biopharceutics ppt (IHSBC).pptx

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Course code: Phar3191
Module Name:
Pat I: Biopharmaceutics and
Part II: Pharmacokinetics Module
Course ECTS: 7
Course prerequisite/s: Physiology II and Pharmacology II
 Course Objective
▪ To develop the ability to logically apply the interrelationship of the
physicochemical properties of the drug, the dosage form and ROA on
the rate and extent of drug absorption.
▪ To develop a graduate with good practical knowledge and
understanding of pk principles in everyday clinical pharmacy
practice.

Introduction
DRUG PRODUCT PERFORMANCE
 Drugs are substances intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease.
 Drugs are given in a variety of dosage forms or drug
products such as solids, semisolids, liquids, etc,
for systemic or local therapeutic activity.
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Introduction cont.
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• Drug products can be considered to be drug delivery
systems if it release and deliver drug to the site of action
such that they produce the desired therapeutic effect.
• In addition, drug products are designed specifically to meet
the patient’s needs including palatability, convenience, and
safety which is a measure of drug product performance.

Introduction cont.
 Drug product performance is defined as the release of the
drug substance from the drug product either for local drug
action or for drug absorption into the plasma for systemic
therapeutic activity.
 Advances in pharmaceutical technology and manufacturing
have focused on developing quality drug products that are
safer, more effective, and more convenient for the patient
which is concerned by biopharmaceutics..
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Biopharmaceutics
In the world of drug development, the term
“biopharmaceutics” narrowly defined as a field of science
that involves the preparation, use, or dispensing of medicines
(Woolf, 1981).
Addition of the prefix “bio,” coming from the Greek “bios,”
relating to living organisms or tissues expands this field into
the science of preparing, using, and administering drugs
to living organisms or tissues.
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Biopharmaceutics…cont’d
Biopharmaceutics:- examines the interrelationship of the
physical/chemical properties of the drug, the dosage form
(drug product) in which the drug is given, and the route of
administration on the rate and extent of systemic drug
absorption.
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Biopharmaceutics…cont’d
The importance of the drug substance and the drug
formulation on absorption, and distribution of the drug to
the site of action, is described as:
A sequence of events that precede elicitation of a
drug’s therapeutic effect.
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 Figure 1: demonstrating the dynamic relationship between
the drug, the drug product, and the pharmacologic effect.
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Cont.…
• First, the drug in its dosage form is taken by the patient in
any route of administration.
• Next, the drug is released from the dosage form in a
predictable and characterizable manner.
• Then, some fraction of the drug is absorbed from the site of
administration into either the surrounding tissue for local
action or into the body (as with oral dosage forms), or both.
Finally, the drug reaches the site of action
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Cont.…
• A pharmacodynamic response results when the drug
concentration at the site of action reaches or exceeds
the minimum effective concentration (MEC).
• The suggested dosing regimen, including starting dose,
maintenance dose, dosage form, and dosing interval, is
determined .
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Cont.…
oFor a drug to be effective, enough of it needs to reach its
site(s) of action and stay there long enough to be able to
exert its pharmacological effect.
oThis depends upon the route of administration, the form
in which it is administered and the rate at which it is
delivered.
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Cont’d
Generally, biopharmaceutics involves factors that influence
1. The design of the drug product,
2. Stability of the drug within the drug product,
3. The manufacture of the drug product
4. The release of the drug from the drug product,
5. The rate of dissolution/release of the drug at the
absorption site, and
6. Delivery of drug to the site of action
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Concept of biopharmaceutics
Factors affect (influence) bioavailability
Food eaten by the patient
Effect of disease state
Age of the patient
The site of administration
Physicochemical properties of drug
Co-administration of drug
The type of dosage form, size & frequency
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Application of biopharmaceutics
provides the scientific basis for drug product design and
drug product development.
• Each step in the manufacturing process to finished dosage
form may potentially affect the release of the drug from
the drug product and the availability of the drug at the
site of action.
Used to increase, monitor and maintain the rate at which a
drug is released from the drug product
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Cont’d
Used to characterize
physiochemical nature of the drug
rate of solubility and
dissolution rate of the drug.
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Cont’d
Relevant to preclinical, clinical, industrial pre-
formulation and formulation development, as well as in
regulatory affairs.
It encompasses the field of characterizing, describing,
evaluating, optimizing and predicting drug absorption,
bioavailability and bioequivalency.
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Barriers of drug transport (epithelia and plasma
membrane)
Membranes are major structures in cells surrounding
 Functionally, cell membranes are semipermeable
partitions that act as selective barriers to the
passage of molecules.
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Cont’d
Properties of the lipid membrane are critically important in
regulating the movement of drug molecules.
Other barrier properties of membranes are transport
proteins and ion channels,
Control the rate of permeation of many solutes.
The relationship between membrane structure, membrane
function, and cell physiology is basic determinant factor for
drug transport.
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Cont’d
Water, some selected small molecules, and
lipid-soluble molecules pass through such
membranes
whereas highly charged molecules and large
molecules, such as proteins and protein-
bound drugs, do not pass.
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Mechanism of drug transport
o For systemic drug absorption, the drug may have to cross
cellular membranes
o After oral administration, drug molecules must cross the
intestinal epithelium by
▫ between the epithelial cells (paracellular
absorption)
▫ going either through (transcellular absorption) or
▫ passive diffusion
▫ Carrier mediated transport
▫ Vascular transport
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Mechanism of drug transport…cont’d
• 90
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1. Paracellular and transcellular routes,
Paracellular transport is a passive transport process that
occurs between adjacent epithelial cells.
The rate-limiting step in this process is transport across the
tight junction.
This makes the tight junction the primary determinant of
paracellular permeability.

