Biopharmaceutical factors effecting bioavailability

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Biopharmaceutical Factors Effecting Bioavailability
Prepared By:
Syed Rashed Faizan Mehdi
170717885012
M. Pharm, Pharmaceutical Analysis
Dept. of Pharmaceutical Analysis
DECCAN SCHOOL OF PHARMACY
Guided by :
DR. Mohammed Younus
M. Pharm, Pharmaceutical Analysis.
Ph D
Dept. of Pharmaceutical Analysis
DECCAN SCHOOL OF
PHARMACY

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TABLE OF CONTENTS
CONTENTS
• Introduction
• Bioavailability
• Factors Influencing Absorption
a) Pharmaceutical Factors.
1. Physicochemical properties of drug molecules
2. Dosage Form Characteristics And Pharmaceutical ingredients
b) Patient related factors.

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Bioavailability can be defined as the fraction of administered drug that
reaches the systemic circulation
Pharmacokinetics
• Evaluate the way in which a drug interacts with various barriers
within a biological system
Pharmacodynamics
• Study of the relationship between systemic exposure of a drug and it’s
biological effects on tissue
Absorption can be defined as the movement of active drug (or prodrug)
from the site of administration across biologic barriers into a site where
it is measured in the blood. This site of measurement is not specified.
Note the difference in endpoint measurement sites
Introduction

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A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
1.Drug dissolution & solubility rate.
2. Particles size & effective surface area.
3. Polymorphism & amorphism.
4. Solvates & hydrates.
5.salt form of drug.
6. Ionization state.
7.Drug pKa & lipophilicity & GI pH - pH partition hypothesis.
Physicochemical properties of drug substances:
A detailed study of physicochemical properties of drug molecules may help to
enhance the rate as well as the extent of drug absorption.
It also serve to formulate the drug in most suitable dosage form.
Biopharmaceutical factors effecting drug absorption:

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1.Drug dissolution & solubility rate:
• Dissolution is the process of solubilization of a substance in a
given solvent.
• Drug dissolution rate is the amount of drug that goes into solution
per unit time under the standard conditions of temperature, pH,
solvent composition and constant solid surface area.
• Dissolution plays a significant role as it is regarded as the rate
determining step in the process of absorption.
• Solutions > Suspensions > Capsules > Tablets > Coated tablets.
Drug in particle
form
Drug in solution
form
Drug in blood
stream
Dissolution is rate limiting
step for lipophilic drugs
e.g. Griseofulvin
Permeation is rate limiting
step for hydrophilic drugs.
e.g., Neomycin

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• Solubility: The quantity of drug that dissolves in the gastrointestinal
fluid is indicative of vivo drug absorption.
• A drug is said to be undergo appreciable bioabsorption if it exhibits
aqueous solubility greater than 10mg/ml at 37℃ and pH ranging
between 1-7.
• When the solubility is less than 1mg/ml, it undergoes undesirable GI
absorption.
• Thus with the aid of solubility and dissolution data, potential
problems related to bioavailability and therapeutic activity of the
drug can be recognized.
• Both solubilty and absorption can be correlated by the concept of
maximum absorbable dose (MAD).

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• maximum absorbable dose
(MAD).
• Biopharmaceutics Classification
Systems (BCS).

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2. Particles size & effective surface area:
Smaller the particle size (by micronization i.e reduction in particle size)
Greater is the effective surface area
More intimate contact b/w solid surface and aqueous solvent
Higher is the dissolution
Rate increase in absorption efficiency
Types of surface area:
1) Absolute surface area: it is
the total solid surface area
2) Effective surface area: it is the
solid surface area of particle exposed
to the dissolution medium.
• In order to convert the absolute surface area to effective surface area,
surfactants like polysorbate 80 or diluents like PEG, dextrose.
• Griseofulvin, chloramphenicol on micronization show increased
absorption and decrease in therapeutic dose.

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3. Amorphism and Polymorphism :
Amorphous forms generally dissolve faster than crystalline forms
because no energy is needed to break up the crystal lattice.
For this reason, the amorphous form is often preferred over the
crystalline form and several drugs, including hydrocortisone and
prednisolone, are marketed in the amorphic form.
Amorphous form
More soluble
Rapidly dissolving
Readily absorbed
Crystalline form
Less soluble
Slower dissolving
Not absorbed to significant extent
The crystalline form of drugs may exist as polymorphs or molecular
adducts or both.

