Biopharmaceutics

Pharmaceutics 3

Dr. Kabara
BIOPHARMACEUTICS
It is defined as the study of factors influencing the rate and amount of drug
that reaches the systematic circulation. It involves the use of this
information to optimize the therapeutic efficacy of the drug products.
The process of movement of drug from its site of adm to the systemic
circulation is known as absorption.
The conc. of drug in plasma and therefore the onset of action, the intensity
and duration of response depend upon the bioavailability of drugs from its
dosage form.
Bioavailability is defined as the rate and eetent (amount) of drug absorption.
Any alteration in the drugs bioavailability is reflected in its pharmacological
effects.
Other processes that play a role in therapeutic activity of drug are
 Distribution
 Elimination

Distribution and elimination are known as drug disposition.

The movement of drug between one compartment and another e.g. between
blood and extravascular tissue is referred to a drug distribution. The site of
action of the drug is usually located in the extra vascular tissue.
The onset, intensity and the duration of action depend upon the distribution
behaviour of the drug.
The intensity and duration of action depend upon the effective conc and time
period for which the conc is maintained at the site of action which in turn
depends on the elimination process.
Elimination: It is the process that tends to remove the drug from the body
and terminate its action. Eliminate occurs by 2 processes

2 Biopharmaceutics Dr. Kabara

1. Biotransformation (metabolism)-the drug is inactivated.

2. Excretion
It is responsible for the exit of drug or metabolite from the body. In order to
achieve optimum actions of the drug, knowledge of the mechanism of drug
absorption, distribution, metabolism excretion (pharmacokinetics) is
required.
Pharmacokinetics: It is the study of the time course of drug i.e ADME and
their relationship with its therapeutic and toxic effects of the drug.
It is the kinetics of ADME. The use of pharmacokinetics principles in
optimizing the drug dosage to suit individual patient needs and achieving
maximum therapeutic utility is called clinical pharmacokinetics.

Drug admin can be divided into four phases or processes

1. Pharmaceutic process
It is concerned with the formulation of an effective dosage form of the drug
for admin by a suitable route.
2. Pharmacokinetic process
Its concerned with ADME of drugs as elicited by the plasma drug conc-time
profile and its relationship with the dose, dosage form, the frequency and
route of admin.
3. Pharmacodynamic process
It is concerned with the biochemical and physiological effects of the drug and
its mechanism of action. It is characterized by the conc of the drug at the
site of action and its relation to the magnitude of effects observed.
Pharmacodynamics deals with what the drug does to the body while
pharmacokinetics is the study of what the body does to the drug.
4. Therapeutic process

3 Biopharmaceutics Dr. Kabara

 It is concerned with the translation of the pharmacological effects into
clinical benefits.

pharmaceutics
Drug + Excipients
Clinical phamacokinetics

Bio Pharmaceutical

Formulation
parenterability

Drug Dosage form

PHARMACO
KINETICS
Oral Adm

Drug release and dissolution

Metabolised /excreted

GIT Absorption

Drug in systematic circulation

Drug disposition

Distribution Elimination

Extravascular tissues Metabolism and excretion

Pharmacological response

Therapeutic or toxic effects

A knowledge of the bioavailability of the drugs helps in designing the

optimum dosage formulation.
Rational use of drugs can be achieved by better understanding of
pharmacokinetics and pharmacodynamics of the drug.
4 Biopharmaceutics Dr. Kabara
A knowledge of biopharmaceutics and pharmacokinetics have an integral
role in the design and dev of new drugs, dosage form, and improvement of
therapeutic efficacy of existing drugs.

ABSORPTION OF DRUGS
Drug absorption is defined as the process of movement of unchanged drug
from the site of adm to systemic circulation. Following absorption ,the
effectiveness of a drug can only be ascertained by its con at the site of
action.
NB: It is difficult to measure the conc of a drug at the site of action. usually
the conc of the drug can be measured more accurately in plasma. There is
co-relation between the plasma conc of a drug and the therapeutic response.
diagram

A drug that is completely but slowly absorbed may fail to show therapeutic
response as the plasma conc for the desired effect is never achieved but a
drug that is rapidly absorbed attains therapeutic level easily to elicit
pharmacological effect.
The rate and extent a absorption of a drug is important. Some of the drug
may not reach systemic circulation after oral adm. due to presystemic
metabolism or 1st pass effect. Drugs that have to enter systemic circulation
to exert their effects can be adm by 3 major routes:-
Oral route
Parenteral route.
Topical route.