Paracellular and transcellular routes…cont’d
• However, two important qualifiers must be added to this simple
statement.
• First, an immutable characteristic of paracellular transport is that
it is passive; therefore, it depends entirely on local concentration
gradients.
• Second, processes independent of tight junction regulation can
affect mucosal permeability.
• These is epithelial damage, including erosion or ulceration.
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Cont’d
The paracellular transport is not suitable for the transport
of large macromolecules.
Several peptide drugs, such as octreotide, vasopressin
analog desmopressin, and thyrotropin-releasing hormone
are believed to absorb by this route (Pauletti et al., 1996).
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Transcellular route
 Transcellular conveyance the transference of solutes via a cell
(Rhoades and Bell, 2012).
The transcellular channel of transportation embraces
transcellular diffusion or active carrier arbitrated
transference.
One typical instance is the passage of glucose from the
intestinal lumen to the extracellular fluid by epithelial cells.
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Transcellular route…cont’d
• Another example is naproxen against Alzheimer’s
disease.
• Overall, at least for polar drugs, it is likely, that the
transcellular route provides the main pathway
during percutaneous absorption
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2. passive diffusion
Passive diffusion is the process by which molecules
spontaneously diffuse from a region of higher concentration
to a region of lower concentration.
If the drug has a low Mwt and is lipophilic, the lipid cell
membrane is not a barrier to drug diffusion and absorption.
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Passive diffusion cont’d
oDrug molecules move forward and back
across a membrane.
oWhen one side is higher in drug
concentration, at any given time, the number
of forward-moving drug molecules will be
higher than the number of backward-
moving molecules

oPassive diffusion is the major absorption process for most drugs.
oThe driving force for passive diffusion is higher drug
concentrations on the mucosal side compared to the blood.
oAccording to Fick's law of diffusion, drug molecules diffuse
from a region of high drug concentration to a region of low drug
concentration.

where dQ/dt = rate of diffusion,
D = diffusion coefficient,
K = lipid water partition coefficient of drug in the
biologic membrane
A = surface area of membrane;
h = membrane thickness, and
C GI – C p = difference between the concentrations of drug
in GIT and in the plasma.

Different factors affect the rate of passive diffusion of drugs
Concentration gradient
If the drug is given orally, C Gl >> C p and a large
concentration gradient is maintained, thus driving drug
molecules into the plasma from the gastrointestinal tract.

Partition coefficient, K,
represents the lipid–water partitioning of a drug across
the membrane in the mucosa.
Drugs that are more lipid soluble have a larger value of K

surface area, A, of the membrane
Drugs may be absorbed from most areas of the
gastrointestinal tract
The duodenal area of the small intestine shows the
most rapid drug absorption
 due to presence Folds of villi and microvilli.

Thickness of membrane (h)
Drugs usually diffuse very rapidly through capillary plasma
membranes in the vascular compartments, in contrast to
diffusion through plasma membranes of capillaries in the
brain.
In the brain, the capillaries are densely lined with glial cells, so
a drug diffuses slowly into the brain as if a thick lipid membrane
existed.

Diffusion coefficient, D,
 Is a constant for each drug and is defined as the amount of
a drug that diffuses across a membrane of a given unit area
per unit time when the concentration gradient is unity
 The dimensions of D are area per unit time

Because D, A, K, and h are constants under usual conditions
for absorption, a combined constant P or permeability
coefficient may be defined.
C p << C GI
If C p is negligible and P is substituted into fick’ law
expression, the following relationship for Fick's law is
obtained:

oNote:
The extravascular absorption of most drugs tends to be a
first-order absorption process
The rate of drug absorption is usually more rapid than
the rate of drug elimination
Due to the large concentration gradient
i.e. C GI >> C p

3. Carrier mediated transport
 Numerous specialized carrier-mediated transport
systems are present in the body esp in the intestine for
the absorption of ions and nutrients including drugs.
 Includes
 Active transport and
 Facilitated Diffusion

Carrier mediated transport…cont’d
 Carrier-mediated transport is a
specialized process requiring a
carrier that binds the drug to
form a carrier–drug complex
that shuttles the drug across the
membrane.

Active Transport
 Active transport is a carrier-mediated transmembrane process
that plays an important role
GI absorption and in renal and biliary secretion of many
drugs and metabolites
 A few lipid-insoluble drugs that resemble natural physiologic
metabolites (such as 5-fluorouracil) are absorbed from GIT by
active transport

 Active transport is characterized by the transport of drug against
a concentration gradient
 The carrier molecule may be highly selective for the drug
molecule.
 If the drug structurally resembles a natural substrate that is
actively transported, then it is likely to be actively transported by
the same carrier mechanism.
drugs of similar structure may compete for sites of
adsorption on the carrier.

Facilitated Diffusion
oFacilitated diffusion is also a carrier-mediated transport system,
differing from active transport in that the drug moves along a
concentration gradient.
oThis system is: saturable, structurally selective for the drug and
shows competition kinetics for drugs of similar structure
play a very important role in drug absorption

Carrier-Mediated Intestinal Transport
oVarious carrier-mediated systems (transporters) are present
at the intestinal brush border and basolateral membrane for
the absorption of specific ions and nutrients essential for the
body.
oMany drugs are absorbed by these carriers because of the
structural similarity to natural substrates

A transmembrane protein, P-glycoprotein (Pgp) is found in the
intestine.
Pgp appears to reduce apparent intestinal epithelial cell
permeability from lumen to blood for various lipophilic or
cytotoxic drugs.
Other transporters in the intestines
E.g. many oral cephalosporins are absorbed through the
amino acid transporter

Intestine transporters and examples of drugs transported
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Transporter Example of drugs
Amino acid transporter Gabapentin Baclofen
Methyldopa L-dopa
Oligopeptide transporter Cefadroxil Cephradine
Cefixime Ceftibuten
Cephalexin Captopril
Phosphate transporter Fostomycine
Monocarboxylic acid
transporter
Salicylic acid Benzoic acid
Pravastatin

4. Vesicular Transport
oVesicular transport is the process of engulfing particles or
dissolved materials by the cell.
oPinocytosis and phagocytosis are forms of vesicular transport
that differ by the type of material ingested.
oPinocytosis refers to the engulfment of small solutes or fluid
ophagocytosis refers to the engulfment of larger particles or
macromolecules
 generally by macrophages

Vesicular Transport…cont’d
During pinocytosis or
phagocytosis, the cell membrane
invaginates to surround the material
and then engulfs the material,
incorporating it into the cell.
Subsequently, the cell membrane
containing the material forms a
vesicle or vacuole within the cell.

