remain uniformly
distributed in a vehicle long enough to ensure
uniformity of dose.
 This problem can be corrected by increasing the
viscosity by adding thickening agent.
 This delays sedimentation by impeding fall of particles
under gravity and by obstructing particle collisions,
which leads to the formation of aggregates that settle
rapidly.
 Eg, calamine, ZnO, Sulphur precipitated
02/03/2023 By Belayneh K. 501
 Poorly wettable solids

 Some substances, e.g sulphur and hydrocortisone,
are both insoluble in water and poorly wetted by it.
 When preparing simple aqueous dispersions it is
difficult to disperse clumps, and the foam produced
on shaking is slow to subside because it is stabilized
by the film of unwettable solid at the liquid/air
interface.
 To ensure satisfactory wetting, the interfacial energy
between the solid and liquid must be reduced.
02/03/2023 By Belayneh K. 502

 This may be achieved by adding a suitable wetting

agent which is adsorbed at the solid/liquid interface
in such a way that the affinity of the particles for the
surrounding medium is increased, while the
interparticular forces are decreased.
 General method of preparation
 Carefully tare the container
 Finely powder any ingredient not already in fine
form.
02/03/2023 By Belayneh K. 503

 Mix the insoluble powders in a mortar,

 Adding first the ingredient of smallest bulk and
diluting it with the others in increasing order of
bulk, using amounts approximately equal to the
bulk already in the mortar.
 Add a portion of the vehicle to mix well and produce
a smooth paste.
 Examine the suspension critically and, if it contain
foreign particles, strain through muslin into the
tared bottle.
02/03/2023 By Belayneh K. 504

 Add any volatile & liquid ingredients into the bottle.

 Rinse the mortar and pestle with successive volumes
of vehicle until they are quite clean and transfer the
rinse to bottle.
 Make up to volume with vehicle and shake
thoroughly.
 Finally, label it
02/03/2023 By Belayneh K. 505

Preparation of suspension from dry powders and
granules for reconstitution
• Reconstitution because of chemical or physical
instability.
• Loosening of powder from bottom of the container.
• The specified amount of cold, purified water should
then be added, sometimes in two or more portions
with shaking.
• Some preparations may be prepared immediately
before taking from individually packed sachets of
powder or from bulk solids.
02/03/2023 Belayneh Kefale

Preparation of suspension from oral solid dosage form
• The tablet will be crushed or capsule contents emptied

into the mortar and a suspending agent added.
• A paste is formed with the vehicle and then diluted to a
suitable volume, with the addition any other desired
ingredients such as preservative or flavour.
• A short expiry of no more than 2 weeks (more likely to
be 7 days) should be given owing to the lack of
knowledge about the stability of the formulation.
02/03/2023 Belayneh Kefale

Containers for suspension
• Suspensions should be packed in amber bottles,
plain for internal use and ribbed for external
use.
• There should be adequate air space above the
liquid to allow shaking and ease of pouring.
• A 5mL medicine spoon or oral syringe should be
given when the suspension is for oral use.

Special label and advice for suspension
• The most important additional label for suspensions is
'Shake well before use',
• Store in a cool place.
• Stability of suspensions may be adversely affected by both
extremes and variations of temperature.
• Some suspensions. such as those made from reconstituting
dry powders, may need to be stored in a refrigerator.
• Extemporaneously prepared and reconstituted are
required to be recently or freshly prepared, with a 1-4-
week expiry date.

150ml Kaolin and Morphine Mixture BP.
Master formula 150ml

Light kaolin 2g 30g
Sodium bicarbonate 500mg 7.5g
Chloroform and
morphine tincture 0.4ml 6ml
Water to 10ml to 150ml

Chalk Mixture, Paediatric BP. Mitte 100ml

Chalk 100mg 2g
Tragacanth 10mg 200mg
Syrup 0.5ml 10ml
Concentrated cinnamon
water 0.02ml 0.4ml
Double strength chloroform
water 2.5ml 50ml
02/03/2023 Belayneh k.
Spironolactone suspension 15mg/5ml. Sig.5ml
t.d.s. Mitte 100ml. For a 4-year-old child.

Spironolactone q.s.* 300mg
Compound orange spirit 0.2% 0.2ml
Cologel 20% 20ml
Water to 100% 100ml
*q.s. means sufficient
02/03/2023 Belayneh K.
Menthol and Eucalyptus Inhalation BP 1980. Mitte
100ml
Master formula
Menthol 2g
Eucalyptus oil 10ml
Light magnesium carbonate 7g
Water to 100ml
200ml Calamine Lotion BP

Calamine 15g 30g
Zinc oxide 5g 10g
Bentonite 3g 6g
Sodium citrate 500mg 1g
Liquified phenol 0.5ml 1ml
Glycerol 5ml 10ml
Key points
• Suspensions can be used to administer an
insoluble solid by the oral route.
• Suspensions may be used to replace tablets, to
improve dissolution rate, to prolong action and to
mask a bad taste.
• Solids may be diffusible or indiffusible and require
different dispensing techniques.
• Stokes' equation can be applied when formulating
a suspension to help ensure accurate dosage of
the drug.
• Flocculated particles settle quickly and redisperse
easily, whilst deflocculated particles settle slowly
but tend to cake.
Key points
• Hydrophobic solids may require wetting agents.
• Suspending agents are added to slow down the rate
of settling of the solid.
• Suspending agents may be natural polysaccharides,
semi synthetic polysaccharides, clays or synthetic
polymers.
• Some suspensions are made by adding water to
reconstitute manufactured powders when stability is
a problem.
• Shake well before use' and 'Store in a cool place‘
should be part of the labels on a suspension.
• Inhalations are suspensions of a volatile material
adsorbed onto a diffusible solid.
Label and storage of suspensions
Label
 The most important additional label for
suspensions is
‘SHAKE WELL BEFORE USE’
Storage
 Reconstituted dry powders, may need to be
stored in refrigerator- ‘STORE I N COOL PLACE’
1-4 week expiry date.
02/03/2023 By Belayneh K. 517

Rheology (flow property) of
suspensions
 The ideal suspending agent should have

a high viscosity at negligible shear ( i.e.,
during storage) and it should have a
low viscosity at high shearing rate, that
is, it should be free flowing during
agitation, pouring, and spreading.
02/03/2023 By Belayneh K. 518

Pharmaceutical emulsions
Introduction
An emulsion is a thermodynamically unstable
system consisting of two immiscible liquid
phases, one of which is dispersed as globules (the
dispersed phase) in the other liquid phase (the
continuous phase) and stabilized by the presence an
emulsifying agent
 Dispersed phase diameter: 0.1 μm to 10 µm
 But dispersed phase diameter as small as 0.01 µm
and as large as 100 µm are also not uncommon
 The dispersed phase is also called as the internal
phase or discontinuous phase and the dispersion
medium is also called as the external or continuous
phase.
Continuous phase
Dispersed phase
To stabilize these droplets,

emulsifying agent should be
added
•At least 2 phases:
 Disperse or internal phase
 Continuous or external phase.
•Macroemulsion: Droplets size range approximately 5 mm.
•Microemulsion: Droplets size range 0.01 to 0.1 mm
02/03/2023 Belayneh K (Bpharm, MSc candidate) 521
Introduction
Emulsions with an oleaginous internal phase and an
aqueous external phase are oil-in-water (o/w) emulsions
Emulsions with an aqueous internal phase and an
oleaginous external phase are termed water-in-oil (w/o)
emulsions
Introduction
 Depending on their viscosity, pharmaceutical

emulsions can vary from liquids of relatively low
viscosity to semisolids of high viscosity ( e.g., creams).
 Based on the constituents and the intended routes of

administration, liquid emulsions may be employed
orally, topically or parenterally.
General Types of Pharmaceutical Emulsions:
 1) Lotions
 2) Liniments
 3) Creams
 4) Ointments
 5) Vitamin drops
02/03/2023 Belayneh K (B.pharm, MSc candidate) 524

