PHARMACEUTICS-PHARMACEUTICS- IVIV

(PHT 414 ) (PHT 414 )

Dr. Shahid JamilDr. Shahid Jamil

SALMAN BIN ABDUL AZIZ UNIVERSITY

COLLEGE OF PHARMACY

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Physical-Chemical Factors Affecting Drug Absorption

Physical-Chemical Factors Affecting Oral Absorption

  Outline of Physical-chemical factors affecting

oral absorption: pH-partition theory Lipid solubility of drugs Dissolution and pH Salts Crystal form Drug stability and hydrolysis in GIT Complexation Adsorption

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For a drug to cross a membrane barrier it must normally be soluble in the lipid material of the membrane to get into membrane, also it has to be soluble in the aqueous phase as well to get out of the membrane.

Most drugs have polar and non-polar characteristics or are weak acids or bases.

pH - partition theory

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pH - partition theory

For weak acid or basic drug, the solubility of the drug and the rate of absorption through the membranes (lining the GI tract) is controlled by:

the dissociation constant (pKa) of the drug

the pH of the fluid in the GI tract

the pH of the blood stream

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pH of GIT & plasma fluid control the process of its transfer

across biomembrane.

This can be explained by the pH partition theory of Brodie (1957).

The theory is based on the assumption that only unionized drug moiety can cross biomembrane.

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Distribution coefficient

g.i.t. in the conc. Total

bloodin conc. TotalD

gIU

IUD

g

bb

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Trans-membrane transfer

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Henderson - Hasselbach equation

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The amount of drug that exists in unionized form

is a function of dissociation constant (pKa) of the

drug and pH of the fluid at the absorption site

The ratio of un-ionized and ionized drug [U]/[I] is

a function of the pH of the solution and the pKa of

the drug, as described by the Henderson -

Hasselbach equation

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pH-pKa Relationship, Henderson -Hasselbach equation

HB

B

I

UpKpH a loglog

For weak acidic drugs:

For weak basic drugs:

where HA is the weak acid and A- is the salt or conjugate base

where B is the weak base and HB+ is the salt or conjugate acid

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For weak acidic drugs: = Ionized unionized

For weak basic drugs = Unionized Ionized

For weak acids:

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1. Very weak acid (pKa > 8) such as phenytoin, ethosuximide and several barbiturates are essentially unionized at all pH values and therefore their absorption is rapid, and independent of GI pH.

2. Acid in the pKa range 2.5-7.5 are greatly affected by changes in pH and therefore their absorption is pH dependent, e.g. several NSAIDs like aspirin, ibuprofen, phenylbutazone and number of penicillin analogs. Such drugs are better absorbed from acidic conditions of stomach (pH<pKa) where they largely exists in unionized form.

3. Stronger acids with pKa < 2.5 such as cromolyn sodium are ionized in the entire pH range of GIT and therefore remain poorly absorbed.

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For Basic drugs:

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1. Very weak bases (pKa < 5) such as caffeine, theophylin and a number of benzodiazepines like diazepam, oxazepam, and nitrazepam are essentially unionized at all pH values and therefore their absorption is rapid, and independent of GI pH.

2. Bases in the pKa range 5-11.0 are greatly affected by changes in pH and therefore their absorption is pH dependent, e.g. several morphine analogs, chloroquine, imipramine and amitriptyline. Such drugs are better absorbed from the relatively alkaline conditions of intestine where they largely exists in unionized form.

3. Stronger bases with pKa > 11 like mecamylamine and guanethidine are ionized in the entire pH range of GIT and therefore remain poorly absorbed.

  

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Lipid solubility of drugs

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Some drugs are poorly absorbed after oral administration even though they are non-ionized in small intestine. Low lipid solubility of them may be the reason. The best parameter to correlate between water and lipid solubility is partition coefficient. Partition coefficient (p) = [ L]conc / [W]conc, where [ L]conc is the concentration of the drug in lipid phase, [W]conc is the concentration of the drug in aqueous phase. The higher p value, the more absorption is observed. Prodrug is one of the option that can be used to enhance p value and absorption as sequence.

