Biopharmaceutics: Introduction

Absorption
 Introduction
Biopharmaceutics
• It is the study of the relation of the physical and chemical
properties of a drug to its bioavailability, pharmacokinetics, and
pharmacodynamics and toxicological effects
• Biopharmaceutics involves factors that influence the:
• Protection and stability of the drug within the product
• The rate of drug release from the product
• The rate of dissolution of the drug at the absorption site
• The availability of the drug at its site of action
1. A drug product is the finished dosage form (eg., tablet, capsule,
suspension etc.) that contains the API in addition with nondrug
ingredients (excipients) that make up vehicle or formulation
matrix.
2. The Drug delivery system includes the formulation and the
dynamic interactions among the drug, its formulation matrix, its
container and the patient
3. Bioavailability is a measurement of the rate and extent
(amount) of systemic absorption of the therapeutically active
drug.
Pharmacokinetics
• It is the study of the time course of drug movement in the body
during absorption, distribution and elimination (excretion and
biotransformation)

Pharmacodynamics
• It is the study of the relation of the drug concentration or
amount at the site of action (receptor) and its pharmacologic
response as a function of time.
 MSC

Therapeutic Window/
range

MEC
 Mechanism of drug transport

• A cell membrane is a semipermeable structure composed

primarily of lipids and proteins
• Drugs may be transported by passive diffusion, partitioning,
carrier-mediated transport, Para cellular transport, or vesicular
transport
• Usually, proteins, drugs bound to proteins, and macromolecules
do not easily cross cell membranes
• Nonpolar lipid-soluble drugs traverse cell membranes more
easily
than do ionic or polar water-soluble drugs
• Low-molecular-weight drugs diffuse across a cell membrane
more
 Passive diffusion and
• partitioning
Within the cytoplasm or in interstitial fluid, most drugs undergo
transport by simple diffusion
• It involves the transfer of drugs fro an area of high
concentration (C1) to an area of m concentratio (C2)
according to Fick’s law of diffusion: lower n
• Passive drug transport across cell membranes involves the
successive partitioning of a solute betweenaqueous and lipid
phases as well as diffusion within the respective phases
• Modified Fick’s law (including partition):

• Ionization of a weak electrolyte is affected by the pH of the

medium in which the drug is dissolved as well as by the pKa of the
drug. The non ionized species is more lipid soluble than the ionized
species, and it partitions more readily across cell membranes
 Carrier-mediated
Active transport transport
• It isthe passage of the drug across a membrane by carrier-
mediated process
1. The drug moves against a concentration gradient
2. The process requires energy
3. The carrier may be selective for certain types of drugs that
resemble natural substrates or metabolites that are normally
actively transported
4. The carrier system may be saturated at a high drug
concentration
5. The process may be competitive (i.e., drugs with similar
structures may compete for the same carrier)
Facilitated diffusion

• It is also a carrier-mediated transport system. However,

facilitated diffusion occurs with (i.e., in the direction of) a
concentration gradient and does not require energy

Paracellular transport

• Drug transport across tight (narrow) junctions between cells or

trans endothelial channels of cells is known as paracellular
transport
• It involves both diffusion and the convective (bulk) flow of
water and accompanying water-soluble drug molecules through
the paracellular channels
Vesicular
transport
• It is the process of engulfing particles or dissolved materials
by a cell
• Vesicular transport is the only transport mechanism that does
not require a drug to be in an aqueous solution to be absorbed
• Endocytosis and exocytosis are the movement of
macromolecules
into and out of the cell, respectively
a. Pinocytosis is the engulfment of small solute or fluid volumes
b. Phagocytosis isthe engulfment of larger particles, or
macromolecules, generally by macrophages
 Other transport
mechanisms Transporter proteins

• Various transporter proteins (e.g.,P-glycoprotein) are

embedded in the lipid bilayer of cell membranes
• These proteins are ATP (energy) dependent “pumps,” which can
facilitate the efflux of drug molecules from the cell and are
found in conjunction with metabolizing enzymes such as
cytochrome P450 3A4
• Their net effect is to reduce intracellular drug concentrations
• Thus they determine, the pharmacokinetic disposition and
circulating plasma concentrations of drugs (e.g., cyclosporine,
nifedipine, digoxin) that are substrates for these proteins.
Drug transport and Absorption
 Time for
recap
1. Which statement best describes bioavailability?
A. Relationbetweenthe physical and the chemical properties of
a
drug and its systemic absorption
B. Measurement of the rate and amount of therapeutically
active drug that reaches the systemic circulation
C. Movement of the drug into body tissues over time
D. Dissolution of the drug in the gastrointestinal tract
E. Amount of drug destroyed by the liver before systemic
absorption
from the gastrointestinal tract occurs
2. After peroral administration, drugs generally are absorbed
best
from the

A. Stomach
B. Duodenum
C. Ileum
D. Rectum

Ans is B
3. The passage of drug molecules from a region of high drug
concentration to a region oflow drug concentration is known as

A. Active transport
B. Bioavailability
C. Biopharmaceutics
D. Simple diffusion
E. Pinocytosis

Ans is D
4. The characteristics of an active transport process include all
of the following except for which one?

