ABSORPTION OF DRUG

Submitted ToDr. Santa Raj Joshi

Department of Pharmacy

School of ScienceKathmandu University

Submitted By

Feb 2008

Table of Content

Anana Sharmat Deep Piyati Yasodha Manandhar M Pharm, 1st Sem M Pharm, 1st Sem M Pharm, 1st SemRoll No. 070019 Roll No. Roll No.000

1. Introduction

Drug absorption is defined as the process of movement of unchanged drug from the site of

administration to systemic circulation.

Most of the drugs produce their effects only after they have entered into the bloodstream.

The rapidity of absorption and site of absorption depend on chemical and physical

properties of the drug. The rate of absorption affects the duration and intensity of the drug

action.

There always exist a correlation between the plasma concentration of a drug and the

therapeutic response and thus the absorption can also be defined as the process of

movement of unchanged drug from the site of administration to the site of measurement i.e.

plasma.

A drug that is completely but slowly absorbed may fail to show therapeutic response as the

plasma concentration for desired effect is never achieved. On the contrary, a rapidly

absorbed drug attains the therapeutic level easily to elicit pharmacological effect, thus both

the rate and the extent of drug absorption are important. Such an absorption pattern has

several advantages:

1. Lesser susceptibility of the drug for degradation or interaction due to rapid

absorption.

2. Higher blood levels and rapid onset of action.

3. More uniform, greater and reproducible therapeutic response.

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2. Methods of absorption

2.1 Oral absorption

After oral administration, absorption of drugs may occur at various body sites between the

mouth and the rectum. In general, the higher is the absorption of drug along the length of

the alimentary tract, the more rapid will be its action. However, because of drug substances

differ in their chemical and physical properties and in the forms in which they are

represented to the body a given drug may be better absorbed from the environment of one

position than from that of another. Physically the oral absorption of drug is managed by

allowing the drug substances to be dissolved and withheld in the oral cavity. Drugs capable

of being absorbed in the mouth may be in concentrated form because they are further

diluted with gastrointestinal fluids in the alimentary tract .Many drugs like nitroglycerine,

sex hormones, morphine, glycerylnitate have been shown to be absorbed faster in

sublingual administration than when swallowed. Drugs which are absorbed through the

buccal mucosa enter the systematic circulation directly and are distributed to the whole

body without passing through the liver fast.

2.2 Rectal absorption

The rectum and t he colon are capable of absorbing many soluble drugs intended for

systemic action. Also, drugs absorbed rectally donot pass through the liver prior to their

entry into the systemic circulation .However rectal absorption is often irregular and

incomplete and therefore many drugs cause irritation of the rectal mucosa.

2.3Parentral absorption

The parentral route is preferred when rapid absorption is desired as in emergency.

Absorption by the parentral route is faster than oral administration and the blood level of

drug that result are is certain because little is lost after subcutaneous or intramuscular

injections. Therefore, subcutaneous or intramuscular injections make sure that the desired

dose of the drug is within the tissues of the body where it is capable of being absorbed into

the circulation. However, such an injection may prove at times failure to ensure rapid or

predictable absorption. If rapid, predictable drug delivery into the circulations is required,

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the intravenous administration is preferable. However, the rate of absorption by parentral

route depends on the blood flow.

2.4 Absorption of drugs through the skin

Drugs are usually applied to the skin for their local actions. Absorption through the skin is

inefficient and variable when systemic actions are required. Drug entry may take place

more easily through the cells lining sweat, sebacious glands, hair follicles and other

anatomic structured of the skin surface. Since blood capillaries are present just below the

epidermal cells, a drug that penetrates the skin is able to traverse the capillary finds ready

access to the general circulation. The rate of absorption of a drug through the skin to some

extent is determined by the site of the skin as well.

2.5Absorption through the respiratory tact

Gaseous and volatile drugs may be inhaled and absorbed through the pulmonary epithelium

and mucosa membrane of the respiratory tract. Here, the access of the drug to the

circulation is rapid because the surface area is large. However, the rate of absorption

depends on the size of the particles of the drug. The size largely determines the depth to

which the particles penetrate the alveolar region, their solubility potential, and the extent to

which they are absorbed. After they come into contact with inner surface of the lungs,

insoluble drug particles are caught in the mucus. Soluble drug particles that are

approximately 0.5 to 1.0 micron in size reach the minute alveolar sacs. They are most

prompt and efficient in providing systemic effects.