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Dissolution, pH

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However, many drugs are given in solid dosage forms and therefore must dissolve before absorption can take place.

However, if dissolution is the slow, rate determining step (the step controlling the overall rate) then factors affecting dissolution will control the overall process.

This is a more common problem with drugs which have a low solubility (below 1 g/100 ml) or which are given at a high dose, e.g. griseofulvin.

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Dissolution, pH

Tablet

Disintegration

De-aggregationGranules

Fine particles

Drug in solution

DISSOLUTION

EXO-DISINTEGRANT ENDO-DISINTEGRANT

Schematic representation of dissolution of a drug particle in the G.I. fluid 04/18/23 L7

Theory of dissolution

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There are a number of factors which

affect drug dissolution. One model that is

commonly used is to consider this process

to be diffusion controlled through a

stagnant layer surrounding each solid

particle.

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Stagnant Layer

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Theory of dissolution First we need to consider that each particle of drug formulation

is surrounded by a stagnant layer of solution. After an initial period we will have a steady state where drug is steadily dissolved at the solid-liquid interface and diffuses through the stagnant layer.

The earliest equation to explain the rate of dissolution when the process is diffusion controlled and involves no chemical reaction was given by Noyes Whitney

dC/dt= dissolution rate of the drug K= dissolution rate constant Cs= conc. of drug in the stagnant layer Cb= conc. of drug in the bulk of the solution

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Diffusion gradient/Concentration Gradient

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If diffusion is the rate determining step we can use Fick's first law of

diffusion to describe the overall process.

If we could measure drug concentration at various distances from the

surface of the solid we would see that a concentration gradient is

developed.

If we assume steady state we can used Fick's first law to describe

drug dissolution.

The Noyes and whitney’s equation was based on Fick's second law of

diffusion. Brunner incorporate Fick's first law of diffusion and modified

the Noyes and whitney’s equation.

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Modified Noyes-Whitney equation

where dC/dt is the rate of dissolution D is the diffusion coefficient of the drug in solution

in g.i. fluid A, is the effective surface area of drug particle in

contact with the g.i. fluid, Kw/o= water/ oil partition coefficient of drug V= volume of dissolution medium h= thickness of stagnant layer (Cs –Cb)= concentration gradient for diffusion of

drug

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Influence of some parameters on dissolution rate of drug

The diffusion coefficient, D, of a drug in the g.i. fluid

may be decreased by presence of substances

which increase the viscosity of the fluids such

as food.

The thickness of the diffusion layer, h, will be

influenced by the agitation experienced by drug

particles due to gastric and/or intestinal

motility.

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A is the surface area per gram (or per dose) of a solid drug

A can be changed by altering the particle size.

Generally as A increases the dissolution rate will also increase.

Improved bioavailability has been observed with griseofulvin, digoxin, etc.

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The concentration of drug, C, will be influenced by the rate of removal of

dissolved drug by absorption through the g.i./blood barrier and

the volume of fluid available for dissolution (fluid intake).

A low value of C will increase the concentration gradient and this forms the basis for the dissolution under the so called “sink” condition.

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Dissolution under Sink condition

If Cb is much smaller than Cs then we have so-called "Sink Conditions" and the equation reduces to

Under sink conditions, if the volume and surface area of solid are kept constant

dC/dt = K Dissolution rate is constant, and follows Zero order

kinetic process.

sDSCdC

dt h

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Effect of drug dissolution Factors affecting rate of release/dissolution

and hence, bioavailability from solid dosage forms:

The rate and extent at which the drug in solution reaches the site (s) of absorption in absorbable form

The rate and extent of absorption across the gastro-intestinal barrier

The extent to which the drug is metabolized during passage through the g.i.t. and/or liver.

