BIOPHARMACEUTIC CONSIDERATIONS IN
DRUG PRODUCT DESIGN AND IN VITRO
DRUG PRODUCT PERFORMENCE
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CONTENTS
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❑ Introduction
Biopharmaceutic factors affecting drug
bioavailability
Rate limiting steps in drug absorption
Physicochemical nature of the drug formulation
factors affecting drug product performance
Reference
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Introduction
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Biopharmaceutics is the study of the
physicochemical properties of the drug and drug
product in vitro, and the bioavailability of the drug
in vivo, to produce a desirable therapeutic effect.
❑ Biopharmaceutics allows for the rational design of
drug products. A primary concern in
biopharmaceutics is bioavailability of drugs.
❑ Bioavailability refers to the measurement of rate and
extent of the drug to reach systemic circulation
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Biopharmaceutical factors affecting
drug bioavailability
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Biopharmaceutical considerations in the design of a drug
product to deliver the active drug with the desired
bioavailability characteristics include
▪ The type of drug product(tablet, capsule, transdermal delivery
system, ointment, paranteral solution),
▪ The route of drug administration including the anatomic and
physiological nature of application site,
▪ Desired pharmacodynamic effect(immediate or delayed
release),
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▪ The physicochemical properties of the drug molecule
▪ The nature of excipients in the drug product
▪ The method of manufacturing.
❑ Each route of the drug application present special
biopharmaceutic considerations in drug product design, eg.
Design of vaginal tablet.
❑ For drug administered by an intramuscular route, local
irritation, drug dissolution and drug absorption from the
intramuscular site are some of the factors that must be
considered.
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If the drug is given by intravascular route(for eg.IV route)
systemic drug absorption is complete or 100% bioavailable,
because the drug is placed directly into the systemic
circulation.
Some drugs have poor bioavailability due to the first pass
metabolism by the enzymes in the GI tract or in liver, then
higher dose may be needed or alternative route of drug
administration is needed.
If bioavailability of solid dosage form is lower than oral
solution then the performance of dosage form is improved by
reformulation.
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Low bioavailability from the oral solution indicates that the
drug is poorly absorbed or is subject to significant first pass
metabolism and is not likely to be improved by formulation.
Increased gastric emptying enhances bioavailability of orally
administered drugs.
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FORMULATION AND MANUFACTURING VARIABLES
THAT COULD INFLUENCE BIOAVAILABILITY
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1.The properties of the drug substance. (salt form, crystalline
structure, formation of solvates and solubility)
2.The composition of the finished dosage form.
(presence or absence of excipients and special coatings)
▪ more the number of excipients in dosage form, more the
potential for absorption and bioavailability problems.
❑ Vehicles-
▪ Rate of absorption- depends upon miscibility with biological
fluid.
▪ Miscible vehicles-rapid absorption
▪ Immiscible vehicles-absorption based on partitioning from oil
and water
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DILUENTS
▪ The hydrophilic powders are very useful in promoting the
dissolution of poorly water soluble, hydrophobic drugs
▪ They forming a coat over onto the hydrophobic surface of
drug particles and rendering them hydrophilic
❑ BINDERS
▪ Hydrophilic binders are frequently used
▪ Large amount of binders increase the hardness and decreases
the rate of disintegration/dissolution.
▪ PEG 6000 was a deleterious binder for phenobarbital as it
forms poorly soluble complex with drug.
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DISINTEGRANTS
▪ Mostly hydrophilic in nature.
▪ Decrease the amount of disintegrants will significantly lowers the
bioavailability.
❑ LUBRICANTS
▪ Commonly hydrophobic in nature.
▪ Inhibits the penetration of water into the tablet so thus inhibits the
rate of disintegration and dissolution.
❑ COLOURANTS
▪ Even a low concentration of water soluble dye can have inhibitory
effect on dissolution
▪ Dye molecules adsorbed onto the crystal surface and inhibit the
dissolution.eg brilliant blue retards dissolution of sulfathiazole.