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3. Amorphism and Polymorphism :
Polymorphism is the ability of compound to exist in more than one
crystalline form. These polymorphs may have different physical
properties, such as dissolution rate and solubility.
Ex:
Chloramphenicol palmitate exists in three crystalline forms, form A, B,
C. form B is the most soluble and therefore exhibits more bioavailability
than the other forms
Stable form
- Lowest energy state
- Highest m.pt.
- Least aq solubility
- Dissolution rate limited
Metastable form
- Less stable form
- Highest energy state
- Lowest m.pt.
- Higher aq solubility
- Better absorption and Bioavailability

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4. Solvates & hydrates:
During their preparation, drug crystals may incorporate one or more
solvent molecules to form solvates.
The solvent trapped is known as solvent of crystallization.
The solvates may exists in varying crystalline forms known as
pseudopolymorphs and the phenomenon is known as pseudo
polymorphism.
The molecular complex is referred as hydrates if water molecules has been
reported as solvent.
Anhydrous – Drug is not associated with water,
monohydrate and Dihydrated – drug is associated with one and more
water molecules respectively.
The anhydrous form have higher energy states, higher aq solubilities,
dissolves at faster rate and hence exhibit higher bioavailability.
Ex: anhydrous ampicillin more soluble than their hydrous form

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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 of drug, pH of the diffusion layer is
important not the pH of the bulk of the solution.
E.g. of salt of weak acid. ---Which increases the pH of the diffusion layer,
which promotes the solubility and dissolution of a weak acid and
absorption is bound to be rapid.

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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.
pH – Partition theory states that drug compounds of molecular weight
more than 100 daltons , which are primarily transported across the
biological membrane by passive diffusion, the process of absorption is
governed by
- Pka of drug (Dissociation constant)
- The lipid solubility of unionized drug
- pH at the absorption site.

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Pka of drug (Dissociation constant)
Amount of drug that exist in unionized form and in ionized form is a
function of pKa of drug & 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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Drugs PKa PH/site of
absorption
Very weak acids e.g.
pentobarbital
Hexobarbital
>8
Unionized at all pH
values; Absorbed along
the entire length of GIT
Moderately weak acids
e.g. aspirin Ibuprofen
2.5 – 7.5
Unionized in gastric pH&
ionized in intestinal pH;
better absorption from
stomach
Stronger acids
E.g. disodium cromogylate < 2.0
Ionized at all pH values;
Poorly absorbed from
GIT
Very weak bases
e.g. theophylline
Caffeine
< 5.0
Unionized at all pH
values; Absorbed along
entire GIT
Moderately weak bases
e.g. codeine 5 – 11
Ionized at gastric pH,
unionized at intestinal pH;
better absorption from
intestine.
Stronger bases e.g.
guanethidine > 11
Ionized at all pH values;
Poorly absorbed from
GIT

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b) Lipophilicity and drug absorption:
Ideally for optimum absorption, a drug should have sufficient aq.
solubility to dissolve in fluids at absorption site and lipid solubility
(Ko/w) 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 (octanol)
Distribution of drug in aq phase
As Ko/w or lipid solubility i.e. partition coefficient increases percentage
drug absorbed increases.

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2] Formulation Factors
1. Disintegration time
2. Manufacturing variables
a. Method of granulation
b. Compression force
3. Nature & type of dosage form
4. Pharmaceutical ingredients
5. Product age & storage conditions
1. Disintegration time (DT):
It is defined as the time taken by the solid dosage form to breakdown
into smaller particles in the body after their ingestion.
Order of disintegration of the solid dosage forms:
Capsules > Tablets > Coated tablets > Enteric coated tablets >
sustained release tablets
2. Formulation Factors.

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1. Disintegration time (DT):
a)Method of granulation:
Wet granulation: By selecting a suitable granulating liquid , the
dissolution rate of insoluble drugs can be enhanced.
Direct compression: dissolution rate of tablets prepared by this method
are higher than the wet granulation method.
b) Compression force:
Higher compression force yields a tablet with greater hardness and
reduced wettability & hence have a long D.T. but on other hand higher
compression force cause crushing of drug particles into smaller ones with
higher effective surface area which in decrease in D.T. So effect of
compression force should be thoroughly studied on each formulation.
2. Manufacturing variables:
• It Harder the tablet, greater is its disintegration time.
• Disintegration of solid dosage forms can be enhanced by incorporating
appropriate amounts of disintegrants in the formulation.

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3. Nature and type of dosage form
• Depending upon the nature and type of dosage form, the absorption
pattern of a drug decreases in the following order
• Solutions > Emulsions > Suspensions > Capsules > Tablets Coated
tablets > Enteric coated tablets > Sustained release tablets

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• More the no. of excepients in dosage form, more complex it is & greater
the potential for absorption and Bioavailability problems.
a) Vehicle:
vehicles are used in parenteral and oral liquids preparations.
Rate of absorption – depends on its miscibility with biological fluid.
Miscible solvents-rapid absorption of drug.
Immiscible solvent-slow absorption of drug.
Non-Aqueous water immiscible
E.g.: Vegetable oil,
Sesame oil,
Peanut oil.
Aqueous
E.g.: Water,
Syrup
Non-Aqueous water miscible
E.g.: Propylene glycol,
Glycerol,
Sorbital.
Vehicles

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b) Diluents
Diluents are added to increase the bulk of the dosage form, especially
in tablets and capsules.
Hydrophilic diluents-form the hydrophilic coat around hydrophobic
drug particles –thus promotes dissolution and absorption of poorly
soluble hydrophobic drug.
Inorganic diluents
E.g.: Dibasic calcium phosphate,
Calcium carbonate.
Organic diluents
E.g.: Dextrose,
Sorbitol,
Mannitol.
Diluents