Definition and Characteristics of Emulsions
Positive Negative
To combine immiscible • Instability of emulsions as
liquids in one medicine; dispersion systems under
influencing of different
To put into the medicine’s factors (temperatures, air,
composition the hydrophilic light);
and hydrophobic medicinal • The possibility of the growth
substances; of microorganisms (emulsions
To regulate the bioavailability are favourable media for the
of medicinal substances (due growth of microorganisms);
to rapid and complete freeing • Relatively long technological
processes of manufacturing,
or prolonging of the medicinal which require the use of
substances action); proper technological
To remove irritations on the operations and special
skin and mucous, which are technological equipment;
typical for certain medicinal • The necessity of using
substances; emulsifiers for stabilization of
the dispersion system.
To mask unpleasant taste and
Pharmaceutical applications of emulsions
 For oral, topical and parenteral administration of oils and
oil soluble drugs.
e.g., mineral oil (laxative), valproic acid (anticonvelsant)
 To enhance palatability of oils when given orally by
masking both test and oiliness (O/W emulsions).
For ex. Oil-soluble vitamins.
 To formulate oil soluble and water soluble drugs
together
 To Increase absorption of oils and oil-soluble drugs
through intestinal walls (to increase bioavailability of a
drug).
For example, griseofulvin (antifungal drug) suspended in oil in an
oil-in-water emulsion.
Pharmaceutical applications of emulsions......cont’d
 To provide slow release of drug from intramuscular

injection
 For administration of lipid nutrients intravenously to
provide a source of calories and essential fatty acids.
 Radiopaque emulsions have application as diagnostic
agents in x-ray examination.
Theories of emulsification
 When two immiscible liquids are agitated together so
that one of the liquids is dispersed as small droplets in
the other, the liquids separate rapidly into two clearly
defined layers.
Theories of Emulsification:
• Incase of two immiscible liquids
Oil
Oil Agitation Oil
Water Water
Water
Separate rapidly into two

clear defined layers

Small droplet  Surface area  Interfacial tension
System is thermodynamically
unstable “ high energy”
System tends to separate in
two layer to reduce the surface area

Theories of emulsification
Immiscibility of the liquids is because:

 Cohesive forces between the molecules of each
separate liquid is greater than adhesive force between
the two liquids.
 When one liquid is broken into small particles  
surface area of the formed globules  surface free
energy  thermodynamic unstability  coalescence (
merging together of droplets)
Theories of emulsification and Interfacial
properties...cont’d
To prevent coalescence or at least to reduce its rate to
negligible proportions, emulsifying agent is used that forms
a film around the dispersed globules.
 Types of emulsifying agents
Surface –active
agents (HLB 3-6 and
8-16)
Emulsifying
agents
Finely divided
Hydrophilic
solid particles
polymers
(clays)
Mechanisms of emulsion stabilization
Surface-active agents (surfactants)
 Adsorb at oil-water interface form monomolecular films
 reduce INTERFACIAL TENSION reduced coalescence
Hydrophilic polymers
adsorb at oil-water interface form multimolecular film
reduced coalescence
Finely divided solid particles (clays)
 adsorbed at oil-water interface  form particulate film
reduced coalescence
 Surface-active agents (surfactants)

Adsorbed molecules or ions of the SAA form a monolayer 
 interfacial tension  surface free energy  reduction of
coalescence
Moreover, the droplets are surrounded by a coherent
monolayer  prevention of coalescence between approaching
droplets
 Furthermore, if the emulsifier is ionized  charged globules or
droplets repulsion between approaching globules prevention
of coalescence
Hydrophilic polymers
 Hydrophilic colloids ( e.g., acacia, gelatin)
form multimolecualr films around droplets of
dispersed oil.
 Their use has declined in recent years

because of the large number of synthetic
surface-active agents available that possesses
well-marked emulsifying properties.
 Hydrophilic polymers
 Even though adsorb at oil-water interface, do not
cause an appreciable lowering in surface tension
 Their efficacy depends on their ability to form
strong coherent multimolecular films coating
around droplets resistant to coalescence
 Non-adsorbed hydrocolloids increase viscosity of
continuous aqueous phase  resistant to
coalescence
 Finely divided solid particles
 Finely divided solid that are wetted to some degree by
both oil and water can act as emulsifying agents.
 Concentrate at the interface  formation of particulate
film  prevention of coalescence
 Powders that are wetted preferentially by water

form o/w emulsions, whereas those more easily
wetted by oil form w/o emulsions.
Primary and secondary emulsion:
– Primary emulsion containing one internal phase, for
example, oil-in-water emulsion (o/w) and water-in-oil
emulsion (w/o).
Secondary emulsion = multiple-emulsion:
It contains two internal phase, for instance, o/w/o or
w/o/w.
It can be used to delay release or to increase the
stability of the active compounds.

Types of Emulsions
 Ordinary emulsions
 O/W emulsions
 W/O emulsions
 Multiple emulsions
 W/O/W emulsions: In which small water droplets are enclosed
within larger oil droplets, which are themselves then dispersed in
water
 O/W/O emulsion: in which small oil droplets are enclosed within
larger water droplets, which are themselves then dispersed in oil.
Types of Emulsions...cont’d
 The most promising use of multiple emulsions is in the area of
sustained-release drug formulations.
 Microemulsions ( colloidal emulsions)
 Are emulsions which contain droplet diameters between
1 nm and 0.5 µm.
 Unlike coarse emulsions, they are quite often transparent or
translucent, do not separate on standing and have narrow

droplet size distribution
 Coarse emulsions are white, tend to separate on standing ,
have broad droplet size distribution and are generally opaque.
Oil
Water
Oil Water
O/W W/O
Water Oil
Oil Water
Oil Water
O/W/O W/O/W

Microemulsions ( colloidal emulsions).... cont’d
 Coarse emulsions contain three components, namely, oil,
water, and surfactant; whereas microemulsions generally require
a fourth component, a cosurfactant.
 Both o/w and w/o types are possible, and one may convert to
the other by the addition of more internal phase or by altering
the type of emulsifier.
 Microemulsions have been used to increase bioavailability of

poorly water soluble drugs by incorporation of the drug into the
internal phase.
Methods used for distinguishing O/W and
W/O emulsion types
Miscibility tests with oil or water
 The emulsion will only be miscible with liquids that are
miscible with its continuous phase.
Conductivity test
 Systems with aqueous continuous phases will readily
conduct electricity, whereas systems with oily continuous
phases will not.
Dye-solubility test
 Water soluble dye will dissolve in the aqueous phase of an
emulsion while an oil soluble dye will be taken up by the oil
phase.
 Emulsion Type and Means of Detection:
using of naked eye, it is very difficult to
differentiate between o/w or w/o emulsions.
 Thus, the four following methods have been
used to identify the type of emulsions.
1) Dilution Test: based on the solubility of
external phase of emulsion.
• o/w emulsion can be diluted with water.
• w/o emulsion can be diluted with oil.

Few drops
of water Water distribute
uniformly O/W emulsion
Few drops Water separate

of emulsion out as layer W/O emulsion

2) Conductivity Test: water is good conductor
of electricity whereas oil is non-conductor.
 Therefore, continuous phase of water runs
electricity more than continuous phase of oil.
Bulb
= Bulb glows with O/W

Electrode = Bulb doesn’t glow with W/O
Emulsion

3) Dye-Solubility Test:
• Water-soluble dye will dissolve in the aqueous phase.
• Oil-soluble dye will dissolve in the oil phase.
What is look like under the microscope after mixing with
suitable dye
Oil-soluble dye (e.g. Scarlet) Water-soluble dye (e.g. Amaranth dye)
W/O O/W O/W W/O

4-Fluorescence test:
• Oils give fluorescence under UV light, while
water doesn’t.
• Therefore, O/W emulsion shows spotty pattern
while W/O emulsion fluoresces.

Quiz
1. One is not true about flocculated suspension
A. Rate of sedimentation is high
B. Sediment is slowly formed
C. Sediment is loosely packed and doesn’t form a hard cake
D. Sediment is easy to redisperse
E. Suspension is not pleasing in appearance
2. According to the Stoke's equation, the velocity of sedimentation
of particles in a suspension can be reduced by:
A. Decreasing the particle size
B. Maximizing the d/ce b/n the densities of the particles and the
vehicle
C. Increasing viscosity of the vehicle
D. All of the above
02/03/2023 By Belayneh K. 549
3. ______are naturally occurring inorganic
materials which are mainly hydrated silicates.
A. Natural polysaccharides
B. Clays
C. Semi-synthetic polysaccharides
D. synthetic polysaccharides
E. none of the above
4. Write down the type of emulsion and means
of detection (2pts)
02/03/2023 By Belayneh K. 550
Emulsion Formulation
 Choice of emulsion type
 Fats or oils for oral administration, either as medicaments
in their own right or as vehicles for oil-soluble drugs, are
always formulated as oil-in-water emulsions.
 Pleasant to take as the inclusion of flavours in the
aqueous phase mask unpleasant taste
 Emulsions for intravenous administration must also be
of the o/w type.
 Intramuscular injections can also be formulated as O/W
or
W/O type.
Choice of emulsion type……….…..cont’d
 Emulsions are most widely used for external

application;
 Semisolid emulsions (creams ) and more fluid
preparations (lotions ),if intended for massage into
the skin, liniments
Both o/w and w/o types are available
o/w emulsions do not have the greasy texture and
easily washed from skin surfaces.
w/o emulsions have greasy texture and difficult to
be washed off from skin surfaces.
02/03/2023 By Belayneh K. 552
Choice of emulsion type……....cont’d
 W/O emulsions have an occlusive effect by

hydration of the upper layers of the stratum
corneum and inhibition of evaporation of eccrine
secretions.
  absorption rates of drugs from these
preparations
 W/O emulsions are useful for cleansing the skin
from oil-soluble dirty materials.
 O/W emulsions are less efficient as dirt cleansers
but are usually more acceptable by consumers.
02/03/2023 By Belayneh K. 553
Oil in water emulsion Water in oil emulsion
For insoluble drug For water soluble drug

