Drug ABSORPTION (factors)Drug ABSORPTION (factors)

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CONTENTSCONTENTS

INTRODUCTION AND DEFINATIONINTRODUCTION AND DEFINATION

MECHANISMS OF DRUG ABSORPTIONMECHANISMS OF DRUG ABSORPTION

FACTORS AFFECTING ABSORPTIONFACTORS AFFECTING ABSORPTION REFERANCESREFERANCES

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INTRODUCTIONINTRODUCTION DRUG ABSORPTION DRUG ABSORPTION –– movement of unchanged drug from

site of administration to systemic circulation.

33 Fig:- Plots showing significance of rate & extent of absorption in drug therapy

GASTROINTESTINAL ABSORPTION GASTROINTESTINAL ABSORPTION OF DRUGSOF DRUGS

Oral route is most common ROA for systemically acting drugs; so Oral route is most common ROA for systemically acting drugs; so more emphasis is given to GI drug absorption.more emphasis is given to GI drug absorption.

It includes all aspects of variability observed in drug absorption.It includes all aspects of variability observed in drug absorption.

CELL MEMBRANE CELL MEMBRANE :- Cell membrane structure & Physiology:- Cell membrane structure & Physiology

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MECHANISM OF DRUG MECHANISM OF DRUG ABSORPTIONABSORPTION

Passive diffusion →90% drugs , conc. gradientPassive diffusion →90% drugs , conc. gradient

Pore transport → low mol.wt.Pore transport → low mol.wt.

Facilitated diffusionFacilitated diffusion Carrier-mediated transportCarrier-mediated transport Active transportActive transport

Ionic or Electrochemical diffusionIonic or Electrochemical diffusion

Ion-Pair transportIon-Pair transport

EndocytosisEndocytosis55

FACTORS INFLUENCING DRUG FACTORS INFLUENCING DRUG ABSORPTION & BIOAVAILABILITYABSORPTION & BIOAVAILABILITY

Biopharmaceutic Consideration in Dosage form designBiopharmaceutic Consideration in Dosage form design By proper biopharmaceutical design, the rate & extent of drug absorption (BA) By proper biopharmaceutical design, the rate & extent of drug absorption (BA)

can be varied from rapid & complete to slow & sustained depending upon can be varied from rapid & complete to slow & sustained depending upon desired therapeutic objective.desired therapeutic objective.

Sequence of events that occur following administration of solid dosage form Sequence of events that occur following administration of solid dosage form until its absorption in systemic circulation.until its absorption in systemic circulation.

The process consists of four steps:-The process consists of four steps:- DisintegrationDisintegration DeaggregationDeaggregation Dissolution Dissolution AbsorptionAbsorption

Rate at which drug reaches systemic circulation is determined by slowest of the Rate at which drug reaches systemic circulation is determined by slowest of the various steps involved in sequence. Such a step is called as Rate- determining/ various steps involved in sequence. Such a step is called as Rate- determining/ Rate- limiting step (RDS)Rate- limiting step (RDS)

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Solid dosage form

Granules or aggregates

Fine particles

Drug in solution At absorption site

Ionic drug Ionic drug

Non-ionic drugNon-ionic drug1

2

3

3

3

4

BloodGI Lumen GI Barrier

1- Disintegration2- Deaggregation3- Dissolution4- Absorption

Sequence of events in the absorption of drugs from orally administered solid dosage forms 77

Physicochemical properties of drug Physicochemical properties of drug substances:-substances:-