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3. Mechanism of drug absorption

The principal mechanisms for transport of drug molecules across the cell membrane are:

1. Passive diffusion

2. Pore transport

3. Facilitated diffusion

4. Active transport

5. Ionic or electrochemical diffusion

6. Ion pair transport

7. Endocytosis

3.1 Passive diffusion

It is also called non-ionic diffusion. The driving force for this process is the

electrochemical gradient. It is defined as the difference in the drug concentration on either

side of the membrane. Since no energy is required, the process is called as passive

diffusion.

Passive diffusion is best expressed by Fick’s first law of diffusion, which states that the

drug molecules diffuse from a region of higher concentration to one of lower concentration

until equilibrium is attained and that the rate of diffusions directly proportional to the

concentration gradient across the membrane.

Mathematically,

[da/dt =DcPcS dc/dx]

Where,

Dc is the diffusion coefficient of the drug through the membrane

Pc if the partition coefficient between membrane and the donor medium containing drug

S is the membrane surface area

And dc & dx are concentration differential across the membrane & membrane thickness

respectively.

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In actual practice concentration on the receptor side of the membrane are low because of

continuous blood flow. Thus when the concentration onto donor side is relatively high,

above equation can be changed to ;da/dt=PmSc

Where c=drug concentration at absorption site & Pm =permeability constant

Pm =DcPc/dx

For the solid dosage forms drug concentration at the absorption site is a function of the

dissolution rate of the drug in the medium at that site

The dissolution is given by the Nayes Whitney equation, dc/dt=Dc S/h (Cs-C)

Where,

C =concentration at time t

Dc=diffusion coefficient of drug in the medium

S =surface area of drug particles

h=thickness of diffusion layer surrounding the particles

Cs=solubility of drug in the diffusion layer

3.2 Pore transport

It is also called as convective transport, bulk flow or filtration. The process is important in

absorption of low molecular weight, low molecular size and water-soluble drug through

narrow, aqueous field channels or pores in the membrane structure e.g. urea, water and

sugar. The driving force is constituted by the hydrostatic pressure or the osmotic

differences across the membrane. Water flux that promotes such a transport is called as

solvent drag.

3.3 Carrier mediated transport

The mechanism is thought to involve a component of the membrane called as the carrier

that binds reversibly or noncovalently with the solute molecules to be transported. This

carrier solute complex traverses across the membrane to the other side where it dissociates

and discharges the solute molecule. The carrier may be an enzyme or some other

component of the membrane.

Important characteristic of carrier mediated transport:

• The transport process is structure specific.

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• Drug having similar to essential nutrient called as false nutrients are absorbed by

the same carrier system.

• There is competition between agents having similar structure.

• A drug absorbed by passive diffusion ,the rate of absorption increases linearly with

the concentration but in the case of carrier mediated processes the drug absorption

increases linearly with concentration until the carriers become saturated after which

it becomes curvilinear and approach a constant value at higher doses. Such a

capacity limits process can be adequately described by mixed order kinetics. Such a

system decrease with increasing dose e.g. vitamins like B1, B2 & B12. Hence, the

administration of a large single oral dose of such vitamins is irrational.

• Occurs from specific sites of the intestinal tract, which are rich in number of

carriers known as absorption window.

Two types of carrier mediated transport systems have been identified, they are

• Facilitated diffusion

• Active transport

Facilitated diffusion:

• It operates down the concentration gradient (downhill transport), driving

force is concentration gradient. E.g. entry of glucose into RBCs and

intestinal absorption of vitamins B1 & B2.

Active transport:

• Drug is transported from a region of lower to higher concentration i.e.

against the concentration gradient or uphill transport.

• Energy is required

• Can be inhibited by metabolic poisons that interfere with energy production

like fluorides, cyanide & lack of oxygen etc.

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3.4 Ionic or electrochemical diffusion

The charge in the membrane influences the permeation of drugs. Of the ionic forms, the

anionic solute permeates faster than the cationic form. Thus at a given pH the rate of

permeation is in the following order-

unionized molecules> anions>cations.

The cationic drugs depend on the potential difference or electrical gradient as the driving

force across the membrane. A cationic drug is repelled due to positive charge on the outside

of the membrane. As a result, only those cations with a high kinetic energy penetrate the

ionic barrier, however, once inside the membrane, the cations are attracted to negatively

charged intracellular

membrane thereby creating an electrical gradient. Such a drug is then said to be moving

downhill with electrical g radiant and the phenomena is called a electrochemical diffusion.

3.5 Ion –pair transport

Absorption of drug like ammonium compounds & sulfonic acids, which ionize under all

pH condition, is ion pair transport.

3.6 Endocytosis

It involves engulfing extra cellular materials with in a segment of the cell membrane to

form a saccule or a vesicle, which is then pinched off intracellularly.

