Download Biopharmaceutics 2nd

1
WHAT IS BIOPHARMACEUTICS?
Biopharmaceutics can be defined as the study of
how
• the physicochemical properties of drugs,
• dosage forms and
• routes of administration
affect the rate and extent of drug absorption.
Bioavailability is therefore defined as:
the rate and extent of drug absorption
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If a drug is given intravenously it is administered
directly into the blood, and therefore we can be sure
that all the drug reaches the systemic circulation.
The drug is therefore said to be 100% bioavailable
All other routes of administration where a systemic
action is required, involve the absorption of the drug
into the blood.
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Plasma Concentration
Absorption
phase
Elimination
phase
MSC
Cmax
MEC
Therapeutic
range
(window)
AUC
tmax
Time
A typical blood plasma concentration-time curve obtained following
the peroral administration of a single dose of a drug in a tablet
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Cmax: the highest plasma drug concentration observed.
Tmax: the time at which Cmax occurs following
administration of an extravascular dose.
AUC: Area under the curve
MSC: Maximum safe concentration
MEC: Minimum effective concentration
Therapeutic range: The range of plasma concentrations
between the minimally effective concentration
and the maximum safe concentration
Absorption phase: Absorption rate > Elimination rate
Elimination phase: Elimination rate > Absorption rate
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Routes of drug administration
The route of administration determines
the site of application of the drug product.
Often the goal is to attain a therapeutic drug
concentration in plasma from which drug enters the tissue
(therapeutic window between toxic concentration and
minimal effective concentration).
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Routes of administration are classified into:
ENTERAL and PARENTERAL
Enteral means through the GI tract and includes oral,
buccal, and rectal.
Parenteral means not through the alimentary canal and
commonly refers to injections such as IV, IM, and SC; but
could also include topical and inhalation
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A. Enteral Routes
1. Sublingual (buccal)
Certain drugs are best given beneath the
tongue (sublingual) or retained in the cheek
pouch (buccal) and are absorbed from these
regions into the local circulation.
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These vascular areas are ideal for lipid-soluble drugs that
would be metabolized in the gut or liver, since the blood
vessels in the mouth bypass the liver (do not undergo first
pass liver metabolism), and drain directly into the
systemic circulation.
This route is usually reserved
for nitrates and certain hormones.
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Diagram of first pass effect
metabolised drug
biliary tract
liver
to circulation
portal
vein
unmetabolised
drug
gut
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2. Oral
By far the most common route.
The passage of drug from the gut into the blood is
influenced by biologic and physicochemical factors and
by the dosage form.
For most drugs, 2- to 5-fold differences in the rate or
extent
of
gastrointestinal
absorption
can
occur,
depending on the dosage form.
Generally, the bioavailability of oral
drugs follows the order: solution >
suspension > capsule > tablet > coated
tablet.
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3. Rectal
The administration of suppositories is usually reserved
for situations in which oral administration is difficult.
This route is more frequently used in small children.
It by-passes the liver
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B. Parenteral Routes
1. Intravenous injection
Used when a rapid clinical response is necessary, e.g., an
acute asthmatic episode.
This route allows one to achieve relatively precise drug
concentrations in the plasma, since bioavailability is
100%.
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Most drugs should be injected over 1-2 minutes in order
to
prevent
the
occurrence
of
very
high
drug
concentrations in the injected vein, possibly causing
adverse effects.
Some drugs, particularly those with narrow therapeutic
indices or short half-lives, are best administered as a slow
IV infusion or drip.
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2. Intramuscular injection
Drugs may be injected into the arm (deltoid), thigh (vastus
lateralis) or buttocks (gluteus maximus).
Because of differences in vascularity, the rates of absorption
differ, with arm > thigh > buttocks.
Drug absorption may be slow and erratic.
Lipid
solubility
and
degree
of
ionization
influence
absorption.
It should not be assumed that the IM route is as reliable as
the IV route.
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3. Subcutaneous injection
Some drugs, notably insulin, are routinely administered SC.
Drug absorption is generally slower SC than IM, WHY?
due to poorer vascularity.
Absorption can be facilitated by heat, massage or
vasodilators.
It can be slowed by coadministration of vasoconstrictors, a
practice commonly used to prolong the local action of local
anesthetics.
As above, arm > thigh.
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4. Topical application
a. Eye
For desired local effects.
b. Intravaginal
For infections or contraceptives.
c. Intranasal
For alleviation of local symptoms.
