2. BIOPHARMACEUTICS:
It is the study of physicochemical properties of drug and drug product in
vitro on the bioavailability of the drug in vivo to produce a desirable
therapeutic effect
It allows for the rational design of drug products. A primary concern in
biopharmaceutics is the bio availability of the drugs
BIOAVAILABILITY:
The measurement of rate and extent of active drug that become available
at the site of action
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3. The type of drug product eg: tablet capsule topical ointment etc
The route of drug administration including the anatomic and
physiologic nature of the application site eg: oral, parentrals, topical,
injectables, implants etc
Desired pharmacodynamic effect eg: immediate or prolonged activity
The physicochemical properties of drug molecules
The method of manufacturing
The nature of excipients in the drug product
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4. Systemic drug absorption from a drug product consists of a
succession of rate process. For solid oral, immediate release
drug products eg: tablets, capsules the rate process include:
1. Disintegration of the drug product and subsequent
release of the drug
2. Dissolution of the drug in an aqueous environment
3. Absorption across cell membranes into the systemic
circulations
In the process of drug disintegration, dissolution, and
absorption, the rate at which drug reaches the circulatory
system is determined
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5. The slowest step in a series of kinetic processes is called the
“rate limiting step”
Except for controlled release products, disintegration of a
solid oral drug product is usually more rapid than drug
dissolution and drug absorption
For drugs that have very poor aqueous solubility, rate at
which the drug dissolve is often the slowest step and
therefore exerts a rate limiting effect on drug bioavailability
For a drug that has a high aqueous solubility, the
dissolution rate is rapid, and the rate at which the drug
crosses or permeates cell membranes is the slowest or rate
limiting step
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6. 1. Drug solubility and dissolution rate
2. Particle size and effective surface area
3. Polymorphism and amorphism
4. Pseudo polymorphism
5. Salt form of drug
6. Lipophilicity of drug
7. pka of drug and gastrointestinal pH
8. Drug stability
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7. Absorption of drug is possible only when the drug is in
solution form, where in molecules are independent and
assume molecular dimensions.
Based on the dosage forms the variation could be described
as:
solution > suspension > capsules > compressed tablets >
coated tablets
Note: except in case of CRDDS
Absolute solubility or intrinsic solubility is defined as the
maximum amount of solute dissolved in the given solvent
under standard conditions of temperature, pressure and
pH
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8. In order to avoid bioavailability problems the drug
must have a minimum aqueous solubility of 1%
The rate determining steps in absorption of orally
administered drugs are:
1. Rate of dissolution
2. Rate of drug permeation through biomembrane
Solid dosage
forms
Solid drug
particles
Drug in
solution in
absorption site
Drug in body
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9. It is the rate determined step for hydrophobic and poorly soluble aqueous
soluble drugs
Eg : griesiofulvin and spirnolactone
Permeation is the rate determining step for hydrophilic and high aqueous
soluble drugs
Eg : neomycin
Given by noyer witneys equation:
dc/dt= a/h × D(S-C)
Where, dc/dt = dissolution rate of drug
a = surface area of solid
h = aqueous diffusion layer thickness
d = aqueous diffusion coefficient
s = aq. Drug solubility at the surface of dissolved solid
c = conc. Of drug in bulk aq. phase
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10. It plays a major role in drug absorption and this case is
important when the drug is poorly soluble dissolution
rate of particles and surface area
Particle size reduction has been used to increase the
absorption of a large number of poorly soluble drugs
Eg : griseofulvin
Types of surface areas :
1. Absolute surface area
2. Effective surface area
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11. To increase the effectiveness surface area, we have to
reduce the size of particle up to 0-1 micron. So these
can be achieved by micronisation process.