This phenomenon is responsible for the cellular uptake of macromolecular nutrient like fat,

starch vit A, D, E, K & insulin.

This includes two types of processes:

Phagocytosis; adsorptive uptake of solid particulates &

Pinocytosis; uptake of fluid solute

Sometime endocytic vesicle is transferred from one extra cellular compartment to another;

such phenomenon is called as transcytosis.

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Fig.1: Summary of various means of transport processes and drug absorption through them

4. Factors affecting bioavailability8

To achieve the desired therapeutic objective the drug product must deliver the active drug

at an optimal rate & amount. The process consists of four steps:

1. Disintegration of the drug product.

2. Deaggregation & subsequent release of the drug.

3. Dissolution of the drug in the aqueous fluids at the absorption site.

4. Movement of the dissolved drug through the GI membrane into the systemic

circulation and away from the absorption site.

The rate at which the drug reaches the systemic circulation is determined by the slowest of

the various steps involved in the sequence. Such a step is called as rate determining or rate

limiting step.

Fig.2: Schematic representation of sequences of drug absorption from a tablet dosage form

5. Factors influencing absorption of drug

5.1Biological factors

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5.2Physicochemical factors

5.3Formulation factors

5.4Patient Related factors

5.1Biological factors

Biological factors are considered to be related to the system in which the drug is absorbed

.Some of the biological factors influencing the absorption rate of drugs are

5.1.1Anotomy of gastrointestinal tract

The gastrointestinal tract is composed of the stomach, small intestine and large intestine or

colon. Although the entire gastrointestinal tract is qualitatively identical, the biological

environment and surface area available for absorption of drugs differ from one end to

another.

Because of the highly convulated surface of its mucusa and villia, the small intestine has

enormous area i.e. 30 times larger than that of the large intestine. It is with blood enough to

carry away tha absorbed material. The small intestine serves as the major absorption

pathway because it has suitable PH and a large surface area approximately 20 feet long

extending from the pylorus at the base of the stomach to the junction with the large

intestine at the cecum.

5.1.2 Gastric motility

Since from the intestines most drugs are absorbed more effectively than that from the

stomach, it is generally desirable to have the drug pass from the stomach into the intestine

as rapidly as possible. Therefore, the gastric emptying time is an important factor in drug

action dependent upon intestinal absorption. A delayed gastric emptying would naturally

delay the absorption of drugs resulting ultimately in the delay the drug action. The gastric

emptying rate also influences the absorption of drugs that are not stable in stomach

example benzyl penicillin. The rate of emptying from the stomach is to be proportional to

the volume of the material present.

Gastric emptying time may be increased by a number of factors as

• The Presence of fatty foods.

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• Position of the body.

• The presence of drugs like morphine that have a qeuting effect on the movements of

the gastrointestinal tract.

• Temperature and viscosity of the meals and their contents. Liquid of lower viscosity

are emptied faster than those of higher viscosity are.

• Similarly, the social status and mental state of the individual may also influence the

gastric emptying rate.

The peristaltic movements of the intestine help to dissolve the drug in intestinal fluid

and bring the drug into intimate contact with a large surface of mucosal surface. Thus

causing increases in absorption.

5.1.3 Gastro intestinal PH

The PH of the gastrointestinal tract increases progressively along its length from a PH of

about 1 in the stomach to approximately a PH of 8 at the far end of the intestines. The

acidity or alkalinity of the gastrointestinal fluids can influence absorption of drugs in the

form of weak organic acids or bases. As a rule, weak acids are largely unionized in the

stomach and are absorbed fairly well from the site whereas weak bases are highly ionized

in the stomach and are not significantly absorbed from the gastric surface. Similarly weakly

basic drugs are rapidly absorbed from the intestines because of the alkaline PH.Srong acids

and bases are generally poorly absorbed on account of their high degree of ionization.

The small intestine acts as the major absorption area for drugs because of its suitable

PH.The PH of the lumen of the intestine is about 6.5 and both weakly acidic and weakly

basic drugs are well absorbed from the intestinal surface. The PH however does not

influence the absorption of drugs that are actively transported through the gastrointestinal

walls.

5.1.4 Blood flow

The carriage of drug in circulation of blood to the site also affects drug absorption

.Increased in blood flow caused by massage or local application of heat enhances

absorption. Decrease in blood blood flow caused by vasoconstrictor agents, shock or other

disease factors can slow down absorption.

