Presentation Topic :

Factor influencing drug Absorption

SUBMITTED TO : SUBMITTED BY DR. SUDIPTA SAHA. MD ASIF ZAWED ASST. PROFESSOR MPHARM 1ST YEAR (PHARMACOLOGY).

DEPARTMENT OF PHARMACEUTICAL SCIENCE ,BABASAHEB BHIMRAO AMBEDKAR UNIVERSITY , LUCKNOW, 226025.

Contents: INTRODUCTION ABSORPTION OF DRUGS.DIFFERENT ROUTE OF DRUG ADMINISTRATION AND THERE ABSORPTIONFACTOR INFLUENCING THE GASTRO INTESTINAL DRUG ABSORPTION

A. PHARMACEUTICAL FACTORS:I. PHYSIOCHEMICAL PROPERTIES OF DRUG SUBSTANCEII. DOSAGE FORM AND PHARMACEUTICAL INGREDIENT

B. PATIENT RELATED FACTOR:

INTRODUCTION

Effect needed

Absorption of drugs

• Defined as the process of transport of unchanged drug from the site of administration to the systematic circulation by crossing biological membrane.

Plas

ma

conc

entra

tion • Why drug

should be Transported ?

• In order to reach his receptor And produce biological Effect.

CONT …INTRAVENOUS ADMINISTRATION HAS NO ABSORPTION PHASEACCORDING TO THE RATE OF ABSORPTION: INHALATION→ SUBLINGUAL→ RECTAL→ INTRAMUSCULAR→ SUBCUTANEOUS→ ORAL→ TRANSDERMAL

Different route of drug administration.

The rate and extent of drug absorption called bioavailability.

Factor influencing the Gastro intestinal drug absorption

A. PHARMACEUTICAL FACTORS:I. PHYSIOCHEMICAL PROPERTIES OF DRUG SUBSTANCE

a) DRUG SOLUBILILTY AND DISSOLUTION RATEb) PARTICLE SIZE SURFACE AREAc) POLYMORPHISM AND AMORPHISMd) SALT FORM OF THE DRUGe) LIPOPHILICITY OF THE DRUG f) pKa OF THE DRUG AND GI PHg) DRUG STABILITYh) STERIOCHEMICAL NATURE OF THE DRUG

II. DOSAGE FORM AND PHARMACEUTICAL INGREDIENT

a) DISINTIGRATION TIMEb) DISSOLUTION TIMEc) MANUFACTURING VARIABLESd) NATURE AND TYPE OF DOSAGE FORMe) PRODUCT AGE AND STORAGE CONDITION

DRUG SOLUBILILTY AND DISSOLUTION RATE

Drug in solution at the

absorption site.

Fine particles

Granules or aggregates

Solid dosage form

Non ioniseddrugs

Ionised drugs

CELL MEMBRANE ionised

drugs

Non ioniseddrugs

DISSOLUTION

G.I. LUMEN BLOODABSORPTION

For Hydrophobic drugs:Dissolution is rate limited step.eg: griseofulvin , spironolactone.

For Hydrophilic drugs:Permeation is rate limited step.eg: cromolyn sodium, neomycin

CONT…• DISSOLUTION IS A PROCESS IN WHICH A SOLID SUBSTANCE SOLUBILISE IN A GIVEN

SOLVENT 1. DIFFUSION LAYER MODEL / FILM THEORY2. INTERFACIAL BARRIER MODEL. 3. PENETRATION OR SURFACE RENEWAL THEORY.

DIFFUSION LAYER MODEL/OR FILM THEORYSIMPLEST AND MOST COMMON PROCESS FOR DISSOLUTION.4. SOLUTION OF THE SOLID TO FORM A THIN FILM OR LAYER AT THE SOLID LIQUID

INTERFACE CALLED THE STENGENT FILM OR DISSOLUTION FILM OR DISSOLUTION LAYER . THIS STEP IS USUALLY RAPID.

5. DIFFUSION OF THE SOLUBLE SOLUTES FROM THE STENGENT LAYER TO THE BULK OF THE SOLUTION ..THIS STEP IS SLOWER AND IS THEREFORE THE RATE DETERMINING STEP IN DRUG DISSOLUTION.

PARTICLE SIZE and EFFECTIVE SURFACE AREA..

PARTICLE S SIZE AND SURFACE AREA OF A SOLID DRUGS ARE INVERSELY RELATED TO EACH OTHER

SMALLER PARTICLE SIZE-> GREATER SURFACE AREA->RAPID DISSOLUTIONMICRONIZATION –GRATER SURFACE AREA-RAPID DISSOLUTION OF HYDROPHILIC DRUGS EG:-GRISEOFULVIN, SPIRANOLACTONEHYDROPHOBIC DRUGS-MICRONIZATION-DECREASE IN EFFECTIVE SURFACE AREA-FALL IN

DISSOLUTION RATECAUSES• ADSORPTION OF AIR TO SURAFCE• PARTICLE REAGGREGATION• SURFACE CHARGE EG:- ASPIRIN , PHENACETIN IN THAT CASE ADD- SURFACTANTS –TWEEN 80• HYDROPHILIC DILUENTS-PEG ,PVP DEXTROSE

POLYMORPHISM AND AMORPHISM POLYMORPHISM

WHEN SUBSTANCE EXISTS IN DIFFERENT CRYSTALLINE FORMS, IT IS POLYMORPHISM.