1.1. Drug solubility & Dissolution rateDrug solubility & Dissolution rate

2.2. Particle size & Effective surface areaParticle size & Effective surface area

3.3. Polymorphism & AmorphismPolymorphism & Amorphism

4.4. Pseudopolymorphism ( hydrates/ solvates)Pseudopolymorphism ( hydrates/ solvates)

5.5. Salt form of the drugSalt form of the drug

6.6. Lipophilicity of the drugLipophilicity of the drug

7.7. pKpKa a of the drug & GI pHof the drug & GI pH

8.8. Complexation and AdsorptionComplexation and Adsorption

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pH- Partition Hypothesis

1)Drug Solubility & Dissolution rate1)Drug Solubility & Dissolution rate

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SOLID DOSAGE

FORM

SOLID DRUG

PARTICLES

DRUG IN SOLUTION

AT ABSORBANC

E SITE

DRUG IN THE BODY

DISINTEGRATION

DEAGGREGATION

DISSOLUTION PERMIATION

RDS FOR LIPOPHILIC

DRUG

RDS FOR HYDROPHILI

C DRUGS

Two rate determining Steps in absorption of drugs from orally administered formulation

Absolute or intrinsic solubilityAbsolute or intrinsic solubility:: It is the maximum amount of solute dissolved in a given It is the maximum amount of solute dissolved in a given

solvent under standard condition of temperature , pressure and solvent under standard condition of temperature , pressure and pH. pH.

Dissolution rate: Dissolution rate: It is defined as the amount of solid substance that goes in to It is defined as the amount of solid substance that goes in to

solution per unit time under standard condition of temperature pH solution per unit time under standard condition of temperature pH and solvent composition and constant solid surface area.and solvent composition and constant solid surface area.

Several drugs have poor solubility to have depend on dissolution Several drugs have poor solubility to have depend on dissolution rate. rate.

The process of drug dissolution is better related to drug absorption The process of drug dissolution is better related to drug absorption

and bioavailability than the absolute solubility.and bioavailability than the absolute solubility.

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THEORIES OF DISSOLUTION:THEORIES OF DISSOLUTION:

1.1. Diffusion layer model/film theoryDiffusion layer model/film theory2.2. Danckwert’s model/surface renewal theoryDanckwert’s model/surface renewal theory3.3. Interfacial barrier model/double barrier theoryInterfacial barrier model/double barrier theory

The factors that can affect dissolution and thus The factors that can affect dissolution and thus absorption are - solubility , particle size, absorption are - solubility , particle size, polymorphism , pseudopolymorphism , salt form polymorphism , pseudopolymorphism , salt form etc.etc.

2. Particle size & effective surface area2. Particle size & effective surface area

Absolute surface area Absolute surface area : : It is the total surface area of solid surface of It is the total surface area of solid surface of any particleany particle..Effective surface area Effective surface area : It is the area of solid surface exposed to : It is the area of solid surface exposed to dissolution mediumdissolution medium..

Larger the surface area, higher the dissolution rate. Surface area Larger the surface area, higher the dissolution rate. Surface area increases with decreasing particle size by Micronisation.increases with decreasing particle size by Micronisation. It increases intrinsic solubility of poorly aqueous soluble drugs like It increases intrinsic solubility of poorly aqueous soluble drugs like griseofulvin,chloramphenicol. griseofulvin,chloramphenicol.

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particle size ἀ 1 surface area

HYDROPHILIC DRUGS

Micronisation results in a decrease in the effective surface Micronisation results in a decrease in the effective surface area.(aspirin, phenacetin , phenobarbital )area.(aspirin, phenacetin , phenobarbital ) REASONSREASONS

1.1. Air adsorptionAir adsorption

2.2. Particle reaggregationParticle reaggregation

3.3. Surface charges reduce wettingSurface charges reduce wetting1313

HYDROPHOBIC DRUGS

3.3.Polymorphism and AmorphismPolymorphism and AmorphismWhen substance exists in more than one crystalline form, different When substance exists in more than one crystalline form, different forms are known as forms are known as polymorphspolymorphs and phenomenon known as and phenomenon known as““Polymorphism”Polymorphism”

It has two typesIt has two types

1) enantiotropic polymorph :reversibly change,ex.sulfur1) enantiotropic polymorph :reversibly change,ex.sulfur

2)monotropic polymorph :unstable &dose not change 2)monotropic polymorph :unstable &dose not change ex. glyceryl stearates.ex. glyceryl stearates.

