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Biopharmaceutics Page 1
Biopharmaceutics
Fall 2014-15
Course Handouts
Prepared by:
Dr. Anil K. Philip
Associate Professor
School of Pharmacy
College of Pharmacy and Nursing
University of Nizwa
Biopharmaceutics Page 2
Welcome Students
Biopharmaceutics (Fall 2014-15)
You are expected to study from Textbooks, Reference books, and internet resources, and not
limit yourself to course handouts. Course handouts are just to help you along with the
presentations. The students are expected to make notes for any explanation as the teacher
explains it to them. The exam questions will not be limited to course handouts.
The students are expected to clear any doubts on the subject with the teacher. The teacher
expects the students of Biopharmaceutics to be sincere in their efforts to learn the subject. Please
bear in mind that you will have to earn your grade.
Thank you and all the best
Biopharmaceutics Page 3
Chapter 1. Introduction to Biopharmaceutics, and concepts of bioavailability
The meaning of the term
“biopharmaceutics” is a confusion to many.
“Pharmaceutics” broadly defined is a
science that involves the preparation, use, or
dispensing of medicines. The addition of the
prefix “bio,” coming from the Greek “bios,”
relating to living organisms or tissues. This
expands the field into the science of
preparing, using, and administering drugs to
living organisms or tissues.
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Definition of Biopharmaceutics
Biopharmaceutics can be defined as the
study of of the physicochemical properties
of the drug, the dosage form in which the
drug is given, and the route of
administration on the rate and extent
(amount) of drug reaching the systemic
circulation.
Note: This systemic circulation is after the
first pass metabolism.
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Biopharmaceutics deals with the factors that
influence the
Protection of the drug activity within the
drug product (stability)
The drug release from the a drug product
The rate of drug dissolution at the
absorption site, and
The systemic absorption of the drug.
Studies of biopharmaceutics involve both in-
vitro and in-vivo methods.
In-vitro methods involve test apparatus
without involving laboratory animals or
humans. E.g. disintegration tests, dissolution
tests etc.
In-vivo test involves measurement of
systemic drug availability (bioavailability)
after giving a drug product to an animal or
human.
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Pharmacokinetics is defined as the study of
rate processes involved in absorption,
distribution, metabolism and excretion
(ADME). What the body does to the drug.
Pharmacodynamics is the study of the
biochemical and physiological effects of
drugs on the body or on microorganisms or
parasites within or on the body and the
mechanisms of drug action and the
relationship between drug concentration and
effect. What the body does to the drug.
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Concept of Bioavialability
A measure of the amount of drug that is
actually absorbed from a given dose.
The rate and extent of drug reaching the
systemic circulation. Systemic circulation
means after liver metabolism.
Bioavailable dose: The fraction of an
administered dose of a particular drug that
reaches the systemic circulation intact.
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Profile B: Gives the therapeutic response.
Profile C: Gives no response and no therapeutic effect
and is not desirable
Profile A: Again is not desirable. Even though it gives
therapeutic efficacy it is associated with toxic effects/
side effects.
Absolute and Relative Bioavailability
Bioavailability (BA) is a subcategory of
absorption and is the fraction of an
administered dose of unchanged drug that
reaches the systemic circulation, one of the
principal pharmacokinetic properties of
drugs. By definition, when a medication is
administered intravenously, its
bioavailability is 100%. However, when a
medication is administered via other routes
(such as orally), its bioavailability generally
decreases (due to incomplete absorption and
first-pass metabolism) or may vary from
patient to patient. Bioavailability is one of
the essential tools in pharmacokinetics, as
bioavailability must be considered when
calculating dosages for non-intravenous
routes of administration.
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Absolute bioavailability compares the
bioavailability of the active drug in systemic
circulation following non-intravenous
administration (after oral, rectal,
transdermal, subcutaneous, or sublingual
administration), with the bioavailability of
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the same drug following intravenous
administration.
The comparison must be dose normalized.
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Relative bioavailability measures the
bioavailability (estimated as the AUC) of a
formulation (A) of a certain drug when
compared with another formulation (B) of
the same drug, usually an established
standard, or through administration via a
different route. When the standard consists
of intravenously administered drug, this is
known as absolute bioavailability.
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Therefore, a drug given by the intravenous
route will have an absolute bioavailability of
100% (f=1), whereas drugs given by other
routes usually have an absolute
bioavailability of less than one. If we
compare the two different dosage forms
having same active ingredients and compare
the two drug bioavailability is called
comparative bioavailability.