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5.1.5 Interaction between drugs and gastrointestinal tract components

Drugs may be altered within the gastrointestinal tract into forms that render them less or

more slowly available for absorption. This alteration may be of the result of the association

of the drug with gastrointestinal constituents, foodstuffs are another drugs. The absorption

of teracyclines group of antibiotics is greatly interfered by the presence of calcium. Various

kinds of protein reduce the activity of aluminium antacids by complexation.Bile salts being

surface active enhance dissolution of sparingly soluble drugs thereby promoting their

absorption. Enzymes have been shown to react with drugs in a number of ways, viz.

Removal of acetyl groups from N-acylated compounds.

Transformation of ester compounds into parent compounds by esterase.

Conversion of chloramphenicol palmitate to chloramphenicol by the pancreatic enzyme.

5.1.6 Presence of foods

The presence of food in the stomach generally delays absorption of drug. The food content

of the stomach tends to over dilute the drug concentration and decrease absorption. The

absorption of teracyclines has shown to be markedly reduced in the presence of milk, milk

products. Therefore, tetracycline drugs must not be taken with milk or other calcium

containing food or drug. Although most drugs are absorbed faster and to a greater extent if

taken into stomach, certain drugs that are irritating to the gastrointestinal tract are

frequently administered with meals to reduce their concentration and irritant action. For

instance, absorption of griseofulvin is enhanced nearly 200 percent by fatty meal. Many

drugs e.g. the analgesic paracetamol and the urinary antibacterial agent nitrofurantoin are

absorbed more rapidly if given when patient is fasting than if given after a meal.

5.2Physicochemical factors

The physiochemical factors that significantly influence the absorption are

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5.2.1 Disintegration and Dissolution

In order for a drug to be absorbed, it must get dissolved in body at the absorption sitse.A

drug taken orally in tablet or capsule form cannot be absorbed until its particles are

solubalized by the fluids at the same point in gastrointestinal tract. When a tablet or capsule

is swallowed, it enters the stomach through oesophagus.Break of tablets into particles is

called disintegration and the time required to complete this process is called disintegration

time. It should be less than 15 minutes for compressed tablets and 60 minutes for coated

tablets. The process by which drug particles dissolve after disintegration is termed

dissolution and the time required for the dissolution of 70 % of the drug is called

dissolution time. Tablet must thus disintegrate and their contents dissolve in gastrointestinal

fluids before they are absorbed from the intestinal wall.

By its solubility in an acidic or basic medium, the drug is solubalized in the stomach and

intestine. Drugs that disintegrate within a specified time may not dissolve adequately in the

fluids. The dissolution rate changes by increase in temperature, agitation and surface

enhances the dissolution rate. The chemical or physical form a drug also enhances the rate

of dissolution.

Sometimes the dissolution of a drug particle is slow. Owing to the physico chemical

characteristics of the drug substance or the dosage form, the dissolution process itself

would be a rate-limiting factor in the absorption process .Some slow soluble drugs may be

incompletely absorbed and some may even remain unabsorbed in the stomach or intestinal

tract after oral administration because of natural time limit. Thus incompletely absorbed or

unabsorbed drug particles are excreted unchanged out of the system.

5.2.2 Drug stability in gastrointestinal tract

Gastro intestinal fluids contain various enzymes and provide a highly reactive media. In

degradation of drug molecules in the gastric fluids, hydrolytic decomposition is most

commonly observed. Penicillin G and insulin are inactivated by this reaction.

5.2.3 Complex formation

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Some drugs may form a complex materials in the gastrointestinal tract.Complexatation

usually slows down the dissolution rate because drug molecules are bound. The rate of

dissolution in such cases is dependent on the rate of release of drug molecules from the

complex.

5.2.4 Viscosity

The viscosity of a suspension will influence the dissolution rate of a drug in body fluids.

The more viscous the suspension, the lesser is the rate of dissolution because viscosity

reduces the diffusion rate.

5.2.5 Surfactants

Surfactants reduce interfacial tension between drug particles and the solvent causing them

to come in contact with each other. The increased contact increases the dissolution rate.

Moreover, some surfactants form micelles that help to solubalize some lipophilic

components.

5.2.6 Drug Concentration

The concentration of a drug influences its rate of absorption .Drugs in solution of high

concentration are absorbed more rapidly than the drugs in solutions of low concentration.

Thus, the absorption rate is propotional to concentration of drug.

5.3Formulation factors

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5.3.1 Dosage form

The dosage of a drug may be in tablet, capsule, mixture, suspension or injection form. The

tablet or capsule form should disintegrate or dissolve prior to absorption. Therefore, its

action is slow compared to the action of any other dosage form. A drug administered in the

form of solution e.g. syrup or an elixir passes into the intestines more rapidly because it

does not have to disintegrate and dissolve.Similarly, suspensions and emulsions contain

drugs in undissolved form. Therefore, they need to be dissolve before absorption. Injections

administered intramuscularly or intradermally have to be absorbed before they pass into the

blood stream. Intravenous injection, which is administered directly into bloodstream so

they shows rapid effect.