Directly from nasal capillaries into
circulation.
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d. Skin
Systemic absorption does occur and
varies with the area, site, drug, and
state of the skin. Dimethyl sulfoxide
(DMSO) enhances the percutaneous
absorption of many drugs.
e. Drug patches
(drug enters systemic circulation by
zero order kinetics – a constant amount
of drug enters the circulation per unit
time).
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5. Inhalation
Volatile anesthetics, as well as many drugs which affect
pulmonary function, are administered as aerosols.
The large alveolar area and blood supply lead to rapid
absorption into the blood.
Drugs administered via this route are not subject to
first-pass liver metabolism.
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6. Other ROA's
Other routes of administration include:
• intra-arterial for cancer chemotherapy to maximize drug
concentrations at the tumor site
• intrathecal directly into the cerebrospinal fluid.
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Why are there different routes?
1.Solubility or stability of the drug
2.The absorption from the different sites. Many drugs
are absorbed from stomach and small intestine and
not absorbed rectally.
3.Toxic when given by certain routes.
4.Ineffective, destroyed or inactivated in certain
organs e.g. penicillin in stomach.
5.Convenience of the patient
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Route for
Administration
Time until Effect
IV
30-60 sec
Inhalation
2-3 min
Sublingual
3-5 min
IM
10-20 min
SC
15-30 min
Rectal
5-30 min
Ingestion
30-90 min
Transdermal (Topical)
Variable (minutes-hours)
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The concentration of the drug in blood plasma depends on
LADME
L = Liberation
the release of the drug from it's dosage form.
A = Absorption
the movement of drug from the site of administration to
the blood circulation.
D = Distribution
the process by which drug diffuses or is transferred from
intravascular space to extravascular space (body
tissues).
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The concentration of the drug in blood plasma depends on
LADME
M = Metabolism
the chemical conversion or transformation of drugs into
compounds which are easier to eliminate.
E = Excretion
the elimination of unchanged drug or metabolite from
the body via renal, biliary, or pulmonary processes.
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Absorption
The absorption of a drug from the GIT is the passage of
the substance from the lumen through several
membranes into the blood stream.
Main factors affecting oral absorption:
• Physiological factors
• Physical-chemical factors
• Formulation factors
GIT
BLOOD
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1. Physiological Factors Affecting Oral Absorption
A- Membrane physiology
B- Passage of drugs across membranes
Active transport
Facilitated diffusion
Passive diffusion
Pinocytosis
Pore transport
Ion pair formation
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C- Gastrointestinal physiology
GIT physiology and drug absorption
Gastric emptying time and motility
Effect of food on drug absorption
Enterohepatic circulation
First pass effect
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A. Membrane physiology
Membrane structure (Fluid Mosaic Model)
The biologic membrane consists mainly of a lipid
bilayer
containing
primarily
phospholipids
and
cholesterol, with imbedded proteins.
The
membrane
contains
also
small
aqueous
channels or pores.
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Phospholipid Bilayers
Phospholipids are amphiphilic in nature. Polar heads
are oriented toward the water and the fatty acid tails
are oriented toward the inside of the bilayer.
The fatty acid tails are flexible, causing the lipid bilayer
to be flexible. At body temperature, membranes are a
liquid with a consistency that is similar to cooking oil.
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Cholesterol
Cholesterol is a major membrane lipid. It may be equal
in
amount
to
phospholipids.
It
is
similar
to
phospholipids in that one end is hydrophilic the other
end is hydrophobic.
Cholesterol makes the membrane less permeable to
most biological molecules.
Proteins
Proteins are scattered throughout the membrane.
They may be attached to inner surface,
embedded in the bilayer, or
attached to the outer surface.
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Functions of Membrane Proteins
Channel
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A. Channel proteins
A protein that allows a particular molecule or ion to
freely cross the membrane as it enters or leaves the
cell.
B. Carrier proteins
A protein that selectively interacts with a specific
molecule or ion so that it can cross the cell
membrane to enter or exit the cell.
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C. Receptor proteins
A protein that has a specific shape so that specific
molecules can bind to them. The binding of a
molecule, such as a hormone, can influence the
metabolism of the cell.
D. Enzyme proteins
An enzyme that catalyzes a specific reaction.
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E. Cell-recognition proteins
Glycoproteins that identify the cell. They make up
the cellular fingerprint by which cells can recognize
each other.