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SUMMARY of CHAPTER 1
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SUMMARY of CHAPTER 1
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Chapter 2. Study of Different In-Vitro and In-Vivo Biological Models
Transpor
t of
Drugs
Across
Biologica
l
Membranes
Many drugs need to pass through one or
more cell membranes to reach their site of
action. A common feature of all cell
membranes is a phospholipid bilayer, about
10 nm thick. Spanning this bilayer or
attached to the outer or inner leaflets are
glycoproteins, which may act as ion
channels, receptors, intermediate
messengers (G-proteins) or enzymes. Cells
obtain molecules and ions from the
extracellular fluid, creating a constant in and
out flow. The interesting thing about cell
membranes is that relative concentrations
and phospholipid bilayers prevent essential
ions from entering the cell. Therefore, in
order for drugs to move across the
membrane these problems must be
addressed. In general, this is completed by
facilitated diffusion or active transport. In
facilitated diffusion, relative concentrations
are used to transport in and out. Active
transports uses energy (ATP) to transfer
molecules and ions in and out of the cell.
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Concept of drug cross the cell membrane
Cellular signals cross the membrane through
a process
called signal
transduction
. This three-
step process
proceeds
when a
specific message encounters the outside
surface of the cell and makes direct contact
with a receptor.
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A receptor is a specialized molecule that
takes information from the environment and
passes it throughout various parts of the cell.
Next, a connecting switch molecule,
transducer, passes the message inward,
closer to the cell. Finally, the signal gets
amplified, therefore causing the cell to
perform a specific function. These functions
can include moving, producing more
proteins, or even sending out more signals.
Protein Binding A membrane transport protein (or simply
transporter) is a membrane protein involved
in the movement of ions, small molecules,
or macromolecules, such as another protein
across a biological membrane. Transport
proteins are integral transmembrane
proteins; that is they exist permanently
within and span the membrane across which
they transport substances. The proteins may
assist in the movement of substances by
facilitated diffusion or active transport.
These mechanisms of action are known as
carrier-mediated transport. Only the
unbound fraction of drug in plasma is free to
cross the cell membrane; drugs vary greatly
in the degree of plasma protein binding. In
practice, the extent of this binding is of
importance only if the drug is highly
protein-bound (more than 90%). Both
albumin and globulins bind drugs, each has
many binding sites, the number and
characteristics of which are determined by
the pH of plasma. In general, albumin binds
neutral or acidic drugs and globulins bind
basic drugs. Protein binding is altered in a
range of pathological conditions.
Inflammation changes the relative
proportions of the different proteins and
albumin concentration falls in any acute
infective or inflammatory process. In
conditions of severe hypoalbuminaemia, the
proportion of unbound drug increases
markedly such that the same dose will have
pharmacological effect.
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•Protein Binding can effect the drugs action
in a number of ways.
Reduce free drug concentration:
Antibiotic effectiveness is affected. As free
antibiotics have antibacterial activity. Eg.
Cephalosporin and penicillin bind reversibly
to albumin. So the free concentration of the
drug is reduced. Moreover the size of the
protein-drug complex increase, which
reduces the absorption.
Reduce Volume of Distribution: Only free
drug cross the pores of the membrane.
Protein binding affects drug transport to
other tissues. If protein binding is high and
the total drug in the body is low, all of the
drug will be in the plasma. Some exceptions
like warfarin, tricyclic antidepressants are
present. In general high protein binding
leads to low volume of distribution.
Reduce elimination: It retards elimination
(excretion and metabolsim). Proteins are not
filtered through glomerulus filtration.
Protein binding reduces the rate of filtration
in the kidneys and metabolism in the liver.
Increase fluctuation of free plasma drug
concentration: in cases where high protein
binding is present (more than 90%), small
changes in binding, protein concentration, or
displacement of drug (drug-drug
interaction), disease state can lead to
fluctuation of the drug in the plasma thereby
affecting efficacy/toxicity.
•Physiological Barriers like Blood Brain
Barrier and Blood Placental Barrier •Permeability of compounds through
membranes is of great interest and
importance for elucidation of many
biological cell functions. The majority of the
metabolically important substances is
transported across membranes by active
transport, but many other intrinsic
compounds as well as the majority of drugs
are known to pass the membrane by passive
diffusion. For a drug substance to act
systemically after administration if has to
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overcome different biological barriers to
reach the point of action.