Thus, prompt action is observed with parentral dosage forms (injections), intermediate

action with liquids (solution, suspensions) and slow with tablets and capsules

5.3.2 Excipients

Drugs are generally modified into convenient dosage form to ensure acceptability,

physicochemical stability during the shelf life, uniformity of composition and dosage, and

optimum bioavailability and function ability of the drug product and are then administered

by a suitable route. Such modification contains inclusion of a number of excipients (non-

drug components of a formulation). Despite their inertness and utility in the dosage form,

excipients can influence absorption of drugs as the number of excipients is increased in a

dosage form, more complex it becomes and greater will be the potential for absorption and

bioavailability problems. Commonly used excipients in various dosage forms are vehicles,

diluents (fillers), binders and granulating agents, disintegrants, lubricants, coatings,

suspending agents, emulsifiers, surfactants, buffers, complexing agents, colorants,

sweeteners, crystal growth inhibitors, etc.

Vehicle

Vehicle or solvent system is the major component of liquid orals and parenterals. The three

categories of vehicles in use are—aqueous vehicles (water, syrup, etc.), nonaqueous water

miscible vehicles (propylene glycol, glycerol, sorbitol) and nonaqueous water immiscible

vehicles (vegetable oils).

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1. Miscibility: Bioavailability of a drug from vehicles depends to a large extent on its

miscibility with biological fluids. Aqueous and water miscible vehicles are miscible

with the body fluids and drugs from them are rapidly absorbed. Quite often, a drug

is more soluble in water miscible vehicles like propylene glycol (serving as a co-

solvent) and show better bioavailability. Sometimes dilution of such vehicles with

the body fluids results in precipitation of drug as fine particles which, however,

dissolve rapidly.

2. Solubilizers: such as tween 80 are sometimes used to promote solubility of a drug in

aqueous vehicles.

3. Partitioning: In case of water immiscible vehicles, the rate of drug absorption

depends upon its partitioning from the oil phase to the aqueous body fluids, which

could be a rate-limiting step.

4. Viscosity: of the vehicles is another factor in the absorption of drugs. Diffusion into

the bulk of GI fluids and thus absorption of a drug from a viscous vehicle may be

slower.

Diluents (Fillers)

Diluents are commonly added to tablet (and capsule) formulations if the required dose is

inadequate to produce the necessary bulk. A diluent may be organic or inorganic. Among

organic diluents, carbohydrates are very widely used—for example, starch, lactose,

microcrystalline cellulose, etc.

1. Hydrophilic powders are very useful in promoting the dissolution of poorly water-

soluble, hydrophobic drugs like spironolactone and triamterene by forming a coat

onto the hydrophobic surface of drug particles and rendering them hydrophilic.

2. Drug-diluent interaction can occur resulting in poor bioavailability for example

tetracycline and DCP. The cause is formation of divalent calcium-tetracycline

complex which is poorly soluble and thus, un-absorbable.

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Binders and Granulating Agents

These materials are used to hold powders together to form granules or promote cohesive

compacts for directly compressible materials and to ensure that the tablet remains intact

after compression. Popular binders include polymeric materials (natural, semi synthetic and

synthetic) like starch, cellulose derivatives, acacia, PVP, etc. Others include gelatin and

sugar solution. In general, like fillers, the hydrophilic (aqueous) binders show better

dissolution profile with poorly

Wettable drugs like phenacetin by imparting hydrophilic properties to the granule surface.

However, the proportion of strong binders in the tablet formulation is very critical. Large

amounts of such binders increase hardness and decrease disintegration/dissolution rates of

tablets. PEG 6000 was found to be a deleterious binder for phenobarbital as it forms a

poorly soluble complex with the drug. Non-aqueous binders like ethyl cellulose also retard

drug dissolution.

Disintegrants

These agents overcome the cohesive strength of tablet and break them up on contact with

water which is an important prerequisite to tablet dissolution. Almost all the disintegrants

are hydrophilic in nature. A decrease in the amount of disintegrant can significantly lower

bioavailability. Adsorbing disintegrants like bentonite and veegum should be avoided with

low dose drugs like digoxin, alkaloids and steroids since a large amount of dose is

permanently adsorbed and only a fraction is available for absorption. Microcrystalline

cellulose is a very good disintegrant (and a binder too) but at high compression forces, it

may retard drug dissolution.