F. Cell Adhesion Proteins
Adjacent
cells
stick
together
via
interlocking
proteins on their membranes
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B. Passage of Drugs Across Membranes
The membrane can be viewed as a semipermeable
lipoidal sieve that allows the passage of:
- lipid-soluble molecules across it by passive lipid
diffusion
- water and small hydrophilic molecules through
its numerous aqueous pores.
-other molecules by a number of transporter
proteins or carrier molecules that exist in the
membrane.
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There are two main mechanisms of drug transport across
the gastrointestinal epithelium:
Paracellular: i.e. between the cells.
Transcellular: i.e. across the cells
The transcellular pathway is further divided into simple
passive diffusion, carrier-mediated transport (active
transport and facilitated diffusion) and endocytosis.
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1. Passive Transport
Most
(many)
drugs
cross
biological
membranes by passive diffusion.
• Diffusion
occurs
when
the
drug
concentration on one side of the membrane
is higher than that on the other side
(according to concentration gradient).
• Drug diffuses across the membrane in an
attempt to equalize the drug concentration
on both sides of the membrane.
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• The rate of transport of drug across the membrane can be
described by Fick's first law of diffusion:-
D: diffusion coefficient
This parameter is related to:
• the size of the drug
• lipid solubility of the drug
• viscosity of the diffusion medium, the membrane.
As lipid solubility increases or molecular size decreases then
D increases and thus diffusion rate also increases.
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A: surface area
As the surface area increases the rate of diffusion also
increase. The surface of the intestinal lining (with villae and
microvillae) is much larger than the stomach. Therefore
absorption is generally faster from intestine compared to
stomach.
x: membrane thickness
The smaller the membrane thickness the quicker the
diffusion process.
e.g. the membrane in the lung is quite thin thus inhalation
absorption can be quite rapid.
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(Ch -Cl): concentration difference.
Since V, the apparent volume of distribution, is at least four
liters and often much higher the drug concentration in blood
or plasma will be quite low compared with the concentration
in the GI tract. It is this concentration gradient which allows
the rapid complete absorption of many drug substances.
Normally Cl << Ch then:Thus the absorption of many drugs from the G-I tract can
often appear to be first-order.
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2. Facilitated Transport
• Is also the movement of molecules from a high
concentration to a low concentration.
• Lipid insoluble substances such as glucose and amino
acids are taken across by "carrier proteins".
• No chemical energy is required in this process, WHY?
• eg. amino acids, glucose and other breakdown products
of food are absorbed by the small intestine facilitated
diffusion
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Active
Transport
3. Active
Transport
It is the movement of molecules across a living membrane
 from an area of low concentration to an area of
high concentration
 with the aid of a carrier protein and
 using energy or ATP .
The rate of drug absorption increases with drug
concentration until the carrier molecules are completely
saturated, the rate then remains constant
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Mechanism of Drug Transport ?
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4. Endocytosis
Surrounding a substance with the cell membrane and
the subsequent formation of a vesicle to bring these
substances into the cell.
This process is energy dependent.
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There are two main kinds of Endocytosis:
a. Phagocytosis (cell eating) - involves the ingestion of
particles larger than 500 nm. This process is important
in the absorption of polio and other vaccines from the
GIT.
b. Pinocytosis (cell drinking) - involves the ingestion of
fluids or dissolved particles. Fat soluble vitamins A, D, E
and K are absorbed via pinocytosis
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5. Pore Transport
• Very small molecules (hydrophilic, water soluble such as
water, urea and sugar) are able to rapidly cross cell
membrane as if the membrane contained pores or
channels.
• This model of transportation is used to explain renal
excretion of drugs and uptake of drugs into the liver.
• A certain type of protein may
form an open channel across
the lipid membrane of cell.
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Ion pair formation
Strong
electrolyte
drugs
are
highly
ionized
and
maintain their charge at physiological pH.
• These drugs penetrate membranes poorly, WHY?
• When linked up with an oppositely charged ion, an
ion pair is formed in which the overall charge of the
pair is neutral.
• The neutral complex diffuses more easily across the
membrane, WHY?
• An example of this in case of propranolol, a basic
drugs that forms an ion pair with oleic acid.
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Paracellular Transport
 Two pathways exist for the passage of water and
electrolytes
across
the
intestinal
mucosa,
transcellular and paracellular.
 The transcellular pathway allows the passage of
hyrophilic molecules of low molecular weight and
with small molecular size through the water filled
pores in the cell membranes.