Vesicular Transport…cont’d
oVesicular transport is the proposed process for the absorption of
orally administered Sabin polio vaccine and various large
proteins.
oAn example of exocytosis is the transport of a protein such as
insulin from insulin-producing cells of the pancreas into the
extracellular space.

 A certain type of protein called transport protein may
form an open channel across the lipid membrane of the
cell.
 Very small molecules, such as urea, water and sugars are
able to rapidly cross the cell membrane through these
pores.
5- Pore (convective) transport:

Transport of Substances Across a Membrane by Channel
Proteins

Factors affecting oral drug absorption
oThe systemic absorption of a drug after oral absorption is
dependent on
 Physiologic Factors
 the physicochemical factors
 Formulation factors
oConsidering all of these factors are important in the
manufacture and biopharmaceutic evaluation of drug
products

GIT anatomy and physiology
oThe GIT is a muscular tube approximately 6 m in length with
varying diameters.
oIt stretches from the mouth to the anus and consists of four
main anatomical areas:
 the oesophagus,
 stomach,
 the small intestine and
 the large intestine or colon
Physiologic Factors

GIT anatomy and physiology…cont’d
The luminal surface of the tube is very
rough
This roughness :
increase the surface area for absorption.

oThe wall of the GIT is
essentially similar in
structure along its length
oconsists of four principal
histological layers
1. Serosa
2. Muscularis externa
3. Submucosa
4. Mucosa

The majority of the GI epithelium is covered by a layer of
mucus.
Mucus is a viscoelastic translucent aqueous gel that is
secreted throughout the GIT,
Acting as a protective layer and a mechanical barrier.
The layer is continuous in the stomach and duodenum, but
may not be so in the rest of the small and large intestines
Mucus is constantly being removed from the luminal surface
of the GIT through
 abrasion and acidic and enzymatic breakdown

Oesophagus
oThe mouth is the point of entry for most drugs (so called
peroral - via the mouth - administration).
 At this point contact with the oral mucosa is usually brief.
oLinking the oral cavity with the stomach is the oesophagus
oThis is composed of a thick muscular layer approximately
250 mm long and 20 mm in diameter.

Oesophagus…cont’d
It joins the stomach at the gastrooesophageal junction, or
cardiac orifice
Squamous epithelium of non-proliferative cells of the
oesophagus is mainly used for protective function.
• secrete mucus into the narrow lumen to lubricate food
and protect the lower part of the oesophagus from
gastric acid.
• The PH ranges between 5 and 6

oThe two major functions of the stomach are:
 to act as a temporary reservoir for foods, drugs and other
ingested materials and
 to deliver it to the duodenum at a controlled rate;
oAnother less function of the stomach is its role in reducing the
risk of noxious agents reaching the intestine.
oIts opening to the duodenum is controlled by the pyloric
sphincter.
Stomach

Stomach…cont’d
oThe stomach can be divided
into four anatomical regions
 the fundus,
 the body,
 the antrum and
 the pylorus.

Stomach…cont’d
The stomach has a capacity of app 1.5 L
 although under fasting conditions it usually contains
NMT 50 mL of fluid (mostly gastric secretions)
These include:
 acid secreted by the parietal cells, which maintains the
pH of the stomach 1 - 3.5 in the fasted state
The release of gastrin hormone, which is a potent
stimulator of gastric acid production is stimulated by
peptides, amino acids and distension of the stomach;

Stomach…cont’d
 pepsins, which are secreted by the peptic cells in the form of
its precursor pepsinogen
Pepsins are peptidases which break down proteins to
peptides at low pH.
Above pH 5 pepsin is denatured;
 Mucus, which is secreted by the surface mucosal cells and
lines the gastric mucosa
In the stomach the mucus protects the gastric mucosa from
autodigestion by the pepsin-acid combination

Stomach…cont’d
olittle drug absorption occurs in the stomach owing to its
small surface area compared to the small intestine.
oThe rate of gastric emptying can be a controlling factor in
the onset of drug absorption from the major absorptive site,
the small intestine.

• The small intestine is the longest (4-5 m) and most convoluted
part of GIT, extending from the pyloric sphincter of the
stomach to the ileocaecal junction where it joins the large
intestine.
• Its main functions are:
Digestion
Absorption
Small intestine

Small intestine…cont’d
oThe small intestine is divided into
 the duodenum, which is 200-300 mm in length
 the jejunum, which is approximately 2 m in
length, and
 the ileum, which is approximately 3 m in length.

oThe wall of the small intestine has a rich network of both
blood and lymphatic vessels.
oMost of cardiac output flows through the gastrointestinal
viscera.
oThe blood vessels of the small intestine receive blood from
the superior mesenteric artery via branched arterioles.

oThe blood leaving the small intestine flows into the hepatic
portal vein, which carries it via the liver to the systemic
circulation.
oDrugs that are metabolized by the liver are degraded before
they reach the systemic circulation.
this is termed hepatic presystemic clearance, or first-
pass metabolism.