Blood Brain Barrier
The blood–brain barrier (BBB) is a
separation of the circulating blood from the
brain extracellular fluid (BECF) in the
central nervous system (CNS). It occurs
along all capillaries and consists of tight
junctions around the capillaries that do not
exist in normal circulation. Endothelial cells
restrict the diffusion of microscopic objects
(e.g., bacteria) and large or hydrophilic
molecules into the cerebrospinal fluid
(CSF), while allowing the diffusion of small
hydrophobic molecules (O2, CO2,
hormones). The blood-brain barrier (BBB)
prevents the brain uptake of most
pharmaceuticals. The BBB is anatomically
and functionally distinct from the blood-
cerebrospinal fluid barrier. Certain small
molecule drugs may cross the BBB via
lipid-mediated free diffusion, providing the
drug has a molecular weight <400 Da and
forms <8 hydrogen bonds. These chemical
properties are lacking in the majority of
small molecule drugs, and all large molecule
drugs. Nevertheless, drugs can be
engineered for BBB transport, based on the
knowledge of the endogenous transport
systems within the BBB. Small molecule
drugs can be synthesized that access carrier-
mediated transport (CMT) systems within
the BBB. Large molecule drugs can be
engineered with molecular Trojan horse
delivery systems to access receptor-
mediated transport (RMT) systems within
the BBB. The blood–brain barrier acts very
effectively to protect the brain from many
common bacterial infections. Thus,
infections of the brain are very rare.
Infections of the brain that do occur are
often very serious and difficult to treat.
Antibodies are too large to cross the blood–
brain barrier, and only certain antibiotics are
able to pass. Direct administration into the
CSF is possible. However, the drugs
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delivered directly to the CSF do not
effectively penetrate into the brain tissue
itself, possibly due to the nature of the
interstitial space in the brain. The blood–
brain barrier becomes more permeable
during inflammation. This allows some
antibiotics and phagocytes to move across
the BBB. However, this also allows bacteria
and viruses to infiltrate the BBB. An
exception to the bacterial exclusion is the
diseases caused by spirochetes, such as
Borrelia, which causes Lyme disease, and
Treponema pallidum, which causes syphilis.
These harmful bacteria seem to breach the
blood–brain barrier by physically tunneling
through the blood vessel walls.
Blood Placental Barrier
Over the last several decades, the
consumption of medicines either shortly
before or during pregnancy has been
increasing. The fetus becomes object of this
therapeutic management. Human beings
have at their disposal the placenta,
characterized by a direct contact of the
developing fetal tissues with the maternal
blood. The human placenta, characterized by
the processes of passive transport and
facilitated diffusion, contains numerous
active transport proteins. These proteins use
either the energy from ATP hydrolysis or
other mechanisms resulting, among others,
from the formation of the maternofetal ion
gradient, which facilitates the transfer of
various endogenous substances or
xenobiotics across the body membranes.
Membrane Structure and Composition •The 'cell membrane' (also known as the
plasma membrane or cytoplasmic
membrane) is a biological membrane that
separates the interior of all cells from the
outside environment. Membranes are made
of very thin films of molecules that enclose
cells, organelles, compartments. Typically
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composed of lipids and proteins, about
50%/50% by mass. Lipids provide basic
structure, while proteins have specific
functional roles. Many different kinds of
lipids but the basic feature is that they are
amphipathic, i.e., have both hydrophobic
and a polar groups. Typical phospholipid
consists of
• phosphate group
• glycerol
• hydrocarbon tail Most common type of
phospholipid in cell membranes is
phosphatidylcholine. Cholesterols are also
ampipathic and found in membranes. The
hydrophobic and polar parts of amphipathic
molecules want to phase separate, but
cannot because they are covalently bonded.
Many proteins are embedded within or
associated with the membrane. These
proteins perform critical cellular functions
like selective transport, anchoring
cytoskeletal components, receptors for
signaling, enzymes.
Davson-Danieli Model
In 1935, Hugh
Davson and
James Danielli
proposed a
model of the
cell membrane
in which the phospholipid bilayer lies
between two layers of globular protein. The
phospholipid bilayer had already been
proposed by Gorter and Grendel in 1925, but
the Davson–Danielli model's flanking
proteinaceous layers were novel and
intended to explain Danielli's observations
on the surface tension of lipid bilayers (It is
now known that the phospholipid head
groups are sufficient to explain the measured
surface tension.). The Davson–Danielli
model predominated until Singer and
Nicolson advanced the fluid mosaic model
in 1972.
