pH partition theory of drug absorption

pH partition theory of drug absorption

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  DRUG ABSORPTION FROMTHE GASTROINTESTINAL TRACT TOPIC : pH partition theory of drug absorption PRESENTED BY, Aravinda P N I M Pharma Department of Pharmaceutics GCP SUBMITTED TO, Dr.Vijaya G Joshi, Department of Pharmaceutics GCP
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  Contents:  Introduction pH-Partition theory DrugpKa and GI pH Lipophillicity and drug Absorption Limitations of pH-partition Hypothesis Conclusion References
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   Introduction A druginjected Intravascular directly enters the systemic circulation and exerts its pharmacological effects. But, Majority of drugs are administered orally which is intended to act systemically. Such drugs can exert their pharmacological actions only when they enter into systemic circulation by the process of absorption. Drug absorption is defined as the process of movement of unchanged drug from the site of administration to systemic circulation.
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  pH- PARTITION THEORY Understandingof the interrelationships between the rate of drug absorption, the dissociation constant (pKa) and the pH of the absorption site is known as the pH-partition theory. The theory states that for drug compounds of molecular weight greater than 100, which are primarily transported across the bio membrane by passive diffusion. The process of absorption is governed by: 1. The dissociation constant (pKa) of the drug. 2. The lipid solubility of the unionized drug. 3. The pH at the absorption site.
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  Brodie proposed thepartition theory to explain the influence of GI pH and drug pKa on the extent of drug transfer or drug absorption. • pH partition theory of drug absorption is based on the GIT is a simple lipid barrier to the transport of drugs and chemicals. • Accordingly the unionized form of an acid or basic drug, if sufficient lipid soluble, is absorbed but the ionized form is not. • The larger the fraction of drug is in the unionized form at a specific absorption site, the faster is the absorption.
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  DRUG pKa andGI pH • The fraction of drug in solution that exist in the unionized form is a function of both dissociation constant of the drug and the pH of the solution. • The dissociation constant is often expressed for both acids and bases as pKa (the basic logarithm of the acidic dissociation constant). • It is customary to express the dissociation constants of both acidic and basic drugs by pKa values. • The lower the pKa of an acidic drug, the stronger the acid i.e., greater the proportion of ionized form at a particular pH. The higher the pKa of a basic drug, the stronger the base.
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  Thus from theknowledge of pKa of the drug and pH at the absorption site (or biological fluid), the relative amount of ionized and unionized drug in solution at a particular pH and the percent of drug in solution at this pH can be determined by Henderson- Hasselbach equation, i.e., for weak acids: 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 [𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔] [𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔] %𝐷𝑟𝑢𝑔 𝐼𝑜𝑛𝑖𝑧𝑒𝑑 = 10(𝑝𝐻−𝑝𝐾𝑎) 1+10(𝑝𝐻−𝑝𝐾𝑎)100 For weak bases: 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 [𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔] [𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔] %𝐷𝑟𝑢𝑔 𝐼𝑜𝑛𝑖𝑧𝑒𝑑 = 10(𝑝𝐾𝑎−𝑝𝐻) 1+10(𝑝𝐾𝑎−𝑝𝐻)100
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  When the concentrationof ionized drug becomes equal, (since log1=0) and thus pH= pka. The pka is the characteristic of the drug. 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 [𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔] [𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔] 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 [50] [50] 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔1 𝑝𝐻 = 𝑝𝐾𝑎 + 0 𝑝𝐻 = 𝑝𝐾𝑎
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  A membrane barrierthat separates the aqueous solutions of different pH such as GIT and plasma then the theoretical ratio R of drug concentration on either side of the membrane can be given by the equation, For weak acids: 𝑅𝑎 = 𝐶𝐺𝐼𝑇 𝐶𝑝𝑙𝑎𝑠𝑚𝑎 = 1 + 10(𝑝𝐻𝐺𝐼𝑇−𝑝𝐾𝑎) 1 + 10(𝑝𝐻𝑃𝑙𝑎𝑠𝑚𝑎−𝑝𝐾𝑎) For weak bases: 𝑅𝑏 = 𝐶𝐺𝐼𝑇 𝐶𝑝𝑙𝑎𝑠𝑚𝑎 = 1 + 10(𝑝𝐾𝑎−𝑝𝐻𝐺𝐼𝑇) 1 + 10(𝑝𝐾𝑎−𝑝𝐻𝑃𝑙𝑎𝑠𝑚𝑎) pH Range In GIT • The pH range in GIT from 1-8 stomach is from 1-3 Intestine (from duodenum to colon) 5-8, • then certain generalization regarding ionization and absorption of drugs can be made, as predicted from pH partition hypothesis.