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 The paracellular pathway allows access of larger
molecules through the junction between the cells.
 Although the intercellular spaces occupy less than
1% of the surface area of the epithelium it is by this
way the hydrophilic drug molecules are absorbed e.g.
ranitidine , acyclovir.
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C. Gastrointestinal (GI) Physiology
I- Characteristics of GI physiology and Drug Absorption
The gastrointestinal tract is a muscular tube approximately
6 m in length with varying diameters.
It stretches from the mouth to the anus and consists of four
main anatomical areas: - oesophagus
- stomach
- small intestine
- large intestine or colon.
The luminal surface of the tube is not smooth but very
rough, thereby increasing the surface area for absorption.56
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Organs
pH
Membrane
Blood
Supply
Surface
Area
Transit Time
Bypass
liver
Buccal
approx
6
thin
Good, fast
absorption
with low
dose
small
Short unless
controlled
yes
Esophagus
6-7
Very thick
no
absorption
-
small
short, a few
seconds,
-
Stomach
1.7-4.5
normal
good
small
30 min
delayed stomach
emptying
 intestinal
absorption
no
Duodenu
m
5-7
normal
good
very
large
very short (6"
long),
no
Small
Intestine
6 -7
normal
good
very
large
about 3 hours
no
Large
Intestine
6.8 - 7
-
good
not
very
large
long, up to 24 hr
lower
colon,
rectum
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yes
II. Gastric emptying and motility
Generally drugs are better absorbed in the small
intestine, WHY? (because of the larger surface
area) than in the stomach, therefore quicker
stomach emptying will increase drug absorption.
e.g. a good correlation has been found between
stomach
emptying
time
and
peak
plasma
concentration for acetaminophen. The quicker
the stomach emptying the higher the plasma
concentration.
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Also
slower
stomach
emptying
can
cause
increased degradation of drugs in the stomach's
lower pH; e.g. L-dopa.
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Factors Affecting Gastric Emptying
Volume of
Ingested
Material
Type of Meal
Bulky material tends to empty more slowly
than liquids
Fatty food
Decrease
Carbohydrate
Decrease
Temperature Increase in temperature, increase in emptying
of Food
rate
Body
Position
Lying on the left side decreases emptying
rate. Standing versus lying (delayed)
Drugs
Anticholinergics (e.g. atropine),
Decrease
Narcotic (e.g. morphine, alfentanil),
Analgesic (e.g. aspirin)
Metoclopramide, Domperidone,
Erythromycin, Bethanchol
Increase
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III. Effect of Food
The presence of food in the gastrointestinal tract can
influence the rate and extent of absorption
Complexation of drugs with components in the diet
e.g. Tetracycline forms non-absorbable complexes with
calcium and iron (don’t take milk or iron preparations
at the same time of day as the tetracycline WHY?).
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Alteration of pH
In general, food tends to increase stomach pH by acting
as a buffer. This is liable to decrease the rate of
dissolution and subsequent absorption of a weakly basic
drug and increase that of a weakly acidic one.
Alteration of gastric emptying
Particularly fatty foods, and some drugs, tend to reduce
gastric emptying and thus delay the onset of action of
certain drugs.
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Stimulation of gastrointestinal secretions
e.g. pepsin produced in response to food may result in
the degradation of drugs that are susceptible to
enzymatic metabolism, and hence in a reduction in
their bioavailability.
Food, particularly fats, stimulates the secretion of bile.
Bile salts are surface active agents and can increase the
dissolution of poorly soluble drugs, thereby enhancing
their absorption.
e.g. Griseofulvin (antifungal)
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Competition between food components and drugs for
specialized absorption mechanisms
In the case of those drugs that have a chemical
structure similar to nutrients required by the body for
which specialized absorption mechanisms exist, there
is a possibility of competitive inhibition of drug
absorption.
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Increased viscosity of gastrointestinal contents
The presence of food in the gastrointestinal tract
provides a viscous environment which may result in a
reduction in the rate of drug dissolution and the rate of
diffusion of a drug in solution from the lumen to the
absorbing membrane.
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Food-induced changes in presystemic metabolism
Certain foods may increase the bioavailability of drugs
that
are
susceptible
to
presystemic
intestinal
metabolism by interacting with the metabolic process.
e.g. Grapefruit juice is capable of inhibiting the
intestinal cytochrome P450 and thus, taken with drugs
that are susceptible to cytochrome P450 metabolism,
is likely to result in their increased bioavailability.
