Biopharmaceutical Study Material

Biopharmaceutics &
clinical
pharmacokinetics
By: Adane Yehualaw (Bpharm., MSc. Pharmaceutics)

1
Objective
 Upon completion of this course, the student will be able to:
➢ Define biopharmaceutics, bioavailability, bioequivalence, and
therapeutic equivalence
➢ Understand
✓ The mechanisms of drug absorption
✓ Factors affecting drug bioavailability from various route of drug
administration
✓ Methods of assessing bioavailability
➢ Logically apply biopharmaceutics principles in everyday clinical
2 pharmacy practice.
Outline
➢ Biopharmaceutics
➢ Barriers of drug transport (Plasma membrane, P-GP)
➢ Mechanisms of drug transport

 Paracellular and transcellular routes,
 Passive diffusion,
 Carrier-mediated transport
o Active transport, facilitated diffusion
 Vesicular transport
3 6/18/2022
Biopharmaceutics
Dosage form
Distribution
The magnitude of
response depends on
Drug release/ the [C] of drug
achieved at the site of
dissolution
action
4
Introduction
Interaction between the drug substance

& cell receptors or enzyme systems
The biologic response
The magnitude of the response is related to the

concentration of the drug achieved at the site
of its action.
5
Biopharmaceutics…
❖Drugs ability to reach the site of action depends on
➢ Physicochemical property of drugs (API)
➢ The type of dosage form
➢ Route of delivery &
➢ Physiological factors
❑ These factors determine whether an administered drug is
therapeutically effective, toxic, or has no apparent effect at all.
6
Biopharmaceutics
 Biopharmaceutics: is the science that examines the interrelationship
b/n the physicochemical properties of a drug, the dosage form in which

the drug is given and the route of administration on the rate and extent
of systemic drug absorption.
 It is the study of the factors influencing the bioavailability of a drug (in
humans and animals) and

➢ The use of this information to optimize pharmacologic or therapeutic activity
of drug product in clinical application.
7
Biopharmaceutics
➢ Absorption: the process of movement of unchanged drug from its site
of administration to the systemic circulation.
➢ Bioavailability: the rate and extent that the active drug is absorbed
from a dosage form and becomes available in the systemic circulation.

✓ Unchanged drug
8
Biopharmaceutics
❑ Thus Biopharmaceutics deals with the factors that influence the:
➢ The stability of the drug within the drug product,
▪ Protection of the activity of the drug within the drug product
➢ The release of the drug from the drug product
➢ The rate of dissolution of the drug at the absorption site
➢ The systemic absorption of the drug.
9
Biopharmaceutics
❖ Studies in biopharmaceutics use both in-vitro and in-vivo methods.
➢ In-vitro methods are procedures employing test apparatus &
equipment without involving laboratory animals or humans.

▪ E.g. Dissolution test
➢ In-vivo test involve measurement of systemic drug bioavailability
after giving a drug to human subjects or laboratory animals.

▪ E.g., Plasma level vs time study
▪ Urinary excretion study
10
Biopharmaceutics…
❖ Apart from IV route, all other routes of administration which are
designed for systemic use, involve the absorption of the drug into the
blood stream.
➢ The drug absorbed and transported to the target tissues produces
pharmacological actions.
➢ However the rate and extent of absorption could be influenced by
many factors influence
11
Biopharmaceutics….
❖ Factors that influence the rate and extent of absorption and hence the
time course of a drug in the plasma and therefore its action may be
➢ Physiologic factors
➢ Physicochemical factors
➢ Pharmaceutical factors
12
Factors affecting drug absorption
❑ Physiological factors
➢ Membrane physiology – The major barrier to drug transport
➢ Route of administration
➢ Gastric emptying time
➢ Intestinal transit time
➢ Gastrointestinal pH
➢ Disease states
➢ Blood flow through the GIT
➢ Pre-systemic metabolism by
▪ Gut wall enzymes, Bacterial enzymes, Hepatic enzymes

13
❑ Physicochemical factors
➢ Drug solubility
➢ Particle size & effective surface area
➢ Lipophilicity of the drug
➢ Drug stability
14
❑Pharmaceutical factors
➢Type of dosage form
➢Disintegration time (tablets/capsules)
➢Dissolution time
➢Manufacturing variables
➢Pharmaceutical ingredients (excipients)
➢Storage condition
15
Barriers to Drug Transport
16
Barriers to Drug Transport
A. The cell membrane

➢ It surrounds cells
➢ Acts as a barrier and separate cellular contents from the external
environment.
➢ Composed primarily of phospholipid bilayer into which proteins and
carbohydrates are imbedded.

➢ Phospholipids has two different ends.
▪ Hydrophilic exterior and hydrophobic interior
17
Barriers to Drug Transport…
The cell membrane

18
 It is a semi-permeable lipoidal sieve which acts as selective barriers to the

passage of molecules
➢ Allows passage of small, lipid-soluble molecules across it
➢ Passage of water and small hydrophilic molecules through its aqueous pores
➢ Passage of highly charged and large molecules
✓ Through transporter proteins or carrier molecules
19
❑ In addition to phospholipids the cell membrane is composed of different

types of molecules.
❖Cholesterol: It interacts with the phospholipids, and give some rigidity to
the membrane otherwise would be more fluid.
❖Carbohydrates are present on the exterior surface of cells
➢ Act as receptor substances for binding hormones, such as insulin
➢ Bind to proteins or lipids at the exterior surface to form glycoproteins or
glycolipids, respectively.
➢ Functionally, glycolipids facilitate cellular recognition while glycoproteins

serve as receptors for chemical signals
20
❑ Membrane proteins
❖ There are two types of proteins found in the membrane
1. Peripheral proteins
▪ Attached only on the surface of the membrane and do not penetrate.
▪ Not deeply embedded and can be disconnected without affecting the
structure of the membrane.
▪ Function as enzymes and hormones
21
2. Integral proteins
▪ Protrude all the way through the membrane.
▪ Many of the integral proteins provide structural channels (Pores)
which allows water soluble substances, especially the ions, to diffuse

between the ECF and ICF.
▪ Some of the integral proteins act as a carrier proteins for
transporting substances against concentration gradients, which is

called active transport.
▪ Still others acts as enzymes.
22
B. P-glycoprotein
➢ Permeability glycoprotein (P-GP) is an adenosine triphosphate (ATP)
dependent transporter which is capable of transporting an extremely

wide variety of drugs out of the cell (efflux pump)
➢ Expressed in intestinal tract epithelia, liver, brain, adrenal gland,
kidney
➢ Over expressed in human cancer cells
23
❑ The number of drugs that can be effluxed from the cell by P-gp include
➢ The immunosuppressive agent: Cyclosporin A,
➢ Vinca alkaloids:Vinblastine (VBL), vincristine (VCR),
➢ Digoxin,
➢ ß-blockers,
➢ Erythromycin and other antibiotics,
➢ Cimetidine etc.…
24
❑ Contribution to the blood-brain barrier.
➢ The blood–brain barrier (BBB) is composed of a tightly sealed
monolayer of brain capillary endothelial cells

➢ P-GP is a gatekeeper in the blood-brain barrier
▪ That is why many drugs are not efficiently delivered to the brain, despite the fact
that the drugs are hydrophobic enough to diffuse through the membranes.
C. Cytochrome P450 3A4 (CYP3A4)

➢ Intestinal barrier provided by CYP3A4 is a major determinant of systemic
bioavailability of orally administered drugs.

▪ E.g., 50% of oral cyclosporine metabolism
25
Mechanisms of drug absorption
26
❖ The two main mechanisms of drug transport across the gastrointestinal
epithelium are:
1. Para-cellular (intercellular): passage of molecules between adjacent
epithelial cells.
➢ Paracellular transport is passive i.e. down a concentration gradient
➢ Allows the permeation of Small hydrophilic and charged molecules that are
not able to permeate through the lipid membrane.
➢ Absorption is quite limited because as this pathway comprises a very small
percentage of the total surface area (~ 0.01% )
27
2. Trans-cellular: across the cells, (i.e. through the lipid membrane)
❑ It is the major pathway for drug absorption in the intestine.