AMORPHISM• THESE DRUGS CAN EXIST WITH NO INTERNAL CRYSTAL STRUCTURE.• SUCH DRUG REPRESENTS THE HIGHEST ENERGY STATE AND CAN BE CONSIDERED AS

SUPER COOLED LIQUIDS AND THUS HAVE GREATER SOLUBILITY. E.G. NOVOBIOCIN.• THUS, THE ORDER OF DISSOLUTION & HENCE ABSORPTION FOR DIFFERENT SOLID

DOSAGE FORMS IS AMORPHOUS > META-STABLE > STABLE.

Plot of Cp Vs Time for three formulations of Chloramphenicol Palmitate

SALT FORM OF THE DRUG

SALT OF WEAK ACID AND WEAK BASES HAVE MUCH

HIGHER AQUEOUS SOLUBILITY THAN THE FREE ACID OR

BASE.

THEREFORE, IF THE DRUG CAN BE GIVEN AS A

SALT, THE SOLUBILITY CAN BE INCREASED AND THE DISSOLUTION THUS CAN BE IMPROVED. Fig 1. It shows the

dissolutionProfile of various salts

pKa OF THE DRUG AND GI pHACCORDING TO PH PARTITION THEORY, THE PROCESS OF ABSORPTION OF DRUG COMPOUNDS OF MOLECULAR WEIGHT GREATER THAN 100 DALTONS TRANSPORTED ACROSS THE BIOMEMBRANE BY PASSIVE DIFFUSION DEPEND UPON THE FOLLOWING FACTOR DISSOCIATION CONSTANT OF THE DRUG I.E., PKa OF THE DRUG LIPID SOLUBILITY OF THE UNIONIZED DRUG. PH AT THE ABSORPTION SITETHE AMOUNT OF DRUG THAT EXIST IN UNIONIZED FORM IS A FUNCTION OF

DISSOCIATION CONSTANT(PKA) OF THE DRUG AND PH OF THE FLUID AT THE ABSORPTION SITE.

FOR WEAK ACIDS FOR WEAK BASE

Conti…FOR WEAK ACIDSVERY WEAK ACIDS(PKA>8)– UNIONIZED AT ALL PH—ABSORPTION IS RAPID—

INDIPENDANT OF GI PH EG:-PHENYTOIN , ETHOSUXIMIDEACIDS IN THE PKA RANGE 2.5 TO 7.5 LARGELY AFFECTED BY PH CHANGE—

ABSORPTION PH DEPENDANT—BETTER ABSORBED FROM ACIDIC CONDITIONS OF STOMACH (PH<PKA)WHERE THEY LARGELY EXIST IN UNIONIZED FORM

EG:-ASPIRIN , IBUPROFEN STRONG ACIDS (PKA<2.5) IONIZED AT ENTIRE PH RANGE OF GIT ---REMAIN

POORLY ABSORBED EG:-CROMOLYN SODIUM

Conti…FOR BASIC DRUGS1. VERY WEAK BASES(PKA<5) UNIONIZED AT ALL PH VALUES ---ABSORPTION IS

RAPID AND PH INDIPENDANT EG:-DIAZEPAM , NITRAZEPAM2. BASES IN PKA RANGE 5 TO 11 IS PH DEPENDANT –BETTER ABSORBED FROM THE RELATIVELY ALKALINE CONDITIONS OF THE INTESTINE EG:-CHLOROQUINE , IMIPRAMINE

3. STRONG BASES (PKA>11) IONIZED AT ENTIRE PH RANGE –POORLY ABSORBED EG:-MECAMYLAMINE GUANETHIDINE

Lipophilicity of the drug• ONLY UNIONIZED DRUG HAVING SUFFICIENT LIPID SOLUBILITY IS ABSORBED INTO

SYSTEMIC CIRCULATION.• SO DRUG SHOULD HAVE SUFFICIENT AQUEOUS SOLUBILITY TO DISSOLVE IN THE

FLUIDS AT THE ABSORPTION SITE AND LIPID SOLUBILITY HIGH ENOUGH TO FACILITATE THE PARTITIONING OF THE DRUG IN LIPOIDAL MEMBRANE AND INTO SYSTEMIC CIRCULATION.

Drug stability• TWO MAJOR STABILITY PROBLEMS ARE• 1.DEGRADATION OF THE DRUG INTO INACTIVE FORM• 2.INTERACTION WITH ONE OR MORE COMPONENT EITHER OF THE DOSAGE FORM

OR THOSE PRESENT IN THE GIT TO FORM A COMPLEX THAT IS POORLY SOLUBLE

Patient related factor

CONT…

a) AGEb) GASTRIC EMPTYING

a) VOLUME OF MEALb) COMPOSITION OF MEALc) PHYSICAL STATE AND VISCOSITY OF MEAL

c) INTESTINAL TRANSIT TIMEd) G.I pHe) DISEASE STATE f) BLOOD FLOW THROUGH THE GITg) GI CONTENTS

• OTHER DRUGS• FOOD• FLUIDS etc…

REFERENCES• BRAHMANKAR D.M;JAISWAL SUNIL.B; “BIOPHARMACEUTICS AND

PHARMACOKINETICS–A TREATISE, SECOND EDITION 2009.

• GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (12TH EDITION)