For local effect Can be use to hydrate the upper layer of
stratum corneum (moisturizing cream)
Easily to wash from skin Can increase the absorption of drug from
these formulation
Doesn’t have greasy Can be used to clean skin from dirt

texture of oily preparation
Acceptable by consumer Not acceptable by consumer

Choice of oil phase
 In many instances the oil phase of an

emulsion is the active agent.
 Liquid paraffin, castor oil and cod liver
oil are examples of medicaments which
are formulated as emulsions for oral
administration.
02/03/2023 By Belayneh K. 555

Choice of oil phase……….cont’d
 Cottonseed oil, soya bean oil, arachis,

sesame, maize and safflower oil are used for
their high calorific value in emulsions for
intravenous feeding.
 They are also rich in vitamins and minerals
 Turpentine oil and benzyl benzoate are
formulated as emulsions for external
applications ( have antimicrobial activity).
02/03/2023 By Belayneh K. 556

Emulsion consistency
 A w/o emulsion preparation will have a greasy
texture and often exhibits a higher apparent
viscosity than o/w emulsions.
 Ideally emulsions should exhibit the rheological
properties of plasticity/pseudoplasticity and
thixotropy.
A high apparent viscosity during storage and
low apparent viscosity when shaken, poured
from the container, spread on the surface of skin
or injected through a hypodermic needle.
02/03/2023 By Belayneh K. 557
Emulsion consistency..cont’d
 The main disadvantage with low-viscosity emulsions

is their tendency to cream easily, especially if
formulated with a low oil concentration.
 Percentage volume of the dispersed phase:
 Theoretically, the percentage volume of the
dispersed phase can be as large as 74% of the
total volume.
 Most pharmaceutical emulsions contain a
volume ratio of 50 parts of oil and 50 parts of
water.
02/03/2023 By Belayneh K. 558
Viscosity of the continuous phase
 There is a direct relationship between the viscosity of an

emulsion and the viscosity of its continuous phase
 The viscosity of the continuous phase can be increased by
incorporation of syrup or glycerol if the emulsion is O/W
type.
 Disadvantage: increase the density difference between the
two phases upon change in temperature, and thus possibly
accelerating creaming
 Hydrocolloids, when used as emulsifying agents in o/w
emulsions not only stabilize by forming multimolecular film
but also by increasing the continuous phase viscosity.
 They do not have the disadvantage of altering the density of
this phase
02/03/2023 By Belayneh K. 559
Viscosity of the continuous phase
 If oil is the continuous phase, then the inclusion
of soft or hard paraffin or certain waxes will
increase its viscosity.
 Nature and concentration of the emulsifying system
  in the concentration of hydrophilic colloids in O/W
emulsions  in viscosity of the continuous phase
 Hydrophilic colloids also form bridge on globules
  in concentration of surface active agents 
flocculation of globules by forming linkages between
adjacent globules   apparent viscosity of the
continuous phase
02/03/2023 By Belayneh K. 560
Choice of emulsifying agent
 Toxicity and irritancy considerations

 The choice of emulgent to be used will depend not only on
its emulsifying ability, but also on its route of administration
and, consequently, on its toxicity.
 Naturally occurring materials and their semisynthetic
derivatives, such as the natural polymers, cellulose
derivatives, glycerol esters, sorbitan esters and polysorbates
are suitable for internally used pharmaceutical emulsions.
 Most of these are non-ionic, less irritant and less toxic than
their anionic, and particularly their cationic counterparts.
02/03/2023 By Belayneh K. 561

Toxicity and irritancy considerations
 At emulsifying conc., ionic emulsifying agents ,
irritate gastrointestinal tract and have a laxative
effect hence not used in oral emulsions.
 Cationic surfactants in general are toxic even at
lower concentrations and limited to externally used
preparations . For example, cetrimide in cetrimide
cream
 Anionic alkali soaps, often have a high pH and are
thus unsuitable for application to broken skin
cause irritation
02/03/2023 By Belayneh K. 562
Toxicity and irritancy considerations
 Even on normal intact skin with a pH of 5.5,
alkaline emulgents can cause irritation.
 For parenteral use, only certain types of non-

ionic emulgents are suitable. These include
lecithin, polysorbate 80, methylcellulose,
gelatin and serum albumin.
02/03/2023 By Belayneh K. 563

Classification of emulsifying agents
 Selection of emulsifying agents

 The selection of emulsifying agent or agents is of prime
importance in the successful formulation of emulsion.
Emulsifying agents
Naturally occurring Synthetic emulsifying

materials and their agents
derivatives
02/03/2023 By Belayneh K. 564
Naturally occurring materials and their derivatives
 Polysaccharides
Acacia
• Acacia is a polysaccharide gum soluble in water
• Acacia stabilizes o/w emulsions by forming a strong multimolecular film
round each oil globule.
• Emulsions prepared with acacia are stable over a wide pH range
• Because of its low viscosity, creaming will occur readily, and therefore a
suspending agent such as tragacanth or sodium alginate can also be
included.
• Because of its sticky nature the use of acacia is limited to products for
internal use.
02/03/2023 By Belayneh K. 565

Acacia..cont’d
• it is necessary to preserve acacia emulsions against microbial
attack by the use of suitable preservatives
• Other polysaccharides include: tragacanth, alginates,
carageenan, xanthan gum and pectin.
• These emulgents form hydrophilic colloids when added to
water and generally produce o/w emulsions.
• They have low surface activity and achieve emulsifying
power by forming multimolecular film and by increasing the
viscosity of the aqueous phase.
02/03/2023 By Belayneh K. 566

Naturally occurring materials and their
derivatives
 Gelatin
 It is a protein which has been used for many years as an
emulsifying agent.
 It forms o/w type of emulsion
 Lecithin
 Lecithin is an emulsifier obtained from both plant
( e.g., soy bean) and animal (e.g., egg yolk)
 It is composed of variety of phosphatides
 The primary component of most lecithins is
phosphatidylcholine
02/03/2023 By Belayneh K. 567

Lecithin …..cont’d
02/03/2023 By Belayneh K. 568

Lecithin..cont’d
 Purified lecithins from egg yolk or soy bean
are the principal emulsifiers for
intravenous fat emulsions.
 Lecithin provides a stable emulsions with
droplet sizes of less than 1 µm in diameter.
 The content of lecithins vary from source
to source and their emulsifying properties
and toxicity may also vary
02/03/2023 By Belayneh K. 569

Finely divided solids (clays, minerals)
 The colloidal clays: bentonite (hydrated

aluminum silicate) and veegum (magnesium
aluminum silicate) and colloidal silicon
dioxide.
 They adsorb at the interface and form
particulate film and also increase the
viscosity in the aqueous phase.
 They are most frequently used for external
purposes such as lotion or cream.
02/03/2023 By Belayneh K. 570
Finely divided solids (clays, minerals)
...cont’d
 Bentonite (hydrated aluminum silicate)
 It is a white to gray, odorless and tasteless powder that
swells in the presence of water to form translucent
suspension with a pH value of about 9.
 Depending on the sequence of mixing it is possible to
prepare both o/w and w/o emulsions
 Veegum (magnesium aluminum silicate)
 Employed mostly as stabilizer in cosmetic lotions and
creams.
02/03/2023 By Belayneh K. 571

Cellulose derivatives
• This include for example, methylcellulose and carmellose

sodium (sodium carboxymethylcellulose).
• They form o/w type of emulsion
• This emulsifying agents are also called auxiliary emulsifying
agents as they alone are not capable of forming stable
emulsions.
• Their main value lies in their ability to function as thickening
agents (suspending agents) and thereby help stabilize the
emulsion.
02/03/2023 By Belayneh K. 572

Cellulose derivatives ...cont’d
02/03/2023 By Belayneh K. 573

Sterol-containing substances
 Sterol-containing substances such as Beeswax, wool
fat and wool alcohols are also used as emulsifying agents
 Beeswax
 It is used mainly in cosmetic creams of both o/w and w/o
type in conjunction with borax.
 Beeswax alone is used as a stabilizer for w/o creams
 Wool fat (anhydrous lanolin)
 Consists chiefly of normal fatty alcohols with fatty acid esters
of cholesterol and other sterols.
 It forms w/o emulsions and it can also be incorporated for its
emollient properties.
02/03/2023 By Belayneh K. 574

Sterol-containing substances
 Cholesterol
02/03/2023 By Belayneh K. 575

Wool fat
 Some individuals exhibit sensitization to Wool fat
 because of its characteristic odour and the need to
incorporate antioxidants, it is not widely used.
 Has high water absorbing properties
 It can be used as an emulsion stabilizer with primary
emulsifying agents
 The principal emulsifying agents in wool fat are wool
alcohols, which consists mainly of cholesterol together
with other alcohols.
 Cholesterol is an effective w/o emulgent, being more
powerful than wool fat
02/03/2023 By Belayneh K. 576