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Singer-Nicolson Model/Fluid Mosaic
Model
The fluid mosaic
model expanded on
the Davson–Danielli
model by including
transmembrane
proteins, and
eliminated the
previously-proposed
flanking protein
layers that were not
well-supported by
experimental evidence.
The results of the performed experiment
were key in the development of the "fluid
mosaic" model of the cell membrane by
Singer and Nicolson in 1972. According to
this model, biological membranes are
composed largely of bare lipid bilayer with
proteins penetrating either half way or all
the way through the membrane. These
proteins are visualized as freely floating
within a completely liquid bilayer. But the
fluid mosaic model was the first to correctly
incorporate fluidity, membrane channels and
multiple modes of protein/bilayer coupling
into one theory.
Summary of Chapter 2
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Summary of Chapter 2
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Chapter 3. Transport Mechanisms Involved in Drug Absorption
Absorption is
the transfer of
a drug from its
site of
administration
to the
bloodstream.
The rate and efficiency of absorption depend
on the route of administration. For IV
delivery, absorption is complete; that is, the
total dose of drug reaches the systemic
circulation. Drug delivery by other routes
may result in only partial absorption and,
thus, lower bioavailability. For example, the
oral route requires that a drug dissolves in
the GI fluid and then penetrates the
epithelial cells of the intestinal mucosa, yet
disease states or the presence of food may
affect this process.
Different Mechanisms of Drug
Absorption
Passive diffusion: the drug moves from a
region of high
concentration
to one of
lower concentration (Fick’s law). The
difference of concentration between the two
areas is often termed as the concentration
gradient, and diffusion will continue until
this gradient has been eliminated. This
means that over time when there is an
equilibrium the passive diffusion should
stop. However, this does not happen due to
the sink condition in our body.
Passive diffusion does not involve a carrier.
The vast majority of drugs gain access to the
body by this mechanism. Lipid-soluble
drugs readily move across most biologic
membranes due to their solubility in the
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membrane bi-layers. Polar substances
dissolve freely in polar solvents and
nonpolar substances dissolves freely in
lipids (non polar substance), therefore,
penetrates cell membrane very freely. It
occurs due to the concentration gradient, it is
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moving from high to low concentration, no
need of energy supply for simple diffusion.
Example: Water- it is moved through the
GIT due to gaps between endothelial and
along with it
smaller water soluble substances can be
passed such as urea and alcohol etc.
Gases: the gases can be diffused in the lungs
by simple diffusion, not due to the
concentration gradient, but due to partial
pressure differences of gases i.e., oxygen.
• The rate of diffusion depends on:
Steepness of Concentration gradient
Temperature
Charge
Diameter of the diffusing molecule
Facilitated Transport: Facilitated diffusion
(also known as facilitated transport or
passive-mediated transport) is the process of
spontaneous passive transport (as opposed to
active transport) of molecules or ions across
a biological membrane via specific
transmembrane integral proteins. Being
passive, facilitated transport does not
involve the use of chemical energy; rather,
molecules and ions move down their
concentration gradient. Facilitated diffusion
is not a form of diffusion, however it is a
transport process in which molecules or ions
which would otherwise cross the membrane
with great difficulty exploit transmembrane
protein channels to help them cross this
membrane. It is similar to passive diffusion
except that there is a need of transport
protein. Some molecules cannot pass the
lipoidal membrane, and these protein
channels undergo conformational shape)
change to allow the molecules to pass into
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the membrane. Glucose is transported along
with sodium from the GIT membrane using
facilitated diffusion as the process.
•Osmosis: Osmosis is the spontaneous net
movement of solvent molecules through a
partially permeable membrane into a region
of higher solute concentration, in the
direction that tends to equalize the solute
concentrations on the two sides. It may also
be used to describe a physical process in
which any solvent moves, without input of
energy, across a semipermeable membrane
(permeable to the solvent, but not the solute)
separating two solutions of different
concentrations. Although osmosis does not
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require input of energy, it does use kinetic
energy and can be made to do the work.
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•The osmotic pressure is defined to be the
pressure required to maintain an
equilibrium, with no net movement of
solvent. Osmotic pressure is a colligative
property, meaning that the osmotic pressure
depends on the molar concentration of the
solute but not on its identity.