5 Biopharmaceutics Dr. Kabara

GIT Absorption of drugs
The oral route of drug adm is the most common for systemically acting
drugs.
Mechanism of drug absorption
1. Passive diffusion/ Non ionic diffusion
It is the major process for absorption of more than 90% of the drugs. The
driving force for the process is the difference in the drug conc on either side
of the membrane. The movement of the drug across the membrane is not
energy dependent.

During passive diffusion the drug present in the Aq soln across the
absorption site partitions and dissolves in the lipid material of the membrane
and finally leaves it by dissolving again in the aq media at the inside of the
membrane.

Passive diffusion is expressed by Fick’s 1 st Law of diffusion which states that

drug molecules diffuse from a region of higher conc to one of lower conc
until equilibrium is attained and that the rate of diffusion is directly
proportional to the gradient across the membrane.
Since the drug moves down the gradient, its also called downhill transport.
Passive diffusion process is non saturable and energy independent.

2. Carrier mediated transport

Some polar drugs cross the membrane more rapidly than that predicted from
their conc gradient and partition coefficient values. This suggests the
6 Biopharmaceutics Dr. Kabara

Passive diffusion
 presence of specialist transport mechanism e.g. the absorption of water
soluble nutrients like monosaccharides, amino acids, vitamins which would
otherwise be poorly absorbed.

In this mechanism, the carrier binds reversibly and non covalently with the
solid molecules to be transported. The carrier-solute complex moves across
the membrane to the other side where it dissociates and discharges the
solute molecule. The carrier then returns to the original site and accepts
another molecule of the solute. The carrier may be an enzyme or some
other component of the membrane. The transport process is structure
specific i.e. the carriers have special activity for the transfer of drug of
specific chemical structure only.
Generally the carriers have special affinity for essential nutrients. Since the
system is structure specific, drugs having structure similar to essential
nutrients called false nutrients are absorbed by the same carrier system e.g.
5flourouracil and 5 – Bromouracil (anti-neoplastic agents / serve as false
nutrients).
The no. of carriers is limited and the transport system is subject to
competition between agents having similar structures. The transport system
is capacity limited and at higher drug conc ,the system become saturated.

Carrier mediated
transport -its limited
Rate of by by the carrier
drug
absorption

Carrier mediated transport occurs at specific site of the intestinal tract which
are rich in the number of carriers. Such an area in which the carrier system is
7 Biopharmaceutics Dr. Kabara
most concentrated is called absorption window. Drugs absorbed through
such a windows are not suitable for controlled release formulation.

Facilitated diffusion
It is a carrier mediated transport system that operates down the conc
gradient (Down hill transport) but at a much faster rate than by simple
passive diffusion. The driving force is conc gradient. It is a passive process
and no energy is required hence the process is not inhibited by metabolic
processes that interfere with energy production.

Examples of facilitated transport:

- Entry of glucose into the RBC
- Intestinal absorption of vitamin B1, B2, B12
The absorption of vitamin B12 requires the presence of an intrinsic factor, a
glycoprotein produced by the cells in the stomach. It forms a complex with
vitamin B12 and then is transported across the membrane by a carrier
system.

Active Transport
It is a more important transport than facilitated diffusion in the
transportation of nutrients and drugs. The drug is transported from a region
of lower to one of high conc i.e. against the conc gradient or uphill transport .

Since the process is uphill, energy is required in the work done by the
carrier. The process requires expenditure of energy and can be inhibited by
metabolic posions i.e. substances which interfere with energy production e.g.
cyanide, dinitrophenol, lack of oxygen etc.
The endogenolic substance transported actively include K+, Na+, Ca+, ion
(fe) ions vitamins like pyridoxine (B6), Ascorbic Acid (antioxidant) Niacin.
Examples of drugs transported by this system
8 Biopharmaceutics Dr. Kabara
5fluoro and 5 bromouracil.
Absorption of methydopa and levodopa via an amino acid transport system.
Absorption of ACE inhibitors via peptide carrier system
Active transport is also important in renal and billiary excretion of many
drugs and their metabolites