❑ Divided into
➢ Simple passive diffusion,
➢ Carrier mediated transport
▪ Active transport and
▪ Facilitated diffusion
➢ Endocytosis
➢ Pinocytosis
28
Mechanism of drug absorption
29
❑ Passive diffusion
➢ Molecules spontaneously diffuse from a region of higher concentration
to a region of lower concentration across the lipoidal membrane
➢ No energy is required
➢ Not saturable
➢Responsible for the absorption of most drugs (about 90%)
➢It depends more or less on the molecular size of drugs
➢Drugs with a molecular size of less than 400 Daltons are effectively
absorbed
30
Passive diffusion
➢ Mathematically described by Fick's first law of diffusion
➢ Fick’s first law of diffusion
𝐷𝑐 𝐷𝐴𝑃
= (Cg-Cb)
𝐷𝑡 ℎ
❖ DC/Dt is the rate of appearance of drug in the blood at the site of absorption
❖ D = diffusion coefficient
❖ P = lipid water partition coefficient of drug
❖ A = surface area of membrane
❖ h = membrane thickness
❖ Cg – Cb= concentration gradient b/n GIT and blood
31
Carrier mediated transport
❑ Transporters also known as carriers are membrane proteins that transport a
variety of ions and molecules across the lipid bilayer membrane.
❑ The drug molecule or ion forms a complex with the carrier/transporter.
❑ The drug-carrier complex then moves across the membrane and liberates the drug
on the other side of the membrane.
32
Carrier mediated…
❑Drugs are absorbed by carrier molecules because of the structural similarity
to natural substrates
❑There are a large number of carrier-mediated active transport systems in

the small intestine.
➢ Amino acid transporter
✓ Gabapentin
✓ Cyclo-serine
✓ L-dopa
➢ Oligopeptide transporter
✓ Cefixime
✓ Cephalexin
✓ Captopril
33
Carrier Mediated…
❑Active transport
o Properties
➢ Need a carrier molecule
➢ Against concentration gradient
➢ Must have a source of energy
➢ Can be competitively inhibited by substrate similarities
➢ At higher concentrations the carrier mechanism becomes saturated and
further increases in drug concentration will not increase the rate of absorption,
i.e. the rate of absorption remains constant
34
Active transport
Fig.3. Relationship between rate of absorption and concentration at the

absorption site for active and passive processes.
35
Carrier mediated…
❑ Facilitated diffusion
➢ It is a type of passive transport that allows substances to cross membranes with the
help of carrier proteins
✓ From high concentration to low concentration
➢ The only difference with passive diffusion is, the molecules go through a protein
channel instead of passing via the phospholipid bilayer.
36 Fig.4. Diagrammatic representation of facilitated diffusion

Vesicular transport
❑ There are two types of vesicular transport
1. Endocytosis
2. Exocytosis
❖ It is a mode of transport for macromolecules (e.g., proteins, lipoprotein)

❖ It requires metabolic energy but is independent of concentration gradient
✓ Are transported into and out of cells selectively via endocytosis and exocytosis
❑ Endocytosis
➢ Phagocytosis
➢ Pinocytosis
37
Vesicular…
1. Pinocytosis (cell drinking): uptake of fluid solute
➢ This process is important in the absorption of oil soluble vitamins & in
the uptake of nutrients.
2. Phagocytosis (cell eating): adsorptive uptake of solid particulates.

➢ Usually used for molecules that are too large to traverse the membrane
easily via another mechanism
❖ Exocytosis: is a process where cells eject waste products or chemical

transmitters from the interior of the cell.
➢ It is similar in function with endocytosis but working in the opposite direction
38
Vesicular transport…
1. Cell membrane invaginate to surround

the material
2. Engulfs the material into the cell.

 n
3. Cell membrane containing the material

forms a vesicle or vacuole within the cell
39
Summary of Mechanisms of drug absorption
Mechanisms of Drug
Absorption
Transcellular Paracellular
Carrier-mediated Vesicular transport

transport Passive diffusion
Active Facilitated Pinocytosis

transport Phagocytosis
diffusion
40
Oral drug absorption
2
41
Introduction
❑ Oral route is the most common and convenient of the existing
administration routes
➢ Natural and convenient for the patient
✓ Affords high patient acceptability b/c it is Natural route
✓ Avoidance of pain
✓ Simplicity of administration
➢ Oral dosage forms
✓ Are easy to manufacture
42
Introduction
❑ The oral route is associated with complexity of absorption site physiology
➢ A fraction of an administered dose of the drug reaches the systemic
circulation in the unchanged form because
➢ A number of factors such as
▪ The physiology of the GIT,
▪ Physicochemical nature of drugs and
▪ Dosage form factors can influence drug absorption from GIT
➢ Therefore bioavailability may not be 100%
43
GI tract
❑ It’s a large, muscular tube that extends from the mouth to the anus.
❑ Complex tube (~ 6 m long) with varying diameters
❑ 5 major anatomical parts.

➢ Mouth
➢ Esophagus
➢ Stomach
➢ Small intestine and
➢ large intestine or colon.
44
Physiology of GIT
45
GI tract
❑ Mouth
➢ Main function
▪ Intake of food and drugs
▪ Mastication (chewing)- mechanical digestion begins here from the action of

chewing your food.
➢ Chemical digestion-depends on the type of food being ingested
▪ Carbohydrate digestion begins in the mouth as saliva contains the enzyme
Amylase
46
GI tract
❑ Esophagus
➢ Links the oral cavity with the stomach
➢ Composed of thick muscular layer ~ 25 cm long and 2 cm diameter.
➢ Esophageal transit time for dosage forms is 10 - 14 seconds.
▪ Capsules or tablets when ingested without water, could remain in the esophagus
up to 2 hours.
➢ Limited biopharmaceutical importance
 Lodging of DFs possible
47
GI tract
❑ Stomach
➢ Has two major functions
▪ Act as a temporary reservoir for ingested food and to deliver it to the
duodenum at a controlled rate;

▪ Reduce ingested solids to a uniform creamy consistency, known as
chyme, by the action of acid and enzymatic digestion.
48
Stomach
➢ Stomach pH is 1–3.5 in fasted state
➢ High biopharmaceutical importance:
▪ Gastric emptying can dictate drug absorption from SI.
➢ Dosage form may remain in the stomach for 0.5–2 h prior to moving to
the SI.
➢ Very little drug absorption occurs
▪ Small Surface Area of around 0.2m2
49
GI tract
❑ Small Intestine
 Portion of the digestive tract that connects stomach and large intestine
 It is the longest (4-5 m) and most complex part of the GIT.
❑ Contains small finger-like projections of tissue called villi which increase
the surface area of the SI for absorption.
❑ Divided into the duodenum, jejunum and ileum
✓ Brunner’s glands (confined to the duodenum) secrete bicarbonate and mucus.
✓ Bicarbonate neutralize acid emptied from stomach
❑ Its pH is b/n 5 and 7.5.
50
Small Intestine
 Main functions:
➢ Digestion: the process of enzymatic digestion, which began in the
stomach, is completed here
➢ Absorption: it is the region where most nutrients and other materials
are absorbed.
✓ High surface area approximately 200 m2 in an adult
✓ The wall of the small intestine has a rich network of blood vessels.
51
GI tract
❑ Large intestine (Colon)
➢ Has no specialized villi
❖ It extends from the ileum of the SI to the anus
❑ Main function:
❖ It absorbs water and salt from solid wastes before eliminated from the body.
❖The storage and compaction of faeces
➢ Unlike the SI, the colon does not play a major role in absorption of foods and
nutrients.
52
GI tract-colon
 Colonized by an extensive number and variety of bacteria

➢ Capable of several metabolic reactions
❑ Intestinal bacteria
 Make vitamins that we use (including vitamin k and biotin)
 Keep harmful microbes under control
53
Summary
54
Physiologic Factors Affecting Oral Drug
Absorption
55
Physiologic factors
◼ Blood flow
◼ GI motility, emptying and transit times
◼ GI pH
◼ The presence of Food
◼ Presystemic metabolism
◼ Presence of other drugs
◼ Disease state, Malabsorption
56
Physiological factors…
❑ Blood flow
➢Blood flow to the GI tract is important in carrying absorbed drug to the
systemic circulation
➢The splanchnic circulation
▪ Provides blood flow to the entire abdominal portion of the digestive system
including hepatobiliary system, spleen, and pancreas
▪ It receives about 1/3 of the cardiac output and is increased after meals
➢Areas with high blood flow maintains a concentration gradient

➢ Decrease in mesenteric blood flow, as in the case of congestive heart failure, will
decrease drug bioavailability
57 ▪ The mesenteric circulation refers specifically to the vasculature of the intestines

❑ GI transit time of pharmaceuticals
▪ Most DFs transit the esophagus in <15 s when taken in an upright position
▪ Transit through the oesophagus is dependent both

➢ On the type of dosage form and
➢ Posture
o Tablets/capsules taken in recumbent (supine) (horizontal) position are liable
to lodge in esophagus especially when taken without water
▪ Chance of adhesion depend on shape, size and type of formulation

➢ Delay in reaching stomach may delay drug's onset of action
➢ Cause damage or irritation to esophageal wall, e.g. KCl tablets
58
❑ Gastric emptying time