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IV. Enterohepatic circulation (Biliary recycling)
•Some drugs when absorbed from intestine they are
carried via the portal vein into the liver.
•In the liver they are metabolized and secreted into
the bile
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• As a conjugated drug they are transported again via
bile duct into intestine (In the conjugated form they are
not absorbed again from intestine).
• After meals the secretion of bile is stimulated. The bile
release the drug from its conjugate, thus it will be
reabsorbed again as if a new dose was given.
• Biliary recycling of a drug results in prolonging drug
action.
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Diagram of biliary recycling
conjugated drug
biliary tract
liver
portal vein
to circulation
unconjugated
drug
gut
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IV. First pass effect
Is a phenomenon of drug metabolism whereby the
concentration of a drug is greatly reduced before it
reaches the systemic circulation.
After a drug is swallowed, it is absorbed by the
digestive system and enters the hepatic portal system.
It is carried through the portal vein into the liver before
it reaches the rest of the body.
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The liver metabolizes many drugs, sometimes to such
an extent that only a small amount of active drug
emerges from the liver to the rest of the circulatory
system .
This first pass through the liver thus greatly reduces
the bioavailability of the drug.
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Diagram of first pass effect
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2. Physicochemical Factors Affecting Oral Absorption
• pH-partition theory
• Lipid solubility of drugs
• Dissolution and pH
• Salts
• Crystal form
• Drug stability and hydrolysis in GIT
• Complexation
• Adsorption
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A. pH - Partition Theory
The pH - partition theory explains the influence of GI
pH and drug pKa on the extent of drug absorption.
As most drugs are weak electrolytes, the unionized
form of weakly acidic or basic drugs (i.e. the lipid-
soluble form) will pass across the gastrointestinal
epithelia, whereas the gastrointestinal epithelia is
impermeable to the ionized (i.e. poorly lipid-soluble)
form of such drugs.
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According
to
the
pH-partition
hypothesis,
the
absorption of a weak electrolyte will be determined
chiefly by the extent to which the drug exists in its
unionized form at the site of absorption.
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The extent to which a weakly acidic or basic drug ionizes
in solution in the gastrointestinal fluid is determined by:
its pKa & the pH at the absorption site and may be
calculated using the appropriate form of the Henderson-
Hasselbach equation
77
What is acid?
acid is a substance that liberates hydrogen ions [H+] in
solution.
What is a base?
A base is a substance that can bind H+ and remove them
from solution.
pH = - log [H+]
Strong acids, strong bases, as well as strong electrolytes
are essentially completely ionized in aqueous solution.
Weak acids and weak bases are only partially ionized in
aqueous solution and yield a mixture of the
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undissociated compound and ions.
In
solutions
equilibria
undissociated
of
exist
weak
acids
between
molecules
HA
H+ + A-
and
their ions.
The ionization constant Ka of a
weak acid can be obtained by
applying the Law of Mass Action:
Ka =
[H+] [A-]
[HA]
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pKa = the negative logarithm
of Ka
pKa = pH - log
For acidic drugs, the lower
[A-]
[HA]
the pKa the stronger the acid
From
the
pKa,
one
can
calculate the proportions of
drug in the charged and
uncharged forms at any pH:
log
[A-]
[HA]
= pH - pKa
Henderson - Hasselbalch
Equation
80
Some Typical pKa Values for Weak Acids at 25 °C
Weak Acid
pKa
Acetic
4.76
Acetylsalicyclic
3.49
Boric
9.24
Penicillin V
2.73
Phenytoin
8.1
Salicyclic
2.97
Sulfathiazole
7.12
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In solutions of weak bases equilibria
exist
between
undissociated
B + H+
BH+
molecules and their ions.
The ionization constant Ka of a
protonated weak base can be
obtained by applying the Law of
Ka =
[H+] [B]
[BH+]
Mass Action:
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pKa = the negative logarithm of Ka
For basic drugs, the higher the
pKa = pH - log
[B]
[BH+]
pKa the stronger the base
From
the
pKa,
one
can
calculate the proportions of
drug in the charged and
uncharged forms at any pH:
log
[B]
[BH+]
= pH - pKa
Henderson - Hasselbalch
Equation
83
Therefore, according to these equations:
a weakly acidic drug, pKa 3.0, will be:
predominantly unionized in gastric fluid at pH 1.2
(98.4%) and almost totally ionized in intestinal fluid at
pH 6.8 (99.98%),
a weakly basic drug, pKa 5, will be:
almost entirely ionized (99.98%) at gastric pH of 1.2
and predominantly unionized at intestinal pH of 6.8
(98.4%).