Disadvantages of naturally occurring materials and
their derivatives
 Show batch-to-batch variation in composition
and hence in emulsifying properties
 Susceptible to bacterial or mould growth
 Not suitable for products requiring a long
shelf-life
 but rather for extemporaneously prepared
emulsions designed for use within a few days
of manufacture
02/03/2023 By Belayneh K. 577

Synthetic surface active agents
Synthetic surface active agents

(surfactants)
Anionic Cationic Non ionic

surfactants surfactants surfactants
02/03/2023 By Belayneh K. 578

Anionic surfactants
 Dissociate to form negatively charged anions that are
responsible for their emulsifying ability
 They are widely used because of their cheapness
 because of their toxicity only used for externally applied
preparations
Anionic surfactants
Alkali metal Sulfated and

Amine soaps
soaps Sulfonated cpds
02/03/2023 By Belayneh K. 579
Alkali metal soaps
 Emulgents in this group consist mainly of the
sodium, potassium or ammonium salts of long-
chain fatty acids such as: Potassium laurate
(C11H23COO-K+ ), Sodium stearate( C17H35COO- Na+ )
 They produce stable O/W emulsions but may in
some instances require the presence of an auxiliary
nonionic emulsifying agent
 At pH < 10 precipitate out from solution
 formation of unionized free fatty acid of low
aqueous solubility  precipitation
02/03/2023 By Belayneh K. 580
Alkali metal soaps
...cont’d
 Ca, Mg, and Al salts of fatty acids, are slightly water
soluble and result in w/o emulsions.
calcium stearate
 They are water insoluble because they dissociate
little.
 Soaps of alkali metal are incompatible with
polyvalent cations, often causing phase reversal
 They do have a disagreeable taste and are irritating
to the gasteroinestinal (GI) tract; this limits them for
emulsions prepared for external use.
02/03/2023 By Belayneh K. 581
Amine soaps
 A number of amines form salts with fatty acids
 the most important of those used is based on
triethanolamine N(CH2CH2OH)3 which is widely used in
both pharmaceutical and cosmetic products.
 These emulsifiers favor formation of o/w emulsions
 their alkalinity is considerably lower than that of alkali
soaps
 They are also less irritating than alkali soaps.
 They are also incompatible with acids and high
concentrations of salts.
 Their use is limited to external applications
02/03/2023 By Belayneh K. 582
Sulfates
 The alkyl sulfates have the general formula ROSO3M+,
where R represents a hydrocarbon chain and M+ is usually
sodium or triethanolamine
 An example is sodium lauryl sulphate, which is widely
used to produce o/w emulsions
 Sodium lauryl sulphate has high water solubility
 Because of its high water solubility and inability to form
condensed films at the oil/water interface, it is always
used in conjunction with a non-ionic oil-soluble
emulsifying agent in order to produce a complex
condensed film
02/03/2023 By Belayneh K. 583

Sulfonates
 Sulfonates are a class of compounds in which the sulfur atom
is connected directly to the carbon atom giving the general
formula: RSO3 M+
 They are much less widely used as emulgents
 Materials of this class include sodium dioctylsulphosuccinate,
and are more often used for their detergency
sodium dioctylsulphosuccinate
02/03/2023 By Belayneh K. 584
Cationic surfactants
 The surface activity in the cationic group resides in the
positively charged cation
 Although these materials are widely used for their
disinfectant and preservative properties, they are also
useful o/w emulsifiers.
 The pH of an emulsion prepared with a cationic emulsion
lies in the pH 4 to 6 ranges.
 Because this includes the normal pH of skin, they are used
in emulsified antiinfective products such as lotions and
creams.
02/03/2023 By Belayneh K. 585

Cationic surfactants
 Because of the toxicity of cationic surfactants they tend to be
used only for the formulation of antiseptic cream
 They alone produce poor emulsions but if used with non-ionic
oil-soluble auxiliary emulgents such as cetostearyl alcohol
they will form stable emulsions
 The most important group of cationic emulgents consists of
the quaternary ammonium compounds.
 An example is cetyltrimethyl-ammonium bromide (cetrimide)
CH3 (CH2)14 CH2N+(CH3)3Br-.
 Cationic emulsifiers should not be used with anionic
emulsifiers
02/03/2023 By Belayneh K. 586

Nonionic surfactants
 Nonionics, undissociated surfactants, find wide spread use as

emulsifying agents
 These emulsifiers range from oil-soluble compounds stabilizing

w/o emulsions to water-soluble materials giving o/w
products.
02/03/2023 By Belayneh K. 587

02/03/2023 By Belayneh K. 588

 Advantages of non-ionic surfactants
 They show low toxicity and irritancy (some of
them can be used for orally and parenterally
administered preparations).
have a greater degree of compatibility with other
materials
less sensitive to changes in pH or to the addition of
electrolytes
02/03/2023 By Belayneh K. 589

 Most non-ionic surfactants are based upon:
 A fatty acid or alcohol (usually with 12-18 carbon atoms),
the hydrocarbon chain of which provides the hydrophobic
moiety
 An alcohol (-OH) and/or ethylene oxide grouping
(-OCH2CH2-), which provide the hydrophilic part of the
molecule.
 By varying the relative proportions of the hydrophilic and
hydrophobic groupings many different products can be
obtained.
02/03/2023 By Belayneh K. 590

 If the molecule contains hydrophobic parts, it tends to migrate
into the oil phase and if it is hydrophilic it tends to migrate
into the aqueous phase
 The best type of non-ionic surfactant to use is one with an

equal balance of hydrophobic and hydrophilic group parts
 An alternative would be to use two emulgents, one

hydrophilic and one hydrophobic.
 The cohesion between their hydrocarbon chains will then hold
both types at the oil/water interface.
02/03/2023 By Belayneh K. 591

Glycerol esters
 For example, Glyceryl monostearate (an ester of glycerol and

stearic acid ) C17H35COOCH2CHOHCH2OH
 Glyceryl monostearate is a strongly hydrophobic material

that produces weak w/o emulsions
 The addition of small amounts of sodium, potassium or
triethanolamine salts of oleic or stearic acids will produce a
'self-emulsifying' glyceryl monostearate, which is a useful
o/w emulsifier.
02/03/2023 By Belayneh K. 592

Sorbitan esters (Spans)
 These are produced by the esterification of one or more of the
hydroxyl groups of sorbitan with either lauric acid
(C11H23COOH), oleic acid ( C17H32COOH) , palmitic acid
(C15H31COOH) or stearic acid (C17H35COOH)
Structure of sorbitan sorbitan monostearate

 Sorbitan esters stabilize W/O emulsions
02/03/2023 By Belayneh K. 593

Polysorbates(Tweens)
 Polysorbates are polyethylene glycol derivatives of
the sorbitan esters
02/03/2023 By Belayneh K. 594

 Polyoxyethylene 20 sorbitan monooleate, for example,
contains 20 oxyethylene groups in the molecule.
 Polysorbates are generally used in combination with the
corresponding sorbitan ester to form a complex condensed
film at the oil/water interface
 Glyceryl monostearate, cetyl or stearyl alcohol or
propylene glycol monostearate, can be incorporated with
polysorbates to produce 'self-emulsifying‘ preparations.
02/03/2023 By Belayneh K. 595

 Polysorbates
 are compatible with most anionic, cationic and non-ionic materials
 stable to the effects of heat, pH change and high concentrations of
electrolyte.
 Have low toxicity
 suitable for oral use and some are also used in parenteral
preparations.
Disadvantages
 Have unpleasant tests
 Expensive
 Can form a complex with some preservatives
02/03/2023 By Belayneh K. 596

Fatty alcohol polyglycol ethers
 These are reaction products of polyethylene glycol and

fatty alcohols, usually cetyl or cetostearyl alcohol
ROH + (CH2CH2O)n  RO(CH2CH2O)nH
Where R is a fatty alcohol chain
 the most widely used is macrogol cetostearyl ether or
cetomacrogol 1000 which is polyethylene glycol monocetyl
ether
 It is a very useful water-soluble o/w emulgent, but because
of its high water solubility it is necessary to include an oil-
soluble auxiliary emulsifier when formulating emulsions.
02/03/2023 By Belayneh K. 597

Fatty alcohol polyglycol ethers....cont’d
macrogol cetostearyl ether or cetomacrogol 1000
02/03/2023 By Belayneh K. 598

Fatty alcohol polyglycol ethers....cont’d
 Combinations of lipophilic and hydrophilic ethers can be

used together to produce stable emulsions.
 These emulgents can be salted out by the addition of high
concentrations of electrolyte
 They are stable over a wide pH range
02/03/2023 By Belayneh K. 599