A. Active transport moves drug molecules against a concentration

gradient
B. Active transport follows Fick’s law of diffusion
C. Active transport is a carrier-mediated transport system
D. Active transport requires energy
E. Active transport of drug molecules may be saturated at high
drug
concentrations

Ans is B
5. The route of drug administration that provides complete (100%)
bioavailability is

A. Intramuscular injection
B. Intravenous injection
C. Intradermal injection
D. Per oral administration
E. Subcutaneous injection

Ans is B
 Factors affecting Drug
Absorption
Physicochemical properties
Drug dissolution
• For most drugs with limited water solubility, the rate at which
the solid drug enters into solution (i.e., the rate of dissolution)
is the rate-limiting step in bioavailability. (Dissolution rate
limited)
• The Noyes–Whitney equation describes the diffusion-controlled
rate of drug dissolution
• It is the mass transfer from surface of the solid to bulk
solution
• Various models/theories which explain dissolution:
1. Diffusion layer model/Film theory
2. Dankwert’s Model (Penetration or Surface renewal theory)
3. Interfacial barrier model (Double Barrier Mechanism OR
Limited
Solvation Theory)
Drug
solubility
• The concentration of drug in a saturated solution
• It is a static (equilibrium) property
• Whereasthe dissolution rate of a drug isa dynamicproperty
related to the rate of absorption
 Particle size and surface
• area related in a given mass of the
These are inversely
substance drug particle size decreases, particle surface area
• increases
As solid in given equal mass of both
• According to Noyes–Whitney equation the dissolution rate is
directly proportional to the surface area
• With certain hydrophobic drugs, excessive particle size
reduction does not always increase the dissolution rate instead
it decreases dissolution rate (reaggregation, air entrapment,
charge generation)
• To prevent the formation of aggregates, small drug particles
are molecularly dispersed in polyethylene glycol (PEG),
polyvinylpyrrolidone (PVP; povidone), dextrose, or other agents
 Partition coefficient and extent of
Partition ionization
coefficient
• It is the ratio of the solubility of the drug, at equilibrium, in a
non aqueous solvent (e.g., n-octanol) to that in an aqueous
solvent (e.g., water; pH 7.4 buffer solution)
• This value dictates the nature of drug, Hydrophilic or lipophilic
• More the value more lipophilic, less the value more hydrophilic
• Balance betweenhydrophilicity and lipophilicity essential for
better Absorption (HLB)
• Hydrophilic drugs with higher water solubility have a faster
dissolution rate than do hydrophobic or lipophilic drugs
Extent of ionization
• The drugs (acidic/basic) exist in both ionized from and
unionized form in solution
• The extent of ionization/unionization depends on:
i. pKa of the drug or electrolyte
ii. pH of the environment/solution
• The ionized form is more polar, and therefore more water
soluble,
than the nonionized form
• The Henderson–Hasselbalch equation describes the relation
between the ionized and the nonionized forms of a drug as a
function of pH and pKa
For weak
acids
(𝐢𝐨𝐧𝐢𝐳𝐞𝐝)
𝐩𝐇 = 𝐩𝐊𝐚 + log (𝐮𝐧𝐢𝐨𝐧𝐢𝐳𝐞𝐝)

For weak bases

𝐩𝐇 = 𝐩𝐊𝐚 + log (𝐮𝐧𝐢𝐨𝐧𝐢𝐳𝐞𝐝)

(𝐢𝐨𝐧𝐢𝐳𝐞𝐝)
Salt
formation
• While considering the salt form of drug, pH ofthe diffusion
layer
is important not the pH of the bulk of the solution
• Salt of weak acid - It increases the pH of the diffusion layer,
which promotes the solubility and dissolution of a weak acid and
absorption is bound to be rapid
• A solid dosage form containing buffering agents may be
formulated with the free acid form of the drug (e.g., buffered
aspirin)
a. The buffering agent forms an alkaline medium in the
gastrointestinal tract, and the drug dissolves in situ
b. The dissolved salt form of the drug diff uses into the bulk fluid
of the gastrointestinal tract, forms a fi ne precipitate that
redissolves rapidly, and becomes available for absorption
 Time to Recap
1. Which one of the following physicochemical properties is more
important for passive diffusion of drugs from the
gastrointestinal tract?
A. Dissolution constant
B. Lipid solubility
C. Partition coefficient
D. pH of the gastrointestinal fluids

Ans is
C
3. The applicability of Noyes-Whitney equation is to describe
the

A. First-order kinetics
B. Zero-order kinetics
C. Mixed-order kinetics
D. Dissolution rate

Ans is D
4. Which equation describes the rate of drug dissolution from a
tablet?

A. Henderson–Hasselbalch equation
B. Law of mass action
C. Michaelis–Menten equation
D. Noyes–Whitney equation

Ans is D
5. Which condition usually increases the rate of drug dissolution
from a tablet?

A. increase in the particle size of the drug

B. decrease in the surface area of the drug
C. use of the free acid or free base form of the drug
D. use of the ionized, or salt, form of the drug

Ans is D
6. The extent of ionization of a weakelectrolyte drug depends on
the

A. pH of the media and pKa ofthe drug

B. oil to water partition coefficient of the drug
C. particle size and surface area of the drug
D. Noyes–Whitney equation for the drug

Ans is A
7. The rate-limiting step in the bioavailability of a lipid soluble
drug formulated as an immediate-release compressed tablet is
the rate of

A. disintegration of the tablet and release of the drug

B. dissolution of the drug
C. transport of the drug molecules across the intestinal mucosal
cells
D. blood flow to the gastrointestinal tract

Ans is B
8. The relation betweenrate of diffusion and concentration
gradient across the barrier is

A. Inversely
proportional
B. Directly proportional
C. log linear
D. Exponential

Ans is B