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3. Type of dosage form
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4.Manufacturing variables
❑ Method of granulation
▪ The wet granulation process is the conventional technique in
the manufacture of tablets
▪ Limitations are formation of solid bridge by the presence of
liquid,the liquid may act as a medium for chemical reactions,
drying step may harm the thermolabile drugs.
▪ APOC(agglomerative phase of communition)-grinding of
drugs in ball mill for long time.
▪ The reason attributed to it was an increase in internal surface
area of the granules prepared by APOC method.
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❑ Compression force
There is a two possibility of compression force
a) High compression force yields greater hardness and reduced
wettability and hence have long disintegration time.
b) On other hand high compression force cause crushing of the
drug particles into smaller one with higher surface area which
in decrease in disintegration time
5.Rate and/ site of dissolution in the gastrointestinal tract.
6.Disintegration time
❑ Rapid disintegration is important to have a rapid absorption
so lower disintegration time is required.
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❑ Disintegration time is directly proportional to the amount of
binder and compression force.
The invitro disintegration test gives no means of guarantee of
drugs bioavailability because if disintegrated drug do not
dissolve then absorption is not possible.
7.Product age and storage condition
❑ Product aging and improper storage conditions adversely
affect bioavailability.
❑ Precipitation of drug in solution, particle size of suspension,
hardening of tablet causes decrease rate of dissolution and
disintegration
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RATE LIMITING STEPS IN DRUG ABSORPTION
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❑ Systemic drug absorption from drug product consists of a
succession of rate processes. For solid oral, immediate release
drug products (tablets, capsules) the rate processes include
1.Disintegration of the drug product and subsequent release
of the drug.
2.Dissolution of the drug in an aqueous environment and
3.Absorption across cell membranes into the systemic
circulation
❑ In the process of drug disintegration, dissolution and
absorption, the rate at which drug reaches the circulatory
system is determined by the slowest step in the sequence.
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❑ 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 very poor aqueous solubility drugs, the rate at which the
drug dissolves is often the slowest step and therefore exerts a
rate limiting effect on drug bioavailability.
For drug that has a high aqueous solubility, the dissolution
rate is rapid, and the rate at which the drug crosses or
permeates cell membranes (absorption) is the slowest or rate
limiting step.
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DISINTEGRATION
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❑ For immediate release, solid oral dosage forms, the drug
product must disintegrate into small particles and release the
drug.
❑ Complete disintegration is defined by the USP as “that state in
which any residue of the tablet, except fragments of insoluble
coating, remaining on the screen of the test apparatus in the
soft mass have no palpably firm core”.
❑ Disintegration tests allow for precise measurement of the
formation of fragments, granules or aggregates from solid
dosage forms.
❑ Solid drug products exempted from disintegration tests
include troches, tablets that are intended to be chewed and
drug products intended for sustained release or prolonged or
repeat action.
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DISSOLUTION AND SOLUBILITY
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Dissolution-process by which a solid drug becomes dissolved
in a solvent
Solubility is the mass of the solute dissolves in a specific mass
or volume of solvent at a given temperature.
❑ Solubility is static property, whereas dissolution is dynamic
property.
The rate at which drugs with poor aqueous solubility dissolve
from an intact or disintegrated solid dosage form in the
gastrointestinal tract often controls the rate of systemic
absorption of the drug.
Thus dissolution tests may be used to predict bioavailability
and may be used to discriminate formulation factors that affect
drug bioavailability.
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❑ Noyes and whitney(1897) studied the rate of dissolution of solid
drugs.
The steps in dissolution include the process of drug dissolution at
the surface of the solid particle, thus forming a saturated solution
around the particle.
The dissolved drug in the saturated solution ,known as the stagnant
layer, diffuses to the bulk of the solvent from regions of high drug
concentration to regions of low drug concentration.
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The overall rate of drug dissolution may be described by the
noyes whitney equation
Where,
dc/dt -rate of drug dissolution at time t,
k- dissolution rate constant
Cs- concentration of drug in the stagnant layer
Cb- concentration of drug in the bulk of the solution at
time t
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❑ The rate of dissolution ,dC/dt, is the rate of drug dissolved per
time expressed as concentration change in the dissolution
fluid.