The wall of the small intestine also contains lacteals,
which contain lymph and are part of the lymphatic system.
The lymphatic system is important in the absorption of
fats and lipid character drugs from GIT.
 The luminal pH of the small intestine b/n 6 and 7.5

It stretches from the ileocaecal
junction to the anus and makes app
1.5 m of the 6 m of GIT.
It is composed of
 caecum (~85 mm in length),
 ascending colon (~200 mm),
 hepatic flexure,
 transverse colon (usually > 450 mm),
 splenic flexure,
 descending colon (~300 mm),
 sigmoid colon (~400 mm) and
 rectum
Colon

Colon…cont’d
oThe colon has no specialized villi.
 However, the microvilli of the absorptive epithelial
cells, the presence of crypts, and the irregularly
folded mucosae serve to increase the surface area of
the colon.
oThe SA of colon is approximately 1/30th that of SI

Colon…cont’d
oThe main functions of the colon are:
 the absorption of sodium ions, chloride ions and water
from the lumen in exchange for bicarbonate and
potassium ions.
Thus the colon has a significant homeostatic role in
the body.
 the storage and compaction of faeces.

Colon…cont’d
• The colon is permanently colonized by an extensive
number (about 1012 per gram of contents) and variety of
bacteria.
This is capable of several metabolic reactions,
including hydrolysis of fatty acid esters and the
reduction of inactive conjugated drugs to their active
form.
the pH of the caecum is around 6-6.5.

Physiological factor…cont’d
Blood flow:
 For most drugs, the optimum site for drug absorption after
oral administration is the duodenum region
 The duodenal region is highly perfused with a network of
capillaries which also gets high amount of bloods
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 GI Motility and gastric emptying time
oGI motility tends to move the drug through the alimentary
canal
the drug may not stay at the absorption site
oThe transit time of the drug in the GI tract depends on
 the physiochemical properties of the drug
 the type of dosage form, and
 various physiologic factors
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Esophageal transit
 Most DFs transit esophagus in < 15 s
 Tablets/capsules taken in supine position are liable to lodge in
esophagus esp. 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

Gastric emptying
oGastric emptying time (GET) is time DFs take to traverse
stomach
oGET is highly variable
Normal GET range b/n 5 min and 2 hrs
GET over 12 hrs for large single units
oGET depends on
DF type
Fed/fasted state of stomach

oMany factors influence gastric emptying:
 DF (liquid vs. solid, unit DFs vs. multiparticulate DFs)
 presence and composition of food
 postural position
 drugs
 disease state

oFactors delaying GET
 Fats and fatty acids in diet
 High viscosity of diet
 Lying on left side
 Diseases: depression, hypothyrodism, gastric ulcer
 Drugs: propantheline, atropine (antimuscarinic)

oFactors promoting GET
 Fasting
 Lying on right side
 Diseases: anxiety, hyperthyrodism
 Drugs: Metoclopramide (antiemetic and
gastroprokinetic)

pre-systemic metabolism/ first-pass metabolism
 Is a phenomenon of drug metabolism whereby
the concentration of a drug, is greatly reduced before it
reaches the systemic circulation
 This first pass through the liver greatly reduce
the bioavailability of the drug.
 Enzymes of the gastrointestinal lumen, gut wall enzymes,
bacterial enzymes, and hepatic enzymes are responsible.
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Gastrointestinal pH
-The gastrointestinal pH may influence the absorption of
drugs in a variety of ways:
A- It may affect the chemical stability of the drug in the
lumen e.g. penicillin G, erythromycin
B- affect the drug dissolution or absorption e.g. weak
electrolyte drug.
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Disease state and physiological disorders:
-Local diseases can cause alterations in gastric pH that can
affect the stability , dissolution and absorption of the drug.
-Partial or total gastrectomy results in drugs reaching the
duodenum more rapidly than in normal individuals.
-This may result in an increased overall rate of absorption of
drugs that are absorbed in the small intestine.
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Effect of Food:
-The presence of food in the GIT can influence the rate and
extent of absorption, via a range of mechanisms.
A- Complexation
• e.g.Tetracycline forms non-absorable complexes with calcium
and iron,
• advised patients not take products containing calcium or iron,
such as milk, iron preparations.

Cont…
B- Alteration of pH
• Food tends to increase stomach pH.
• This leads decrease the rate of dissolution and
absorption of a weakly basic drug and increase that of a
weakly acidic one.
C- Alteration of gastric emptying
• Fats and some drugs tend to reduce gastric emptying and
thus delay the onset of action of certain drugs.

D- Stimulation of gastrointestinal secretions
-GI secretions (e.g. pepsin) produced in response to food
may result in the degradation of drugs that are susceptible
to enzymatic metabolism.
-Fats stimulate the secretion of bile.
-Bile salts can increase the dissolution of poorly
soluble drugs (griseofulvin).
-can form insoluble and non-absorbable complexes
with some drugs, such as neomycin and kanamycin.

E-Competition between food components and drugs for
specialized absorption mechanisms
• There is a possibility of competitive inhibition of drug
absorption in case of drugs that have a chemical
structure similar to nutrients required by the body for
which specialized absorption mechanisms exist.

Cont…
F-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 the rate of diffusion
-Hence, there is reduction in drug bioavailability.

G- Food-induced changes in pre-systemic metabolism
-Certain foods may increase the bioavailability of drugs
that are susceptible to pre-systemic intestinal metabolism
by interacting with the metabolic process.
-E.g. Grapefruit juice is capable of inhibiting the intestinal
cytochrome P450 (CYP3A) and thus taken with drugs that
are susceptible to CYP3A metabolism which result in
increase of their bioavailability.