But in this case one of the most important thing to be
kept in mind that what type of drug is needed to be
micronised if it is a :
1. Hydrophilic
2. Hydrophobic
Hydrophilic drugs : in this case the small particles
have higher energy than the bulk of the solid
resulting in an increased interaction with the solvent
Eg : griesiofulvin – the dose reduced to half due to
micronisation
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12. Hydrophobic drugs :
In this technique the results decreased effective surface
area and thus fall in dissolution rate
Reasons for such change include :
1. Air entrapment
2. Surface free energy
Polymorphism:
These are the types of morphological structures which
differ in molecular packing but share the same chemical
composition
These have profound influence on development as it may
exhibit different solubility, dissolution rate, and
hygroscopicity etc
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13. Some of the drugs can exist in amorphous form i.e
having o internal crystal structure such drugs
represents the highest energy state
The order of different solid dosage forms of the drugs
are :
AMORPHOUS > METASTABLE > STABLE
The amorphous form of novo biocin is 10 times more
stable than the crystalline form
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14. When the solvent molecules are entrapped in the
crystalline structure of the polymorph it is known as
pseudo polymorphism
Types :
1. Solvates
2. Hydrates
Solvates : where the solvent molecules are
incorporated in the crystal lattice of the solid are
called as solvates
Hydrates : when the solvent in association with the
drug in water, the solvate is know as hydrate
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15. It is a method of converting a drug into the salt form by
virtue of which its solubility dissolution and there by
absorption increases to many folds
While considering the salt form of drug pH of the diffusion
layer is important not the pH of the bulk of the solution
Eg : salt of weak acid, it increases the pH of the diffusion
layer, which promotes the solubility and dissolution of a
weak acid and absorption is bound to be rapid
But sometimes more soluble salt form of drug may results
in poor absorption
Eg : sodium salt of phenobarbitone, its tablet swells and
did not get disintegrated thus dissolved slowly and results
in poor absorption
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16. A drug for oral use may be destabilize either during its
shelf life or in the GIT
The 2 major stability problems resulting in poor
bioavailability of an orally administered drug are :
1. Degradation of drug into inactive form
2. Interaction with one or more components either of
dosage forms or those present in GIT to form a
complex that is poorly soluble
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17. This theory expresses the inter relationship between
dissociation constant and partition coefficient of the
drugs with the pH of GIT for the drug absorption
It states that for the drug compounds of molecular
weights more than 100 which are primarily transported
across the bio membrane by passive diffusion the
process of absorption is governed by :
1. The dissociation constant pka of the drug
2. The lipid solubility of the unionized drug
3. The pH at the absorption site
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18. Amount of drug that exists in unionized form and in
ionized form is a function of pka of drug and pH of the
fluid at the absorption site .
For weak acids :
pH = pka + log ionized/unionized
% drug ionized = 10pH- pka/1+10pH-pka × 100
For weak bases :
pH = pka + log unionized/ionized
% drug ionized = 10pka-pH/1+10pka-pH × 100
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19. It is a test which measures the rate and extent of dissolution
or release of the drug substances from a drug product,
usually aq. Medium under specified conditions.
Need for dissolution testing :
1. Evaluation of bioavailability
2. Batch to batch drug release uniformity
3. Development of more efficacious and therapeutically
optical dosage forms
4. Ensures quality and stability of the product
5. Product development, quality control, research and
application.
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20. Compendial : it is referred as MONOGRAPH in
pharmacopeia.
it means dissolution of dosage forms as per USP
monographs which contain all the specifications and
apparatus used for it.
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21. APPARATUS NAME DRUG PRODUCT
APPARATUS- 1 ROTATING BASKET TABLETS
APPARATUS- 2 PADDLE TABLETS, CAPSULES
APPARATUS- 3 RECIPROCATING
CYLINDER
EXTENDED RELEASED
DRUG PRODUCT
APPARATUS- 4 FLOW CELL LOW WATER SOLUBLE
DRUGS
APPARATUS- 5 PADDLE OVER DISC TRANSDERMAL DRUG
PRODUCTS
APPARATUS- 6 CYLINDER TRANSDERMAL DRUG
PRODUCTS
APPARATUS- 7 RECIPROCATING DISC TRANSDERMAL DRUG
PRODUCTS
ROTATING BOTTLE NON-USP EXTENDED RELEASE
DRUG PRODUCT
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22. Used for : capsules, beads, floating dosage forms
Standard volume : 900/1000ml
Advantages : full pH change during the test can be
easily automated which is important for routine work
Disadvantages : disintegration-dissolution interactions
hydrodynamic dead zone under the
basket, degassing is important
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24. Used for : tablets, capsules, delayed release drugs
Standard volume : 900/1000ml
It is the method of 1st choice
Advantages : easy to use, robust
can be easily adapted to apparatus 5
long experience
can be easily automated
Disadvantages : pH change is difficult
hydrodynamics are complex
limited volume- sink conditions for poorly
soluble drugs
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26. Used for : tablets, beads, controlled release
formulations
Standard volume : 200-250ml per station
Advantages : easy to change pH
Disadvantages : small volume
little experience
limited data
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28. Used for : low solubility drugs, implants, suppositiries,
controlled release formulations.