Poloxamers
 Poloxamers are polyoxyethylene/polyoxypropylene block
copolymers with the general formula:
OH(C2H4O)a(C3H6O)b(C2H4O)cH
 The oxyethylene portion imparts hydrophilicity and
oxypropylene portion imparts lipophilicity
 Some poloxamers are used as emulsifying agents for
intravenous fat emulsions
 Best emulsions are obtained when combined with other a
W/O emulsifier
02/03/2023 By Belayneh K. 600

Higher fatty alcohols
 The hexadecyl (cetyl) and octadecyl (stearyl) members of

this series of saturated aliphatic monohydric alcohols are
useful auxiliary emulsifying agents
 Part of their stabilizing effect comes from their ability to
increase the viscosity of the preparation, thereby retarding
creaming
 Cetyl and stearyl alcohol form complex interfacial films
with hydrophilic surface-active agents such as sodium
lauryl sulphate, cetrimide, cetomacrogol 1000, and
stabilize o/w emulsions.
02/03/2023 By Belayneh K. 601

Formulation of emulsion by the HLB method
02/03/2023 By Belayneh K. 602

Formulation of emulsion by the HLB method
 A blend of an oil-soluble emulsifying agent with a water-

soluble one produces the most satisfactory emulsions.
 HLB method is used to determine the quantities of emulgents
necessary to produce the most physically stable emulsion for a
particular oil-water emulsions.
 Each surfactant has an HLB number representing the relative
proportions of the lipophilic and hydrophilic parts of the
molecule.
 Higher HLB number indicates high hydrophilicity whereas low
HLB indicates high lipophilicity.
02/03/2023 By Belayneh K. 603

Required HLB value
 Required HLB value is the HLB value required by a
particular material if it is to be emulsified
effectively.
 The required HLB value differs depending on
whether the final emulsion is O/W or W/O.
 This does not necessarily mean that every
surfactant having the required HLB value will
produce a good emulsion, as specific surfactants
may interact with the oil, with another component
of the emulsion, or even with each other.
02/03/2023 By Belayneh K. 604
Required HLB value
 Mixtures of surface-active agents give more stable
emulsions than when used singly. mixture of
emulsifiers may
 Produce densely packed complex film at oil-
water interface
 Increase viscosity of the interfacial emulsifier
film inhibit thinning at the points of droplet
to droplet contact
Provide more elastic interfacial film  resist
rupture upon collision of emulsion droplets.
02/03/2023 By Belayneh K. 605
Required HLB value
 The HLB of a mixture of surfactants, consisting of

fraction x of A and (1 - x) of B, is assumed to be an
algebraic mean of the two HLB numbers:
HLBmix = x HLBA + (1-x) HLB B
 Each type of oil used will require an emulgent of a
particular HLB number in order to ensure a stable
product
Calculation of Required HLB
02/03/2023 By Belayneh K. 606

Emulsions......cont’d
 Preparation of emulsions
 The preparation of emulsion requires work to reduce the
internal phase into small droplets and disperse them
throughout the external phase.
 This can be accomplished by a mortar and pestle or high-
speed homogenizer.
02/03/2023 By Belayneh K. 607

Emulsions......cont’d
 Preparation of emulsions
02/03/2023 By Belayneh K. 608

Preparation of emulsions………..cont’d
Emulsions are prepared by four principal

methods:
 Addition of internal phase to external phase
 Addition of external phase to internal phase
(the dry gum technique )
 Mixing both phases after heating
 Alternate addition of the two phases to the
emulsifying agent
02/03/2023 By Belayneh K. 609
Preparation of emulsions...cont’d
 Addition of internal phase to external phase

 The most satisfactory method for preparing
emulsions as there is always an excess of the
external phase present that promotes the type of
emulsion desired.
 In this method, water soluble ingredients are
dissolved in water and oil soluble ingredients are
dissolved in oil.
 If the external phase is water, the oil phase is
gradually added to water phase and then stirred
gently.
02/03/2023 By Belayneh K. 610
 Addition of external phase to internal phase (the dry

gum technique ) (4:2:1 method)
 4 parts of oil :2 parts of water: 1 part of surfactant is used
 In this method, acacia or other O/W emulsifier is triturated
with the oil in dry mortar.
 After the oil and gum have been mixed, water is added all at
once, and the mixture is triturated immediately
 Other formulation ingredients that are soluble in or miscible
with the external phase may then be mixed in to the primary
emulsion.
02/03/2023 By Belayneh K. 611

 Solid substances such as preservatives, stabilizers, colorants,
and any flavoring material are usually dissolved in a suitable
volume of water (assuming water is the external phase) and
added as a solution to the primary emulsion.
 Mixing both phases after heating
 This method is used when waxes or other substances that
require melting are used.
 The oil-soluble emulsifying agents, oils and waxes are
melted and mixed thoroughly.
 The water-soluble ingredients dissolved in the water are
warmed to a temperature slightly higher than the oil
phase.
02/03/2023 By Belayneh K. 612
Mixing both phases after heating.... cont’d
 The two phases are then mixed and stirred

until cold. For convenience, but not necessity,
the aqueous solution is added to the oil
mixture.
 This method is frequently used in the
preparation of ointments and creams.
02/03/2023 By Belayneh K. 613

 Alternate addition of the two phases to the

emulsifying agent
 Oil-soluble emulsifying agents are added to a
portion of oil and mixed
 Then equal quantity of water containing water-
soluble emulsifying agents are added to the oil
phase and stirred until the emulsion is formed.
 Further portions of the oil and water are added
alternatively until the final product is formed.
02/03/2023 By Belayneh K. 614

Factors which affect the type of emulsion formed:

• Volume of internal and external phases.
 The smaller volume will be the internal phase and the
larger volume will be external phase. In some cases,
internal phases can be more than 50% of the total volume.
• Dominance of polar and non-polar characteristic of
emulsifying agents (relative solubility of emulsifying agent in
water and oil). Dominance of polar part results in formation of
o/w emulsion and dominance of non-polar part results in
formation of w/o emulsion. Note that polar groups are better
barriers than non-polar; therefore, o/w emulsion can be
prepared with more than 50 % of oil phase “ internal phase”.
02/03/2023 By Belayneh K. 615
Stability of emulsions
 Physical instability of emulsions

 Probably the most important consideration with respect to
pharmaceutical and cosmetic emulsions is the stability of
the finished product.
 Physical instability of pharmaceutical emulsion may be
classified as follows:
 Creaming and sedimentation
 Flocculation, coalescence and breaking
 Phase inversion
02/03/2023 By Belayneh K. 616

Physical instability of emulsions..cont’d
02/03/2023 By Belayneh K. 617

Physical instability of emulsions...cont’d
Creaming
 Is the upward movement of dispersed droplets relative to
the dispersed phase.
 A creamed emulsion is inelegant in appearance, provides
the possibility of inaccurate dosage, and increases the
likelihood of coalescence as the globules are close together
in the cream.
 Sedimentation
 Sedimentation is the downward movement of dispersed
droplets relative to the continuous phase.
02/03/2023 By Belayneh K. 618

 Factors that influence the rate of sedimentation are similar to
those involved in the sedimentation rate of particles in
suspension formulations.
(Stoke’s equation)
 Sedimentation can be decreased by:

1. Reduction in the globule size
2. Decrease in the density difference between the two
phases
3. An increase in the viscosity of the continuous phase
02/03/2023 By Belayneh K. 619
Coalescence
 Coalescence is the fusion of droplets
 Depends on the structural properties of the
interfacial film.
 It decreases the number of droplets and
ultimately leads to separation of the two
immiscible phases breaking (cracking)
02/03/2023 By Belayneh K. 620

 Flocculation (aggregation)
 In flocculation , the dispersed globules come together
but do not fuse.
 Caused by alteration of electrical potential and van
der Waals forces on droplets.
02/03/2023 By Belayneh K. 621

 Breaking( cracking)
 Separation of an emulsion into its constituent
phases is termed cracking or breaking .
 It is an irreversible process
 When breaking occurs, simple mixing fail to
resuspend the globules in a stable emulsified form
because the film surrounding the particles has
been destroyed.
 It follows that any agent that will destroy the
interfacial film will break (crack) the emulsion
02/03/2023 By Belayneh K. 622
 Factors that cause an emulsion to break/crack:
The addition of a chemical that is incompatible
with the emulsifying agent
Bacterial growth
Temperature change
02/03/2023 By Belayneh K. 623

Phase inversion
 Phase inversion is the process in which an emulsion
changes from one type to another, say O/W to W/O or vice
versa
 The higher the fraction of one phase, the greater likelihood
it will form the external phase.
 Factors which contribute phase inversion:
 excess amount of internal phase
 change in the type of emulgent and