H- Food-induced changes in blood flow
• Food serve to increase the bioavailability of some drugs
(e.g. propranolol)
• Blood flow to the GIT and liver increases after a meal.
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II, Physical-Chemical Factors
Physical-chemical factors affecting oral absorption
include:
A- pH-partition theory
B- Lipid solubility of drugs
C- Dissolution and pH
D- Drug stability and hydrolysis in GIT
E- Complexation
F- Adsorption

A. pH - Partition Theory:
-According to this theory, the GI epithelia acts as a lipid barrier
for drugs absorbed by passive diffusion, and those that are lipid
soluble will pass across the barrier.
-The unionized form of weakly acidic or basic drugs (the
lipid-soluble form) will pass across the GI epithelia, but
impermeable to the ionized (poorly-lipid soluble) form of such
drugs.
-Consequently, the absorption of a weak electrolyte will be
determined by the extent to which the drug exists in its
unionized form.

B. Lipid solubility of drugs:
-Some drugs are poorly absorbed after oral administration
even though they are non-ionized in small intestine.
-
-Low lipid solubility of them may be the reason.
-The best parameter to correlate between water and lipid
solubility is partition coefficient.

Lipid solubility of drugs…cont’d
Partition coefficient (p) =
𝑳 𝒄𝒐𝒏𝒄
𝑾 𝒄𝒐𝒏𝒄
where, [ L] conc is the concentration of the drug in lipid
phase.
[W] conc is the concentration of the drug in aqueous
phase.
-The higher p value, the more absorption is observed.
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C. Drug Dissolution:
- Many drugs are given in solid dosage forms and therefore
must dissolve before absorption can take place
- If dissolution is the slow, it will be the rate determining step
(the step controlling the overall rate of absorption) then
factors affecting dissolution will control the overall process.

Drug Dissolution…cont’d
-Drug dissolution is considered to be diffusion controlled
process through a stagnant layer surrounding each solid
particle.
Diagram Representing
Diffusion through the
Stagnant Layer

Drug Dissolution…cont’d
-Drug dissolution is described by the Noyes-Whitney
equation:
-Where D; diffusion coefficient, A: the surface area, Cs: the solubility
of the drug, Cb con. of drug in the bulk solution, and h the thickness of
the stagnant layer.
-If Cb is much smaller than Cs then we have so-called
"Sink Conditions" and the equation reduces to:

Factors affecting drug dissolution in the GIT:
I Physiological factors:
 Diffusion coefficient, D:
Presence food in the GIT increase the viscosity of the GI
fluids reducing the rate of diffusion of the drug molecules
away from the diffusion layer (↓ D) decrease in dissolution
rate of a drug.

Cont’d
 Drug surface area, A:
Surfactants increase the wettability of the drug which
increase the drug solubility.
 The thickness of diffusion layer, h:
An increase in GI motility decrease the thickness of
diffusion layer around each drug particle, increase the
dissolution rate of a drug.

II Physicochemical factors affecting the dissolution
rate of drugs:
 Surface area, A:
The smaller the particle size the greater the effective
surface area of drug particle.
 Diffusion coefficient, D:
The value of D depends on the size of the molecule and the
viscosity of the dissolution medium.
 Solubility in the diffusion layer, Cs:
The dissolution rate of a drug is directly proportional to its
intrinsic solubility in the diffusion layer surrounding each
dissolving drug particle

Drug Dissolution (cont.):
 Salts:
Salts of weak acids and weak bases generally have much
higher aqueous solubility than free acid or base.
dissolution rate of a weakly acidic drug in gastric fluid
(pH 1 – 3.5) will be relatively low.
If the pH in the diffusion layer increased, the solubility,
Cs, of the acidic drug in this layer, and hence its
dissolution rate in gastric fluids would be increased.

-pH of the diffusion layer will increased if the chemical nature
of the weakly acidic drug changes from free acid to a basic
salt (the sodium or potassium form of the free acid).
-The pH of the diffusion layer would be higher (5-6) than the
low bulk pH (1-3.5) of the gastric fluids because of the
neutralizing action of the strong (Na+, K+ ) ions present in the
diffusion layer.
-The drug particles will dissolve at a faster rate and diffuse
out of the diffusion layer into the bulk of the gastric fluid,
where a lower bulk pH.

-Thus the free acid form of the drug in solution, will
precipitate out
-This precipitated free acid will be in the form of:
very fine,
non-ionized,
wetted particles, which have a very large surface area in
contact with gastric fluids, facilitating rapid
redissolution when additional gastric fluid is available.

Dissolution process of a salt form of a weakly acidic drug
in gastric fluid.

-One example is the dissolution and bioavailability profiles
of Penicillin V with various salts.
These results might support the use of the benzathine or
procaine salts for IM depot use and the potassium salt for
better absorption orally.

 Crystal form:
1. Polymorphism:
• Some drugs exist in a number of crystal forms or
polymorphs.
• These different forms may have different solubility.
• Chloramphenicol palmitate is one example which exists in
three crystalline forms A, B and C.
A, is the stable polymorph
B, is the metastable polymorph (most soluble)
C, is the unstable polymorph

2. Amorphous solid:
• The amorphous form dissolves more rapidly than the
corresponding crystalline form.
• For example, amorphous form of novobiocin antibiotic was
readily absorbed following oral administration but, slowly
converts to the more stable crystalline form, with loss of
therapeutic effectiveness.

 Solvates:
Solvates: If the drug is able to associate with solvent
molecules to produce crystalline forms known as solvates.
 Hydrates: drug associates with water molecules.

The greater the solvation of the crystal, the lower are the
solubility and dissolution rate in a solvent identical to the
solvation molecules
The faster-dissolving anhydrous form of ampicillin was
absorbed to a greater extent from hard gelatin capsules and
an aqueous suspension than was the slower-dissolving
trihydrate form.

D-Drug stability and hydrolysis in GIT:
• Drugs that are susceptible to acidic or enzymatic hydrolysis
in the GIT, suffer from reduced bioavailability.
• Therefore, these drugs should be:
Enteric coated
Administration of chemical derivatives of the parent
drug that exhibit limited solubility in gastric fluid, but
liberate the drug in the small intestine.