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Stoichiometric complexes

Nonstoichiometric complex

Organic solvates Hydrates

Enantiotropic Monotropic

Classification of internal structure of compound

Depending on relative stability polymorphic form may beDepending on relative stability polymorphic form may be

Lowest energy state highest energy state Lowest energy state highest energy state

Highest melting point lowest melting pointHighest melting point lowest melting point Low aqueous solubility high aqueous solubilityLow aqueous solubility high aqueous solubility Ex: chloramphenicol palmitate – A,B,C of which ‘B’ form shows Ex: chloramphenicol palmitate – A,B,C of which ‘B’ form shows

best bioavailability and ‘A’ form is inactively biologically.best bioavailability and ‘A’ form is inactively biologically. Amorphous: high Aq. Solubility.Amorphous: high Aq. Solubility. E.g. amorphous form of chloramphenicol, cortisone acetate and E.g. amorphous form of chloramphenicol, cortisone acetate and

phenobarbitol.phenobarbitol. Amorphous > metastable > stableAmorphous > metastable > stable

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Stable Metastable

4.HYDRATES AND 4.HYDRATES AND SOLVATES(Pseudo polymorphismSOLVATES(Pseudo polymorphism))

When the solvent molecules are incorporated in the crystal lattice of When the solvent molecules are incorporated in the crystal lattice of the solid are called as the SOLVATES. and trapped solvent as the solid are called as the SOLVATES. and trapped solvent as solvent solvent of crystallization.of crystallization.

Different crystalline form of solvates PseudopolymorpsDifferent crystalline form of solvates Pseudopolymorps phenomenon Pseudopolymorphism.phenomenon Pseudopolymorphism.

When a solvent in association with the drug is water, the solvate is When a solvent in association with the drug is water, the solvate is known as HYDRATE.known as HYDRATE.

The anhydrous form has greater aqueous solubility than the hydrates.The anhydrous form has greater aqueous solubility than the hydrates. But the organic solvate have greater aqueous solubility than the non But the organic solvate have greater aqueous solubility than the non

solvate. Ex. Chloroform solvate of griseofulvin.solvate. Ex. Chloroform solvate of griseofulvin.1717

5.Salt form of the drug5.Salt form of the drug Most drugs-weak acids/weak bases Easiest approach to enhance solubility and dissolution rate weak acid + strong base salt ex. sodium , potassium salts of barbiturates and

sulphonamides Weak base + strong acid salt ex. hydrochloride or sulphate salts of alkalidal drugs

Role of counter ion? 1)The pH of the diffusion layer differs from the bulk pH.

2)Cs at the diffusion layer determines the dissolution rate rather than Cb

3)Salt of weakly acidic drug shows higher pH at the diffusion layer so it dissolves faster in diffusion layer.FOR SALT OF WEAK ACIDS:(H+)d<(H+)bFOR SALT OF WEAK BASES:(H+)d>(H+)b

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Buffering action Buffering action of a strong base cation and strong of a strong base cation and strong acid anion is responsible for increase and decrease acid anion is responsible for increase and decrease in pH of diffusion layer respectively. in pH of diffusion layer respectively.

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What is pH-partition theory?What is pH-partition theory?

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Brodie (Shore, et al. 1957) proposed it. (Mol wt >100,passive diffusion)

It’s Assumptions It’s Assumptions

The GI membrane act like simple The GI membrane act like simple lipid barrierlipid barrier..

Larger the fraction of Larger the fraction of unionizedunionized drug , faster the drug , faster the absorption.absorption.

Greater the Greater the lipophilicity (Klipophilicity (Ko/wo/w )of the unionized )of the unionized drugdrug ,better the absorption.,better the absorption.

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6)Drug pKa and GI pH 6)Drug pKa and GI pH Drug in Drug in unionizedunionized form is a function of pKa of drug and pH of fluid form is a function of pKa of drug and pH of fluid

at absorption site. at absorption site. The lower the pKa of an acidic drug , stronger the acid and greater The lower the pKa of an acidic drug , stronger the acid and greater

the proportion of ionized form at the perticular pH. the proportion of ionized form at the perticular pH.