▪ The time a DF takes to traverse stomach
✓It is highly variable
▪ Gastric emptying time Plays a major role in the absorption of drugs
▪ Any factor that delay emptying rate, generally delay absorption
▪ Gastric emptying time depends on
✓Type of dosage form &
✓The fed/fasted state of the stomach.
59
Physiologic factors…
❑Gastric emptying occurs during fasting as well as fed states
▪ The pattern of motility is however distinct in the 2 states
❑ In Fed State
▪ The motor activity in the fed state is induced 5–10 min after the
ingestion of a meal and persists as long as food remains in the stomach
▪ Liquids, Pellets and Disintegrated tablets empty faster
▪ Large unit DFs (Sustained R or Controlled R) can be retained for long
60
Physiological…
❑ In fasted state
➢ Stomach is less discriminatory b/n DFs
➢ Gastric motility is characterized by cyclic fluctuations of
contractions, called Interdigestive Migrating
Myoelectric Complex (IMMC)
➢ IMMC
▪ Initiate in antrum and migrates distally to small
intestine
▪ Governs gastric emptying of dosage forms in fasting
state
61 ▪ Characterized by a repeating cycle of 4 phases

❑Phase I - relatively inactive (quiescent) period of 45 - 60 min
▪ with only rare contractions
❑Phase II - intermittent and irregular contractions of ~ 30 min
❑Phase III - powerful evenly spaced peristaltic contractions,
▪ open pylorus and clear stomach residual materials
▪ HousekeeperWave
▪ 5 to 15 min
▪ Play important role in emptying indigestible solids, bone, fiber and foreign bodies
▪ Critical for large unit DFs!
62
❑ Phase IV - short transition period b/n Phase III and Phase I
❑ IMMC cycles every 1.5 to 2 hours until a meal is ingested and the fed state
motility is initiated.
❑ Peristalsis - contractions of the distal stomach – serve to mix and break
down food particles and move them towards the pyloric sphincter.
63
Factors influencing gastric emptying
Factors Factors promoting GE Factors delaying GE
Food Fasting, liquids, light diet, Fats and fatty acids in diet, High viscosity
Hot of diet, solid, cold food
Postural position Lying on right side Lying on left side
Dosage form Liquid, multiparticulate DFs solid unit DFs
Diseases hyperthyroidism, Depression, hypothyroidism, gastric

ulcer
Drugs Metoclopramide (antiemetic and propantheline, atropine (antimuscarinic)

gastroprokinetic)
Emotional state Stress, aggression Depression, vigorous exercise (divert as

much blood as it can to feed your
64
muscles and your lungs)
❑ Small Intestinal Transit
▪ It is the time of transit between the pylorus and the caecum
▪ The drug must have a sufficient residence time at the absorption site
for optimum absorption.
✓ important factor with respect to drug bioavailability.
▪ Small intestinal transit has been found to be relatively constant, at around 3 to 6 hours
for most healthy subjects.
65
❖ Small Intestinal Transit (SITT) is particularly important for
✓ DFs that release slowly (e.g. Sustained release );

✓ Delayed release DFs (Enteric coated) release drug in the SI.
✓ Drugs absorbed by intestinal carrier-mediated transporters (E.g., Vit B)
❖ Anticholinergic drugs and pregnancy retard intestinal transit

✓ Anticholinergic drugs Promote absorption of poorly soluble drugs (e.g.
Nitrofurantoin, hydrochlorothiazide)
66
Physiological…
❑ Diarrhea, laxatives promote intestinal transit
▪ Increase intestinal motility- the drug gets a very brief residence time and less
opportunity for adequate absorption.
❑ Colonic Transit
▪ Long and variable, vary from 2-48 hrs.
▪ Characterized by short bursts of activity followed by long period of stasis
67
GI pH
▪ Luminal pH varies considerably along the length of the GIT
▪ Gastric fluid is highly acidic (pH ~ 1 - 3.5) in fasted state
▪ Following ingestion of meal, buffered to less acidic pH (3 - 5 )
✓ Returns to fasted-state pH value in 2 - 3 hrs. depending on meal size
✓ Thus only a dosage form ingested with or soon after a meal will encounter these
higher pH values.
68
Physiological…
❑ Intestinal pH values are higher than gastric pH owing to neutralization

with bicarbonate ions secreted by the pancreas
❑ There is a gradual rise in pH along the length of the small intestine (5-
7.5)
69
Physiological…
❑ Chemical degradation due to pH-dependent hydrolysis can occur in the
GIT
➢ This result in incomplete bioavailability.
❑ pH-dependent hydrolysis
▪ Penicillin G (Benzylpenicillin)
▪ Extent of degradation depends on gastric residence time and pH
▪ Gastric instability preclude oral use
❑ Erythromycin and omeprazole degrade rapidly at acidic pH

▪ Formulated as enteric-coated DFs
70
❑ ENZYMES
➢ Pepsins and proteases break down protein and peptide drugs
✓ Drugs resembling nutrients, such as nucleotides may be susceptible to enzymatic

degradation
➢ Gut wall Cytochrome P450 enzyme, CYP3A4 (mainly present in the

intestinal mucosa) metabolize substrates of this enzyme. e.g. Cyclosporin
➢ Hepatic Cytochrome P450 enzyme greatly reduces the bioavailability

of many drugs.
71
Physiological…
❑ Colonic bacterial enzymes
➢ Colonic bacteria secrete enzymes capable of range of reactions
▪ Explored for colon targeted drug delivery systems
➢ Sulphasalazine is a prodrug of 5-aminosalicylic acid linked via an azo

bond to sulphapyridine
➢ 5-aminosalicylic acid linked to sulphapyridine via azo bond
▪ Makes it too large and hydrophilic to be absorbed
▪ Transported intact to colon
▪ Bacterial enzymes reduce azo bond to release 5-ASA
72
Physiological…
Effect of food on drug absorption
▪ The presence of food in the GIT can influence the rate and extent of absorption.
❑ 1. Complexation of drugs with components in the diet is possible.
➢ TTC, for example, forms non-absorbable complex with Ca2+ and Fe2+
❑ 2. Alteration of pH
➢ Food increase stomach pH by acting as a buffer
▪ Decrease rate of dissolution and absorption of weakly basic drug and increase
that of weakly acidic ones
73
Physiological…
❑ 3. Increased viscosity of gastrointestinal contents
▪ The presence of food in the GIT provides a viscous environment which

may result in:
✓ Reduction in the rate of drug dissolution &
Reduction in drug
✓ Rate of diffusion bioavailability
74
Physiological…
❑ 4. Alteration of gastric emptying
▪ Fatty foods delay gastric emptying; reduce rate of absorption of some drugs and hence
delays onset of action.
❑ 5. Stimulation of GI secretions
▪ GI secretion (e.g. Pepsin) produced in response to food may degrade drugs which are
susceptible for enzymatic degradation.
▪ Fats stimulate secretion of bile
▪ Bile salts are one of the primary components of bile and they are surface-active agents
➢ Merit: Increase dissolution of poorly soluble drugs (e.g. griseofulvin) and enhance
their absorption
➢ Demerit: Bile salts form insoluble and non-absorbable complexes with some
drugs, such as neomycin, kanamycin and nystatin
75
Physiological…
❑ 6. Competition between food components and drugs for specialized
absorption mechanisms
▪ Competitive inhibition of drug absorption due to structural similarity to

nutrients
▪ E.g. L-dopa and methyldopa use the same transporter mechanism as
aromatic amino acids from proteins
➢ Absorption of these drugs is decreased if high-protein meal is taken
76
Physiological…
❑ 7. Food-induced changes in presystemic metabolism
➢ E.g., Grapefruit juice is capable of inhibiting intestinal

cytochrome P450 (CYP3A4)
➢ If taken with drugs that are susceptible to CYP3A4, it result in increase
of their bioavailability
➢ Clinically relevant interactions exist between grapefruit juice and
terfenadine, cyclosporin, saquinavir and verapamil
77
Physiological…
▪ Food effects are not always predictable
➢ Drug absorption may be delayed, reduced, increased or, may not be
affected by the presence of food.
Table 1: Influence of food on drug absorption
78
Physiological…
79
Physiological…
❑ 8. Disease
➢ Physiological disorders associated with GIT are likely to influence the
absorption of administered drugs
➢ Local diseases can cause alterations in gastric pH that can affect the
stability, dissolution and/ or absorption of the drug
▪ Lower pH values are often seen in disease states of the colon such as Crohn’s
disease and ulcerative colitis
➢ Hepatic cirrhosis: increase bioavailability of drugs that undergo

considerable first-pass hepatic metabolism
▪ E.g., propranolol
80
❑ 9. Presence of other drugs
 Like food, presence of other drugs can affect drug absorption from
GIT in a number of ways

1. Adsorption: Antidiarrheal preparations containing adsorbents such as
charcoal Silica gel, Alumina & kaolin-pectin can retard or prevent
absorption of co-administered drugs
▪ (E.g., Promazine, lincomycin)
81
2. Forming unabsorbable complexes: Antacids or other formulations
containing Al+3, Ca+2, Mg+2 Zn+2, Fe+3(2) retard absorption of
tetracyclines
3. Altering pH: Basic drugs (E.g., tetracycline) dissolve in gastric pH, co-
administration of such drugs with antacids such as Sodium bicarbonate
results in elevation of stomach pH and hence decrease dissolution rate
or cause precipitation of drug.
82
4. Decrease GI motility, retard GI transit