Lubricants/Antifrictional Agents

These agents are added to tablet terminations to aid flow of granules, to reduce interparticle

friction and sticking or adhesion of particles to dies and punches. The commonly used

lubricants are hydrophobic in nature (several metallic stearates and waxes) and known to

inhibit wettability, penetration of water into tablet and their disintegration and dissolution.

This is because the disintegrant gets coated with the lubricant if blended simultaneously

which however can be prevented by adding the lubricant in the final stage. The best

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alternative is use of soluble lubricants like SLS and carbowaxes which promote drug

dissolution.

Coatings

In general, the deleterious effect of various coatings on drug dissolution from a tablet

dosage form is in the following order: enteric coat > sugar coat > nonenteric film coat. The

dissolution profile of certain coating materials change on aging; e.g. shellac coated tablets,

on prolonged storage, dissolve more slowly in the intestine. This can, however, be

prevented by incorporating little PVP in the coating formulation.

Suspending Agents/Viscosity Imparters

Suspending agents are hydrophilic polymers like vegetable gums (acacia, tragacanth, etc.),

semisynthetic gums (CMC, MC) and synthetic gums which primarily stabilize the solid

drug particles by reducing their rate of settling through an increase in the viscosity of the

medium. These agents and some sugars are also used as viscosity imparters to affect

palatability and pourability of solution dosage forms. The macromolecular gums often form

unabsorbable complexes with drugs as incase of sodium CMC forming a poorly soluble

complex with Amphetamines or an increase in viscosity acting as a mechanical barrier to

the diffusion of drug from the dosage form into the bulk of GI fluids and from GI fluids to

the mucosal lining by forming a viscid layer on the GI mucosa. Moreover, they also retard

the GI transit time.

Surfactants

They are widely used as wetting agents, solubilizers, emulsifiers, etc in formulations and

may either enhance or retard drug absorption by interacting with the drug or membrane or

both. Mechanisms involved in the increased absorption of drug by use of surfactants

include;

1. Promotion of wetting by increase in effective surface area and dissolution of drugs.

E.g.; Tween 80 with Phenacetin.

2. Better membrane of the drug for absorption.

3. Enhanced membrane permeability of the drug.

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The beneficial effect at pre-critical micelle concentration levels has also been observed.

However, physiologic surfactants like bile salts and lysolecithin promote absorption of

hydrophobic drugs as such steroids, oil soluble vitamins and Griseofluvin by their micellar

solubilizing property.

Likewise, decreased absorption of drugs due to surfactants is due to;

1. Formation of unabosrbable drug-micelle complex at surfactant concentrations

above critical micelle concentration.

2. Laxative action induced by a large surfactant concentration.

Buffers

Sometimes buffers are useful in creating the right atmosphere for drug dissolution as was

observed for buffered aspirin tablets. However, certain buffer systems containing potassium

cations inhibit the drug absorption as incase of vitamin B2 and sulfanilamide and the reason

attributed to it was the uptake of fluids by the intestinal epithelial cells due to which the

effective drug concentration in the tissue is reduced and the absorption rate is decreased.

Such an inhibitory effect of the various buffer cations on the drug transfer rate is in the

following order: K+ > NH41> Li+ > Na+ > TRIS+. Hence, the buffer system for a salt of a

drug should contain the same cation as the drug salt and introduce no additional cations.

Complexing Agents

Alteration of physicochemical and biopharmaceutical properties of a drug can be achieved

through complex formation. A complexed drug may have altered stability, solubility,

molecular size, partition coefficient and diffusion coefficient. Basically, such complexes are

pharmacologically inert and must dissociate either at the absorption site or following

absorption into the systemic circulation. Several examples where complexation has been

used to enhance drug bioavailability are:

• Enhanced dissolution through formation of a soluble complex e.g. ergotamine

tartarate-caffeine complex and hydroquinone-digoxin complex.

• Enhanced lipophilicity for better membrane permeability e.g. caffeine-PABA

complex.

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• Enhanced membrane permeability e.g. enhanced GI absorption of heparin (normally

not absorbed from the GIT) in presence of EDTA which chelates calcium and

magnesium ions of the membrane.

Complexation can be deleterious to drug absorption due to formation of poorly soluble or

poorly absorbable complex e.g. complexation of tetracycline with divalent and trivalent

cations like calcium (milk, antacids), iron (hematinics), magnesium (antacids) and

aluminium (antacids). Poor bioavailability results because of some complexes fails to

dissociate at the absorption site and large molecular size of the complex cannot diffuse

through the cell membrane—for example, drug-protein complex.

