biopharmaceutics - eduwavepool.unizwa.edu.om · biopharmaceutics page 2 welcome students...

Biopharmaceutics

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

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

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

Biopharmaceutics

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

Biopharmaceutics

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

___________________________________

____________________________________

____________________________________

____________________________________

____________________________________

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

Biopharmaceutics

the same drug following intravenous

administration.

The comparison must be dose normalized.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

SUMMARY of CHAPTER 1

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

Biopharmaceutics

____________________________________

____________________________________

____________________________________

____________________________________


____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

Biopharmaceutics

____________________________________ __________________________________

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

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.

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

NOTES

____________________________________

____________________________________

Biopharmaceutics

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

•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

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

Biopharmaceutics

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

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

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

Biopharmaceutics

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

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

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

___________________________________

Biopharmaceutics

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

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.

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

Biopharmaceutics

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

___________________________________

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

__________________________________

___________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

___________________________________

____________________________________

____________________________________

____________________________________

____________________________________

Biopharmaceutics

____________________________________

____________________________________

___________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

___________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

___________________________________

Summary of Chapter 2

____________________________________

____________________________________

___________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

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

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

___________________________________

Biopharmaceutics

____________________________________

___________________________________

____________________________________

___________________________________

____________________________________

___________________________________

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

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

____________________________________

____________________________________

____________________________________

__________________________________

____________________________________

___________________________________

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

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

Biopharmaceutics

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

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

____________________________________

__________________________________

__________________________________

NOTES

____________________________________

____________________________________

__________________________________

____________________________________

___________________________________

___________________________________

__________________________________

__________________________________

__________________________________

__________________________________

require input of energy, it does use kinetic

energy and can be made to do the work.

__________________________________

•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

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

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

___________________________________

NOTES

____________________________________

____________________________________

___________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

___________________________________

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.

____________________________________

____________________________________

__________________________________

NOTES

____________________________________

____________________________________

__________________________________

____________________________________

____________________________________

____________________________________

___________________________________

____________________________________

___________________________________

__________________________________

__________________________________

__________________________________

____________________________________

____________________________________

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

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.

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

NOTES

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

____________________________________

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.

NOTES

___________________________________

__________________________________

____________________________________

____________________________________

____________________________________

__________________________________

__________________________________

__________________________________

__________________________________

___________________________________

____________________________________

__________________________________

__________________________________

NOTES

Biopharmaceutics

__________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

___________________________________

__________________________________

___________________________________

__________________________________

____________________________________

__________________________________

__________________________________

__________________________________

NOTE

__________________________________

___________________________________

___________________________________

__________________________________

___________________________________

____________________________________

____________________________________

If we make the urine alkaline (by

administering sodium bicarbonate),

decreased reabsorption of acidic drugs take

place, a phenomenon known as ion trapping

____________________________________

____________________________________

____________________________________

__________________________________

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

_________________________________

_________________________________wit

_________________________________

____________________________________

reabsorbed, with the result that more of it is

excreted out.


__________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

____________________________________

___________________________________

____________________________________

___________________________________

____________________________________

___________________________________

___________________________________


___________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

____________________________________

___________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

____________________________________

____________________________________

____________________________________

____________________________________

__________________________________

____________________________________

____________________________________

____________________________________

__________________________________

Biopharmaceutics

____________________________________

___________________________________

____________________________________

___________________________________

____________________________________

___________________________________

____________________________________

___________________________________

____________________________________

___________________________________

____________________________________

___________________________________

____________________________________

___________________________________

_______________________________________________________________________

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.

NOTES

___________________________________

____________________________________

___________________________________

____________________________________

__________________________________

__________________________________

___________________________________

NOTES

____________________________________

____________________________________

___________________________________

Biopharmaceutics

___________________________________

___________________________________

__________________________________

___________________________________

____________________________________

__________________________________

___________________________________

___________________________________

____________________________________

NOTES

____________________________________

__________________________________

__________________________________

__________________________________

__________________________________

___________________________________

____________________________________

____________________________________

__________________________________

___________________________________

__________________________________

____________________________________

__________________________________

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

NOTES

____________________________________

____________________________________

___________________________________

__________________________________

___________________________________

__________________________________

___________________________________

__________________________________

__________________________________

__________________________________

____________________________________

____________________________________

____________________________________

__________________________________

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

NOTES

____________________________________

____________________________________

___________________________________

___________________________________

___________________________________

__________________________________

__________________________________

adsorbed on the surface).

Biopharmaceutics

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.

NOTES

____________________________________

____________________________________

___________________________________

___________________________________

___________________________________

__________________________________

__________________________________

____________________________________

____________________________________

___________________________________

___________________________________

___________________________________

__________________________________

__________________________________

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.

____________________________________

____________________________________

___________________________________

___________________________________

___________________________________

__________________________________

__________________________________

____________________________________

____________________________________

___________________________________

Biopharmaceutics

___________________________________

___________________________________

__________________________________

__________________________________

____________________________________

____________________________________

___________________________________

___________________________________

___________________________________

__________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

NOTES

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

____________________________________

____________________________________

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.

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

NOTES

Biopharmaceutics

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

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

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

Biopharmaceutics

__________________________________

____________________________________

__________________________________

____________________________________

Summary Chapter 4

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

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?

NOTES

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

Biopharmaceutics

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

•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.

NOTES

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

__________________________________

____________________________________

__________________________________

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

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

Biopharmaceutics

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

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.

NOTES

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

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

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

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

____________________________________

__________________________________

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.

Biopharmaceutics

biopharmaceutics - eduwavepool.unizwa.edu.om · biopharmaceutics page 2 welcome students...

Documents