An increased in temperature will increase the kinetic energy of
the molecules and increase the diffusion constant, D.
An increase in agitation of the solvent medium will reduce the
thickness, h, of the stagnant layer, allowing for more rapid
drug dissolution.
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Drug in the body, particularly in the gastrointestinal tract is
considered to be dissolving in an aqueous environment.
❑ Permeation of drug across the gut wall is affected by the
ability of the drug to diffuse(D) and to partition between the
lipid membrane.
A favorable partition coefficient (Koil/water)will facilitate drug
absorption.
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FACTORS AFFECTING DRUG PRODUCT
PERFORMANCE
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Physicochemical factors which affect the performance of the
drug product. They are
a) Chemical factors
b) Physicochemical factors
1.Drug solubility& dissolution rate
2.Particle size & surface area
3.Polymorphism & amorphism
4.Solvates & hydrates
5.Salt form of drug
6.Ionization rate
7.Drug pKa & lipophilicity
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a) CHEMICAL FACTORS
❑ A variety of chemical options can be used to improve the
stability and systemic availability of drugs
eg. The esters can be prepared of both acids and bases to
produce more stable derivatives, which hydrolyse to the active
parent once absorbed.
❑ The stability and solubility of both acids and bases tend to
increase when they are in the form of salts.
eg. Administration of soluble salts of penicillin give rise to
higher circulating antibiotics levels than free acid.
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b) PHYSICOCHEMICAL FACTORS
1.DRUG SOLUBILITY AND DISSOLUTION RATE
❑ The rate of dissolution and rate of permeation through the bio
membrane is the rate determining steps in absorption of drug.
❑ Dissolution is the rate limiting step for lipophilic drugs.eg.
Griseofulvin
❑ Permeation is rate limiting step for hydrophilic drugs. eg.
neomycin.
❑ Important prerequisite for the absorption of a drug is that it
must be present in aqueous solution and this depends on
drug’s aqueous solubility and its dissolution rate.
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2.PARTICLE SIZE AND EFFECTIVE SURFACE AREA
❑ Smaller the particle size(by micronization)
Greater is the effective surface area
More intimate contact between solid surface and aqueous solvent
Higher the dissolution rate
Increase in absorption efficiency
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eg. Poorly soluble nonhydrophobic drugs like
chloramphenicol, griseofulvin whose dissolution is rate
limited.
Particle size reduction has been used to increase the
absorption of a large number of poorly soluble drugs, such as
bishydroxycoumarin, digoxin, griseofulvin ,nitrofurantoin and
tolbutamide.
Microsize particles improve absorption, but it is even more
when it is formulated in ultramicrosized particles as
monomolecular dispersion in polyethylene glycol.
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3. POLYMORPHISM AND AMORPHISM
❑ When a substance exists in more than one crystalline form, the
different forms are designated as polymorphs and the
phenomenon as polymorphism
❑ Many compound forms crystals with different molecular
arrangements, or polymorphs. These polymorphs may have
different physical properties, such as dissolution rate and
solubility.
❑ eg. vitamin riboflavin
❑ Polymorphs that have no crystalline structure, or amorphic
form have different physical properties than a crystalline form.
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Difference between stable form and metastable form
STABLE FORM METASTABLE FORM
LOWEST ENERGY STATE LESS STABLE FORM
HIGHEST MELTING POINT HIGHEST ENERGY STATE
LEAST AQUEOUS LOWEST MELTING POINT
SOLUBILITY
DISSOLUTION RATE HIGHER AQUEOUS
LIMITED SOLUBILITY
BETTER ABSORPTION
AND BIOAVAILABILITY
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Amorphous form is dissolve faster than the crystalline form
because no energy is needed to breakup the crystal lattice. for
this reason amorphous form is preferred over crystalline form.
eg. Prednisolone and hydrocortisone
Difference between amorphous form and crystalline form
AMORPHOUS FORM CRYSTALLINE FORM
More soluble Less stable
Rapidly dissolving Slower dissolving
Readily absorbed Not absorbed to significant
extent
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4. SOLVATES / HYDRATES
❑ During their preparation, drug crystals may incorporate one or
more solvent molecules to form solvates.