Colorants

A very low concentration of water-soluble dye can have an inhibitory effect on dissolution

rate of several crystalline drugs. The dye molecules get adsorbed into the crystal faces and

inhibit drug dissolution e.g.; brilliant blue retards dissolution of sulfathiazole. Dyes have

also been found to inhibit micellar solubilization effect of bile acids which may impair the

absorption of hydrophobic drugs like steroids. Cationic dyes are more reactive than the

anionic ones due to their greater power for adsorption on primary particles.

Crystal Growth Inhibitors

The initial physical properties of a drug in suspension can be inhibited by crystal growth

inhibitors like PVP and PEG by conversion of a high energy metastable polymorph into

stable, less soluble polymorph.

Nature and Type of Dosage Form

The proper selection of dosage form of a drug relates to clinical success to a great extent.

For a given drug, a 2 to 5 fold or perhaps more difference could be observed in the oral

bioavailability of a drug depending upon the nature and type of dosage form. Such a

difference is due to the relative rate at which a particular dosage form releases the drug to

the biological fluids and the membrane. The relative rate at which a drug from a dosage

form is presented to the body depends upon the complexity of dosage form. The more

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complex a dosage form, greater the number of rate-limiting steps and greater the potential

for bioavailability problems.

Fig.3: Course of events that occur following oral administration of various dosage forms

The bioavailability of a drug among various dosage forms decreases in the following order:

Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated Tablets > Enteric

Coated tablets >Sustained Release Products. Thus, absorption of a drug from solution is

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fastest with least potential for bioavailability problems whereas absorption from a sustained

release product is slowest with greatest bioavailability risk.

Several factors, especially the excipients which influence bioavailability of a drug from its

dosage form are:

Solutions

A drug in a solution (syrups, elixirs, etc.) is most rapidly absorbed since the major rate-

limiting step drug dissolution is absent. Factors that influence bioavailability of a drug from

solution dosage form include the nature of solvent (aqueous, water miscible, etc.),

viscosity, surfactants, solubilizers, stabilizers, etc. Quite often, dilution of a drug in solution

with GI fluids results in precipitation of drug as fine particles which generally dissolve

rapidly. Factors that limit the formulation of a drug in solution form include stability,

solubility, taste, cost of the product, etc.

Emulsions

Emulsion dosage forms have been found to be superior to suspensions in administering

poorly aqueous soluble lipophilic drugs. Emulsion dosage form present a large surface area

of oil to the GIT for absorption of a drug. Scientists have claimed that a drug administered

in oily vehicle (emulsified and solubilized in the GIT by bile salts to form mixed micelles)

can direct the distribution of drug directly into the lymphatic system thereby avoiding the

hepatic portal vein and first-pass metabolism.

Suspensions

The major rate-limiting step in the absorption of a drug from suspension dosage form is

drug dissolution which is generally rapid due to the large surface area of the particles.

Important factors in the bioavailability of a drug from suspensions include particle size,

polymorphism, wetting agents, viscosity of the medium, suspending agents, etc.

Powders

Major factors to be considered in the absorption of a drug from powders are particle size,

polymorphism, wettability, etc.

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Capsules

Powders and granules are popularly administered in hard gelatin capsules whereas viscous

fluids and oils in soft elastic shells. Factors of importance in case of hard gelatin capsules

include drug particle size, density, polymorphism, intensity of packing and influence of

diluents and excipients. Hydrophilic diluents like lactose improve wettability,

deaggregation and dispersion of poorly aqueous soluble drugs whereas inhibitory effect is

observed with hydrophobic lubricants like magnesium stearate. A hydrophobic drug with a

fine particle size in capsule results in a decrease in porosity of powder bed and thus,

decreased penetrability by the solvent with the result that clumping of particle occurs and

can be overcome by incorporating a large amount of hydrophilic diluent (upto 50%), a

small amount of wetting agent cum lubricant such as SLS (upto 1%) and/or by wet

granulation to convert an impermeable powder bed to the one having good permeability.

Other factors like possible interaction between the drug and the diluent (e.g. tetracycline-

DCP) and between drug and gelatin shell.

Soft elastic capsules as such dissolve faster than hard gelatin capsules and tablets and show

better drug availability from oily solutions, emulsions or suspensions of medicaments

(especially hydrophobic drugs). E.g.; faster dissolution of indoxole (equivalent to that of an

emulsion dosage form) when formulated as soft gel in comparison to hard gelatin capsule

and aqueous suspension. Such poorly soluble drugs can be dissolved in PEG or other

suitable solvent with the aid of surfactants and encapsulated without difficulty. Soft gels are

thus of particular use where the drug dose is low, drug is lipophilic or when oily or lipid

based medicaments are to be administered. A problem with soft gels is the high water

content of the shell (above 20%). This moisture migrates into the shell content and

crystallization of drug occurs during the drying stage resulting in altered drug dissolution

characteristics.