➢ E.g., Atropine, propantheline, morphine, alfentanil
➢ Promote absorption of drugs which are absorbed slowly (e.g.,
ranitidine, digoxin, vitamins B12 & C)

➢ Delayed gastric emptying
▪ Retard absorption of enteric coated drugs,
▪ Reduce bioavailability of drugs unstable in the stomach(e.g.

penicillin's)
83
5. Increased GI motility
➢ E.g., Metoclopramide, Domperidone
➢ Reduce absorption of drugs which are absorbed slowly
➢ Enhance absorption of drugs which are affected in stomach
▪ Tetracycline, pivampicillin, levodopa…. ???
84
6. Alter GI metabolism
❑ Antibiotics may inhibit bacterial metabolism of drugs
➢ E.g., Digoxin is inactivated in the lower intestine by bacterial
metabolism
✓ Absorption enhanced by co-administration with antibiotics
❑ Antibiotics are suspected to diminish oral contraceptive efficacy
 Induction of the cytochrome P450 group of hepatic microsomal

enzymes and
 Interference with enterohepatic cycling of ethinylestradiol
85
➢ Induction of the cytochrome P450 group of hepatic microsomal
enzymes
 E.g., Rifampin induces cytochrome P450 enzymes, results in
increased hepatic hydroxylation of estrogens
86
Physicochemical Factors Affecting Oral
Drug Absorption
87
Physicochemical factors…
▪ Dissolution rate
▪ Drug solubility
▪ The drug dissociation constant (pKa value)
▪ Oil/water partition coefficient
88
❑ In the oral administration of solid dosage forms two critical steps occur
➢ Dissolution
➢ Absorption/permeation
❑ They are rate determining steps in absorption of orally administered drugs
❑ Dissolution is the rate determining step for hydrophobic & poorly aqueous
soluble drugs
▪ E.g., Griseofulvin & Spironolactone
❑ Permeation is the rate determining step for hydrophilic & high aqueous soluble
drugs
▪ E.g., Cromolyn sodium , Neomycin
89
RDS=Rate determining step
90
❑ Absolute or Intrinsic solubility
➢ The maximum amount of solute that dissolve in a given solvent under standard
condition of pressure, temperature and pH, which is a static property
❑ Dissolution rate
➢ The process by which a solid substance goes into solution
per unit time under standard condition of temp, pH and solvent composition
which is a dynamic process
❑ Dissolution is the process ,whereas solubility is the outcome of dissolution.
▪ Solubility is measured in g/L and dissolution is measured in g/sec.
91
 For a drug to be absorbed it must first be dissolved in the fluid at the site of
absorption
◼ Rate of absorption of poorly soluble drugs depends, on the rate of
dissolution of the drugs in the GI tract
92
Physicochemical…
 The rate of dissolution of drugs can be described by the Noyes-Whitney
equation
𝐷𝑐 𝐷𝐴 𝐶𝑠−𝐶𝑏
=
𝐷𝑡 ℎ
𝐷𝑐
➢ = Rate of dissolution of the drug
𝐷𝑡
➢ D is the diffusion coefficient of the drug
➢ A is the effective surface area of the drug i.e. in contact with the GI fluid
➢ h is the thickness of the diffusion layer around each drug particle

➢ Cs concentration of drug in the stagnant layer &
➢ Cb concentration of the drug in the GI fluid/bulk solution
93
Physicochemical…
94
❑ Factors affecting rate of dissolution
1. Surface area
❑ Particle size plays a major role in drug absorption, particularly for

drugs with poor aqueous solubility
❑ The smaller the particle size, the greater the effective surface area
exhibited by a given mass of drug, and the higher the dissolution rate
❑ Particle size reduction has been used to increase the absorption of a

number of poorly soluble drugs
➢ E.g. digoxin, griseofulvin
95
❑ Types of surface area
➢ Absolute surface area (total area of the solid surface of any particle)
➢ Effective surface area (Area of the solid surface exposed to the
dissolution medium)
❑ In absorption studies, the effective surface area is of much important than
absolute
❑ To increase the effective surface area, we have to reduce the size of particles up to
0.1 micron.
➢ So these can be achieved by “micronisation process’’.
96
➢ As the drugs particles get smaller result in an increased interaction with the
solvent
➢ Examples
 Griseofulvin: Dose reduced to half due to micronisation
 Spironolactone: the dose was decreased to 20 times.
 Digoxin: the bioavailability was found to be 100% in micronized tablets
➢ After micronisation, it was found that the absorption was highly increased
97
➢ In general, micronization of a compound enhances the dissolution rate
due to an increase in surface area.
➢ But there are instances in which particle size reduction fails to increase
the absorption rate of a drug.
➢ For drugs with aqueous solubilities below 1% (0.01mg/mL),

micronization may not be enough to get complete oral absorption
98
Physicochemical…
➢ Sometimes it dramatically increases the tendency of drug powder
aggregation.This may be due to

1) Increased hydrophobic interactions, particles reaggregates
2) Hydrophobic surface of the drugs entrap air and inhibits wettability
➢ This leads to a decrease in effective surface area
➢ E.g., Aspirin, Phenacetin and Phenobarbitone
99
Physicochemical…
❑ Such problems can be prevented by
➢ a) Use of surfactant as a wetting agent (e.g. Tween 80)

✓ Decrease the interfacial tension
✓ Displace the absorbed air with the solvent
➢ b) Add hydrophilic diluents like PEG, PVP

✓ Coat the surface of hydrophobic drugs and render them hydrophilic
or results in a more hydrophilic surface
100
Physicochemical…
2. Drug Solubility
❑ Aqueous solubility is the major factor that affect dissolution rate.
❑ Minimum aqueous solubility of 1% is required to avoid potential
solubility limited absorption problems.
➢ pH dependent
❖ The solubility of weak acids increases with increasing pH
❖ The solubility of weak bases decreases with increasing pH
101
3. Salt form
❑ It is one of the common approaches used to enhance drug solubility and
dissolution rate
➢ E.g. Sodium and potassium salts of Penicillin G
❑ The salt form of a drug generally has more solubility and dissolution rate
than that of the parent compound
➢ Improved bioavailability.
 The dissolution rate of the Tolbutamide sodium in 0.1 M HC1 is 5000 times
faster than that of the free acid.
 Sodium salts of acidic drugs and the hydrochloride salts of basic drugs are
by far the most common pharmaceutical salts.
102
Physicochemical…
❑ But, Some salts have a lower solubility and dissolution rate than the free
form.
➢ Delay absorption and may therefore be used to sustain the release of the drug
❑ Although salt forms are often selected to improve bioavailability, other
factors
➢ Chemical stability, hygroscopicity, will all be considered during selection and may
preclude the choice of a particular salt
✓ E.g., Sodium salt of aspirin, is much more prone to hydrolysis than the parent drug
itself.
103
4. Drug form: Crystal or Amorphous
❑ Solid drug materials may occur as:
➢ Crystalline substances of definite identifiable shape
➢ Amorphous particles without definite structure
✓ Amorphous form usually dissolves more rapidly than crystalline form(s)
▪ In amorphous form, inter molecular bonding between amorphous form of
drug and water is easier than crystalline form. Crystalline form is more
rigid and intra-molecular force is more. Due to this reason, crystalline
form will not form bond easily and dissolution rate will be less.
✓ Significant differences in bioavailability exists b/n amorphous and
104
crystalline forms of drugs
Physicochemical…
E.g. Novobiocin (antibiotic)
➢ Amorphous is at least 10X more soluble than crystalline form

✓ Amorphous form is readily absorbed from oral suspension
✓ Crystalline form is not absorbed to any significant extent
▪ Therapeutically ineffective
105
Physicochemical…
❑ Polymorphism
➢ Many drugs can exist in more than one crystalline form, this property
is termed as polymorphism.
✓ Substance with same chemical composition but d/nt conformation
or crystalline structure (different arrangement)

✓ Due to d/nt conformation or crystalline structure
▪ They have different physical properties, such as solubility, density, hardness and
compression characteristics
106
❑ Polymorphs can be:
1. Stable
2. Metastable (unstable)
❑ Metastable tend to transform to most stable form
❑ Metastable polymorphs have lower m.pt., greater solubility and dissolution
rates
➢ Different solubilities and dissolution rate of drug and consequently different
bioavailability in the body
❑ Usually the stable form is preferred in market as the metastable form may
107
transform to other stable forms
Physicochemical…
❑ But the metastable form has higher solubility than the stable form
✓ As a result, whenever possible, metastable forms that can survive years
without changing are selected for formulation
❑ Example:Chloramphenicol palmitate
➢ A - stable polymorph
➢ B - metastable polymorph
➢ C - unstable polymorph
➢ The extent of absorption of chloramphenicol increases as the proportion of
the polymorphic form B of chloramphenicol palmitate is increased.

▪ Due to the rapid in vivo dissolution rate of polymorph B
108
Physicochemical…
❑ Pseudo polymorphism
 Applicable for hydrates and solvates.