E- Complexation:
-Complexation of a drug may occur within the dosage form
and/or in the GI fluids, and can be benefecial or
deterimental to absorption.
1-Intestinal mucosa (mucin) + Streptomycin = poorly
absorbed complex
2-Calcium + Tetracycline = poorly absorbed complex
(Food-drug interaction)

F- Adsorption:
• Certain insoluble substances may adsorbed co-
administrated drugs leading to poor absorption.
Charcoal (antidote in drug intoxication).
Kaolin (antidiarrheal mixtures)
Talc (in tablets as glidant)

III. Formulation Factors Affecting Oral
Absorption:
• The role of the drug formulation in the delivery of drug to
the site of action should not be ignored.
• Since a drug must be in solution to be absorbed efficiently
from the G-I tract, you may expect the bioavailability of a
drug to decrease in the order solution > suspension >
capsule > tablet > coated tablet.

Formulation Factors…cont’d
A.Solution dosage forms:
- In most cases absorption from an oral solution is rapid
and complete, compared with administration in any other
oral dosage form.
12/14/2022 114

-Some drugs which are poorly soluble in water may be:
1-dissolved in mixed water/alcohol or glycerol solvents
(cosolvency),
2- given in the form of a salt (in case of acidic drugs)
3-An oily emulsion or soft gelatin capsules have been used
for some compounds with lower aqueous solubility to
produce improved bioavailability.

B. Suspension dosage forms:
• A well formulated suspension is second to a solution in terms
of superior bioavailability.
• A suspension of a finely divided powder will maximize the
potential for rapid dissolution.
• A good correlation can be seen for particle size and
absorption rate.
• The addition of a surface active agent will improve the
absorption of very fine particle size suspensions.

C. Capsule dosage forms:
• The hard gelatin shell should disrupt rapidly and allow
the contents to be mixed with the G-I tract contents.
• If a drug is hydrophobic a dispersing agent should be
added to the capsule formulation
• These diluents will work to disperse the powder,
minimize aggregation and maximize the surface area
of the powder.

D. Tablet dosage forms:
Blood

 The tablet is the most commonly used but, also quite
complex in nature.
1-Ingredients
Drug : may be poorly soluble, hydrophobic
Lubricant : usually quite hydrophobic
Granulating agent : tends to stick the ingredients
together
Filler: may interact with the drug, etc.,
Disintegration agent: break the tablet apart

Bioavailability
And
Bioequivalence

What is Bioavailability?
 Drugs must cross several biological membranes to reach
their sites of action.
 Extent and rate of penetration and hence systemic
effect depends on ROA and absorption.

Cont’d
Bioavailability: is a term that describes the rate and
extent of drug absorption from a drug product and its
availability at the site action.
•Drug con. usually cannot be readily measured directly
at the site of action.
•Hence it is usually determined in the blood or urine
•Bioavailability: how quickly and how much of a drug
appears in the blood after a specific dose is
administered.

Cont’d
 Bioavailable dose: The fraction of an
administered dose of a particular drug that reaches
the systemic circulation intact.

Factors Affecting Drug Bioavailability
 Physiologic Factors Related to Drug Absorption
 Passage of drug across cell membrane
 Gastric emptying rate and Transit time of drug in
GIT
 Blood perfusion of the GIT,
 Intestinal motility
 Route of administration
 Variations in pH of GI fluids

Cont’d
 Interactions with other substances
 Pre-systemic and first-pass metabolism
 Exposure to various pH conditions, gut flora and
enzymes
 Age, sex, weight, disease states of patient
 Physicochemical Nature of the Drug

Cont’d
Nature of membrane
The extent of ionization
Fick’s law of diffusion
•(dQ/dt =DAK/h (CGI – Cp)
Interactions with other substances
Fluid volume

Physicochemical Properties of the Drug
•Drug bioavailability is also dependent on Permeability, Solubility
and Dissolution rate In vivo, and Luminal degradation of the drug
with in the body
Fig 2.2: Dissolution and permeability of drug.

Pharmaceutic Factors
Dosage Forms (DFD)
Parenteral (e.g. IV, IM)
Buccal: (Nitroglycerin sublingual tablet, fast dissolving
excipient, better availability than oral, not affected by first-
pass effect)
Oral preparations:
Solutions (elixirs, syrups, or simple solutions) generally
result in faster and more complete absorption of drug,
since a dissolution step is not required

Pharmaceutic Factors…cont’d
Hard gelatin shell should disrupt rapidly and allow the
contents to be mixed with the G-I tract contents
Enteric-coated tablets, on the other hand, do not even
begin to release the drug until the tablets empty from the
stomach

 Formulation Factors
Tablets (additives)
Filler: Type, amount, interaction with drug?
Granulating/binding agent: (bonding) type, concentration,
viscosity?
Wetting agent: (+/-)
Disintegrating agent: Amount, type
Lubricant: Amount, type
Special coatings: Film/enteric, amount/thickness

Manufacturing/Process Variables
•Granulation: Method, blend uniformity, equipment (high
shear mixers, fluidized bed)
•Drying: Rate, Temp., equipment (tray, tunnel,
fluidized bed), moisture level?
•Coating method: Spraying, pouring,
•Blending: Time, rate, equipment used
•Compression force, dwell time, tooling used

Absolute and Relative Bioavailability
Absolute Bioavailability (Fab)
 The systemic availability of an orally administered drug is
calculated in comparison to its IV administration, it is called as
absolute bioavailability.
• It can be calculated by comparing the total amount of intact
drug that reaches the systemic circulation following non-
intravenous administration (e.g., oral, rectal, etc.) with its
drug in systemic circulation following intravenous
administration.