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c) Binding Agents
Although binders are incorporated to produce cohesive bonding
between granules during the process of compaction of tablets.
Hydrophilic binders are for enhancing the dissolution rate of poorly
soluble drug. e.g. starch, gelatin, PVP.
More amount of binder increases hardness of tablet and decrease
dissolution & disintegration rate.
d) Disintegrating Agents
They are added to the tablet to disrupts the cohesive forces between
the granules, thereby causing the breakdown of the tablet to attain
faster dissolution.
Mostly hydrophilic in nature, increase in disintegration increase the
bioavailability.
e.g.: Guar gum, Starch, Microcrystalline cellulose

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e) Lubricating Agents
These agents when added to a tablet formulation decrease the
friction between the granules and die wall of the tablet press.
Commonly hydrophobic in nature – therefore inhibits penetration of
water into tablet and thus dissolution and disintegration.
Insoluble Lubricants
E.g.: Mineral oil,
Talc
Soluble Lubricants
E.g.: PEG 4000,
PEG 6000.
Lubricant

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f) Surfactants
They are commonly used in the formulations as solubilizers, emulsifiers,
wetting agents etc.
At lower concentrations, they increase the rate of absorption of poorly
water soluble drugs.
Physiologic surfactants like bile salts they promotes absorption
e.g.: Griseofulvin, steroids
g) Complexing Agents
They increase the absorption rate of other drugs due to
• Formation of soluble complexes which enhances the dissolution.
• Increased the lipophilicity which enhances membrane permeability.
h) Colorants
Water-soluble dyes even inleast concentrations get adsorbed on the
crystal faces and delay their dissolution rate.
e.g.: Brilliant blue retards dissolution of sulfathiazole.

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5. Product age and storage Conditions:
Alterations in storage conditions and prolonged duration of storage of
drug products may modify their physicochemical properties resulting in
altered drug absorption patterns.
B. Patient related factors:
1) Age
2) Gastric Emptying
3) Intestinal Transit
4) Diseases
5) Effect of Food
6) Blood Flow to GIT
7) First pass metabolism

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1) Age:
Absorption pattern of drugs may vary among different age groups.
Infant have less acidic G.I fluids, smaller intestinal surface area and
comparatively less blood flow than adults.
Intestinal surface area and blood flow, bacterial overgrowth in small
intestine, altered gastric emptying, retard the drug absorption
2) Gastric Emptying:
Gastric emptying is the entry of gastric content into the small intestine.
Gastric emptying rate: It is the rate at which gastric contents empty into
the small intestine.
Gastric emptying time: It is the time required for gastric content to empty
into the small intestine.
Rapid Gastric Emptying is required when the consumed drugs
• Are unstable in gastric pH (Penicillin G)
• Are better absorbed from the small intestine (Vit B12)
Delayed Gastric Emptying is required when
• The drug (Griseofulvin) dissolves slowly.
• Food enhances the dissolution and absorption of drugs.

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3) Intestinal Transit:
The residence time of foodor drug substance in intestine is known as
intestinal transit time.
As small intestine is major site of absorption longer or delayed transit
time is required for the complete absorption of drugs
Delayed intestinal transit is recommended for those drugs which
• Exhibits sustained release action.(Diclofenac sodium)
• Are enteric coated and hence dissolves only in the intestine.
4) Diseases:
(A) GI Diseases and Infections
Drug absorption may be influenced by several pathophysiological
conditions of GIT.
Malabsorption syndrome like celiac disease and Chrons disease.
(B) Gastrointestinal Surgery.
Gastrointestinal surgery especially gastrectomy may cause drug dumping
in the intestine.

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5) Effect of Food:
The presence of food in the GI tract can affect the bioavailability of the
drug from an oral drug product.
Food contain amino acids, fatty acids, and many nutrients that may affect
intestinal pH and solubility of drugs.
The effects of food are not always predictable and can have consequences.
Some effects are:
• Delay in gastric emptying
• Stimulation of bile flow
• A change in the pH of the GI tract
• A change luminal metabolism of the drug substance
• Physical or chemical interaction of the meal with the drug product or
drug substance
The absorption of some antibiotics, such as penicillin and tetracycline, is
decreased with food; whereas other drugs, particularly lipid-soluble
drugs such as griseofulvin and metazalone, are better absorbed when
given with food containing a high fat content.

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7) First pass metabolism:
A drug administered orally, passes through the GIT and liver where it
undergoes extensive metabolism before reaching the systemic circulation,
thereby leading to decreased bioavailability, this phenomenon is called as
first pass metabolism.
6) Blood Flow to GIT:
Increase in the blood flow to the site of absorption (GIT), increases the
drug absorption as rapid removal of drug from its absorption site helps
to maintain sink conditions.
Drug (Administered Orally)
Destroyed in the gut
Unabsorbed drug
Destroyed in the gut wall
Reaches the systemic circulation
Destroyed by the liver

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References:
1) Brahmankar D.M., Jaiswal S.B., First edition, “Absorption of Drugs”
Biopharmaceutics and Pharmacokinetics – A treatise, Vallabh Prakashan,
Delhi 1995, Page No. 5-75.

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