BPHARM SEM 7

NDDS (BP704TP)

Presented by:
Ms. Kaushika Patel
Asst Professor,
Dept of Pharmaceutical Technology
L. J. Institute of Pharmacy, Ahmedabad
The properties of drugs to be considered for
the designing of CRDDS are

• Biopharmaceutic Properties
1.

• Pharmacokinetic Properties
2.

• Pharmacodynamic Properties
3.
 A. Biopharmaceutic Properties of drug

DRUG IN THE RELEASE DRUG AT THE ABSORPTION DRUG IN THE

DOSAGE ABSORPTION
FORM SITE BODY

RATE LIMITING RATE LIMITING

FACTOR FOR FACTOR FOR
CRDDS IR DOSAGE FORM

The type of delivery system and route of administration of

drug in CRDDS depends upon the physico-chemical properties
and biopharmaceutic characteristics of drug
 1. Molecular weight of the drug

• Drugs with lower molecular weight have faster

and more complete absorption.
• Drugs with higher molecular weight are not
preferred for oral CRDDS
Transport Upper limit of Mol wt
mechanism
Pore 150 Dalton (spherical
transport compounds)
400 Dalton (linear compounds)
Passive 600 Dalton
diffusion
 2. Solubility of the drug

• For all mechanisms of absorption, the drug must be

present at the site of absorption in the form of
solution. During the Pre-formulation study , it is
necessary to determine the solubility of the drug at
various pH values

• The lower limit of aqueous solubility for drug to be

designed as CRDDS is 0.1 mg/ml

• Solubility of drug limit the choice of mechanism for

CRDDS. For eg: Diffusional systems are not suitable
for poorly soluble drug since their absorption is
dissolution rate limited.
SOLUBILITY CONCLUSION EXAMPLE
PATTERN OF DRUG
Good pH independent Good candidate for Pentoxiphylline
aqueous solubility oral CRDDS
(> 0.1 mg/ml)

pH dependent aqueous Suitable for Phenytoin

solubility parenteral CRDDS
eg: im depot

Solubility in non-aqueous Suitable for steroids

solvent parenteral CRDDS
eg: im depot
3. Partition coefficient and lipophilicity of
drug
• Partition coefficient is the fraction of drug in an oil phase to
that of an adjacent aqueous phase. It is determined by n-
octanol /buffer system for the entire pH range in the GI
tract

• Higher the apparent partition coefficient of the drug, more is

its lipophilicity. Such lipophilic compound have higher
permeation rate into the biological membrane of body
(including selective barriers like BBB) showing greater rate
and extent of absorption

• Such lipid soluble compounds have very low aqueous

solubility and thus these compound persist in the body for
long periods.
 4. Drug pKa and Ionization at
physiological pH
• Drug pKa is an important parameter that influences
its absorptive behavior and aqueous solubility (if it’s a
weak acid or base)

• The pKa range for acidic drugs whose ionization is pH

sensitive is 3-7.5 and that for basic drug is 7-11

• For optimum passive absorption, the drug must be in

unionized form upto the extent of 0.1-5%. Drugs
existing largely in ionized form are poor candidate of
CRDDS
 5. Drug Permeability
• The 3 important parameters that determine the
permeability of drug for passive transport through
intestinal membrane are

• Lipophilicity (log P)
1.

• The polarity of drug measured by

2. number of H- bond donors and H-
bond acceptors on drug molecule

3. • Molecular size
 6. Drug stability
• The stability of drug in environment to which it is exposed, is
another physico-chemical factor to be considered in design at
sustained/ controlled release systems
Drugs conclusion Formulation strategy Example
unstable in
Throughout Cannot be Alternative route of Nitroglycerine
GIT formulated as oral administration to be
CRDDS preferred like
Parenteral or
Transdermal
gastric pH The drug release in Sustained release in Propanetheline
gastric pH should intestine (Delayed
be avoided release)
Intestinal pH The drug transit to Gastro-retentive Probanthine
intestine should be formulation
avoided
 7. Absorption mechanism and site

• The absorption of drug depend on the drug’s

pKa, the pH at site, binding of drug to mucus,
blood flow rate, etc

Preferred Not Preferred

Absorption Passive diffusion Carrier mediated
Mechanism Transport
Site of Throughout the Window
absorption entire GIT absorption
 8. Biopharmaceutic aspects of ROA

• Oral and Parenteral are most suitable routes

for CRDDS followed by Transdermal route

• The other routes of minor importance are

buccal/sublingual, nasal, rectal, ocular, vaginal,
pulmonary, etc.

• The selection of preferable route of administration

depends upon the characteristics of drug, duration
of action required, dose size, absorption efficiency,
etc.
 ORAL ROUTE
CHARACTERISTICS OF DRUG
SUITABLE FOR ORAL CRDDS
Absorption through the entire
length of GIT
Dose – up to 1000 mg
Duration of action- 12-24 hrs
[due to transit time of around
14 hrs]
CHARACTERISTICS OF DRUG
NOT SUITABLE FOR ORAL
CRDDS
pH dependant absorption
Absorption through window
Destabilized by GI pH or
enzymes
Extensive pre-systemic
metabolism
Affected by gut motility
Absorption through active
transport
 PARENTERAL ROUTE
CHARACTERISTICS OF
DRUG SUITABLE FOR
ORAL CRDDS
Dose – up to 2 ml/2 g
Duration of action- 24 hrs to
12 months
IMPORTANT FACTORS
FOR DRUG RELEASE
Solubility in surrounding
tissues
Molecular weight
Partition coefficient
Drug pKa
Contact surface between drug
and surrounding tissues
 TRANSDERMAL ROUTE
CHARACTERISTICS OF IMPORTANT FACTORS
DRUG SUITABLE FOR FOR DRUG RELEASE
ORAL CRDDS
Extensive presystemic Partition coefficient of drug
metabolism
Dose – preferably up to 10 mg Skin condition
maximum 50 mg
Skin perfusion rate
Contact area
Drug permeability through
skin
B. Pharmacokinetic Properties of drug

• A detailed knowledge of drug ADME

characteristics is essential for the proper
designing of CRDDS

• An optimum range of each pharmacokinetic

parameter is desired for making the controlled
release possible
 1. Absorption rate
• The absorption rate of the drug should be higher
than the desired release rate of the drug from the
CR dosage form, in order to ensure that release rate
is the rate controlling step.