Absolute Bioavailability (Fab)…cont’d
• Hence, absolute bioavailability of a drug is the systematic
availability of a drug after extra vascular administration
compared to intravenous administration.
• There are different methods available to determine the extent
of systemic availability.
12/14/2022 133

• One of the most commonly used methods is comparing
AUC (area under the plasma drug concentration–time
curve) after an intravenous and an extra vascular
administration.
• It ranges from F = 0 (no drug absorption) to F =1(complete
drug absorption).
12/14/2022 134

Fig : AUC after IM and IV administration of same dose of a
drug

• Extra vascular administration of the drug includes routes such as
oral, rectal, nasal, subcutaneous, etc.
• IV dose is used as a standard/reference to compare the systemic
availability of the drug administered via different routes.
• When a drug is administered IV, no absorption barriers to cross
and hence, it is considered to be totally (100%) bioavailable.
• Absolute bioavailability is expressed as percentage.
12/14/2022 136

12/14/2022 137

Relative Bioavailability
• When the systemic availability of a drug after
administration is compared with that of standard of the same
drug, it is known as relative bioavailability.
• Relative bioavailability can be calculated by comparing the
plasma drug concentration-time-curves (AUC - area under
the curve) after the administration of two different
formulations of the same compound (e.g. capsule vs. tablet).
12/14/2022 138

Relative Bioavailability…cont’d
 Thus, relative bioavailability is the systematic availability of
the drug from a dosage form as compared to the reference
standard given by the same route of administration.
12/14/2022 139

• A drug which cannot be administered through IV route,
then instead of absolute bioavailability, the relative
bioavailability can be calculated.
• In this scenario, the bioavailability of a given drug is
compared to that of the same drug administered in a
standard dosage form (standard can be clinically proven
preparation).
• Relative bioavailability is expressed as percentage.
12/14/2022 140

Fig AUC after administration of same dose of Product A and Product
B of same drug

12/14/2022 142

Methods of Assessing Bioavailability
• Assessment of Bioavailability is required for various
purposes.

Methods of Assessing Bioavailability in vivo
Bioavailability in vivo can be assessed by:
Pharmacokinetic parameters and
pharmacodynamic parameters:
12/14/2022 144

Pharmacokinetic parameters
AUC (Area Under the Curve)
• AUC is a measurement of the extent of drug bioavailability.
• The AUC reflects the total amount of active drug that reaches the
systemic circulation.
• is expressed in mcg/ml * hours.
Cmax (Peak plasma drug concentration)
• It is the maximum plasma drug con. after oral admn of drug
• Cmax is expressed in mcg/ml.
Tmax (Time of peak plasma drug concentration)
• The time required to reach maximum drug con, in plasma after
extravascular drug administration.
• Useful in estimating the rate of absorption & expressed in hours.
12/14/2022 145

Pharmacodynamic parameters
Minimum Effective Concentration (MEC) / Minimum
Inhibitory Concentration (MIC)
• MEC/MIC is the minimum con, of drug in plasma required to
produce the therapeutic effect.
• The con, of drug below MEC is said to be in the sub‐therapeutic
level.
• MIC term is generally used in case of antibiotics and it describes
the minimum concentration of antibiotic in plasma required to kill
or inhibit the growth of micro-organisms.
12/14/2022 146

Pharmacodynamic parameters…cont’d
Maximum Safe Concentration (MSC) / Maximum Safe
Dose (MSD)
• MSC/MSD is the con, of drug in plasma above which
adverse or unwanted effects are expected to happen.
• Concentration of drug above MSC is said to be in the
toxic level.
12/14/2022 147

Duration of action
• The time period for which the plasma con, of drug
remains above the MEC level is known as duration of
(drug) action.
• It can also be defined as the difference between onset
time and time for the drug to drop back to MEC.
Onset of action
• When plasma drug concentration just exceeds the
required MEC, the pharmacological response starts and
this is called as onset of action.
12/14/2022 148

Onset time
• It is the time required by the drug to start producing
pharmacological response.
• It corresponds to the time for the plasma con, to reach (MEC)
after administration of drug.
Intensity of action (Peak response)
• It is the maximum pharmacological response produced by the
peak plasma concentration of drug.
Therapeutic Range (Therapeutic window)
• The con, of drug between MEC and MSC is known as therapeutic
range.
12/14/2022 149

In -Vitro Approaches
• Drug dissolution studies under a certain condition give an
indication of drug bioavailability.
• Dissolution studies are often the preferred method in
several test formulations of the same drug.
• The test formulation that demonstrates the most rapid rate
of drug bioavailability in-vitro will generally have the most
rapid rate of drug bioavailability in-vivo.
12/14/2022 152

In Vitro/ in Vivo Correlations (IVIVC)
• An IVIVC is a predictive mathematical model that
describes the relationship between an in vitro property of a
dosage form and a relevant in vivo response.
• When performing IVIVC for formulation development,
the in vitro property is primarily dissolution or drug release
and the in vivo response is primarily a drug’s plasma con,.
12/14/2022 153

Why Conduct IVIVC?
• An IVIVC model is recommended by regulatory authorities
for most modified release DF.
• The main advantage of IVIVC is to provide a mechanism
for evaluating the change in in vivo absorption based on in
vitro dissolution changes when there are small changes in a
formulation.
12/14/2022 154

Cont’d
• Once a validated IVIVC model has been established, it can
be used to predict bioavailability and bioequivalence
(BA/BE) based on in vitro data that are already available
• In such cases, dissolution test results can be used to provide
the desired information without the need for any clinical
BE studies with human subjects.
12/14/2022 155

Cont’d
• Another advantage of IVIVC is that, it conveys a better
understanding of the drug product itself.
• This can help establish a wider drug product acceptance
criteria and formulation stability.
• IVIVC can also be especially useful for predicting the in
vivo effects of changes to the formulation components,
manufacturing site, or process.
12/14/2022 156