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This
means
that,
according
to
the
pH-partition
hypothesis, a weakly acidic drug is more likely to be
absorbed from the stomach where it is unionized,
and a weakly basic drug from the intestine where it is
predominantly unionized.
However, in practice, other factors need to be taken into
consideration.
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Lipid solubility :weak acids and weak bases
HA <==> H+ + A[ UI ]
[I]
pKa=pH + log (HA/A-)
ASPIRIN pKa = 4.5 (weak acid)
100mg orally
0.1 = [ I ]
Stomach
pH = 2
99.9 = [ UI ]
Blood
pH = 7.4
[ UI ]
Aspirin is reasonably absorbed
from stomach (fast action)
B + HCl <==> BH+ + Cl[ UI ]
[I]
pKa= pH + log(BH+/B)
STRYCHNINE pKa = 9.5 (weak base)
100mg orally
99.9 = [ I ]
Stomach
pH = 2
0.1 = [ UI ]
Blood
pH = 7.4
[ UI ]
Strychnine not absorbed until
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enters duodenum
Limitations of the pH-partition hypothesis
 Weak acids are also absorbed from the small intestine
due to:
 The significantly larger surface area that is
available for absorption in the small intestine in
contrast to stomach
 The longer small intestinal residence time
 The microclimate pH, that exists at the surface
of the intestinal mucosa and is lower than that
of the luminal pH of the small intestine
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 The pH -partition hypothesis cannot explain the fact
that certain drugs (e.g. tetracyclines) are readily
absorbed despite being ionized over the entire pH
range of the gastrointestinal tract. One suggestion for
this is that such drugs interact with endogenous
organic ions of opposite charge to form an absorbable
neutral species - an ion pair - which is capable of
partitioning into the lipoidal GIT barrier and be
absorbed via passive diffusion.
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B. Lipid Solubility of Drugs
Barbitone and thiopentone, have similar dissociation
constants - pKa 7.8 and 7.6, respectively - and
therefore similar degrees of ionization at intestinal pH.
However, thiopentone is absorbed much better than
barbitone. WHY? the absorption of drugs is also
affected by the lipid solubility of the drug.
Thiopentone, being more lipid soluble than barbitone,
exhibits a greater affinity for the gastrointestinal
membrane and is thus far better absorbed.
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How can we measure lipid solubility??
An indication of the lipid solubility of a drug, and (its
absorption) is given by its ability to partition between a
lipid-like solvent (usually octanol) and water.
This is known as the drug's partition coefficient, and is a
measure of its lipophilicity.
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The partition coefficient P is the ratio of the drug
concentration in the organic phase to its concentration
in the aqueous phase
Partition coefficient (p) = [ L] conc / [W] conc
[ 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.
Polar molecules, i.e. those that are poorly lipid soluble
and relatively large, such as heparin are poorly
absorbed after oral administration and therefore have
to be given by injection.
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The drug is too hydrophilic, what can be done??
Prodrug is one of the options that can be used to
enhance p value and absorption as sequence.
A prodrug is a chemical modification,
frequently an ester of an existing drug.
The
ester
linkage
increases
lipophilicity of the compound
enhances the absorption.
the
thus
A prodrug has no pharmocological activity
itself but it converts back to the parent
compound as a result of metabolism by
the body. (e.g. Rivampicillin a prodrug for
ampicillin)
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C. Drug Dissolution
So far we have looked at the transfer of drugs in
solution in the G-I tract, through a membrane, into
solution in the blood.
However, many drugs are given in solid dosage forms
and therefore must dissolve before absorption can take
place.
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If absorption is slow relative to dissolution then all we
are concerned with is absorption. However, if dissolution
is the slow, rate determining step (the step controlling
the overall rate) then factors affecting dissolution will
control the overall process.
The rate of solution may be explained using Fick’s First
Low of Diffusion: It is the rate at which a dissolved
solute particle diffuses through the stagnant layer to the
bulk solution
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Fick's first law
By Fick's first law of diffusion:
h
Solid Cs
D diffusion coefficient,
Stagnant
Layer
A surface area,
Cs solubility of the drug,
Cb concentration of drug in the bulk solution,
h thickness of the stagnant layer.
