Absorption of Drugs

Presented by VICTOR JAGARAJA.T AACP Copy to:

Definition

Absorption is the process of movement of unchanged drug from the site of administration to systemic circulation. It is the process of movement of unchanged drug from the site of administration to the site of measurement (plasma). Factors affecting absorption 1. Physico chemical factors a. Solubility & dissolution rate b. Particle size & effective SA c. Polymorphism & amorphism d. Pseudo polymorphism e. Salt form of the drug f. Ionization constants (pH & pKa) g. Lipophilicity of the drug 2. Dosage form factors a. Disintegration time b. Manufacturing variables c. Pharmaceutical ingredients d. Nature & type of dosage forms e. Product age & storage conditions 3. Patient related factors a. Age b. Gastric emptying time c. Intestinal transit time d. Gastro intestinal pH e. Diseased states f. Blood flow through the GIT g. Gastrointestinal contents h. Pre-systemic metabolism 1. Physico chemical factors 1a.Solubility & dissolution rate For absorption, the drug must present in aqueous solution which depends on its solubility & dissolution rate. Absolute solubility is the max amount of solute dissolved in a given solvent, under standard conditions of temperature, pressure & pH. Dissolution is the process in which a solid substance soluble in a given solvent i.e., mass transfer from the solid surface to the liquid phase. Dissolution

rate is the amount of solid substance that goes into solution per unit time under standard conditions of temperature, pH, and solvent composition. Theories of dissolution Diffusion layer model / film theory. Danckwerts model / surface renewal theory. Interfacial barrier model. Diffusion layer model/ film theory Diffusion layer is the thin film/ layer at the solid liquid interface, which is saturated with drug (rapid step). Then the solute from the diffusion layer diffuses into the bulk of the solution. The rate of diffusion is given by Brunner equation dc/dt=D A KW/O (Cs-Cb) / V h D=diffusion coefficient of the drug A=surface area of the solute KW/O=water/oil partition coefficient of aqueous soluble drug Cs=conc. of drug in diffusion layer Cb=conc. of drug in bulk of the solution V=volume of dissolution medium h=thickness of the diffusion layer. Surface renewal theory The agitated fluid consisting of macroscopic mass of eddies/ packets reach the solid-liquid interface in a random fashion. These packets absorb the solute by diffusion and carry it to the bulk of the solution. Since the solvents are exposed to new solid surface each time, the theory is so called. dc/dt=A (Cs-Cb) D / V A=surface area of the solute Cs=conc. of drug in diffusion layer Cb=conc. of drug in bulk of the solution =rate of surface renewal D=diffusion coefficient of the drug V=volume of dissolution medium

Interfacial barrier model Its is propose based on 2 assumptions The rate determining step that controls dissolution is the mass transport Solid-solution equilibrium is achieved at the solid-liquid interface. An intermediate concentration can exist at the interface as a result of solvation rather than diffusion mechanism. In crystals, each face will have different interfacial barrier, which is given by the equation G = Ki (Cs-Cb) G=dissolution rate per unit area Ki=effective interfacial transport constant 1b.Particle size & effective SA Absolute SA:- The total area of solid surface of any particle Effective SA:- The area of solid surface exposed to dissolution medium Micronisation reduces the particle size below 0.1 , increases intrinsic solubility and dissolution rate. Smaller particles have energy higher than bulk of drug resulting in increased interaction with the solvent. Micronisation enabled decrease in dose of certain drugs. E.g.. Griseofulvin reduced to half, Spironolactone reduced 20 times. 1c.Polymorphism When a substance exists in more than one crystalline form, the different forms are designated as polymorphs. Its of 2 types Enantiotropic polymorph: the one which can reversibly change to another form by altering the temperature or pressure. E.g. sulfur. Monotropic polymorph: the one which is unstable at all temperature and pressure. E.g., glyceryl stearates. Depending on their relative stability, polymorphs are of 2 types.