•Osmosis is an essential aspect in biological
systems, as biological membranes are
semipermeable. In general, these membranes
are impermeable to large and polar
molecules, such as ions, proteins, and
polysaccharides, while being permeable to
non-polar and/or hydrophobic molecules
like lipids as well as to small molecules like
oxygen, carbon dioxide, nitrogen, nitric
oxide, etc. Permeability depends on the
solubility, charge, or chemistry, as well as
solute size. Water molecules travel through
the plasma membrane, tonoplast membrane
(vacuole) or protoplast by diffusing across
the phospholipid bilayer via aquaporins
(small transmembrane proteins similar to
Biopharmaceutics Page 17
those in facilitated diffusion and in creating
ion channels). Osmosis provides the primary
means by which water is transported into
and out of cells. The turgor pressure of a cell
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is largely maintained by osmosis, across the
cell membrane, between the cell interior and
its relatively hypotonic environment.
Active transport: Active transport is the
movement of all types of molecules across a
cell membrane against its concentration
gradient (from low to high concentration). In
all cells, this is usually concerned with
accumulating high concentrations of
molecules that the cell needs, such as ions,
glucose and amino acids. If the process uses
chemical energy, such as from adenosine
triphosphate (ATP), it is termed primary
active transport. Secondary active transport
involves the use of an electrochemical
gradient include the uptake of glucose in the
intestines in humans and the uptake of
mineral ions into root hair cells of plants.
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This mode of drug entry also involves
specific carrier proteins that cross the
membrane. Active transport is energy-
dependent and is driven by the hydrolysis of
adenosine tri-phosphate. It is capable of
moving drugs against a concentration
gradient that is, from a region of low drug
concentration to one of higher drug
concentration.
Endocytosis and exocytosis: This type of
drug delivery transports drugs of
exceptionally large size across the cell
membrane. Endocytosis involves
engulfment of a drug molecule by the cell
membrane and transport into the cell by
pinching off the drug-filled vesicle.
Exocytosis is the reverse of endocytosis and
is used by cells to secrete many substances
by a similar vesicle formation process. For
example, vitamin B12 is transported across
Biopharmaceutics Page 18
the gut wall by endocytosis. Certain
neurotransmitters (for example, nor
epinephrine) are stored in membrane-bound
vesicles in the nerve terminal and are
released by exocytosis.
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Pinocytosis: It is also called as drinking of
cell. The drug molecule, when comes in
contact with membranes the invagination
occurs (pseudopods). They trap the drug
molecule and forms vesicles in which the
drug molecule is present and taken into the
cell. In the cell, some lysozymes are present
which acts on the drug molecule and forms
active form. This process occurs rarely.
Example: Barium sulfate. Some molecules
like insulin can enter to BBB (blood brain
barrier) by this process.
In follicular cells of the thyroid, the colloids
are taken by the same process and releases
T3 and T4 which are useful residues.
Pore Filtration: It is also called connective,
bulk flow or filteration. Filtration involves
the aqueous channels or pores (protein
channel) through which hydrophilic drugs
can pass. The driving force is the osmotic
pressure difference across the membrane.
The water flux that promotes such a
transport is called solvent drag. Process
important for low molecular weight
compounds (< 100 D). Filtration occurs in
the jejunum and proximal tubules of
kidneys. It is absent in the stomach and the
lining of the urinary bladder. Only certain
ions like Na+ and drugs of low molecular
weight, like ethanol and glycerol can
undergo filtration.
Ion-Pair Formation: this mechanism is
responsible for compounds which ionizes at
all pH. Most of the drugs are reabsorbed
from the proximal tubules of kidneys.
Acidic drugs are better reabsorbed from
acidic urine. This is an important fact, which
can be manipulated to get desired results, as
is the case of poisoning with acidic drugs.
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If we make the urine alkaline (by
administering sodium bicarbonate),
decreased reabsorption of acidic drugs take
place, a phenomenon known as ion trapping
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In case of poisoning with basic drug, urine
can be made more acidic (by administering
ammonium chloride), by virtue of which the
basic drug becomes ionized and is not
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reabsorbed, with the result that more of it is
excreted out.
SUMMARY of CHAPTER 3
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SUMMARY of CHAPTER 3
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Chapter 4. In Vitro Dissolution
In the pharmaceutical industry, drug
dissolution testing is routinely used to
provide critical in vitro drug release
information for both quality control
purposes, i.e., to assess batch-to-batch
consistency of solid oral dosage forms such
as tablets, and drug development, i.e., to
predict in vivo drug release profiles.
Example of a Dissolution Cell
In vitro drug dissolution data generated from
dissolution testing experiments can be
related to in vivo pharmacokinetic data by
means of in vitro-in vivo correlations
(IVIVC). A well established predictive
IVIVC model can be very helpful for drug
formulation design and post-approval
manufacturing changes. The main objective
of developing and evaluating an IVIVC is to
establish the dissolution test as a surrogate
for human bioequivalence studies, as stated
by the Food and Drug Administration
(FDA).