Endocytosis
It is a minor transport mechanism which involved engulfing extracellular
materials within a segment of the cell membrane forming a vescible which is
then pinched off intracellulary.
this transport system is responsible for the cellular uptake macro molecular
nutrients e.g. fats, starch, oil soluble vitamins and drugs such as insulin.
The process is important in the drugs absorbed in the lymphatic circulation
or by passing hepatic metabolism. Endocytosis are of 2 types:
Phagocytosis – cell eating
Pinocytosis – cell drinking
Orally adm polio vaccines are absorbed by pinocytosis.

Drugs may be absorbed by more than are mechanism e.g cardiac glycosides
are absorbed both passively and by active transport.

FACTORS INFLUENCING DRUG ABSORPTION AND BIO AVAILABILITY

Pharmaceutic factors
Chemical properties of the drug substance
Drug solubility
Dissolution rate
Particle size and effective surface area
Polymorphism
Salt form of the drug

9 Biopharmaceutics Dr. Kabara

Lypophillicity of the drug and the pKa of the drug, influence in partition
coefficient
The drug stability
Dosage form characteristics
Disintegration time
Solution time
Manufacturing variables – hardness of tablets, porosity, density.
Formulation additives
Nature and type of dosage form
Product and storage conditions

Patient related factors

These are related to the anatomy, physiology and pathological
characteristics of the patient.
Age of patient
Gastric emptying time
Intestinal transit time
Disease states
Blood flow through the GIT
GIT contents can be – other drugs, foods, fluids

Systemic metabolism - gut lumen enzymes

- gut wall enzymes
- Bacterial enzymes
- Hepatic enzyme

Biopharmaceutic consideration in dosage form design

To achieve the desired therapeutic effect the drug product must deliver the
active drug at an optimum rate and amount. The bioavailability or the
systemic delivery of the drug to the body can be varied from rapid and
10 Biopharmaceutics Dr. Kabara
complete absorption to slow and sustained absorption depending upon the
desired therapeutic objective.

Events that occur following adm of a solid dosage form until it is absorbed
into systemic circulation.

Summary
Disintegration of drug.
De aggregation and subsequent release of the drug.
Dissolution of the drug in the aq fluids at the absorption site
Movement of the dissolved drug through the membrane into systemic
circulation and away from the absorption site.
Unless the drug goes into solution, it cannot be absorbed into the systemic
circulation.
The rate at which the drug reaches systematic circulation is determined by
the slowest of the various steps involved in the sequence i.e. the rate
determining step (RDS) or the Rate limiting step
Physicochemical properties
Drug Solubility and Dissolution rate
Except in the case of controlled release formulations, disintegration and
deagregation occurs rapidly if it’s a well formulated dosage form.
The rate determining processes in the absorption of orally adm drug are:
1. The rate of dissolution
2. The rate of drug permeation through the biomembranes
(absorption)

Dissolution is the RDS for hydrophobic drugs (poorly aq. soluble drugs) e.g.
Griseofulvin and spironolactone. Absorption of such drugs is said to be
dissolution rate limited. If the drug is hydrophilic with high aq solubility
e.g.cromolyn sodium or neomycin then dissolution is rapid and the RDS is
11 Biopharmaceutics Dr. Kabara
 the absorption of such drugs. The rate of permeation of such drugs through
the biomembrane is poor. Such drugs are said to be permeation rate limited.

Permeation
Dissolution across the bio
membranes

Disintegrate Solid
Solid drug Drug in Drug in
Dosage particle solution Blood
at stream
Deaggregation
absorptio
RDS n site RDS for
lipophiilic hydrophilic
drugs

In all mechanisms of drug absorption with the exception endocytosis, the

drug must be present in aq solution to be absorbed. A drug in aq solution
depends on the drug’s aq solubility and its dissolution rate.
Absolute solubility / intrinsic solubility is defined as the maximum
amount of solute dissolved in a given solvent under standard condition of
temperature, pressure and pH. It is a static property.

The dissolution rate is defined as the amount of solid substance that goes
into solution per unit time under standard condition of temperature, pH,
solvent composition and constant solid surface area. It’s a dynamic process
Drugs with poor aq. solubility have an influence on the dissolution rate.