 Heating ( e.g., polysorbates)
 temperature dependent change on the
solubility of the emulsifier
02/03/2023 By Belayneh K. 624
Colloids
Introduction
 The term “ colloid” (derived from the Greek

word for glu) was used in1850 by British
chemist Thomas Graham.
 He used the term to polypetides such as
albumin and gelatin; polysaccharides such as
acacia, starch, and dextrin; and inorganic
cpds such as metal hydroxides and Prussian
blue (ferric ferocyanide).
02/03/2023 By Belayneh K. 626

Introduction..Cont’d
 Colloidal dispersions consist at least two phases-

one or more dispersed (internal phases) and
continuous phase called dispersion medium
(external phase )
02/03/2023 By Belayneh K. 627

Introduction...Cont’d
 Colloidal dispersions contain one or more

substances that have at least one
dimension in the range of 1-10 nm at the
lower end, and a few µm (0.5 µm) at the
upper end.
 Colloidal dispersions are distinguished
from solutions and coarse dispersions by
the particle size of the dispersed phase,
not its composition.
02/03/2023 By Belayneh K. 628
Classification of colloidal dispersions in terms
of the physical states of the internal and
external phases
 Classification of colloidal systems is based upon the

state of the dispersed phase and the dispersion
medium ( i.e., whether they are solid, liquid, or
gaseous)
02/03/2023 By Belayneh K. 629

Classification of colloidal dispersions in terms of the
physical states of the internal and external phases
Dispersion Dispersed phase Colloid type Examples
medium
Solid solid Solid sol pearls, opals
solid Liquid Solid emulsion Cheese, butter
Solid gas solid foam Pumice
Liquid solid sol, gel Jelly, paint
Liquid Liquid Emulsion milk
Liquid gas Foam whipped cream,
shaving cream
Gas Solid Solid aerosols smoke, dust
02/03/2023 By Belayneh K. 630
Gas Liquid Liquid aerosols clouds, fog
Pearls, opals
02/03/2023 By Belayneh K. 631

Pumice,
02/03/2023 By Belayneh K. 632

jelly paint
02/03/2023 By Belayneh K. 633

Dust Fog
02/03/2023 By Belayneh K. 634

Introduction..Cont’d
 The terms sols and gels are often applied to colloidal
dispersions of a solid in a liquid or gaseous medium.
 Sols tend to have a lower viscosity and are fluids.
 If the solid particles form bridge structures and possess
mechanical strength the system is called a gel.
 Prefixes typically designate the dispersion medium. For
example, hydrosol (or hydrogel), alcosol (or alcogel) and
aersol (or aerogel), designate water, alcohol, and air,
respectively.
02/03/2023 By Belayneh K. 635

Introduction...Cont’d
 Based on affinity or interaction between the
dispersed phase and the dispersion medium,
colloidal systems are divided as lyophilic,
lyophobic and association colloids.
 Lyophilic dispersions
 These types of dispersions are also called “ solvent-
loving).
 There is considerable attraction between the dispersed
phase and the liquid vehicle (i.e., extensive solvation).
 The system is said to be hydrophilic if the dispersion
medium is water.
02/03/2023 By Belayneh K. 636

Colloids.......Cont’d
 Lyophilic dispersions........
 Hydrophilic colloids often contain ionizable groups
that dissociate into highly hydrated ions (e.g.,
carboxylate, sulfonate, and alkylammonium ions)
or organic functional groups that bind water
through hydrogen bonding ( hydroxyl, carbonyl,
amino and imino groups)
 Hydrophilic colloidal dispersions can be further
subdivided as :
 True solutions: water soluble polymers
(e.g., acacia and povidone)
02/03/2023 By Belayneh K. 637
 Lyophilic dispersions..........
 Gelled solutions, gels, or jellies: polymers present at
sufficiently high conc. and/or at temperatures where their
water solubility is low.
 Examples, relatively high conc. solutions of gelatin and
starch (which set to gels upon cooling) and
methylcellulose (which gels upon heating)
 Particulate dispersions:
 Solids that do not form molecular solutions but remain as
minute particles form particulate dispersions.
Example, Bentonite and microcrystalline cellulose
02/03/2023 By Belayneh K. 638

 Lyophilic dispersions..........
 Note: the term lyophilic meaning only when
applied to the material dispersed in a specific
dispersion medium. A material that forms a
lyophilic colloidal system in one liquid (e.g.,
water) may not do so in another liquid (e.g.,
benzene)
02/03/2023 By Belayneh K. 639

Lyophobic dispersions
 The dispersion is said to be lyophobic (solvent-hating)
when there is little attraction between the dispersed
phase and the dispersion medium.
 If the dispersion medium is water it is called hydrophobic.
 Hydrophobic dispersions consist of particles that are only
hydrated slightly or not at all because water molecules
prefer to interact one another instead of solvating the
particles. Therefore, such particles do not disperse or
dissolve spontaneously in water.
02/03/2023 By Belayneh K. 640

 Lyophobic dispersions.........
 Examples of materials that form hydrophobic dispersions
include organic compounds consisting largely of
hydrocarbon portions with few, if any, hydrophilic
functional groups.
 Cholesterol and other steroids; some non ionized
inorganic substances (e.g., sulfur); organic lipophilic
drugs, paraffin wax, magnesium stearate, cottonseed
or soybean oils.
 Materials such as sulphur, silver chloride, and gold form
hydrophobic dispersions without being lipophilic.
02/03/2023 By Belayneh K. 641

 Association (amphiphilic) colloids
 Amphiphilic molecules have two distinct regions of
opposing solution affinities within the same molecule or
ion.
 The individual molecules are generally too small to be in
the colloidal size range.
 They tend to associate into larger aggregates when
dissolved in water or oil.
  conc. of molecules  aggregation of 50 or more
molecules called micelles (colloidal in size) occur in the
bulk of the dispersion medium.
 The concentration of monomer at which the micelles
form is termed the critical micelle concentration (CMC).
02/03/2023 By Belayneh K. 642
 Association (amphiphilic) colloids
 Below CMC, amphiphiles conc. ,  the number
(concentraton) of amphiphile at air-water interface.
 Further  amphiphiles conc.  saturation of the
interface  Micelles formation.
 Spherical micelles exist at conc. close to CMC.
 At higher conc. the laminar micelles form and exist in
equilibrium with spherical micelles.
 Size and shape of colloidal particles
 Colloidal particles possess high surface area compared
with the surface area of an equal volume of large
particles.
02/03/2023 By Belayneh K. 643
 Size and shape of colloidal particles........
 Possession of large specific surface results in
many of the unique properties of colloidal
dispersions.
 For example, platinum is effective as a
catalyst only when in the colloidal form as
platinum black adsorbing the reactants onto
its surface
 Particle shape depends upon the chemical
nature of the particle and the method employed
to prepare the dispersion .
02/03/2023 By Belayneh K. 644
Optical properties of colloids
Light scattering
 Scattering is the emission of light in all directions,
which decreases the intensity of the ordered beam.
 The optical property of a medium is determined by
its refractive index.
 Light will pass through the medium undeflected
when the refractive index is uniform throughout.
 When there are discrete variations in the refractive
index due to the presence of particles or caused by
small scale density fluctuation, part of the passing
light will be scattered in all directions.
02/03/2023 By Belayneh K. 645
Optical properties of colloids.......Cont’d
Light scattering ............

 When an intense, narrowly defined beam of light
is passed through a colloidal dispersion, its path
becomes visible because of the light scattered by
the particles.
 Because of the scattered light the sol appears

turbid: this is known as the Tyndall effect.
02/03/2023 By Belayneh K. 646

02/03/2023 By Belayneh K. 647
Optical properties of colloids.....Cont’d
Light scattering ............

 The turbidity of a sol is given by the
expression:
I0 is the intensity of the incident beam,

I intensity of the transmitted light beam,
L the length of the sample and
is the turbidity.
 Turbidity depends on size, shape, conc.of subs.
02/03/2023 By Belayneh K. 648
Optical properties of colloids.....Cont’d
 Light scattering measurements are important

for estimating particle size, shape and
interactions, particularly of dissolved
macromolecular materials.
 Kinetic properties of colloids
Brownian motion
 Colloidal particles are subject to random collisions
with molecules in the dispersion medium.
02/03/2023 By Belayneh K. 649
Kinetic properties of colloids...cont’d
Hence each particle pursues an irregular and

complicated zigzag path.
If the particles are observed under a
microscope or the light scattered by colloidal
particles is viewed using an ultramicroscope
an erratic motion is seen.
02/03/2023 By Belayneh K. 650

Kinetic properties of colloids...cont’d
Diffusion
Particles diffuse spontaneously from region of higher
concentration to lower concentration until the concentration of
the system is uniform throughout the medium
Diffusion is direct result of Brownian movement
The rate of diffusion is expressed by Fick's first law:
02/03/2023 By Belayneh K. 651

Kinetic properties of colloids....cont’d
Diffusion
 dq is the amount of substance diffusing in time dt