Cb
Bulk Solution
As Cb is much smaller than Cs
the equation reduces to :
95
There are a number of factors which affect drug dissolution:
Surface area, A
The surface area per gram (or per dose) of a solid drug
can be changed by altering the particle size.
e.g. a cube 3 cm on each side has a surface area of 54
cm2. If this cube is broken into cubes with sides of 1 cm,
the total surface area is 162 cm2.
96
Generally as A increases the dissolution rate will also
increase. Improved bioavailability has been observed
with griseofulvin, digoxin, etc.
Methods of particle size reduction include mortar and
pestle, mechanical grinders, fluid energy mills, solid
dispersions in readily soluble materials (PEG's).
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Diffusion layer thickness, h
This thickness is affected by the agitation in the bulk
solution.
In vivo we usually have very little control over this
parameter.
It is important though when we perform in vitro
dissolution studies because we have to control the
agitation rate so that we get similar results in vitro as
we would in vivo.
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Diffusion coefficient, D
The value of D depends on the size of the molecule and
the viscosity of the dissolution medium.
Increasing the viscosity will decrease the diffusion
coefficient and thus the dissolution rate.
This could be used to produce a sustained release
effect by including a larger proportion of something
like sucrose or acacia in a tablet formulation.
99
Drug solubility, Cs
Solubility is another determinant of dissolution rate.
As Cs increases so does the dissolution rate.
We can look at ways of changing the solubility of a drug:
100
D. (1) Salt Form
If we look at the dissolution profile of various salts.
Salts of weak acids and weak bases generally have
much higher aqueous solubility than the free acid or
base, therefore if the drug
can be given as a salt the
solubility can be increased
and
we
improved
should
have
dissolution.
One
example is Penicillin V.
101
E. (2) Crystal Form
Some drugs exist in a number of crystal forms or
polymorphs.
These different forms may well have different solubility
properties and thus different dissolution characteristics.
Chloramphenicol palmitate is one example which exists
in at least two polymorphs.
102
The B form is apparently more bioavailable. This is
attributed to the more rapid in vivo rate of dissolution.
The
recommendation
might
be
that
manufacturers
should
use
B
polymorph
for
maximum solubility and
absorption.
Plot of Cp versus Time for
Three
Formulations
of
103
Chloramphenicol Palmitate
In addition to different polymorphic crystalline forms, a
drug may exist in an amorphous form.
Because the amorphous form usually dissolves more
rapidly than the corresponding crystalline forms there
will be significant differences in the bioavailabilities.
e.g. antibiotic novobiocin. The more soluble and rapidly
dissolving amorphous form of novobiocin was readily
absorbed.
However,
the
less
soluble
and
slower-dissolving
crystalline form of novobiocin was not absorbed to any
significant extent thus therapeutically ineffective.
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F. Drug Stability and Hydrolysis in GIT
Acid and enzymatic hydrolysis of drugs in GIT is one of
the reasons for poor bioavailability.
Penicillin G (half life of degradation = 1 min at pH= 1)
Rapid dissolution leads to poor bioavailability WHY? (due
to release large portion of the drug in the stomach, pH =
1.2)
How to protect the drug from the gastric juice?
1. Enteric coating the tablet containing the drug.
2. Prodrug that exhibits limited solubility in gastric fluid
but liberates the parent drug in intestine to be absorbed.
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G. Adsorption
Certain insoluble substances may adsorb
co-administrated drugs leading to poor
absorption.
Charcoal (antidote in drug intoxication).
106
H. Complexation
Complexation of a drug in the GIT fluids may alter rate
and extent of drug absorption.
1. GIT component- drug interaction:
Intestinal mucosa + Streptomycin = poorly absorbed
complex
2. Food-drug interaction:
Calcium + Tetracycline = poorly absorbed complex
3. Tablet additive – drug interaction:
Carboxyl methylcellulose (CMC) + Amphetamine =
poorly absorbed complex
107
4. Complexing agent + polar drugs:
Dialkylamides + prednisone = well-absorbed lipid
soluble complex
5. Lipid soluble drug + water soluble complexing agent
Miconazole + cyclodextrine = water soluble complex
108
3. Formulation Factors Affecting Oral Absorption
Role of dosage forms
 Solutions
 Suspensions
 Capsules
 Tablets
- uncoated
- coated
109
With any drug it is possible to alter its bioavailability
considerably by formulation modification.
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.
This order may not always be followed but it is a useful
guide.
One example is the results for pentobarbital.