THEORIES OF DRUG DISSOLUTION

12 Biopharmaceutics Dr. Kabara

This is the simplest model in the explanation of the dissolution of drug
particles. The process of dissolution consist of 2 consecutive steps:
i) Solution of the solid to form a layer at the solid-liquid interphase
called the stagnant layer / diffusion layer. In this layer the drug is
saturated and the step is usually rapid.
ii) Diffusion of the soluble solute to the bulk of the solution and this
step is usually slower and the rate determining step in drug
dissolution.

The earliest eq. to explain the rate of dissolution when the process is
diffusion controlled was given by Noye and Whitney and the eq. is.

Where = Dissolution rate of the drug

K= Dissolution rate constant (1st order)

Cs = Conc. of drugs in the stagnant layer also called saturation maximum
drug solubility
Cb – conc. of drug in the bulk of the solution at time t.

This equation is based on Fick’s 2nd law of diffusion.

inco-operating Ficks 1st law of diffusion and the Noye-Whitney equation
gives:

D – diffusion coefficient of the drug

A – surface area of the dissolving drug
Kw – water oil partition coefficient of the drug considering the fact that the
dissolution body fluids are aq.
V- volume of the dissolution medium
h – thickness of the stagnant layer
13 Biopharmaceutics Dr. Kabara
Cs–Cb= conc gradient.
How they influence dissolution drug
D – The greater the value the faster the dissolution
Diffusion decreases as the viscocity of the dissolution medium
increases.
K – The greater the surface area, the faster the dissolution. This can be
increased by milling the drug or micronisaiton
KWo – Water / Oil partition coefficient of the drug. The higher the value the
more hydrophilic the drug and the faster the dissolution in aq. phase.
Cs- Cb – The greater the conc gradient, the faster the diffusion and drug
dissolution. This can be increased by increasing drug solubility and the
volume of dissolution medium.
h- The grater the thickness the lesser the diffusion and drug dissolution.

The Bunner modified equation represents 1 st order dissolution process and

the driving force for this is the conc gradient (Cs – Cb). Under such a
situation the dissolution is said to be under Non sink conditions.
This is true in the case of in-vitro dissolution in a limited dissolution medium.
Dissolution slows down after sometimes due to build up in the conc of the
drug in the bulk of the medium.
In vivo, the dissolution is always rapid than in invitro because the moment
the drug dissolves it is absorbed into the systemic circulation. As a result Cb
≈O (almost) and the dissolution is at its maximum.
For in-vivo conditions, there is no concentration build up in the bulk of the
solution and no retarding effect on the dissolution rate of the drug i.e. Cs
>>Cb always and sink conditions prevail.
Under sink conditions, if the volume and surface area of solid are kept

constant the eqn become

14 Biopharmaceutics Dr. Kabara

And this mean under sink conditions, the dissolution rate is constant and
follows zero order kinetics.
In the Noye Whitney’s equation is assumes that the surface area of the
dissolving drug /solid remains constant during dissolution which is practically
not possible for dissolving particles.
Particle size and effective SA of a drug are inversly related. There are two
types of surface area:

i) Absolute S.A – it is the total area of solid surface of any particle

ii) Effective S.A – It is the area of the solid surface exposed to the
dissolution media
From the modified equation, the larger the surface area, the slower the
dissolution rate. The S.A increases with decreasing particle size and a
decrease in particle size can be accomplished by micronisation.
This results in a higher dissolution rate

Micronisation has enabled the formulators to decrease the dose of certain

drugs because of increased absorption efficiency e.g. Griseofulvin dose was
reduced to ½ following micronisation. This is particularly true in the case of
non hydrophobic drugs e.g. micronisation of poorly aq. soluble drugs e.g.
griseofulvin, chloramphenical and tetracyline results in superior dissolution
rates.

For hydrophobic drugs e.g. aspirin, phenacetin, phenobarbitone

micronisation actually results in a decrease in effective S.A of such powders
and thus a fall in the dissolution rate.
The hydrophobic surface of the drug absorb air onto their surface which
inhibits their wettability. Particle the aggregation to form larger particles
due to their high surface free energy and extreme particle size reduction
may impart surface charges that may prevent wetting.
15 Biopharmaceutics Dr. Kabara
Particles size reduction is not always advisable when the drugs are unstable
and degrade in solution form.