Cont’d
• IVIVC is extremely important during initial product
development.
• Establishing an IVIVC model can be even more valuable
after the product has been approved by determining the
impact of post-approval manufacturing changes.
• All of this can be determined without having to repeat
costly in vivo BE studies.
12/14/2022 157

Benefits of IVIVC
IVIVC analyses can be used to support:
• Abbreviated New Drug Applications (ANDA)
• New Drug Applications (NDA) for oral drugs with
extended release characteristics
• Abbreviated Antibiotic Drug Applications (AADA) as a
surrogate for in vivo BE determinations
12/14/2022 158

Levels of IVIVC
• There are three primary IVIVC categories, known as Levels
A, B, and C.
• There is also a subcategory known as multiple Level C
correlation.
• Level A is the most common type of IVIVC and historically
used primarily for NDAs and investigational new drug
(IND) applications.
• Level C can be useful in the early stages of development
and is the second most common.
• Level B and Multiple Level C correlations are
comparatively rare.
12/14/2022 159

Level A
• Level A correlation is generally linear and represents a point-
to-point relationship between in vitro dissolution rate and in
vivo input rate.
• Level A should be used when demonstrating an IVIVC
relationship for two or more formulations with different
release rates.
• Correlation is usually estimated by a two-stage procedure:
• deconvolution followed by comparison of the fraction of
drug absorbed to the fraction of drug dissolved.
12/14/2022 160

Level A…cont’d
 In a linear correlation, the in vitro dissolution and in vivo
input curves may be directly superimposable.
fig:Fa versus Fd profile for diltiazem HCl ER capsules.
release is rate-limiting, resulting in a linear profile (Level A)

Level B
• Level B correlation uses the same data used in Level A, but
is based on the principles of statistical moment analysis.
The mean in vitro dissolution time of the drug is compared
to either:
The mean in vivo residence time or
The mean in vivo dissolution time
• Level B is the least useful for regulatory purposes because
it does not reflect the actual in vivo plasma level curves..
12/14/2022 162

Level C
• Level C correlation involves determining the relationship
between in vivo pharmacokinetic (PK) parameters (e.g.
Cmax, AUC,) and in vitro dissolution data at a single point.
• Level C can predict Cmax and AUC, which can help you to
establish BA and BE.
• But, Level C does not reflect the complete shape of the
plasma con, time curve.
12/14/2022 163

Multiple Level C
• Multiple Level C correlation relates one or several PK
parameters of interest to the amount of drug dissolved at
several time points and can be as beneficial as Level A
correlation.
12/14/2022 164

Biopharmaceutical Classification System (BCS)
BCS is an experimental model that measures permeability
and solubility under prescribed conditions.
The original purpose of the system was to aid in the
regulation of post-approval changes and generics,
providing approvals based solely on in vitro data when
appropriate.
Importantly, since the majority of drugs are orally dosed,
the system was designed around oral drug delivery.
12/14/2022 165

BCS…cont’d
• This system can be used to flag drugs that should not be
tested clinically unless appropriate formulation strategies
are employed.
• For example, a BCS Class II compound permeable but
relatively insoluble would likely not be a good clinical
candidate without the use of enhanced formulation
techniques aimed at increasing solubility or rate of
dissolution.
• BCS used as a tool in drug product development.
12/14/2022 166

Bioequivalence
 "two pharmaceutical products are bioequivalent if they are
pharmaceutically equivalent and
Their bioavailabilities (rate and extent) after
administration in the same molar dose are similar to such
a degree that their effects, with respect to both efficacy
and safety, can be expected to be essentially the same.

Bioequivalence…cont’d
• Pharmaceutical equivalence implies the same amount of
the same active substance(s), in the same dosage form, for
the same route of administration and meeting the same or
comparable standards."
12/14/2022 169

12/14/2022 170
Fig: pharmaceutical equivalence of two drugs

•For a generic drug to be considered bioequivalent to a
pioneer product, there must be no statistical differences (as
specified in the accepted criteria) between their plasma
concentration-time profiles
•Because two products rarely exhibit absolutely identical
profiles, some degree of difference must be considered
acceptable.

Two dosage forms are not
bioequivalent
Two dosage forms are
bioequivalent:

Therapeutic Equivalence & Related Terms
Pharmaceutical equivalence
Are drug products in identical DF and ROA that contain
identical amounts of the identical active drug ingredient.
Meet the identical compendial or other applicable
standard of:
12/14/2022 173
• Identity
• Strength
• Quality
• Purity
• Potency
• Content uniformity
• Disintegration time
• Dissolution rate

Cont’d
Pharmaceutical Alternatives.
 Are drug products that contain the identical therapeutic
moiety, or its precursor, but not necessarily in the same
amount or dosage form, or the same salt or ester.
• E.g. quinidine sulfate, 200mg tablets vs. quinidine
sulfate, 200mg capsules
 Different dosage forms and strengths within a product line
by a single manufacturer are pharmaceutical alternatives,
12/14/2022 174

Cont’d
Therapeutic Equivalents.
 Approved drug products are considered to be therapeutic
equivalents if they are pharmaceutical equivalents for
which bioequivalence has been demonstrated, and they
can be expected to have the same clinical effect and
safety profile.
12/14/2022 175

Therapeutic Equivalence…cont’d
Two products are considered to be "therapeutic
equivalents" if they each meet the following criteria:
1. They are pharmaceutical equivalents,
2. they are bioequivalent (demonstrated either by a
bioavailability measurement or an in vitro standard),

Therapeutic Equivalence…cont’d
3. They are in compliance with compendial standards for
strength, quality, purity and identity,
4. They are adequately labeled, and
5. they have been manufactured in compliance with Good
Manufacturing Practices as established by the FDA.
12/14/2022 177

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