Several dissolution apparatuses exist. In
United States Pharmacopeia (USP) General
Chapter <711> Dissolution, there are four
dissolution apparatuses standardized and
specified. They are:
• USP Dissolution Apparatus 1 - Basket
(37°C)
• USP Dissolution Apparatus 2 - Paddle
(37°C)
• USP Dissolution Apparatus 3 -
Reciprocating Cylinder (37°C)
• USP Dissolution Apparatus 4 - Flow-
Through Cell (37°C)
USP Dissolution Apparatus 2 is the most
widely used apparatus among these four.
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Noyes- Whitney’s Dissolution Rate Law
Defines the dissolution from spherical
particle. It is based on the Fick’s first law of
diffusion. The relationship between the rate
of dissolution, dm/dt, and the solubility, CS,
is described by the Noyes-Whitney
equation:
dm/dt = DAKw/o (Cs-Cb)
Vh
where:
Rate of Dissolution, dm/dt
Diffusion Coefficient, D
Surface Area, A
Water/ Oil Partition Coefficient, Ko/w
Concentration Gradient, Cs-Cb
Volume of Dissolution Media, V
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Thickness of boundary layer,h
The rate of dissolution quantifies the speed
of the dissolution process. The rate of
dissolution depends on:
nature of the solvent and solute,
temperature (and to a small degree
pressure), degree of undersaturation,
presence of mixing, interfacial surface area,
presence of inhibitors (e.g., a substance
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adsorbed on the surface).
Biopharmaceutics Page 22
Compendial Methods of Dissolution
Basket Method
Introduced in 1970. Basket good for
submerging floating products, swelling
formulations, bead formulations, coated and
uncoated formulations, suppository,
immediate and modified release
formulations.
The tablet or capsule is placed in a stainless
steel cylindrical mesh basket. The basket is
placed in a vessel kept at a constant
temperature. The basket is rotated at a
constant speed (between 25 and 150
revolutions per minute). Samples are
withdrawn for analysis from the same
position each time.
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The apparatus for the paddle method is
similar to that for the rotating basket method
The design of the paddle and the speed at
which it rotates are important. The paddle
must rotate smoothly with no wobbling and
no vortex should form when the paddle is
turning. The tablet or capsule is allowed to
sink to the bottom of the vessel before the
paddle starts rotating. The apparatus is
useful for tablets, capsules and suspensions.
Both Method I (Basket) and Method II
(paddle) are known as closed method
because of fixed amounts of dissolution
media used.
Both the USP Apparatus 1 and 2 share some
common advantages and disadvantages.
Advantages include: i) widely accepted
apparatus for dissolution test, ii) apparatus
of first choice for solid oral dosage forms,
iii) standardized, iv) easy to operate, v)
robust and vi) broad experience.
Disadvantages include: i) limited volume of
the dissolution media, ii) simulation of the
gastrointestinal transit is not possible and iii)
hydrodynamic conditions are not known.
Dissolution results obtained with USP
Apparatuses 1 and 2 may be significantly
affected by shaft wobble, location,
centering, and coning.
In Vitro- In Vivo Correlation
An In-vitro in-vivo correlation (IVIVC) has
been defined by the U.S. Food and Drug
Administration (FDA) as "a predictive
mathematical model describing the
relationship between an in-vitro property of
a dosage form and an in-vivo response".
Generally, the in-vitro property is the rate or
extent of drug dissolution or release while
the in-vivo response is the plasma drug
concentration or amount of drug absorbed.
Typically, the parameter derived from the
in-vivo is AUC or Cmax, while the in- vitro
property is the in vitro dissolution profile.
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The main roles of IVIVC are:
1.To use dissolution test as a surrogate for
human studies.
2.To supports and/or validate the use of
dissolution methods and specifications.
3.To assist in quality control during
manufacturing and selecting appropriate
formulations
Levels of IVIVC
There are four levels of IVIVC that have
been described in the FDA guidance, which
include levels A, B, C, and multiple C.
Level A correlation: An IVIVC that correlates the entire in vitro
and in vivo profiles has regulatory relevance
and is called a Level A Correlation. This
level of correlation is the highest category of
correlation and represents a point-to-point
relationship between in vitro dissolution rate
and in vivo input rate of the drug from the
dosage form.