Tablet

Due to the most convenience and cost effective dosage forms compressed tablets are most

widely used. The bioavailability problems with tablets arise from the reduction in the

effective surface area due to granulation and subsequent compression into a dosage form.

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Since dissolution is most rapid from primary drug particles due to their large surface area,

disintegration of a tablet into granules and subsequent deaggregation of granules into fine

particles is very important. However, incase of coated tablets the coating acts as yet another

barrier which must first dissolve or disrupt to give way to disintegration and dissolution of

tablet. Of the two types of coatings, the film coat, which is thin, dissolves rapidly and does

not significantly affect drug absorption. The sugar coat which though soluble, is generally

tough and takes longer to dissolve however, the sealing coating is generally of shellac type,

which is deleterious and is difficult to coat. Hence, press coated tablets are superior to

sugar coated.

Likewise, Enteric coated tablets targeted to dissolve in alkaline PH of intestine only have

great potential in creating bioavailability problems and may take as long as 2 to 4 hours for

such a tablet to empty from the stomach into the intestine depending upon the meals and

the GI motility. Hence, the pharmacologic response may eventually be delayed by as much

as 6 to 8 hours. The problem of gastric emptying can, however, be overcome by enteric

coating the granules or pellets and presenting them in a capsule or compressing into a

tablet. The thickness during aging of enteric coat is yet another determinant factor in drug

dissolution, hence increasing thickness being more problematic.

Sustained Release Products

Drug release from such products is most unpredictable, the problems ranging from dose

dumping to unsatisfactory or no drug release at all. However, with the development of

newer innovations and technologies, it is becoming increasingly reliable and the results

reproducible with little intersubject variations. A number of changes, especially in the

physicochemical properties of a drug in dosage form, can result due to aging and alterations

in storage conditions which can adversely affect bioavailability. With solution dosage form,

precipitation of drug due to altered solubility, especially due to conversion of metastable

into poorly soluble, stable polymorph can occur during the shelf life of the product.

Changes in particle size distribution have been observed with a number of suspension

dosage forms resulting in decreased rate of drug dissolution and absorption. In case of solid

dosage forms, especially tablets, disintegration and dissolution rates are greatly affected

due to aging and storage conditions. An increase in these parameters of tablets has been

attributed to excipients that harden on storage (e.g. PVP, acacia, etc.) while the decrease is

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mainly due to softening/crumbling of the binder during storage (e.g. CMC). Changes that

occur during the shelf life of a dosage form may be due to large variations in temperature

and humidity.

5.3.3 Manufacturing Process

Manufacturing processes influence drug dissolution.Processes of such importance in the

manufacture of tablets are

• Method of granulation

• Compression force

The processing factor of importance in the manufacture of capsules that can influence its

dissolution is the intensity of packing of capsule contents.

5.4 Patient related factors

It includes factor relating to the anatomic, physiologic and pathologic caracteristics of the

patient such as

• Age

• Sex

• Disease state

• Body weight

• Food

• Medicines

• Activity and posture

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6. Conclusion

Thus, absorption may be defined as the movement of active drugs from the administration

site, across biological barriers, into a site where it is measured in the blood. Absorption

affects bioavailability how quickly and how much of a drug reaches its intended (target)

site of action. Factors that affect absorption its bioavailabilty and chemical properties, and

the physiologic characteristics of the person taking the drug vary individually. Physiologic

characteristics that may affect the absorption of drugs taken by mouth include how long the

stomach takes to empty, what the acidity (pH) of the stomach is, and how quickly the drug

is moved through the digestive tract.

A drug product is the actual dosage form of a like tablet, capsule, suppository, transdermal

patch, or solution that consists of the active ingredient and additives as in case of

formulation of tablet which is a mixture of drug and diluents, stabilizers, disintegrants, and

lubricants. The mixture is granulated and compressed into a tablet. The type and amount of

additives and the degree of compression affect how quickly the tablet disintegrates and the

drug is absorbed. Drug manufacturers adjust these variables to optimize absorption.

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7. References

1. Dr. Shanta Raj Joshi, A Text Book of Pharmaceutics.

2. D.M. Brahmankar and Sunil B.Jaiswal, Biopharmaceutics and Pharmacokinetics A

Treatise.

3. Dr.Javed Ali, Dr R.K.Khar, Dr AlkaAhuja, A Text Book of Biopharmaceuticss

and Pharmacokinetics.

4. J.S Kulkarni, A.P Pawar, V.P Shedbalkar, Biopharmaceutics and Pharmacokinetics.

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