Drug Stability
A drug for oral use may destabilize in the GIT resulting in poor bioavailability
of the drug. A drug may undergo degradation into inactive form or interact
with some components either of the dosage form or fluids resulting in poor
absorption of the drug.

Dosage form factors affecting drug absorption:

a) Distergration time (DT)
Its important in the case of solid dosage form e.g. tablets and capsules. If a
solid dosage form doesn’t conform to the Dt, the process of dissolution will
be much slower and the absorption may be insufficient e.g. sugar coated
tablets have long disintergration time. DT of tablets is directly related to the
amount of bulk present and the compression force /hardness of a tablet.
A harder tablet with a large amount of binder has a long disintergration
time. Disintegration can be aided by inco-oporating disintegrants in suitable
amounts during formulation. Rapid disintegration is improtnat in the
therapeutic success of a solid dosage form.

Dissolution Time.
Drug dissolution is the most important factor in the absorption of a drug for
solid dosage forms e.g. tablets and capsules.
The dosage form related factors that influence dissolution and hence
absorption of a drug are:
1. Excipients
2. Manufacturing process
Excipients such as Binders, lubricants, disintegrants influence rate of drug
dissolution. The manufacturing process also influence drug dissolution from
16 Biopharmaceutics Dr. Kabara
solid drugs forms. The process of manipulating tablets is important e.g.
method of granulation and the compression force.
Nature of dosage form
The bioavailability of drugs from various dosage forms decrease in the
following order:
solutions > emulsion > susp > Caps > tablets > coated tablets > entenic
coated > sustain release products.
Absorption of a drug from solution is fastest with least potential for
bioavailability problems where as absorption from sustained release
products is slowest with greatest bioavailability risks.
Product Age and storage conditions
A no. of changes in the physicochemical properties of a drug is dosage form
can result due to ageing. Alteration in the storage condition can adversely
affect bioavailability. Changes that occur during the shelt life a dosage form
are mainly due to temp changes and humidity. E.g prednisone containing
lactose as a diluent has increase in temperature and humidity resulting in
harder tablets that disintergrate and dissolve slowly.

Patient related factors

Disease condition of the patient e.g. diarrhoea, constipation, GIT perfusion,
GIT contents, age of patient.

DRUG DISTRIBUTION
After entry into the systemic circulation by I.V or by absorption the drug is
subjected to processes called disposition processes. Disposition tends to
lower the plasma conc.of the drug.
There are 2 major drug disposition processes.
1. Distribution

17 Biopharmaceutics Dr. Kabara

It’s a reversible transfer of a drug between the intra and the extra vascular
fluids and tissues.

2. Elimination
Its irreversible loss of drug from the body either by biotransformation
(metabolism) or excretion.
The process of drug distribution is carried out by the circulation of blood from
one compartment to the other. One compartment is blood plasma and the
other represents extravascular fluid and body tissue.
Drug distribution is a passive process and the driving force is conc gradient
between blood and extravascular tissues. The process occur by diffusion of
free drug until equilibrium is achieved.
NB. The pharmacological action of a drug depends on its conc at the site of
action.
The distribution of a drug in the body is not uniform because different tissues
receive the drug from the plasma at different rates and to different extents.

Factors that influence drug distribution in tissues

Tissue permeability of the drug

Physicochemical properties of drug e.g. molecules size, pKa, partition
coefficient
Physiological barriers to the diffusion of the drug e.g. BBB, placental barrier,
blood testis barrier CSF barrier, simple cell membrane barriers, simple
capillary endothelial barriers.
Organ or tissue size and perfusion rate
18 Biopharmaceutics Dr. Kabara
Binding of drugs to blood or tissue components
Miscellaneous :
Age
Pregnancy
Obesity
Disease state
Drug interaction

Physicohemical Properties of the drug

Almost all drugs have low molecular wt and can easily cross the capillary
membrane to the extracellular fluid by diffusion.
The penetration of drug from ECF into the cells is a function of molecular
size, ionization constant and lipophilicity of the drug.