The higher the pKa of a basic drug,the stronger the base.The higher the pKa of a basic drug,the stronger the base.Thus by the knowledge of drug’s pKa and pH at at absorption site, the Thus by the knowledge of drug’s pKa and pH at at absorption site, the

relative amount of ionized and unionized and the percent ionized can relative amount of ionized and unionized and the percent ionized can be determined by- be determined by-

Handerson-Hasselbach equationHanderson-Hasselbach equation for weak acids,for weak acids, pH = pKa + log (ionized drug/unionized drug)pH = pKa + log (ionized drug/unionized drug) % drug Ionized= ˣ100% drug Ionized= ˣ100 for weak bases,for weak bases, pH = pKa + log (unionized drug/ionized drug)pH = pKa + log (unionized drug/ionized drug) % drug Ionized= ˣ100% drug Ionized= ˣ100

2222 10pH-pKa

1+10pH-pKa

10pKa-pH

1+10pKa - pH

Absorption of weak acidic drug-Absorption of weak acidic drug- for ex. salicylic acid pKa 3.0,pH of gastric fluid-1.2 and of blood is7.4 then for ex. salicylic acid pKa 3.0,pH of gastric fluid-1.2 and of blood is7.4 then

from HH eq.from HH eq. pH-pKa=log (I/U)pH-pKa=log (I/U) 1.2-3.0=log (I/U)1.2-3.0=log (I/U)

(I/U)=antilog(-1.8)=0.016(I/U)=antilog(-1.8)=0.016 ratio of (I/U)=0.016/1 i.e. 98.4% of drug in GI exists in the unionized form ratio of (I/U)=0.016/1 i.e. 98.4% of drug in GI exists in the unionized form

i.e. absorbable form and 1.6% in ionized form (unabsorbable)i.e. absorbable form and 1.6% in ionized form (unabsorbable) hence , this drug is absorbed rapidly from gastric fluid and enters the hence , this drug is absorbed rapidly from gastric fluid and enters the

blood(pH=7.4)blood(pH=7.4) Then the extent of ionization in blood will be Then the extent of ionization in blood will be reversedreversed as- as- 7.4-3.0=log(I/U)7.4-3.0=log(I/U) I/U=antilog(4.4)=25,119I/U=antilog(4.4)=25,119 Ratio of(I/U)=25119/1Ratio of(I/U)=25119/1 i.e. 99.996% in ionized(unabsorbable) &0.004% in unionized i.e. 99.996% in ionized(unabsorbable) &0.004% in unionized (absorbable)(absorbable)

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concentration gradient always maintained towards the blood concentration gradient always maintained towards the blood irrespective of sink condition .irrespective of sink condition .

Hence their will not be any tendency for weak acidic drug in Hence their will not be any tendency for weak acidic drug in the blood to be absorbed back into the stomach.the blood to be absorbed back into the stomach.

Conclusion :Conclusion :

STOMACH BLOOD Ph=1.2 pH=7.4

ionized ─ → unionized unionized ─ →Ionized 0.016← ─ 1.0 1.0 25119

Weak acidic drug

Unionized in stomach

Better absorbed from stomach

Weak basic drug

Unionized in intestine

Better absorbed from intestine

If pH range in GIT is fromIf pH range in GIT is from1 to 81 to 8,that of stomach is,that of stomach is1-3,1-3,& intestine & intestine 5-85-8 Then certain Then certain generalization generalization about ionization and absorption of drug about ionization and absorption of drug can be made, as predicted from the pH-partition hypothesis can be made, as predicted from the pH-partition hypothesis

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ACID/BASE DRUG pKa IONISATION OF DRUGVERY WEAK ACIDS