 S diffusion area
 D is the diffusion coefficient (the amount of material diffusing per unit time
across a unit area when, dC/dX called the concentration gradient, is unity.
dC is change in concentration with distance travelled, dx.
( D has the dimension of area per unit time)
02/03/2023 By Belayneh K. 652

Electrical properties of colloids
Electrokinetic phenomena
 Electrokinetics is a general term used to
describe the movement of particles due to the
action of electric field.
 There are four electrokinetic phenomena:
 Electrophoresis,
Electroosmosis,
Sedimentation potential,
Streaming potential
02/03/2023 By Belayneh K. 653
Electrical properties of colloids....cont’d
 Electrophoresis
 Involves the movement of charged particles
through a liquid under the influence of an
applied potential difference.
02/03/2023 By Belayneh K. 654

Electrical properties of colloids....cont’d
Electroosmosis
 It is the movement of liquid relative to a
stationary charged surface under the influence
of an applied potential difference.
02/03/2023 By Belayneh K. 655

Electrical properties of colloids.......cont’d
Sedimentation potential
• It is the creation of a potential when
particles undergo sedimentation.
• It is the reverse of electrophoresis.
 Streaming potential
• It is the potential created when liquid is
made to flow along a stationary charged
surface.
02/03/2023 By Belayneh K. 656

Pharmaceutical applications of colloids
 Proteins are important natural colloids and are found
in the body as components of muscle, bone and skin.
 Certain drugs possess increased therapeutic properties
when formulated in colloidal state. For example,
Colloidal silver chloride, silver iodide are effective
germicides and do not cause irritation that is
characteristic of ionic silver salts.
 Coarsely powdered sulphur is poorly absorbed when
administered orally, yet the same dose of colloidal
sulphur may be absorbed so completely as to cause a
toxic reaction and even death
02/03/2023 By Belayneh K. 657

Pharmaceutical applications of colloids...Cont’d
 Colloidal copper has been used in the treatment of cancer,
colloidal gold as a diagnostic agent for paresis( partial loss of
movement), and colloidal mercury for syphilis.
 Naturally occurring plant macromolecules such as starch and
cellulose that are used as pharmaceutical adjuncts are
capable of existing in the colloidal state
 Hydroxyethyl starch is a macromolecule used as plasma
substitute.
 Other synthetic polymers are applied as coatings to solid
dosage forms to protect drugs that are susceptible to
atmospheric moisture or degradation under the acid
conditions of the stomach.
02/03/2023 By Belayneh K. 658

Pharmaceutical applications of colloids (Cont’d)
In general, pharmaceutical application of colloids include:

Therapeutic
Diagnostic agents,
pharmaceutical excipients.
Drug delivery systems
02/03/2023 By Belayneh K. 659

Rheology
Introduction
 Rheology is the branch of physics that deals with the flow

of liquids and the deformation of solids.
 It is derived from, the Greek word rheo (“to flow”) and
logos (“science”)
 Viscosity is an expression of the resistance of a fluid to
flow.
 The higher the viscosity, the greater is the resistance to
flow.
 Water, which is easier to stir than syrup, is said to have
the lower viscosity.
02/03/2023 By Belayneh K. 661

Introduction...........cont’d
 Drug release from dosage forms and delivery systems is
often controlled or modulated by the rheological properties
of the formulation matrix.
 Although at a molecular level, diffusion is governed, in part,

by the rheological behavior of the environment.
 Rheological principles govern the circulation of blood and

lymph through capillaries and large vessels, the flow of
mucus, the transit of luminal contents through
gasterointestinal tract, the bending of bones, the stretching
of cartilage, and the contraction of muscle.
02/03/2023 By Belayneh K. 662
Fundamentals
 In rheology, stress means a system of forces

whether applied in a compressive, extensional,
or shear mode.
 Strain means a change in size or shape.
 Rheological principles stem from two
fundamental laws derived in the late 17th
century: Robert Hooke’s law of elasticity (1676)
and Issac Newton’s law of flow (1687)
 The corresponding equations, which symbolize
these laws, characterize Hookean and Newtonian
02/03/2023
materials. By Belayneh K. 663
Fundamentals……..cont’d
 When a force is applied to a body, the two
rheological extremes of behaviour are the pure
elastic deformation of a Hookean solid and the
pure viscous flow of a Newtonian liquid.
 Pure (ideal) elasticity means that the body
returns to its original form once the stress is
removed, while pure (ideal) viscosity means that
the liquid flows even under the smallest stress
and does not return to its original shape or form
once the stress is removed.
02/03/2023 By Belayneh K. 664
Fundamentals……....cont’d
 The resistance to deformation, or flow, is
described by the modulus of elasticity or Young’s
modulus, E, for an elastic body undergoing
extension, and by η, the coefficient of viscosity
for a liquid
 Elastic deformation of solids is described by
Hooke’s law,
dl is the elastic deformation or extension in length

L caused by application of stress σ
02/03/2023 By Belayneh K. 665
Fundamentals……cont’d
 Viscous deformation, i.e., viscous flow, occurs in
accordance with Newton’s law

 the applied stress results in flow with velocity
gradient, γ. or rate of shear. The proportionality
constant η is termed viscosity.
 The rate of shear or velocity gradient, γ. indicates
how fast the liquid flows when a shear stress is
applied to it. Its unit is s-1
02/03/2023 By Belayneh K. 666

Fundamentals……..cont’d
 The reciprocal of viscosity is fluidity.

 Viscosity has also been described as the
internal friction in the fluid as it
corresponds to the resistance of the fluid
to the relative motion of adjacent layers of
liquid.
02/03/2023 By Belayneh K. 667

Newtonian system
 The viscosity of simple liquids, i.e., pure liquids
consisting of small molecules and solutions
where solute and solvent are small molecules,
depends only on composition, temperature and
pressure.
 It increases moderately with increasing pressure
and markedly with decreasing temperature.
 For solutions of solid solutes, the viscosity
usually increases with concentration.
02/03/2023 By Belayneh K. 668

Newtonian system......cont’d
 Simple liquids follow Newton’s law (

) of direct proportionality between shear
stress and rate of shear, so that their
viscosity is independent of the shear stress
or the rate of shear. Their flow behaviour
is thus referred to as Newtonian.
 Substances such as water, ethanol, ethyl
ether, glycerine are Newtonian fluids.
02/03/2023 By Belayneh K. 669

Newtonian system..........
 Plots of shear stress (on the y-axis) as a function
of the rate of shear (on the x-axis) are referred to
as flow curves or rheograms.
 The rheograms of typical Newtonian liquids, like

those of Figure above, are straight line going
through the origin. Viscosity is the slope of such a
line or the tangent of the angle it makes with the
horizontal axis
02/03/2023 By Belayneh K. 670
Newtonian system.........cont’d
 In the CGS system, viscosity is defined as the
tangential force per unit area, in dynes/cm2, required
to maintain a difference in velocity of 1cm/s between
two parallel layers of a liquid 1 cm apart. Its unit is
therefore dynes/cm2 sec-1 or g/cm.s, which is called a
poise.
 Because many liquids including water have
viscosities of the order of 1/100 of a poise, their
viscosity is often expressed in centipoises.
 In the SI system, the unit of viscosity is Newton x sec /m2 or
Pascal.s, which equals 10 poise.
02/03/2023 By Belayneh K. 671
Newtonian system..........cont’d
Temperature dependence of viscosity

 Whereas the viscosity of a gas increases
with temperature, that of a liquid decreases
as temperature is raised ( rise in kinetic
energy  rise in motion of molecules).
02/03/2023 By Belayneh K. 672

Temperature dependence of viscosity
 The variation of viscosity with temperature is described

by an Arrhenius equation
 A is a constant depending on the molecular weight and

molar volume of the liquid
 Ev is an “activation energy” required to initiate flow
between molecules
 T is the absolute temperature
 R is the molar gas constant
 The activation energy for flow has been found to be about
one-third that of the energy of vaporization
02/03/2023 By Belayneh K. 673
Non-Newtonian system
 Fluids that do not obey Newton’s Law ( ) are

often termed as non- Newtonian fluids.
 Non- Newtonian behaviour is generally exhibited
by liquid and solid heterogeneous dispersions
such as colloidal dispersions, suspensions and
ointments.
02/03/2023 By Belayneh K. 674

Plastic flow
 Semisolids that do not flow at low shear stresses

(exhibiting reversible deformation like elastic solids)
but flow like liquids above their yield value (i.e.,
yield stress) are termed plastic or Bingham bodies.
This type of rheological behaviour is termed as
plasticity.
 Plastic flow curves do not pass through the
origin, but rather intersect the shearing stress
axis (or will if the straight part of the curve is
extrapolated to the axis) at a particular point
referred to as the yield value.
02/03/2023 By Belayneh K. 675
Plastic flow………...cont’d
• Plastic flow is often exhibited by semisolids
characterized as structured media, ie, semisolids
that have a cross-linked three-dimensional network
of polymers, macromolecules, or particulates
extending throughout the system.
02/03/2023 By Belayneh K. 676