The degree of ionization of a drug determine its tissue penetrability

The blood and ECF influence the diffusion of drugs into cells. A drug that
remains ionized permeates the cells more rapidly. Most drugs are weak acids
/bases and their degree of ionization depends upon their pKa. All drugs that
ionize at plasma pH or are polar cannot penetrate the lipid cell membrane
and tissue permeability is the rate limiting step. Only the unionized drugs
which are generally lipophilic rapidly cross the cell membrane.

Physiological barriers
Highly polar drugs are most likely to pass the blood brain barrier.
BBB is a lipid barrier and only allows the drugs having high oil/water partition
coefficient to diffuse passively where as moderately lipid soluble and
partially ionized molecule penetrate at a slow rate.
Polar natural substance e.g. sugars and amino acids are transported to the
brain actively.
19 Biopharmaceutics Dr. Kabara
Structurally similar foreign molecules can also penetrate BBB by the same
mechanism.

Protein binding of drugs

A drug in the body can interact with
1. Blood components e.g plasma proteins and blood cells
2. The extravascular tissue components - tissue proteins, fats bones etc

The interacting macromolecules in tissue are the protein, DNA and Adipose
tissues.
The plasma protein binding is the most significant. Protein binding of drug is
a phenomenon of complex formation with proteins. The bound drug is both
p’cokinetcially and p’dynamically inert i.e. neither metabolized.
It is restricted to the compartment for which it has greater affinity. Bound
drugs have long plasma t½.

The binding of drugs involve weak chemical bonds E.g. Hydrogen bonding,
ionic and van der waals forces. These processes are reversible. Irreversible
bonding e.g. covalent bonds result in carcinogenicity, tissue toxicity of the
drug e.g chloroform and paracetamol metabolites are toxic to the liver.

Binding of drugs to blood components

Upon absorption of drug into systemic circulation, it interacts with blood
components i.e. plasma protein, blood cells and haemoglobin. The binding
of drugs to plasma protein is reversible . The order of binding of drugs to
various proteins is:
Albumn > 1 acid glycoprotein> lipoproteins >globulins

Human Serum Albumin (HSA)

20 Biopharmaceutics Dr. Kabara

They bind all types of drugs – weak acids, neutral and weak bases. They also
bind endogenous substances e.g. fatty acid, billirubin and tryptophan

1-acid glycoprotein
Binds basic drugs e.g. imipramine, guanidine, lidocaine

Lipoprotein
Binds basic lipophilic drugs e.g. chlorpromazine.

Globulins
1 globulins bind steroids e.g. cortisone, thyroxine and cyanocobalamin
B12).
2 globulin – binds vitamin A D E K (fat soluble)
Blood cells
Haemoglobin – bind phenytoin, phenobarb, phenothiazines, Acetazolamide

Cell membrane binds imipramin.

Factors Affecting Protein drug binding

1. Factors related to the drug

Physicochemial characteristics of the drug
- Conc of the drug in the body
- Affinity of a drug for a particular binding component
2. Factors related to the protein
- Physicochemical characteristics of the protein
Conc of the proteins
No. of binding sites
21 Biopharmaceutics Dr. Kabara
3. Drug interactions
a) Competition between drugs for the binding sites (Displacement
interaction Warfarin and phenylbutazone)
phenyl butazone and sulphonamin – toxicity suto
b. Competition between drugs and normal body constituents
c. Allosteric changes- involve alteration of the protein structure by the
drug / its metabolites – modifying its binding capacity
4. pH related factors

Excretion of drugs
Excretion is the process whereby drugs and their metabolites are irreversibly
transferred from internal to external environment. The organs of excretion
are
a) Kidneys (renal route)
b) Non renal routes:- lungs (pulmonary)
Billary system
Intestine
Salivary gland
Mammary gland
Sweat glands
Genital routes
Renal excretion of drugs
Agents that are water soluble, non volatile, small in molecular size and which
are metabolized slowly are excreted in the urine.
22 Biopharmaceutics Dr. Kabara
The basic functional unit involved in excretion is the nephron which consists
of the proximal tubule, loop of Henle and collecting duct.
The principle processes that determine urinary excretion of drugs are:
i) Glomerular filtration (Gf)
ii) Active tubular secretion
iii) Active or passive tubular reabsorption

23 Biopharmaceutics Dr. Kabara