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  For Weak AcidsFor Basic Drugs 1. Very weak acids (pKa > 8) are essentially unionized at all pH values and therefore their absorption is rapid and independent of Gl pH. 1. Very weak bases (pKa, < 5.0) are essentially unionized at all pH values and there fore their absorption is rapid and pH-independent. 2.Moderately weak Acids in the pKa, range 2.5 to 7.5 are greatly affected by changes in pH and therefore their absorption is pH-dependent. Such drugs are better absorbed from acidic conditions of stomach (pH <pKa) where they largely exist in unionized form. 2.Moderately weak Bases in the pKa, range 5 to 11.0 are greatly affected by changes in pH and hence their absorption is pH-dependent. Such drugs are better absorbed from the relatively alkaline conditions of the intestine where they largely exist in unionized form. 3. Stronger acids with pKa, < 2.5 are ionized in the entire pH range of GIT and therefore remain poorly absorbed 3. Stronger bases with pKa, > 11.0 are ionised in the entire pH range of GIT and therefore poorly absorbed
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  Drugs pKa pHsite of absorption Very weak acids (pKa,> 8.0) Pentobarbital Phenytoin Ethosuximide 8.1 8.2 9.3 Unionised at all pH values Along the entire length of GIT Moderately weak acids(pKa, 2.5 to 7.5) Cloxacillin Aspirin Ibuprofen 2.7 3.5 4.4 Unionised in gastric pH & Ionised in intestinal pH Better absorbed from stomach Stronger acids (pKa < 2.5) Disodium cromoglycate 2.0 Ionised at all pH Poorly absorbed from GIT Very weak bases (pKa<5.0) Theophylline Caffeine Diazepam 0.7 0.8 3.7 Unionised at all pH values Absorbed along the entire length of GIT Moderately weak bases (pKa 5 to 11.0) Reserpine Codeine Amitriptyline 6.6 8.2 9.4 Ionised at gastric pH relatively unionised at intestinal pH better absorbed from intestine Stronger bases (pKa > 11.0) Guanethidine 11.7 Ionised at all pH values poorly absorbed from GIT Influence of Drug pKa and GI pH on Drug Absorption
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  LIPOPHILICITY (𝑲𝒐/𝒘) ANDDRUG ABSORPTION • The unionised drug -> if sufficiently lipid soluble-> is absorbed into the systemic circulation. • If it has poor lipid solubility ->it will be poorly absorbed. • Therefore for optimum absorption -> a perfect HLB should be required. • The lipid solubility of a drug is determined from its oil/water partition coefficient (𝑲𝒐/𝒘) value.
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  Limitations of pH-partitionHypothesis: 1. Presence of virtual membrane pH 2. Absorption of ionized drug 3. Influence of GI surface area and residence time of drug 4. Presence of aqueous unstirred diffusion layer.
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  1. Presence ofvirtual membrane pH: pH-absorption curve for Acidic and basic drugs. Dotted lines – Curves predicted by pH-partition hypothesis (only unionised drug absorbed) Bold lines – the practical curves (less sleep and shifted) The Virtual pH also called as the microclimate pH, is different from the luminal pH exists at the membrane surface.
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  2. Absorption ofionized drugs : • As per hypothesis – only unionised form of drug absorbed and ionised drug is negligible ( 3to4 times less) – Principle of non-ionic diffusion. • pH absorption curve shift suggested that ionised forms of some drugs also get absorbed to a some extent. • If such drugs have large lipophilic group in their structure, despite their ionization , they will be absorbed passively or by active transport , ion pair transport and convective flow.
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  3.Influence of GIsurface area and residence time of drug • According to theory – (condition of unionized form in large extent) Acidic drugs are best absorbed from stomach Basic drugs are best absorbed from intestine • But Surface area of Stomach and intestine is different. • Once a Acidic drug reaches the intestine, the remaining fraction will be poorly absorbed . • It may not be attain its therapeutic level. • But irrespective of GI pH and degree of ionization both acidic and basic drugs are more rapidly absorbed from intestine, because of its large surface area , long residence time.
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  4. Presence ofaqueous unstirred diffusion layer • The bulk of the luminal fluid is not in direct contact with the membrane but a barrier called as aqueous unstirred diffusion layer present in between them. • Such layer has thickness and it acts as barrier to absorption of drugs. • As per pH- partition theory the rate limiting step in the absorption was partitioning in the lipid barrier. • Presence of aqueous unstirred diffusion layer, a drug must diffuse first through this barrier and then through the lipoidal barrier. • Thus , drugs having large Partition coefficient can rapidly penetrate the lipid membrane but diffusion through aqueous unstirred layer is the rate limiting step.
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  CONCLUSION • In manycases, the ionized and unionized forms of a drug are appreciably transported across lipophilic membrane. • But the extension of pH partition theory to incorporate the effects of the unstirred layer and microclimate pH provides a far more satisfactory rationalization of the experimental data. • Despite its limitation the pH –Partition theory is still useful in the basic understanding of drug absorption and movement of drug between various body compartments
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  REFERENCE 1. D.M.Brahmankar AndS.B.jaiswal, Textbook of Biopharmaceutics and Pharmacokinetics A treatise, Sixth edition,Vallabh Prakashan. 2. Jollow .D.J and Brodie B.B, Mechanism Of Drug Absorption And Of Drug Solution.
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