Variations : open system and closed system
Advantages : easy to change pH
pH profile possible
Disadvantages : deaeration necessary
high volume of media
labour intensive
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30. Used for : transdermal patches
Standard volume : 900ml
Advantages : standard equipment can be used, only
add a stain less steel disc assembly
Disadvantages : disk assembly restricts patch size
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34. Useful for : transdermal products
non disintegrating controlled release
preparations.
Samples are placed a holders using inert porous
cellulosic support. It reciprocates vertically at
frequency of 30 cycles
This test is carried out at 32˙c
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36. The US FDA defines IVIVC as a predictive mathematical model
describing the relationship between an invitro property of an
extended release dosage form and a relavant invivo response eg :
plasma drug conc. Or amount or drug absorbed
This correlation is applicable to all the dosage forms being
developed
They are 5 levels in this IVIVC :
1. Level- a
2. Level- b
3. level- c
4. Multiple Level- c
5. Level- d
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37. Level- a : it is highest level of correlation
point to point correlation exists between
invitro and invivo data
%drug absorbed calculated by method of residual,
wagner-nelson method
Level- b : it uses the principles of statistical moment
analysis. The mean invitro dissolution time is
compared either to the mean residence time or to the
mean invivo dissolution time
Level- c : it uses a single point relationship between a
dissolution parameter
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38. Multiple level- c : relation ship between one or more
pharmacokinetic parameters of interest and amount of
drug dissolved at several point of dissolution profile
it should be based on least three
dissolution time points covering early, middle, and last
stages of the dissolution profile.
Level- d : it is a semi quantitative and rank order
correlation. It is not considered useful for regulatory
purpose but can be serves as an aid in the development
of an formulation or processing procedure.
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39. In vitro parameters for correlations In vivo parameters for correlation
Dissolution rate Absorption rate
Percent drug dissolved Percent drug absorbed
Percent drug dissolved Max. plasma conc. Cmax
Percent drug dissolved Serum drug conc. Cp
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40. Difference factor f1 Similarity factor f2 inference
0 100 Dissolution profiles are
identified
≤15 ≥50 Similarity or equivalance
of 2 profiles
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41. The evaluation of similarity between dissolution
profiles are based on following conditions :
1. Minimum of 3 dissolution time points are measured
2. Standard deviation of mean of any product should
not be more than 10% from second to last dissolution
time point
3. Not more than one mean value of > 85% dissolved
for each other
4. Number of drug products tested for dissolution is
12hrs for both test and reference
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42. Pharmacodynamic considerations
Drug considerations
Drug product considerations
Patient considerations
Manufacturing considerations
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44. Drug considerations
• Chemical and
physical
properties
• pka
• Particle size
• Polymorphism
• solubility
Drug product
considerations
• Pharmacokinetics
of drug
• Bioavailability of
drug
• Desired dose of
drug
• Dosing frequency
Manufacturing
considerations
• Stability
• cost
• Quality control
• Availability of raw
materials
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45. The resistance of the drug to various chemical,
physical, microbiological reactions that may change
original properties of the preparations during
transport, storage and use
Quantitatively it is expressed as shelf life
Shelf life : it is the time during which the medicinal
product is predicted to remain fit for its intended use
under the specified conditions of storage
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46. They are 5 types of stability that must be consider for
each drug :
1. Chemical
2. Physical
3. Microbiological
4. Therapeutic
5. Toxicological
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47. Depending upon the particular dosage form involved, the
variables may or may not exert a pronounced effect on the
rate of dissolution of the drug or drug product
The centering and alignment of the paddle is critical in the
paddle method
Turbulence can create increased agitation, resulting in a
higher dissolution rate
Wobbling and tilting due to worn equipment should be
avoided
The basket method is more sensitive to clogging due to
gummy materials.
Dissolved gas in the medium may form air bubbles on the
surface of the dosage form unit and can affect dissolution
in both the basket and paddle method.
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48. Brahmakar D.M Jaiswal S.B., first edition “Absorption
of Drugs” Biopharmaceutics and Pharmacokinetics –
treatise, vllabh Prakashan, Delhi 1995.
Shargel L., Andrew B.C., Fourth edition “Physiologic
factors related to drug absorption” Applied
Biopharmaceutics and Pharmacokinetics. Prentice hall
international, INC., Stanford 1999.
www.pharmascience.org.
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