❑ Most common solvate is water.
❑ If water molecules is already present in a crystal structure, the
tendency of a crystal to attract the additional water molecules
to initiate the dissolution is reduced.
❑ The solvated(hydrated) crystals tend to dissolve slowly than
anhydrous form.
❑ Solvates have greater solubility than their nonsolvates.eg
chloroform solvates of griseofulvin, n-pentanol solvate of
fludrocortisone.
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5. SALT FORM OF DRUG
❑ At given pH, the solubility of drug, whether acidic/basic or its
salt, is a constant.
❑ While considering the salt form the drug, pH of the diffusion
layer is important not the pH of bulk of the solution.
Eg. Salt of weak acid which increases the pH of diffusion
layer, which promotes the solubility and dissolution of a weak
acid and absorption is bound to be rapid.
❑ Reverse in the case of weak bases, it lowers pH of the
diffusion layer and promoted the absorption of basic drugs.
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Other approach to enhance the dissolution and absorption rate
of certain drugs is by formation of insitu salt formation i.e
increasing in pH of microenvironment of drug by
incorporating the buffer agent.
eg. aspirin, penicillin.
❑ But sometimes more soluble salt form of drug may result in
poor absorption.
eg. Sodium salt of phenobarbitone and phenobarbitone.
❑ Tablet of salt of phenobarbitone swelled, it did not get
disintegrate thus dissolved slowly and results in poor
absorption.
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Selection of appropriate salt form for better dissolution rate is
also important. It has been shown that the choline and the
isopropanolamine salts of theophylline dissolve 3 to 4 times
more rapidly than the ethylenediamine salt and show better
bioavailability
A factor that influence the solubility of salt forms of the drug
is the size of the counter ion.
Smaller the size of counter ion, greater the solubility of salt
whereas the counter ion is very large in size, the solubility
may be much lower than the free drug itself.
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6. IONIZATION STATE
❑ Unionized state is important for passive diffusion through
membrane so important for absorption.
❑ Ionized state is important for solubility.
7.DRUG pKa AND LIPOPHILICITY
❑ pH partition theory states that for drug compounds of
molecular weight more than 100,which are transported across
the biomembrane by passive diffusion. The absorption is
governed by
a) pKa of drug
b)the lipid solubility of the unionized drug.
c)pH at the absorption site
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a)pKa of drug
❑ Amount of drug that exists in a unionized form is a function
of pKa of drug and pH of the fluid at the absorption site and
it can be determined by Henderson – hesselbach equation
pH = pKa +log [ionized form] for acidic drugs
[unionized form]
pH= pKa +log [unionized form] for basic drugs
[ionized form]
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b) Lipophilicity and drug absorption
❑ Ideally for optimum absorption, a drug should have sufficient
aqueous solubility to dissolve in fluids at absorption site and
lipid solubility high enough to facilitate the partitioning of the
drug in the lipoidal membrane. i.e. drug should have perfect
HLB for optimum bioavailability.
❑ Ko/w= distribution of drug in organic phase
distribution of drug in aqueous phase
❑ As lipid solubility (partition coefficient) increases percentage
drug absorbed increases.
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REFERENCE
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Textbook of Biopharmaceutics and pharmacokinetics-A
treatise by D.M.Brahmankar and Sunil B.jaiswal.
Shargel L, Andrew B.C, “Physiologic factors related to drug
absorption” Applied Biopharmaceutics and pharmacokinetics.
Fourth edition. Stanford 1999.
M.E.Aulton. Pharmaceutics, the science of dosage form
design.
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❑ Review of rate and extent-limiting factors of oral absorption:
theory and applications by kiyohiko sugano, katsuhide terada,
december , 2014.
❑ Review journal of factors affecting drug absorption and
distribution by Barbara J Pleuvry. Volume -6, issue 4, april
2005.page no 135-138.
❑ Effect of particle size reduction on dissolution and oral
absorption of poorly water soluble drugs by jun-ichi jinho.
Volume111, issues 1-2,march 2006, pages 56-64.
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