Stable form: it represents lowest energy state, has highest M.P and least aqueous solubility. Meta-stable form: it represents higher energy state, have lowest M.P and higher aqueous solubility (better bioavailability). The polymorphic form of riboflavin III is 20 times more water soluble than form I. Amorphism Amorphous particles have no internal crystal structure. They represent higher energy state and considered as super cooled liquids. They have greater aqueous solubility than crystalline form (less energy to transfer molecules). E.g. Amorphous novobiocin is 10 times more soluble than its crystalline form. Increase Order of dissolution Amorphous > metastable > stable 1d. Pseudo polymorphism The stoichiometric type of adducts where the molecules are incorporated in the crystal lattice of the solid are called as the solvates. The solvates can exist in different crystalline forms called pseudo polymorphism. The trapped solvent is the solvent of crystallization. If the solvent is water, then the solvate is known as hydrates. The anhydrous form of the drug has greater aqueous solubility than the hydrates. E.g. The anhydrous form of theophylline & ampicillin has greater aqueous solubility, hence better bio availability than their monohydrate & trihydrate form respectively. 1e.Salt form of the drug To enhance the solubility and dissolution rate of drugs, they are converted into their salt forms. With weakly acidic drug, strong base salt is prepared such as potassium & sodium salts of sulfonamides & barbiturates. With weakly basic drugs, a strong acid salt is prepared like hydrochloride or sulfate salts of several alkaloids drugs. The effect of salt formation on dissolution can be explained by considering the pH of the diffusion layer. The pH of the diffusion layer of the salt of weak acid is higher than the pH of free acid. Increase in pH, promotes the dissolution of weak acid.

For salts of weak acid [H+] d < [H+] b For salts of weak base [H+] d > [H+] b 1f. Ionization constants (pH & pKa) The pH partition theory: for drug compounds of mol.wt more than 100, which are primarily transported by passive diffusion, the absorption process is governed by The dissociation constant of the drug (pKa) The lipid solubility of the unionized drug The pH at the absorption site. The lower the pKa of an acidic drug, stronger the acid. Very weak acids (pKa>8): Phenytoin, ethosuximide and other barbiturates are unionized at all pH hence absorption is rapid independent of pH. Acids (2.5-7.5): NSAIDs like aspirin, ibuprofen are better absorbed from acidic conditions. Stronger acids (pKa<2.5): Cromolyn sodium is ionized in the entire pH of the GIT hence poorly absorbed The higher the pKa of a basic drug, stronger the base. Very weak bases (pKa<5): Caffeine, theophylline and many benzodiazepines are unionized at all pH hence absorption is rapid independent of pH Bases (5-11): Several morphine analogs, chloroquine and amitriptyline are better absorbed from alkaline conditions of intestine Strong bases (pKa >11): Mecamylamine and guanethidine are ionized in the entire pH of GIT hence poorly absorbed. Henderson-Hasselbach equation For weak acids pH=pKa + log ([ionized drug]/ [unionized drug]) % Drug ionized= (10pH-pKa/1+10pH-pKa) X100 For weak bases pH=pKa + log ([unionized drug]/ [ionized drug]) % Drug ionized= (10pKa-pH/1+10pKa-pH) X100 When the concentration of ionized and unionized drug becomes equal, pKa = pH 1g. Lipophilicity of the drug

Even if the drug exists in unionized form, poorly absorbed if it has poor lipid solubility (low Ko/w) The drug should have high lipid solubility to facilitate partitioning in the lipoidal bio-membrane. HLB should be there in the structure of the drug for optimum bioavailability. The lipid solubility is determined from the oil/water partition coefficient (Ko/w) value of the drug. This value is the measure of the degree of distribution of drug between one of the several organic, water immiscible, lipophilic solvents and an aqueous phase. 2. Dosage form factors 2a. Disintegration time Time taken for disintegration of a solid dosage form into granules. The granules disaggregate into fine particles called dissolution. Rapid DT is important in the therapeutic success of an oral solid dosage form. Coated tablets have long DT. 2b. Manufacturing variables 1. Method of granulation: Wet granulation is the most conventional technique Its limitations include Formation of Crystal Bridge by the presence of liquid The liquid may act as a medium for affection reactions like hydrolysis Drying step may harm thermo liable substances The method of direct compression yields tablets having dissolve at faster rate Recent method include agglomerative phase of communion (APOC) The process involves grinding of drugs in a ball mill for a time long enough to affect spontaneous agglomeration The tablets so produced are strong and showed rapid rate of dissolution 2. Compression Force Influence on density, porosity, hardness, DT and dissolution of tablets On one hand, higher CF increases the density & hardness, decreases porosity hence retards penetrability & wettability

On other hand, higher CF causes deformation, crushing or fracture of drug into smaller particles, thus increases in effective SA and hence dissolution. 1. Packing of capsule contents Like compression for tablets, packing density in case of capsule. Capsules with finer particles and intense have poor drug release due to decrease in pore size and poor penetration by GI fluids. 2c.Pharmaceutical ingredients Any formulation contains a number of excipients (non drug components) They ensure acceptability, uniform of composition & dosage, and optimum bioavailability and function ability of the drug More the excipients, more the complex for absorption and bio-availability. Vehicle They are the major component of liquid orals 3 categories of vehicles Aqueous vehicle Non aqueous water miscible vehicle (propylene, glycol, glycerol) Non aqueous water immiscible vehicle (veg.oils) Bio-availability depends on the extend of miscibility of vehicle with biological fluids. Solubilizer like Tween 80 is added sometimes.