 It is a phenomenon in which solvent molecules get incorporated into
crystal lattice of solid crystal.
➢ When water is the solvent, the solvate formed is called a hydrate.
 Solvated and non-solvated forms usually exhibit differences in

dissolution rates.
➢ Differences in bioavailability
109
Physicochemical…
 Greater solvation of crystal leads to lower solubility and dissolution rate
in solvent identical to solvation molecule
➢ The solvate has already interacted intimately with the solvent . E.g.
Ampicillin (antibiotic)
✓ Anhydrous form is ~ 25% more soluble than trihydrate form.
▪ Absorbed to greater extent from both capsule and aqueous suspension forms
than trihydrate form.
110
❑ Analog of Indinavir (HIV protease inhibitor)
➢ Anhydrous form of HCl salt has much faster dissolution rate than
dihydrate form in water

✓ Anhydrous form achieves > 2X bioavailability
111
Physicochemical…
❑The drug dissociation constant (pKa value)
▪ Most drugs ionize in aqueous solution.
✓ They are either weak acids or weak bases.
✓ Those that are weak acids ionize in water to give acidic solutions while weak
bases ionize to give basic solutions.
Drug molecules that are weak acids Drug molecules that are weak bases
HA + H2O H3O+ + A- B + H 2O BH+ + OH-

where, HA = acid (the drug molecule) where, B = base (the drug molecule)
H2O = acid
H2O = base
A- = conjugate base (the drug anion) OH- = conjugate base (the drug anion)
112 H3O+ = conjugate acid BH+ = conjugate acid

❑ The drug dissociation constant (pKa value)
 Interrelationship b/n degree of ionization of weak electrolyte drug and
extent of absorption is embodied in pH-partition hypothesis.

 According to pH-partition hypothesis, GI epithelia act as lipid barrier
toward drugs absorbed by passive diffusion

➢ Unionized form of weak electrolyte drugs (i.e., lipid-soluble form)
pass across GI epithelia

➢ GI epithelia is impermeable to ionized (i.e., poorly lipid-soluble)
form of such drugs
113
❑ Extent to which weakly acid or base drug ionize in solution in GI fluid
is calculated using Henderson-Hasselbalch equations
❑ For a weakly acidic drug
❑ For a weakly basic drug
114
❑ According to equations,Weakly acidic drug, pKa 3.0
➢ Predominantly unionized (98.4 %) in gastric fluid at pH 1.2
➢ Almost totally ionized (99.98 %) in intestinal fluid at pH 6.8
❑ According to pH-partition hypothesis
➢ weakly acidic drug is more likely to be absorbed from stomach
➢ weakly basic drug from intestine
❑ However in practice, other factors need to be taken into consideration
115
❑ Limitations of the pH-partition hypothesis
1. Extent to which drug exists in unionized form is not the only factor
determining rate and extent of absorption
❑Despite high degree of ionization, weak acids are well absorbed
from SI
➢ Intestinal absorption of weak acid is often higher than in stomach
▪ Huge SA in SI more than compensates for high degree of

ionization
▪ Longer SI residence time and microclimate pH at intestinal surface
116
2. pH-partition hypothesis cannot explain why certain drugs (e.g.,
quaternary ammonium compounds and tetracyclines) are readily absorbed
despite being ionized over the entire pH range of the gastrointestinal
tract.
➢ Ion-pair formation
3. Convective flow or solvent drag

➢ The movement of water molecules into and out of the
gastrointestinal tract will affect the rate of passage of small water-

soluble molecules across the gastrointestinal barrier
117
❑ Lipid solubility
➢ Number of drugs are poorly absorbed from GIT despite their unionized forms
predominate
➢ Measure of lipid solubility is partition coefficient, P
➢ Determined by drug partitioning b/n water and suitable organic solvent
(Octanol) at constant temperature
118 P>1 implies lipophilicity (log p >0)

❑ Polar (poorly lipid soluble) (log P < 0) and relatively large molecules such as
gentamicin, ceftriaxone, heparin and streptokinase are

poorly absorbed after oral administration
 Given by injection
❑ Lipid soluble drugs with favorable partition coefficients (i.e. log P > 0)
are usually absorbed after oral administration
119
Molecules with acceptable hydrophilicity

and acceptable lipophilicity
Good oral bioavailability
120
Physicochemical…
❑To be absorbed, a drug should not be so-lipid soluble

➢If lipid soluble it will not dissolve in the aqueous fluids of the GIT
❑ Not so water-soluble that

➢If water soluble it will not penetrate the lipid GI membrane
121
❑ Molecular size
➢ For paracellular absorption, mol. wt. ideally be < 200 Da
➢ For transcellular passive diffusion, mol. wt. < 500 Da is prefered
122
Formulation Factors Affecting Oral Drug
Absorption
123
Formulation factors…
 The bioavailability of a drug can also be influenced by factors associated

with the formulation of the dosage form.
➢ The type of dosage form
➢ The excipients used
➢ Method of preparation
124
Formulation factors …
❑ Type of dosage form

➢ Influence number of intervening steps between administration
and the appearance of dissolved drug in the GI fluids.
➢ The greater the number of intervening steps, the greater will be the
number of potential obstacles to absorption.
➢ Thus, whether a particular drug is administered in the form liquid,
or solid dosage form can influence its rate/extent of absorption
from the GIT.
125
Major dissolution
126
❑ In general, drugs must be in solution form in the GI fluids for absorption
to occur
❑ Hence the bioavailability of a given drug tends to decrease in the

following order
➢ Aqueous solutions >aqueous suspensions > solid dosage forms
127
❑ Aqueous solutions
❖ With rare exceptions, drugs are absorbed more rapidly from solution
than any other oral DF
✓ Eliminates in vivo dissolution step and presents drug in most readily available form for
absorption
❖ Factors influencing drug bioavailability from aqueous solutions

✓ The chemical stability exhibited by the drug in aqueous solution and the gastrointestinal
fluids;
✓ The viscosity of a solution dosage form

o viscous solutions will retard the diffusion of the drug & retard the rate of gastric
emptying
➢ Hence retard the absorption of most drugs
128
❑ Aqueous suspensions
❖A useful dosage form for administering an insoluble or poorly water-
soluble drug.
❖ Usually the absorption of a drug from this dosage form is dissolution-
rate limited
❖ However, as aqueous suspension results in a large surface area of the
dispersed drug
➢ It facilitates dissolution and hence absorption of the drug.
129
➢ Dissolution of all drug particles begins immediately on dilution of the
suspension in the GI fluid.
 Formulation factors affecting bioavailability

➢ The particle size and effective surface area of the dispersed drug
➢ The crystal form of the drug
➢ The inclusion of a surfactant as a wetting agent
➢ The viscosity of the suspension.
130
❑ Liquid-filled capsules
❖ Liquids can be filled into capsules made from soft gelatin
➢ Combine the convenience of a unit dosage form and rapid drug
absorption associated with aqueous solutions and/ or suspensions.

➢ Drugs encapsulated in liquid-filled capsules are dissolved or
dispersed in non-toxic, non-aqueous vehicles.

✓ Such vehicles may be water immiscible (Like, vegetable oils) or
✓ water miscible (PEG).
131
❑ Release of the content of the gelatin is affected by splitting of the flexible
shell and dissolution rate.
❑ Following release, the drug disperses and/or dissolves readily in the GI
fluid, (depending on its solubility) as either a solution or fine suspension,

which is conducive to rapid absorption.
132
 Formulation factors affecting bioavailability
✓ The solubility of the drug in the vehicle and GI fluids
✓ The particle size of the drug if suspended in the vehicle
✓ The nature of the vehicle, i.e. hydrophilic or lipophilic
✓ The inclusion of a suspending agent (viscosity enhancing agent)
✓ Complexation, i.e. formation, of a non-absorbable complex between the drug and
any excipient
133
❑ Powder filled capsules
▪ Generally bioavailability of a drug from a well formulated powder-filled

hard gelatin capsule is better than compressed tablets.
▪ A relatively large effective surface area of drug facilitate dissolution.
134
❑The overall rate of dissolution of drugs from capsules appears to be a
complex function of the rates of different processes
➢ The dissolution rate of the gelatin shell
➢ The rate of penetration of the GI fluids into the encapsulated mass
➢ The rate at which the mass disperses in the GI fluid
➢ The rate of dissolution of the dispersed drug particles
➢ The nature and quantity of the diluent, and wetting agents
135
136
❑Tablets
➢ Tablets are the most widely used dosage forms.
➢ When a drug is formulated as a compressed tablet there is an enormous
reduction in the effective surface area of the drug
➢ As a result, it necessitate the addition of excipients, which serve to return
the surface area of the drug back to its original pre-compressed state.
137
❑ Because the effective surface area of a poorly soluble drug is an important

factor influencing its dissolution rate,
➢ Rapid disintegration affects rate of dissolution and absorption.
❑ The rate of tablet disintegration is influenced by several factors,