PENTOBARBITALHEXOBARBITALPHENYTOIN

>8 UNIONISED AT ALL pH VALUES, ABSORB FROM ENTIRE LENGTH OF GIT

MODERATELY WEAK ACIDS

CLOXACILINASPIRIN

2.5-7.5

UNIONISED AT GASTRIC pH , IONISED AT INTESTINAL pH;BETTER ABSORBED FROM STOMACH

STRONG ACIDS DISODIUM CROMOGLYCATE

<2.5 IONISED AT ALL pH VALUES;POORLY ABSORBED FROM STOMACH

VERY WEAK BASES

THEOPHYLLINECAFFEINE

<5 UNIONISED AT ALL pH VALUES, ABSORB FROM ENTIRE LENGTH OF GIT

MODERATELY WEAK BASES

RESERPINECODEINE

5-11 IONISED AT GASTRIC pH , UNIONISED AT INTESTINAL pH,BETTER ABSORBED FROM INTESTINE.

STRONG BASES GUANETHIDINE >11 IONISED AT ALL pH VALUES;POORLY ABSORBED FROM GIT.

7) Lipophilicity of drug 7) Lipophilicity of drug pH &pKa → degree of ionization. pH &pKa → degree of ionization. But lipophilicity of unionized fraction will determine it’ But lipophilicity of unionized fraction will determine it’

permeabilitypermeability For optimum absorption drug should haveFor optimum absorption drug should have aqueous solubility → to dissolveaqueous solubility → to dissolve lipid solubility(logP or Klipid solubility(logP or Ko/wo/w) → for permeation) → for permeation It is determined from it’s oil/water partition coefficient.It is determined from it’s oil/water partition coefficient. ‘‘It is the measure of degree of distribution of drug between one of It is the measure of degree of distribution of drug between one of

several organic lipophilic several organic lipophilic solvent(octanol,chloroform,heptane)and an aqueous phase’.solvent(octanol,chloroform,heptane)and an aqueous phase’.

KKo/w o/w value in range of 1-2 is sufficient for passive absorption.value in range of 1-2 is sufficient for passive absorption. 2626

Limitations of pH-partition hypothesis

Presence of virtual membrane pH . (determines extent Presence of virtual membrane pH . (determines extent ionization of drugs & absorption)ionization of drugs & absorption)

Absorption of ionized drug (passive absorption).Absorption of ionized drug (passive absorption). Influence of GI surface area and residence time of drug.Influence of GI surface area and residence time of drug. Presence of aqueous unstirred diffusion layerPresence of aqueous unstirred diffusion layer

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8)8) Complexation and Adsorption Complexation and Adsorption The drug is complexed with some agent or adsorbed on inert The drug is complexed with some agent or adsorbed on inert

substance with a large surface area to increase it’s solubility.substance with a large surface area to increase it’s solubility. Drug may form complex with components of –Drug may form complex with components of – formulation, GIT or diet.formulation, GIT or diet. This binding may causes poor absorption.This binding may causes poor absorption. Ex:1)mucin with streptomycin, dihydrostreptomycin Ex:1)mucin with streptomycin, dihydrostreptomycin 2)tetracycline with milk.2)tetracycline with milk. Certain insoluble substances adsorb with co-administered drugs.Certain insoluble substances adsorb with co-administered drugs.

Ex .charcoal has been used for various gastro intestinal disorder Ex .charcoal has been used for various gastro intestinal disorder &effective antidote in drug intoxication.&effective antidote in drug intoxication.

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ReferancesReferances1. Brahmankar,

DM,&Jaiswal,SB1995,Biopharmaceutics And Pharmacokinetics a treatise,1st edn,Vallabh prakashan,Delhi.

2. Venkateswaralu,V2004, Biopharmaceutics And Pharmacokinetics, Pharma book syndicate,Hydrabad.

3. Pradkar,A&Bakliwal,S2006, Biopharmaceutics And Pharmacokinetics,2nd edn,Nirali prakashan,Pune.

4. Kulkarni,JS,Pawar,AP & Shedbalkar,VP2006,Biopharmaceutics and pharmacokinetics,CBS Publishers,New Delhi. 2929

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