Here the order was found to be:
aq solution > aq suspension = capsule > tablet of free
acid form.
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I. Solution dosage form
Drugs are commonly given in solution in cough/cold
remedies and in medication for the young and elderly.
In general, drugs must be in solution in gastrointestinal
fluids before absorption can occur.
For drugs that are water soluble and chemically stable
in aqueous solution, formulation as a solution normally
eliminates the in vivo dissolution step and presents the
drug in the most readily available form for absorption 111
therefore absorption from an oral solution is rapid and
complete, compared with administration in any other
oral dosage form.
The rate limiting step is often the rate of gastric
emptying since absorption will generally be more rapid
in the intestine.
• However, dilution of an aqueous solution of a poorly
water-soluble drug whose aqueous solubility had been
increased by:
formulation techniques such as 1cosolvency, 2complex
formation or 3solubilization can result in precipitation
of the drug in the gastric fluids.
112
• Similarly, exposure of an aqueous solution of a 4salt of
a weak acidic compound to gastric pH can also result in
precipitation of the free acid form of the drug.
In most cases the extremely fine nature of the resulting
precipitate permits a more rapid rate of dissolution
than if the drug had been administered in other types
of oral dosage forms, such as aqueous suspension, hard
gelatin capsule or tablet.
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II. Suspension dosage form
 A well formulated suspension is second to a solution
(nonprecipitating)
in
terms
of
superior
bioavailability.
 Absorption may well be dissolution limited, however
a suspension of a finely divided powder and hence
large surface area will maximize the potential for
rapid dissolution.
 With very fine particle sizes the dispersibility of the
powder becomes important.
114
 The addition of a surface active agent will improve
dispersion of a suspension.
 As a suspension ages there is potential for increased
particle size with an accompanying decrease in
dissolution rate.
115
III. Capsule dosage form
Provided:
 the hard gelatin shell dissolves
rapidly in the GI fluids
 encapsulated mass disperses
rapidly and efficiently,
a
relatively
large
effective
surface area of drug will be
exposed to the gastrointestinal
fluids,
thereby
facilitating
dissolution.
116
The capsule contents should not be subjected to high
compression forces which would tend to reduce the
effective surface area, thus tightly packed capsules
may have reduced dissolution and bioavailability.
The inclusion of excipients (e.g. diluents, lubricants and
surfactants) in a capsule formulation can have a
significant effect on the rate of dissolution of drugs,
particularly
those
that
are
poorly
soluble
and
hydrophobic.
117
If a drug is hydrophobic a dispersing agent should be
added to the capsule formulation.
A hydrophilic diluent (e.g. sorbitol, lactose) often serves
to increase the rate of penetration of the aqueous
gastrointestinal fluids into the contents of the capsule,
and to aid the dispersion and subsequent dissolution of
the drug in these fluids.
However, the diluent should exhibit
no tendency to adsorb or complex
with the drug, as either can impair
absorption from the gastrointestinal
tract.
118
119
IV. Tablet dosage form
Uncoated tablets
Tablets are the most widely used dosage form.
When a drug is formulated as a compressed tablet there is
an enormous reduction in the effective surface area of the
drug,
owing
to
the
granulation
and
compression
processes involved in tablet making.
The tablets should disintegrate rapidly and completely in
the GIT fluids so that a fine, well dispersed suspension of
drug particles in the GIT fluids is generated following the
administration of a tablet.
120
The overall rate of tablet disintegration influenced by
several interdependent factors: the concentration and
type of drug, diluent, binder, disintegrant, lubricant and
wetting agent as well as the compaction pressure.
121
Film Coated Tablet
Tablet coatings may be employed to:
- mask an unpleasant taste or odour or
- to protect an ingredient from
decomposition during storage.
122
Enteric Coated Tablet
An enteric coat is designed to:
resist the low pH of gastric fluids but to disrupt or dissolve
when the tablet enters the higher pH of the duodenum.
Enteric
coating
protects
which
would
otherwise
drugs
be
destroyed if released into gastric
fluid
and
also
protects
the
stomach against drugs which can
produce
nausea
or
mucosal
irritation (e.g. aspirin, ibuprofen)
if released at this site.
123
The presence of a coating presents a physical barrier
between the tablet core and the gastrointestinal fluids.
Coated tablets therefore not only possess all the
potential
bioavailability
problems
associated
with
uncoated conventional tablets, but are subject to the
additional potential problem of being surrounded by a
physical barrier.
124