➢ Diluent, binder, disintegrant, lubricant and wetting agent, as well as the
compaction pressure
138
 The overall formulation factors affecting bioavailability
➢ The physicochemical properties of the liberated drug particles in the GI
fluid, e.g. effective surface area, crystal form, stability
➢ The nature and quantity of the diluent, binder, disintegrant, lubricant
and any wetting agent
➢ Type of the tablet (uncoated, coated, enteric-coated )
➢ Drug-excipient interactions (e.g. complexation)
➢ The compaction pressure
➢ Storage conditions of the tablet
139
Dosage form factors
❑ The dosage form factors affecting drug absorption are:
➢ Disintegration time: Directly related to the amount of binder & the
compression force.
▪ Incorporation of suitable amount of disintegrant will aid disintegration.
❑ Manufacturing/processing variables
➢ Method of granulation Wet granulation involves a number of steps
each of which can negatively affect drug dissolution

▪ Direct compression yields tablets that dissolve at a faster rate
140 6/18/2022
Dosage form factors
❑ Compression force: Influences density, porosity, hardness,
disintegration time and dissolution

➢ Influence of compression force on dissolution rate is difficult to
predict, should be studied on each formulation.
❑ Intensity of packing of capsule contents
➢ Intense packing result in decrease in pore size of compact and poor
penetrability by GI fluid
• Poor drug release and bioavailability
141 6/18/2022
❑ Effect of excipients
➢ Drugs are almost never administered alone
▪ Drug(s) + Excipients
➢ Excipients are added to ensure

▪ Acceptability
▪ Stability during the shelf life,
▪ Uniformity of dosage
▪ Manufacturability and
▪ Optimum bioavailability
142
❑ Excipients are historically considered as inert
❑ But have ability to influence rate and/or extent of absorption.
1. Diluents(fillers):
 Hydrophilic diluents (e.g. Lactose, MCC, Mannitol)

➢ Promote dissolution of poorly water soluble and hydrophobic drugs
(such as spironolactone) by forming a coat on hydrophobic drug
particles and rendering them hydrophilic
143
 Drug diluent interaction may result in poor bioavailability/toxicity
❖ E.g., Poorly absorbable or unabsorbable complex

➢ Tetracyclines and dicalcium phosphate
➢ Amphetamine and sodium CMC
➢ Phenobarbitone and PEG 4000
144
❑ Australian outbreak of phenytoin intoxication in epileptic patients
(phenytoin overdose (1968/69))
➢ As a result of change of the diluent calcium sulphate dihydrate with lactose.
➢ Calcium sulphate dihydrate was responsible for decreasing the GI
absorption of phenytoin
❖ Form poorly absorbable calcium- phenytoin complex
✓ Decrease GI absorption
➢ Lactose increased bioavailability of phenytoin
❖ Higher plasma levels exceeded max. safe conc.
✓ Produced toxic side-effects
145
2. Disintegrants
 Required to break down capsules, tablets and granules into primary

powder particles
➢ Increase SA
❖ Amount & type of disintegrants is crucial
✓ A decrease in the amount of disintegrant can significantly lower
BA.
146
3. Binders
 The type and concentration of binder may retard the disintegration of

tablets and slow dissolution rate of drugs
➢ Increasing the conc. of binder,
▪ Will increase the tablet cohesiveness,
▪ Increases hardness & hence retards its disintegration.
147
❑ Some binders forms a coat around the drug particles and retard
dissolution
➢ E.g., Methyl hydroxy ethyl cellulose, HPMC
❑ Some impart hydrophilic properties to granule surface

(Hydrophilic binders)
➢ Results in better dissolution of poorly wettable drug
▪ E.g., starch, gelatin, Polyvinylpyrrolidone (PVP)
148
4. Lubricants
 Included for tablets and capsule filling operations to reduce friction b/n
powder and metal surfaces during manufacturing
 Often hydrophobic in nature

➢ E.g., Magnesium stearate
➢ Retards wettability and liquid penetration into capsule and tablet
➢ Decrease dissolution rate (& BA)
149
 Overcome by:
➢ Addition of wetting agent (i.e. water-soluble surfactant) and use of
hydrophilic diluent.
➢ Use of soluble lubricants such as sodium stearyl fumarate.
150
5. Surfactant
 Used in DFs as emulsifying, wetting, solubilizing agents or suspension
stabilizers
 Their ability to reduce the solid/liquid interfacial tension will permit

the GI fluids to wet the solid more effectively
 Surfactants can increase absorption of drugs by:

➢ Promoting wetting e.g. Tween 80
151
6. Viscosity-enhancing agents
 Employed in liquid DFs for oral use to control palatability, pourability

and rate of sedimentation of dispersed particles
 Often hydrophilic polymer (e.g. Acacia, tragacanth, ) or semi

synthetic gums (e.g., CMC, MC)
152
 Affect GI absorption of drug, by:
➢ Increasing viscosity
✓ Act as mechanical barrier to the diffusion of drug from dosage

form into the bulk of GI fluid and from GI fluid to mucosal lining.
➢ Complex formation b/n drug and hydrophilic polymer
✓ Reduce drug in solution available for absorption
✓ E.g., Sodium CMC forms complex with amphetamine
153
7.Vehicles or solvent systems
Could be:
 Aqueous (e.g.Water, syrup),
 Non aqueous water miscible (e.g. Propylene glycol, glycerol, sorbitol) or
 Non aqueous water immiscible (vegetable oils)
154
➢ Aqueous & water miscible vehicle are miscible with GI fluid, drugs from
them are rapidly absorbed

➢ Release from water immiscible vehicles depend on the partition of the
drug from the oil phase into the aqueous GI fluid.

➢ Viscosity of the vehicle is another factor
155
8. Coatings
❑ Coating can add another barrier between the solid drug and GI fluid
❑ Sugar coating : Sealing by shellac, and thickness of the coat delay
dissolution
❑ Film coating, non-enteric: soluble, dispersible in GI fluid
➢ Hydroxypropyl methylcellulose, povidone, polyethylene glycol
156
❑ Film coating, enteric: resistant to gastric fluid, soluble at PH≥5
➢ Cellulose acetate phthalate, eudragit (acrylate polymer)
❑ In general, the deleterious effect of coating materials on drug dissolution
from tablets is in the order of

➢ Enteric coat>sugar coat>non-enteric film coat
157
Bioavailability and Bioequivalence
By: Adane Yehualaw (BPharm, MSc)

158
Objectives
❑ At the end of the chapter, students are expected to be able to:
➢ Define bioavailability, bioequivalence and other related terms
➢ Describe methods of assessing bioavailability
➢ Understand & be able to calculate absolute & relative bioavailabilities
➢ Explain bioequivalence
159
Introduction
❑ Essential to ensure uniformity in standards of quality, efficacy & safety of
Pharmaceutical products
❑ Reasonable assurance is to be provided that various products containing

same active ingredient, marketed by different licensees are clinically
equivalent & interchangeable
❑ Release of an active substance should be known & reproducible
❑ Both Bioavailability & Bioequivalence focus on release of drug substance

from its dosage form & subsequent absorption in circulation
160
Bioavailability
❑ Defined as: the rate and extent to which an active drug ingredient is
absorbed from a drug product and becomes available at the site of action.
➢ Drug conc. usually cannot be readily measured at site of action
➢ However drug at site of action is in equilibrium with drug in blood
▪ Indirect measure of drug response
➢ Most bioavailability studies involve determination of drug conc. in

blood or urine
161
Bioavailability
❑ Bioavailability is more commonly defined as "the rate and extent that
the active drug is absorbed from a dosage form and becomes available in
the systemic circulation.“
❑ It is concerned with how quickly and how much of drug appears in blood
after specific dose is administered
➢ Concerned with fraction of dose that actually reaches blood stream
➢ Represents "effective dose" of drug
❑ Bioavailability of drug from DF is critical element of drug product's

clinical efficacy
162
Purposes of Bioavailability
 Bioavailability studies are performed for both approved active drug
ingredients and drugs not yet approved for marketing by FDA
 For new drugs
➢ To establish essential PK parameters including
✓ Rate and extent of systemic absorption
✓ Rates of excretion and metabolism and
✓ Elimination half-life
163
Purposes of bioavailability
➢ Data from the in-vivo bioavailability studies helps to establish
recommended dosage regimens
✓ Dose, Frequency of administration, Treatment duration
➢ To determine influence of
✓ Excipients
on biological performance of
✓ Manufacturing procedures
new drug formulation
✓ Patient related factors
164
Purposes of bioavailability
For approved drugs
❑ To develop new DF or to improve an existing DF