Level A correlation is the most preferred to
achieve; since it allows bio-waiver for
changes in manufacturing site, raw material
suppliers, and minor changes in formulation.
Level B correlation:
A level B IVIVC is based on the principles
of statistical moment analysis. In this level
of correlation, the mean in vitro dissolution
time (MDT vitro) of the product is
compared to either mean in vivo residence
time (MRT) or the mean in vivo dissolution
time (MDTvivo). It is least useful for
regulatory purposes.
Level C correlation:
Level C correlation relates one dissolution
time point (t50%, t90%, etc.) to one mean
pharmacokinetic parameter such as AUC,
tmax or Cmax. Due to its obvious
limitations, the usefulness of a Level C
correlation is limited in predicting in vivo
drug performance. In the early stages of
formulation development Level C
correlations can be useful.
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Multiple Level C correlations:
This level refers to the relationship between
one or more pharmacokinetic parameters of
interest (Cmax, AUC, or any other suitable
parameters) and amount of drug dissolved at
several time point of dissolution profile.
Multiple point level C correlation may be
used to justify a biowaivers provided that
the correlation has been established over the
entire dissolution profile with one or more
pharmacokinetic parameters of interest. A
multiple Level C correlation should be based
on at least three dissolution time points
covering the early, middle, and late stages of
the dissolution profile.
Summary Chapter 4
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Summary Chapter 4
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Chapter 5. Factors Influencing the Absorption of Drug
Physical, Chemical Properties of Drug
Substances
Drug Solubility and Dissolution Rate
Solubility is the property of a matter called
solute to dissolve in a solvent to form a
homogeneous solution. The solubility of a
substance fundamentally depends on the
physical and chemical properties of the
solute and solvent as well as on temperature,
pressure and the pH of the solution.
The extent of solubility ranges widely, from
infinitely soluble (without limit) (fully
miscible such as ethanol in water, to poorly
soluble, such as silver chloride in water. The
term insoluble is often applied to poorly or
very poorly soluble compounds.
Dissolution is the process by which a solute
forms a solution in a solvent. The solute
(solids), has its crystalline structure
disintegrated as separate ions, atoms, and
molecules form. For liquids and gases, the
molecules must be adaptable with those of
the solvent for a solution to form. The
outcome of the process of dissolution is
governed by the thermodynamic energies
involved, such as the heat of solution and
entropy of the solution.
Dissolution testing is widely used in the
pharmaceutical industry for optimization of
formulation and quality control.
Dissolution is not always an instantaneous
process. It is fast when salt and sugar
dissolve in water but much slower for a
tablet of aspirin. It may be due to the surface
area (crystallite size) and the presence of
polymorphism.
The rate of dissolution and solubility should
not be confused as they are different
concepts, kinetic and thermodynamic,
respectively.
HOW will DRUG SOLUBILITY and
DRUG DISSOLUTION AFFECT
ABSORPTION of DRUG?
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•For a drug to be absorbed, it must first be
dissolved in the fluid at the absorption
site.When the solubility of a drug depends
on either an acidic or basic medium, the
drug dissolves in the stomach or intestines,
respectively. As a drug particle undergoes
dissolution, the drug molecules on the
surface are the first to enter into solution,
creating a saturated layer of drug solution
that envelops the surface of the solid drug
particle. This layer of solution is the
diffusion layer. From this diffusion layer the
drug molecules pass throughout the
dissolving fluid and make contact with the
biological membranes, and absorption
ensues. As the molecules of the drug
continue to leave the diffusion layer, the
layer is replenished with the dissolved drug
from the surface of the drug particle and the
process of absorption continues.
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FOR YOUR READING
Solubility of the drug: Very hydrophilic drugs are poorly absorbed because of their inability to
cross the lipid-rich cell membranes. Paradoxically, drugs that are extremely hydrophobic are also
poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot
gain access to the surface of cells. For a drug to be readily absorbed, it must be largely
hydrophobic, yet have some solubility in aqueous solutions. This is one reason why many drugs
Biopharmaceutics Page 27
are weak acids or weak bases. There are some drugs that are highly lipid-soluble, and they are
transported in the aqueous solutions of the body on carrier proteins such as albumin.