Diluents (fillers) Added to tablets to promote bulk Diluents may be Organic diluents: Promotes the dissolution of hydrophobic drugs like spironolactone. E.g. starch, lactose, MCC. They form a coat on drug particles, rendering them hydrophilic. Inorganic diluents: Dicalcium phosphate (DCP) is most common. Binders & Granulating agents They promote cohesive compacts for directly compressible materials to keep the tablet intact. Binders include polymeric materials like starch, cellulose derivatives, acacia, PVP.

Hydrophilic binders show better dissolution of poorly wettable drugs like phenacetin Large amount of binders increase hardness and decrease disintegration/ dissolution rates of tablets. Disintegrants Disintegrants are hydrophilic in nature These agents overcome the cohesive strength of tablet and break them up on contact with water Adsorbing Disintegrants like bentonite and veegum should be avoided with low doses drugs Micro crystalline cellulose is a very good disintegrant. Lubricants They aid the flow of granules, by reducing interparticle friction Avoids sticking or adhesion of particles to dies and punches. Soluble lubricants like SLS and carbowaxes promote dissolution. Coatings The effect of various coatings of tablets, on drug dissolution Enteric coated > sugar coated > non enteric film coated The dissolution profile of certain coating materials change on ageing. E.g. shellac coated tablets. Suspending agents They are hydrophilic polymers; reduce the rate of settling of solid drug particles, by increasing the viscosity of the medium. Vegetable gums: Acacia, tragacanth. Semi-synthetic gums: CMC, MC Synthetic gums. A macromolecular gum often forms unabsorbable complexes with drugs. E.g. CMC with amphetamine

Increase in viscosity acts as mechanical barrier to the diffusion of the drug from dosage form They form a viscid layer in the GI mucosa. Surfactants Widely used in formulations as wetting agents, solubilizers, emulsifiers etc. They may enhance or retard absorption by interacting with drug and/or membrane. Mechanisms involved are Promotion of wetting Better membrane contact of drug for absorption Enhanced membrane permeability Complexing agents Complex formation is used to alter the physicochemical and bio-pharmaceutical properties of a drug. A complexed drug may have altered stability, solubility, mol. size, and partition and diffusion coefficient. These complexes are pharmacologically inert & dissociates at absorption site or into systemic circulation. E.g. caffeine- PABA complex, enhanced lipophilicity. Colorants Even low conc. of colorants has inhibitory effect on dissolution rate of several crystalline drugs The dye molecules get adsorbed onto the crystal phases and inhibit drug dissolution. E.g. brilliant blue retards the dissolution of sulfathiazole. 2d.Nature & Type of dosage form The bio-availability of a drug from various dosage form decreases in the following order, Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated tablets > Enteric coated tablets > Sustained release products. Solutions The major rate limiting step

(drug dissolution) is absent. Factors that influence bio-availability includes Nature of solvent Viscosity Surfactants Solubilizers Stabilizers etc.

Emulsions They are superior to suspensions in administering lipophilic drugs Emulsion provides a large SA of oil to the GIT for absorption of drug Emulsion of indoxole (an NSAID) in vegetable oil emulsified in water, has 3 fold increased absorption over is aqueous suspension. Suspensions The dissolution rate is more due to large SA of particles in the suspension Factors influencing bio-availability includes Particle size Polymorphism Wetting agents Viscosity of the medium Suspending agents etc. Capsules Powders and granules are administered in hard gelatin capsules Viscous fluids and oils are in soft gelatin capsules Factors influencing Particle size Density Polymorphism Intensity of packing Influence of diluents & excipients Tablets Compressed tablets are most widely used dosage forms Dissolution is most rapid from primary drug particles due to their large SA.