➢ New formulations of active drug ingredients must be approved by the FDA
before marketing
➢ In approving drug product for marketing, FDA ensure that drug product is
safe and effective for its labeled indications of use
➢ Drug product must meet all applicable standards of identity, strength,

quality, and purity
165
Methods of assessing drug bioavailability
❑ In vivo methods
❑ In vitro studies
➢ Drug dissolution
166
PK Methods
➢ Widely used and based on assumption that PK profile reflects the
therapeutic effectiveness of a drug
1). Plasma Level-Time Studies:
❑ Most common type of human bioavailability studies.
➢ Time for peak plasma (blood) concentration (Tmax)
➢ Peak plasma drug concentration (Cmax)
➢ Area under the plasma drug concentration–time curve (AUC)
a)
167
Plasma drug concentration
❖ Measurement of drug concentrations in blood, after drug administration is the
most direct way to determine systemic drug bioavailability.
❖ Based on the assumption of a direct relationship b/n the concentration of drug in
blood and the concentration of drug at the site of action.
Plasma drug conc. Equilibrium Tissue drug conc.
168
Plasma drug concentration
 Data is generated: Following the administration of dose of a drug,

plasma samples will be taken at various time intervals and analyzed for
drug content.
 The concentration of drug in each plasma sample is plotted against the

corresponding time at which the plasma sample was removed.
169
Plasma drug conc…..
170
Plasma drug conc…
 As the drug reaches the systemic circulation, plasma drug concentrations

will rise up to a maximum.
 Initially, absorption of a drug is more rapid than elimination.
 As the drug is being absorbed into the systemic circulation, the drug is
distributed to all the tissues in the body and is also simultaneously being
eliminated.
171
Plasma drug conc…
❑ Peak Plasma concentration (Cmax)
➢ Cmax represents the maximum drug concentration observed after oral
administration of drug.
✓ The peak represents the point of time when absorption rate equals elimination rate
of drug.
172
Plasma conc…
Time of Peak Concentration (tmax):
➢ Corresponds to the time required to reach maximum drug conc. (C

max) after drug administration
 expressed in terms of hours or minutes
 useful in estimating the rate of absorption.
173
Plasma conc…
Area Under the Curve (AUC):
➢ It represents the total amount of drug that reaches into the systemic
circulation after its administration.
➢ It is the most important parameter in evaluating the bioavailability of a

drug as it measure the extent of bioavailability.
174
Plasma conc…
Minimum Effective Concentration (MEC):
➢ It is defined as the minimum concentration of drug in plasma required

to produce the therapeutic effect.
➢ The smallest concentration which is able to elicit the desired

pharmacological response.
➢ The concentration of drug below MEC is said to be in the

sub‐therapeutic level.
175
Plasma conc…
Maximum safe concentration (MSC)
➢ It is the concentration of drug in plasma above which adverse or
unwanted effects are precipitated.
➢ Concentration of drug above MSC is said to be in the toxic

level.
176
Plasma conc…
 Onset of action
➢ The time at which the administered drug reaches the therapeutic range (MEC) and
begins to produce the effect.
 Termination of action
➢ The time at which the drug concentration in the plasma falls below the minimum
effective concentration (MEC).
❑ Duration of action
➢ The time span from the beginning of the onset of action up to the termination of
action.
177
Plasma conc…
❑ E.g. Figure below shows the plasma profile of three formulations (A,
B and C) of the same dose of the same drug.
178
Plasma conc…
Formulation A Formulation B Formulation C
AUC of formulation A & B are similar indicating that the drug is Formulation C gives a smaller
absorbed to a similar extent
AUC, indicating that a lower
The drug is absorbed faster from formulation A than B
proportion of the dose has been
Formulation A has faster onset of therapeutic action than B & C
absorbed.
but the peak conc. exceeds MSC
Duration of action obtained with formulation B is longer than A Slower rate of absorption,
doesn’t reach MEC
➢ Therefore Formulation B appears to be superior than A
from a clinical viewpoint , in that its peak plasma conc. lies
within the therapeutic range of the drug & the duration of
➢ Formulation C does not
the therapeutic effect is longer produce a therapeutic effect
and consequently is
clinically ineffective.
179
Absolute and Relative Bioavailability
1. Absolute bioavailability
 Bioavailable fraction (F): Refers to the fraction of administered dose that
actually enters the systemic circulation
𝐵𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑙𝑒 𝑑𝑜𝑠𝑒
𝐹=
𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 𝑑𝑜𝑠𝑒
 By definition when a medication is administered through IV its bioavailable
fraction (F) is 1 that is 100% bioavailability
 However, for other routes, bioavailability decreases due to incomplete absorption

and first pass effect
180
Absolute bioavailability
➢ Therefore, absolute bioavailability of a drug is: systemic availability (AUC)

of a drug after extravascular (ev) administration (e.g., oral, rectal…) relative
to IV bioavailability of the same dose of a drug.
𝐴𝑈𝐶 𝑒𝑣
❖ 𝑨𝒃𝒔𝒐𝒍𝒖𝒕𝒆 𝒃𝒊𝒐𝒂𝒗𝒂𝒊𝒍𝒂𝒃𝒊𝒍𝒊𝒕𝒚 =
𝐴𝑈𝐶 𝑖𝑣
❖ IV is the reference standard for absolute bioavailability.
181
Relative bioavailability
2. Relative bioavailability
 Relative bioavailability refers to availability of drug product as

compared to recognized Standard (non-IV)
 The fraction (F) of drug from a formulation that reaches the systemic
circulation relative to a different formulation
182
Relative bioavailability
➢ A common standard dosage form is considered an aqueous oral solution of the

drug
➢ where drug product B is reference/recognized standard.
➢ Both product A & B are same drug with the same dose.
183
Practice example
❑ Assume that an intravenous injection (Product A) and two oral dosage forms
(Product B and Product C), all containing the same dose of the same drug, are
given to a group of subjects in a crossover study. Suppose each product gave the
values for AUC indicated in the Table below:
❑ Q. Calculate absolute Bioavailability for the oral dosage forms and relative
bioavailability of Product C as compared to Product B
184
Bioequivalence
185
Introduction
❑ Drugs are marketed from different sources
➢ A multisource drug product: is a drug product that contains the same active drug
substance in the same dosage form and is marketed by more than one pharmaceutical
manufacturer.
➢ Single-source drug products: are drug products for which the patent has not
yet expired or has certain exclusivities so that only one manufacturer can make it.
▪ Single-source drug products are usually brand-name (innovator) drug products
186
Intro…
❖ Patented drug product (innovator or brand product) produced by
the first manufacturer who has got a patent.
❖ Generic drug product: produced by different manufacturer after the

period of patent for the innovator brand has ended.
✓ Generic products are cheaper
187
Intro…
❑After the patent for the brand product expires, a pharmaceutical company
may manufacture a generic drug product that can be substituted for the
branded drug product.
❑But for the generic products to receive approval, the manufacturer must
establish that its product is therapeutically equivalent with the
innovator product.
188
Terminologies
❑Pharmaceutical equivalents
✓ Drug products that contain the same active ingredient,
➢ (i.e. the same salt or ester of the therapeutic moiety)
✓ Identical dosage forms , strength & route of admin.
✓ Not necessarily containing the same inactive ingredients
✓May differ in characteristics such as shape, release mechanisms, packaging, excipients
(including colors, flavors, preservatives), expiration time, and, within certain limits, labeling.
TTC HCl, 250mg capsule

TTC phosphate, 250mg capsule
Quinidine sulfate, 200mg tablets

Quinidine sulfate, 200mg capsules
189
Terminologies
❑ Pharmaceutical alternatives
➢ Drug products that contain the same therapeutic moiety but are
different salts, esters, or complexes of that moiety
➢ Not necessarily the same
• Salt or ester of the therapeutic moiety
• strength and
• dosage form TTC HCl, 250mg capsule
TTC phosphate, 250mg capsule
Quinidine sulfate, 200mg tablets

Quinidine sulfate, 200mg capsules
190
Terminologies…
❑ Pharmaceutical Equivalence does not necessarily imply bioequivalence.
Excipients and/or the manufacturing process can lead to faster or slower
dissolution and/or absorption.
Test Reference
Possible Differences
 Drug particle size
 Excipients
 Manufacturing
Equipment or
Process
 Site of manufacture
These aforementioned factors could lead to differences in product