If the dissolution of a given drug particle is rapid or if the drug is administered as a solution and
remains present in the body as such, the rate at which the drug becomes absorbed depends
mainly on its ability to traverse the membrane barrier. However, if the rate of dissolution for a
drug particle is slow because of the physicochemical characteristics of the drug substance or the
dosage form, dissolution itself is a rate-limiting step in absorption. Slowly soluble drugs such as
digoxin may not only be absorbed at a slow rate; they may be incompletely absorbed or in some
cases largely unabsorbed following oral administration because of the natural limitation of time
that they may remain within the stomach or the intestinal tract. Thus, poorly soluble drugs or
poorly formulated drug products may be incompletely absorbed and pass unchanged out of the
system via the feces.
Biopharmaceutics Page 29
Particle Size and Surface Area
When a drug particle is broken up, the total
surface area is increased. For drug
substances that are poorly or slowly soluble,
this generally results in an increase in the
rate of dissolution.
The particle size of a drug can affect its
release from dosage forms that are
administered orally, parenterally, rectally
and topically. The physical stability and
pharmacological response also depend on
the particle size achieved in the
formulations.
Particle size and surface area influence the
release of a drug from a dosage form that is
administered. Higher surface area brings
about intimate contact of the drug with the
dissolution fluids in vivo and increases the
drug solubility and dissolution.
Particle size and surface area influence the
drug absorption and subsequently the
therapeutic action. Higher the dissolution,
faster the absorption and hence quicker and
greater the drug action.
Micromeritic properties of a particle, i.e. the
particle size in a formulation, influence the
physical stability of the suspensions and
emulsions. Smaller the size of the particle,
better the physical stability of the dosage
form owing to the Brownian motion of the
particles in the dispersion.
Total surface area available for absorption:
Because the intestine has a surface rich in
microvilli, it has a surface area about 1000-
fold that of the stomach; thus, absorption of
Biopharmaceutics Page 30
the drug across the intestine is more
efficient.
Smaller the particle size (by micronization)-
greater is the effective surface area- more
intimate contact between solid surface and
aquoues solvent- higher is the dissolution
rate-increase in absorption efficiency.
e.g. poorly aq soluble nonhydrophobic drugs
like Griseofulvin, chloramphenicol whose
dissolution is rate limited.
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Particle size reduction has been used to
increase the absorption of a large number of
poorly soluble drugs, such as
bishydroxycoumarin, digoxin, griseofulvin,
nitrofurantoin, and tolbutamide.
Salt of the Drug
At given pH, the solubility of drug, whether
acidic/basic or its salt, is a constant.
While considering the salt form of drug, the
pH of the diffusion layer is important not the
pH of the bulk of the solution.
E.g. of salt of weak acid. ---Which increases
the pH of the diffusion layer, which
promotes the solubility and dissolution of a
weak acid and absorption is bound to be
rapid.
Reverse in the case of salts of weak bases,
it lowers the pH of diffusion layer and the
promoted the absorption of basic drugs.
Other approach to enhance the dissolution
and absorption rate of certain drugs is by
formation of in – situ salt formation i.e.
increasing in pH of microenvironment of
drug by incorporating buffer agent.e.g.
aspirin, penicillin
But sometimes more soluble salt form of
drug may result in poor absorption.e.g.
Biopharmaceutics Page 31
sodium salt of phenobarbitone and
phenobarbitone, tablet of salt of
phenobarbitone swelled, it did not get
disintegrate thus dissolved slowly and
results in poor absorption.
pKa of the Drug and Gastrointestinal pH
A poorly soluble drug when in the
dissolution fluid will not ionize and hence
absorption will be slow as compared to the
salt form of the drug, which will dissolve
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because it ionizes. Absorption of
undissociated drug is more than dissociated
form. However, it should be in solution
form. At a pH equal to the pKa of a drug
(acidic or basic), the concentrations of the
dissociated and un-dissociated drug will be
equal or the ratio of these concentrations
will be 1. On the other hand, a different pH
value of a solvent/environment than the pKa
for drugs will force uneven concentrations
of dissociated vs un-dissociated
concentrations.
A solvent having a pH one unit higher for
acidic drugs or lower for basic drugs than
the pKa of dissolved drug will increase the
dissociation (ionization) of the drugs to
90%, while a 2 pH unit differences from the
pKa value will increase the ionization to
99.9%. Therefore, the larger the pH
differences between the pKa of a drug and
pH of the solvent, the larger the ionization.
As the pH of a solvent and pKa of a drug are
fixed which provides high dissociated drug,
then to maintain the equation balance
correspondingly the concentration of an un-
dissociated form must also increase. This
means that the higher the dissociation, the
higher the concentration of the undissociated
drug as well i.e. higher ionization favours
higher concentration of undissociated drug.
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