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Factor affecting dissolution (Physicochemical properties of drug )Drug solubility, Cs, Salt form

Dissolution rate increases with Cs

Salts of weak acids and weak bases generally have much higher

aqueous solubility than the free acid or base

If the drug can be given as a salt the solubility and dissolution

rate can be increased .

For example, sodium salt of tolbutamide gave in vitro dissolution

rate significantly greater than the acid form.

Other examples are salt forms of penicillin, novobiocin and

barbiturates.

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Effect of salt form on solubility

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Effect of salt form on dissolution rate

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Physicochemical properties of drug

Crystal form

Polymorphism –

Some drugs exist in a number of crystal forms or polymorphs.

These different forms may well have different solubility

properties and thus different dissolution characteristics.

Drugs exhibiting polymorphism include chloramphenicol

palmitate, cortisone acetate, tetracyclines, sulphathiazole and

paracetamol.

Chloramphenicol palmitate is one example which exists in at

least two polymorphs. The B form is apparently more

bioavailable.

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Effect of Crystalline/polymorphic form on dissolution rate of Chloramphenicol palmitate

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Amorphous form (noncrystalline form):

Amorphous form of novobiocin is effective

while its crystalline forms are ineffective.

Ester form – Chloramphenicol, erythromycin

& Pivaloyloxymethylester of ampicillin

(Pivampicillin).

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Physicochemical properties of drug (Cont)

Solvates and hydrates:

The stoichiometric type of abducts where the solvent

molecules are incorporated in the crystal lattice of the solid

are called as the solvates .

When the solvents are water then it called as hydrates.

For instance, the anhydrous form of ampicillin showed

greater extent of absorption from hard gelatin capsule or

aqueous suspension dosage forms than the less soluble,

slower dissolving crystalline form.

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Drug stability and hydrolysis in GIT

Acid and enzymatic hydrolysis of drugs in GIT is one of the reasons for poor

bioavailability.

Penicillin G (half life of degradation = 1 min at pH= 1)

Rapid dissolution leads to poor bioavailability (due to release large portion of the

drug in the stomach, pH = 1.2)

Pro-drug ( conversion in the GIT to parent compound is rate limiting step in

bioavailability, either positively or negatively).

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Pro-drugs Rationale:

I. A drug may be too water insoluble for i.v. dosage form.

Chemical modification may produce significant water

solubility for its i.v. formulation

II. A drug required to alter some CNS function may be too polar

and therefore not well absorbed across the lipoidal blood-brain-

barrier.

III. Rapid metabolism of a drug at the site of absorption leading

to a decrease in systemic bioavailability after oral dosing.

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Complex form Molecular complex consists of components held together by weak forces

such as hydrogen bond

Bonding interaction between the two molecules is rapidly reversible,

provided the complex is soluble in biological fluids.

Properties of drug complexes such as solubility, molecular size and lipid-

water partition coefficient differ significantly from those of the respective

free drugs.

Complexation is often a deliberate attempt in dosage form design to

increase solubility or stability of the drug e.g. solid-in-solid complex.

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Complex form (Cont.) Complexation of a drug in the GIT fluids may alter rate and

extent of drug absorption. Intestinal mucosa + Streptomycin = poorly absorbed complex Calcium + Tetracycline = poorly absorbed complex (Food-

drug interaction) Carboxyl methylcellulose (CMC) + Amphetamine = poorly

absorbed complex (tablet additive – drug interaction)

Polar drugs + complexing agent = well-absorbed lipid soluble complex ( dialkylamides + prednisone)

Lipid soluble drug + water soluble complexing agent = well-absorbed water soluble complex ( cyclodextrine)

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Adsorption

Concurrent administration of drugs and medicinal substances

containing solid adsorbents (e.g. antidiarrhoeal mixtures) may

result in interference with the absorption of drugs in the git.

Drug may be adsorbed onto kaolin, attapulgite or charcoal with

consequent decrease in the rate and extent of its absorption.

Examples of documented interactions are promazine/charcoal,

lincomycin/kaopectate, talc/cyanocobolamin.

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