• Compounds that demonstrate low absorption rate

constants will probably be poor candidates for
CRDDS because continuous drug release leads to
pool of unabsorbed drug eg: Iron

• Aqueous soluble but poorly absorbed potent

drugs are also unsuitable for CRDDS because slight
variation in absorption may lead to potential toxicity
eg: Decamethonium
 2. Distribution Rate
• The distribution of drugs into tissues can be important
factor in the overall drug elimination kinetics. Distribution
constant not only lowers the concentration of drug but
it also can be rate limiting step in achieving equilibrium
with blood and extra vascular tissue

• For designing of CRDDS, one must have information of

parameters that are used to describe distribution
characteristics like apparent volume of distribution and
clearance. They play key role estimating the required
dose rate for CRDDS, and predicting the steady state
concentration
 3. Rate of metabolism
• There are two aspects of metabolism that significantly
hamper the designing of CRDDS
1. If drug upon chronic 2. If there is a variable
administration is capable of blood level of drug
enzyme induction or through a first-pass
inhibition, making the effect, reducing the
attainment of steady state bioavailability of drug.
plasma concentration difficult

• A drug with extensive metabolism is suitable for CRDDS

provided that the metabolism rate is not too rapid

• The extent of metabolism should be predictable and

constant for all routes of administration
 4. Elimination half life
• For an ideal CRDDS, the rate of absorption (for
extended period of time) should be equal to rate of
elimination

• A drug must have half life that is correlated with its

pharmacological response. For some drugs like
MAO inhibitors, the duration of action is longer than
their half life

• A drug in CRDDS should have MRT (mean residence

time) significantly longer than that in conventional
formulation
Drugs with
Elimination Outcome Example
half life
< 2 hrs poor candidates for CRDDS Furosemide,
because it requires large amount levodopa
of dose for sustaining the effect

> 8 hrs poor candidates for CRDDS since Amlodipine,

their effect is already sustained, Digoxin,
unless it is simply intended for a Warfarin
reduction in fluctuation of
steady state blood levels.

2 – 8 hrs Ideal candidates for CRDDS for propanolol

reduction in dosing frequency
 5. Dosage form index (DI)
• The therapeutic concentrations are the desired or
target steady state peak concentrations (Css max), the
desired or target steady state minimum concentrations
(Css min), and the mean steady state concentration
(Css avg)

• The ratio of Css max to Css min is known as Dosage

form index

• Ideally its value should be as close to 1 as possible to

reduce the fluctuations between Css max and Css min
and maintain the steady state plasma concentration
within therapeutic window
C. Pharmacodynamic Properties of drug

1. Dose size

 A single dose of 0.5 - 1.0 gm is considered ideal

for CRDDS. [maximum dose limit: 1g]

 If an oral product has a dose size greater that

500mg, it is a poor candidate for sustained
release system, since addition of sustaining dose
and possibly the sustaining mechanism will, in
most cases generates a substantial volume
product that is unacceptably large.
 2.Therapeutic Range

• Therapeutic range is the difference between

MEC and MSC

• A candidate drug for CRDDS should have wide

therapeutic range, so that the fluctuation in
release rate does not lead to concentration
beyond this limit
 3.Therapeutic Index (TI)
• TI is the ratio of MSC to MEC
• Larger the TI ratio, the safer is drug
• Drugs with narrow TI are poor candidates of
CRDDS, because their therapeutic concentration and
toxic concentration are nearer to each other making
the precise control of release rate difficult
• If drug with narrow TI is used in CRDDS, the release
rate must be controlled within therapeutic range
• Drugs with narrow TI and short half life are
administered more frequently than twice a day
 4. PK/PD relationship
• The relationship between plasma
concentration and pharmacological response
is very significant in the designing of CRDDS

• The drugs whose pharmacological response is

independent of plasma concentration are
poor candidates of CRDDS
Eg: Reserpine
SUMMARY OF FACTORS IN THE DESIGN OF
CRDDS
A. BIOPHARMACEUTIC DESIRED FEATURES
PROPERTIES OF DRUG
1 Mol. wt > 600 mg
2 Aqueous solubility > 0.1 mg/ml
3 Partition coefficient 1-2
4 pKa Acidic drug: 3-7.5
Basic drug: 7-11
5 Ionization at physiological pH NMT 95%
6 Stability Stable at both gastric and
intestinal pH
7 Absorption mechanism Passive, but not through
window
SR B. PHARMACOKINETIC DESIRED FEATURES
NO PROPERTIES OF DRUG
1 Absorption rate high
2 Metabolism rate Not too high
3 Elimination half life 2 – 8 hrs
4 Dosage form Index 1

SR C. PHARMACODYNAMIC DESIRED FEATURES

NO PROPERTIES OF DRUG
1 Dose Maximum 1 g
2 Therapeutic Range Wide
3 Therapeutic Index (TI) Wide
4 PK/PD relationship Good
 FAQs

1. Discuss the factors affecting the

designing of CRDDS
2. Explain the characteristics of drug to be
considered in the design of CRDDS