191 performance in-vivo
Terminologies…
❑ Therapeutic equivalence
o Drug products are considered to be therapeutic equivalents only if
➢ They are pharmaceutical equivalents
➢ With the same clinical effect & safety profile as derived from
appropriate studies such as:
▪ Bioequivalence studies
▪ Pharmacodynamic studies
▪ Clinical studies
▪ In-vitro studies
192
Terminologies…
❑Therapeutic alternatives
➢Drug products containing different active ingredients that are indicated
for the same therapeutic objectives
➢Have to be in the same pharmacologic class and are expected to have the
same therapeutic/clinical effect
193
Terminologies…
❑Bioequivalence
➢Two drugs (test drug and reference-brand) to be considered as
bioequivalent:
▪ Pharmaceutical equivalent / alternative
▪ when administered at the same molar dose,
✓ The rate and extent of absorption of the test drug do not show a statistically
significant difference from that of the reference product
▪ BE assesses the relative BA of two drug products, and thus, focuses on

comparative drug product performance.
194
Requirement of BA & BE Studies
▪ The basis for the approval and use of generic drug products.
Bioequivalence studies are conducted:
✓ When a generic formulation is tested against an innovator brand.
✓ Where a proposed dosage form is different from that used in a

clinical trial.
✓ When significant changes are made in composition &/or

manufacturing process.
✓ Control of quality of drug products, influence of processing factors, storage &
stability
195
Requirement of BA & BE Studies…
❑ For IND/NDAs:
➢ To establish equivalence between:
▪ Early & late clinical trial formulations.
▪ Formulations used in clinical trial & stability studies.
▪ Clinical trial formulations & to-be-marketed drug product
196
Bioequivalence studies
Subjects
❑ The typical number of subjects is 24–36 with the minimum number of subjects
in the study being 12.
❑ Healthy subjects are recommended for BE studies for many reasons:
➢ Patients may be taking Other drugs and the physiological changes etc.
▪ May modify drug absorption pattern
➢ Strict study conditions such as fasting state are difficult for patients
➢ Patients require continuous treatment that does not allow for a washout period
▪ Patients are generally used only when drug is not safe to administer in healthy
subjects.
197
❑ 20-50 years of age and 120-200 lb of body weight
❑ Males are preferred
➢ Menstrual cycle, pregnancy, lactation and menopause stages may affect
blood level profiles of drug

✓ Females are included taking these points into consideration
❑ Subjects are distributed randomly to different groups to achieve uniform
distribution with respect to age, sex, and body weight to avoid bias.
198
❑ Study design
➢ Parallel Design and Cross-over Design
❖Parallel Design
 Subjects are divided randomly into groups and each group receive
only one treatment (take either the test or the reference product)
➢ if for example, the volunteers are divided into two groups;
➢ One group will take the test product and the other will take the reference
product
➢ Recommended when the half life of the drug is so long (b/s each subject take
only one treatment only once: no washout period)
199
❑ Disadvantage:
➢ Inter-subject variation isn’t addressed
➢ Require larger numbers of subjects
200
❖Cross-over Design
 Each subject receives two or more different treatments on successive

occasions.
➢ The subjects will take both the test and the reference product on different days
▪ The second treatment will be given after washout period
➢ Minimizes inter-subject variability
✓ Each subject serves as his own control (i.e., we can compare

Test to Reference on each subject).
201
Waivers of In-Vivo Bioequivalence Studies (Biowaivers)
❑ For some drug products, there is sufficient understanding of the

physicochemical properties and biological factors that affect BA that there is no
need for in vivo BE studies.
➢ In-vitro dissolution testing may be used in place (lieu) of in-vivo bioequivalence
studies
❑ Sponsors may request abandonments (waivers) of BE studies (biowaivers) for
solutions, products with a range of strengths, and biopharmaceutical
classification system (BCS) Class I drugs.
202
Waivers of In-Vivo Bioequivalence...
❑ Solutions: In vivo BA/BE is self-evident for certain drug products, such as topical
solutions, nasal spray solution, oral solutions, elixirs, syrups, tinctures or

other solubilized forms of the drug.
➢ In-vivo BA/BE can be waived, assuming that release of the drug substance from the
drug product is self-evident and that the solutions do not contain any excipient that
significantly affects drug absorption.
203
❑ Lower Strengths: Waiver of in vivo studies for different strengths of a drug
product can be granted when

➢ The drug product is in the same dosage form, but in a different strength
(e.g., a tablet of 50mg, 100mg, 25mg);
➢ This different strength is proportionally similar in its active and inactive
ingredients to the strength of the product for which the same manufacturer
has conducted an appropriate in vivo study; and
➢ The new strength meets an appropriate in vitro dissolution test.
204
❑ E.g., Immediate-release tablet available in 200mg, 100mg and 50mg
strengths
❖ 100mg and 50mg tablets are made in same way as 200mg
❖ Human bioequivalence study is performed on highest or 200mg
strength
❖ Comparative in-vitro dissolution studies are performed on 100-mg
and 50-mg dose strengths and meet requirements
205
❑ If products have no known bioavailability problems, are well absorbed
systemically, are well correlated with in-vitro dissolution, and have large
margin of safety
➢ Manufacturer needn’t perform additional in-vivo bioequivalence studies
on lower-strength products if they meet all in-vitro criteria
206
Biopharmaceutical Classification System
❑ A scientific framework that predicts the in vivo absorption of drugs from
aqueous solubility and intestinal permeability data.
❑ A drug substance is considered highly soluble when the highest dose
strength is soluble in 250 ml or less of aqueous media over the pH range

of 1.0–7.5.
➢ Otherwise, the drug substance is considered poorly soluble
❑ The volume estimate of 250 ml is derived from the minimum volume
anticipated in the stomach when a dosage form is taken in the fasted state
with a glass of water.
207
Biopharmaceutical Classification…
❑ A drug substance is considered to be highly permeable when
gastrointestinal absorption in humans is determined to be 90% or more of
an administered dose
➢ Otherwise, the drug substance is considered to be poorly permeable.
❑ According to BCS, drug substances are classified as
➢ Class I: High Solubility – High Permeability E.g. verapamil, Metoprolol, propranolol
➢ Class II: Low Solubility – High Permeability E.g., Ketoprofen, naproxen,
glibenclamide
➢ Class III: High Solubility – Low Permeability E.g., Cimetidine, ranitidine, atenolol
➢ Class IV: Low Solubility – Low Permeability E.g., Hydrochlorothiazide, furosemide
208
Table: Biopharmaceutical Classification System
209
❑ Limitation of this classification method
➢ This approach assumes that no other components in the formulation affect
the membrane permeability and/or intestinal transport.
210
THANK YOU
211
Group Assignment
 Drug absorption through the eye, ear and nose
 Percutaneous drug absorption
 Parenteral drug absorption
 Rectal drug absorption
212

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Biopharmaceutics &

By: Adane Yehualaw (Bpharm., MSc. Pharmaceutics)

➢ Barriers of drug transport (Plasma membrane, P-GP)

➢ Mechanisms of drug transport

o Active transport, facilitated diffusion

Interaction between the drug substance

The biologic response

The magnitude of the response is related to the

➢ Physicochemical property of drugs (API)

➢ The type of dosage form

➢ Route of delivery &

b/n the physicochemical properties of a drug, the dosage form in which

 It is the study of the factors influencing the bioavailability of a drug (in

humans and animals) and

of drug product in clinical application.

of administration to the systemic circulation.

from a dosage form and becomes available in the systemic circulation.

➢ The stability of the drug within the drug product,

▪ Protection of the activity of the drug within the drug product

➢ The release of the drug from the drug product

➢ The rate of dissolution of the drug at the absorption site

➢ The systemic absorption of the drug.

➢ In-vitro methods are procedures employing test apparatus &

equipment without involving laboratory animals or humans.

after giving a drug to human subjects or laboratory animals.

➢ Membrane physiology – The major barrier to drug transport

➢ Gastric emptying time

➢ Intestinal transit time

➢ Blood flow through the GIT

▪ Gut wall enzymes, Bacterial enzymes, Hepatic enzymes

➢ Particle size & effective surface area

➢ Lipophilicity of the drug

➢Disintegration time (tablets/capsules)

➢Pharmaceutical ingredients (excipients)

A. The cell membrane

➢ Acts as a barrier and separate cellular contents from the external

carbohydrates are imbedded.

▪ Hydrophilic exterior and hydrophobic interior

The cell membrane

 It is a semi-permeable lipoidal sieve which acts as selective barriers to the

❑ In addition to phospholipids the cell membrane is composed of different

➢ Functionally, glycolipids facilitate cellular recognition while glycoproteins

❖ There are two types of proteins found in the membrane

▪ Protrude all the way through the membrane.

▪ Many of the integral proteins provide structural channels (Pores)

which allows water soluble substances, especially the ions, to diffuse

transporting substances against concentration gradients, which is

dependent transporter which is capable of transporting an extremely

➢ The immunosuppressive agent: Cyclosporin A,

➢ Vinca alkaloids:Vinblastine (VBL), vincristine (VCR),

➢ Erythromycin and other antibiotics,

➢ The blood–brain barrier (BBB) is composed of a tightly sealed

monolayer of brain capillary endothelial cells

C. Cytochrome P450 3A4 (CYP3A4)

bioavailability of orally administered drugs.

❑ It is the major pathway for drug absorption in the intestine.

❖ P = lipid water partition coefficient of drug

❖ A = surface area of membrane

❖ Cg – Cb= concentration gradient b/n GIT and blood

❑ The drug molecule or ion forms a complex with the carrier/transporter.

❑There are a large number of carrier-mediated active transport systems in

Fig.3. Relationship between rate of absorption and concentration at the

36 Fig.4. Diagrammatic representation of facilitated diffusion