Disintegration of a tablet into granules and subsequent deaggregation of granules into fine particles Coated tablets The coating acts as barrier which must dissolve first to aid disintegration and dissolution of a tablet Types Film coat: Thin and dissolves rapidly doesnt affect absorption significantly Sugar coat: Tough and take longer time to dissolve. Enteric coated tablets The coat dissolves only in alkaline pH Such tablets may take 2-4 hrs to pass from stomach to intestine Hence pharmacologic response may delayed by 6-8 hrs Thickness of enteric coat is a determinate factor Ageing of dosage form affects drug release, especially with shellac. 2e.Product age & storage conditions In solution dosage form, precipitation of drug due to conversion of meta-stable into poorly soluble stable form during shelf life Decreased rate of dissolution and absorption in case of suspensions due to change in particle size distribution Disintegration and dissolution rate of tablets affected due to ageing 3. Patient related factors 3a.Age In infants, altered absorption due to high gastric pH, low intestinal SA & blow flow to GIT. In elderly patients, altered gastric emptying, decreased intestinal SA, higher incidents of achlorhydria and bacterial overgrowth in intestine. 3b.Gastric emptying Its the passage of stomach contents to the small intestine Rapid GE increases bio-availability of a drug Its required where, Rapid onset of action is desired Dissolution of drug occurs in the intestine The drugs not stable in gastric pH The drug is best absorbed from the distal part of the small intestine. GE is delayed by co-administering food

Delay in GE is recommended where Food promotes drug dissolution & absorption Absorption promoted by gastric fluids The drugs are administered from the proximal part of the small intestine Prolonged absorption-site contact is required. 3c.Intestinal transit SI is the major site of drug absorption Long intestinal transit is desirable for complete drug absorption Transit time for regions of intestine: Duodenum-5 min Jejunum-2 hrs Ileum-3 to 6 hrs Ceacum-0.5 to 1 hr Colon-6 to 12 hrs Anti-cholinergic drugs retard intestinal transit and promote the absorption of poorly soluble drugs Delayed intestinal transit is desirable for Sustained release products Enteric coated formulations Drugs absorbed from specific sites in the intestine (vitamin B) 3d.Gastrointestinal pH The GI pH increases when moves down the stomach to the colon and rectum Drugs are either weak acid or weak base whose pH is greatly affected by GI pH. Weakly acidic drugs dissolve rapidly in alkaline pH of the intestine Weakly basic drugs dissolve rapidly in acidic pH of the stomach

With enteric coated formulations, the coat dissolves only in the intestine followed by the disintegration of the tablet With basic drugs, formation of insoluble drug hydroxide in the alkaline pH of the intestine. The acidic pH influences the degradation of penicillin.

2. Cardiovascular disease Congestive heart failure influence bio-availability of a drug viz. Edema of the intestine Decreased blood flow to GIT Gastric emptying time Altered GI pH.

3. Hepatic disease Hepatic cirrhosis influences the bio-availability of drugs that undergo considerable first-pass metabolism. 3f.Blood flow to the GIT The blood flow to GIT (splanchnic circulation) is about 28% of the CO Only few drugs (low mol. wt lipid soluble compounds) are removed by lymphatic system The high perfusion rate of GIT maintains the sink conditions 3g.GI contents 1. Food-drug interactions: Drugs are better absorbed under fasting conditions and presence of food retards or prevents it This may be due to Delayed gastric emptying Formation of poorly soluble and unabsorbable complex Increased viscosity due to food 2. Fluid volume: Administration of drug with large fluid volume results in Better dissolution Rapid gastric emptying Enhanced absorption 3. Drug interaction with GI contents:

GI contents like mucin, bile salts and enzymes Mucin interacts with streptomycin and retards their absorption Bile salts aid solubilization & absorption of lipophilic drugs like griseofulvin & vitamins

4. Drug-drug interactions: Anti-diarrheal preparations prevent the absorption of co-administered drug Antacids & mineral substitutes retards the absorption of tetracycline Precipitation of tetracycline by sodium bicarbonate which causes elevation in pH 3h. Pre-systemic metabolism 2 reasons for decrease bio-availability of orally administered drug Decreased absorption First-pass metabolism The loss of drug through biotransformation by such eliminating organs during its passage to systemic circulation. Lumenal enzymes This includes the enzymes for intestinal and pancreatic secretions Hydrolases hydrolyze ester drugs like chloramphenicol palmitate into active drug Peptidases split amide linkages and inactivate protein/polypeptides. Gut wall enzymes Mucosal enzymes present in stomach, intestine and colon Alcohol dehydrogenase is an enzyme of stomach mucosa that inactivates ethanol. Bacterial enzymes The GI flora is present in stomach and SI but rich in colon Most orally drugs are unaffected by them These enzymes hydrolyze the conjugates of drugs actively secreted via bile such as glucuronide of digoxin and oral contraceptives Hepatic enzymes

Drugs undergo first-pass metabolism by hepatic enzymes include Isoprenaline Propranolol Nitroglycerine Nifedipine Morphine Non-oral extra vascular routes Buccal/sublingual Rectal Topical Pulmonary Intranasal Intraocular Vaginal