Plastic flow......cont’d
• A yield value exists because of the contacts between
adjacent particles (brought about by van der Waals forces),
which must be broken down before flow can occur.
• Frictional forces between moving particles can also
contribute to yield value.
• Once the yield value is exceeded, any further increase in
shearing stress (i.e., σ−σyield) brings about a direct
proportional increase in rate of shear.
• In effect a plastic system resembles a Newtonian system at
shear stresses above the yield value
02/03/2023 By Belayneh K. 677

Pseudoplastic flow (shear thinning fluids)
 Many colloidal systems, especially polymer solutions and

flocculated suspensions become more fluid the faster
they are stirred .
 In shear thinning fluids, the viscosity decreases with
increasing shear.
 As the increase in shear rate is greater than the increase
in the corresponding shear stress, the flow curve is
concaved toward the shear rate axis.
 There is an apparent viscosity for each value of shear rate
or shear stress.
02/03/2023 By Belayneh K. 678

Pseudoplastic flow (shear thinning fluids)
02/03/2023 By Belayneh K. 679

Pseudoplastic flow (shear thinning
fluids).......cont’d
 Many pharmaceutical products, including liquid
dispersions of natural and synthetic gums e.g.,
tragacanth, sodium alginate, methyl cellulose and sodium
carboxymethylcellulose exhibit pseudoplastic flow.
 The shear-thinning behaviour of polymer or

macromolecule solutions arises from the alignment of
neighbouring macromolecules and the degree of their
entanglement.
02/03/2023 By Belayneh K. 680

fluids)........cont’d
 When shear is applied, the randomly coiled,
entangled macromolecules tend to disentangle
themselves and to align themselves in the
direction of flow.
02/03/2023 By Belayneh K. 681

fluids)......cont’d
• The imposition of increasing shear in these systems enables
the macromolecule “chains” to uncoil progressively and
become streamlined or elongated, thereby offering less
resistance to flow than the original, approximately spherical
shapes.
• At very high shear rates, the dissolved polymer chains are
wholly disentangled and well align in the direction of flow,
and the aggregates of particles are broken up as far as
possible. There is no residual structure left which can be
broken up by further increment in shear rate: the viscosity
levels off at a constant value called the upper Newtonian
viscosity, ηinfinity.
02/03/2023 By Belayneh K. 682
Dilatant flow
 Certain suspensions with a high percentage of dispersed

solids exhibit an increase in resistance to flow (increased
viscosity with increase rates of shear).
 Such systems actually increase in volume when sheared
and hence termed dilatants.
 Substances possessing dilatant flow properties are
invariably suspensions containing a high concentration
( about 50% or greater) of small deflocculated particles.
02/03/2023 By Belayneh K. 683

Thixotropy (Time dependent non-
Newtonian flow)
 Materials whose consistency depends on the
duration of shear are said to be thixotropic.
 If a suspension is viscous and /or the particles are
large and heavy, their Brownian motion is too
slow to restore the broken interparticle links
“instantaneously.”
 Likewise, the entanglement of polymer chains
are slow to be reestabilished by Brownian
motion if their solution is viscous.
02/03/2023 By Belayneh K. 684

Newtonian flow)....cont’d
 If the rate of link restoration by Brownian motion
is lower than the rate of link breakdown by shear,
the apparent viscosity decreases even while the
system is under constant shear, as the size of the
particles aggregates or the extent of
macromolecular entanglement is progressively
reduced.
 Furthermore, the apparent viscosity at a given
shear rate is lower if the system is stirred recently
at high speed than if that the shear rate was
approached from low speed or from rest.
02/03/2023 By Belayneh K. 685
Thixotropy (Time dependent non-Newtonian flow).......cont’d
 The apparent viscosity depends not only on

temperature, composition, rate of shear or shear
stress, but on the previous shear history and time
under shear.
 The differences between the up and down
branches of a flow curve illustrates a common
phenomenon called hysteresis.
 The area enclosed by two branches and the
stress axis is called hysteresis loop.
 Its size is the measure of the extent of
thexotropic breakdown in the structure of the
02/03/2023 system. By Belayneh K. 686
Newtonian flow).....cont’d
 The decrease in the hysteresis loop parallels a
decrease in the amount of structural breakdown
of the system as each cycle leaves intact less
residual structure to be broken dawn in the next
cycle. When no structure remains, the
Newtonian flow curve results.
 The absence of hysteresis in the flow curves is
due to the rebuilding of structure by Brownian
motion is as fast as or faster than the shear-
induced structural breakdown or the response
time of the viscometer.
02/03/2023 By Belayneh K. 687
02/03/2023 By Belayneh K. 688
Viscoelasticity
• When stressed, viscoelastic materials

simultaneously exhibit some of the
properties of elastic solids and some of the
properties of viscous liquids: some
deformation occur instantaneously upon the
application of stress and continuous as long
as the stress is applied.
• Viscoelasticity may be viewed as a
combination of viscous and elastic properties
when undergoing deformation.
02/03/2023 By Belayneh K. 689
Viscoelasticity………...cont’d
• Upon the removal of the stress, there is partial
recovery of the original shape.
• In effect, viscoelastic systems are capable of storing

part of the deformation energy elastically and
reversibly.
• Viscoelastic materials are molten polymers,

chewing gums and most gels.
02/03/2023 By Belayneh K. 690

Pharmaceutical applications of rheology
Fluids
• Mixing
• Particle size reduction of disperse systems with
shear.
• Passage through orfices, including pouring, package in
bottles, and passage through hypodermic needles.
• Fluid transfer, including pumping and flow through
pumps.
• Physical stability of disperse systems.
02/03/2023 By Belayneh K. 691

Pharmaceutical applications of
rheology.........cont’d
2. Quasisolids (semisolids)
- Spreading and adherence on the skin
- Removals from jars or extrusion from tubes
- Release of drug from base
3. Solids
- Flow of powders from hoppers and into die cavities in
tableting or into capsules during encapsulation
- Packagability of powdered or granular solids
4. Processing
- Production capacity of the equipment
- Processing efficiency
02/03/2023 By Belayneh K. 692

Integrated Pharmacy PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Integrated Pharmacy PDF

Uploaded by

Copyright:

Available Formats

Integrated Physical Pharmacy &

Belayneh K. Gelaw (B.pharm, Msc)

Introduction to dosage forms

• Some drugs may cause local irritations or injury

• Some drugs can have unpleasant organoleptic

 The extremely low aqueous solubility of the base

 Paracetamol is also available in a range of dosage

Solid dosage Semi-solid Liquid dosage

Solid dosage forms

Semi-solid dosage forms 

 They consist of a cylindrical body and cap, both with

 They are larger than suppositories (3-5 g) in weight.

 They are globular, oviform or cone shaped.

 Colouring, flavouring and sweetening agents, may

 Some laxatives are among the drugs currently

 In the case of contraceptive implants the effect

 These are large tablets designed to be sucked and

 The main use of lozenges is in the treatment of mouth

 Suspensions are available for both oral and external

 These are mixtures of two immiscible liquids, usually

 The oil, in a very fine state of subdivision, is

 Many drugs are formulated as enemas and are used to

 They are administered via a thin, soft, rubber or

 Previously many linctuses contained a level of

 The therapeutic action of drugs present as elixirs

 Mouth washes are less concentrated than gargles.

 The active ingredients are usually antiseptics.

 The base usually contains the medicament in solution

 Are a class of gels containing high proportion of

 These devices are fitted with metering valve which

• Drug substances are rarely administered alone rather

• Some excipients are added to specific dosage forms

 Generally, the pharmaceutical ingredients may be

2. Inactive pharmaceutical ingredients (Additives or

 Pharmaceutical solvents may be aqueous or

Ointment, cream & paste bases

Diluents (or fillers)

02/03/2023 Belayneh Kefale 70

02/03/2023 Belayneh Kefale 71

02/03/2023 Belayneh Kefale 72

02/03/2023 Belayneh Kefale 73

• According to their solubility

02/03/2023 Belayneh Kefale 74

02/03/2023 Belayneh Kefale 75

02/03/2023 Belayneh Kefale 76

02/03/2023 Belayneh Kefale 77

• Glidants act to enhance the flow properties of the powders

02/03/2023 Belayneh Kefale 78

 Route of drug administration is the way through

 Enteral routes are routes related with GIT and

 Parentral route of drug administration include:

 The highly vascular nature of the tongue and buccal

 For administration by this route, drugs are formulated

 To promote evacuation of the bowel to relieve

02/03/2023 By Belayneh K. 100

 Patients who are vomiting, e.g. gastrointestinal

02/03/2023 By Belayneh K. 101

02/03/2023 By Belayneh K. 102

 By this route, dosage forms are administered in the

 For administration, drugs may be formulated as

02/03/2023 By Belayneh K. 104

 Most often this route is used for a local effect (used to

 However, drugs absorbed from the vagina are not