pH -Partition Hypothesis

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pH-partition hypothesis: The pH-partition hypothesis was proposed by Brodie and his associates (in 1957) to explain the influence of GI pH and drug pKa on the extent of drug transfer or drug absorption. {1} According to this theory for drug compounds of molecular weight greater than 100 and those which are primarily transported across the membrane by passive diffusion, the process of absorption is governed by three important factors like:{1} 1.The dissociation constant i.e pKa of the drug. 2.The lipid solubility of the unionised drug i.e partition coefficient (Ko/w). 3.pH at the absorption site. As most of the pharmaceutical drugs are weak electrolytes, their absorption will be chiefly determined by the extent to which the drug exists in unionized form at the site of absorption. {2} The above hypothesis of the theory was based on the following assumptions: {1} 1.GIT is a simple lipoidal barrier to the transport of drugs. 2.Larger the fraction of unionised drug, faster is its absorption. 3.Greater the lipophilicity (Ko/w) of the unionised drug , better is the absorption. The amount of the drug present in unionised form is a function of pKa of the drug and pH of the fluid at the absorption site.{1} The pKa value for either the acidic or the basic drug indicates the amount of undissociated drug present available for absorption at the absorption site. The lower the pKa value of the acidic drug, stronger is the acid i.e greater is the proportion of ionised form at a particular pH. Simillarly, higher the pKa value of a basic drug, the stronger is the base. {1} Thus the relative amount of ionised and unionised drug in a solution at a particular pH and the percent of drug ionised at this ph is given by Henderson -Hasselbach Equations:{1} For weak acids: pH = pKa + Log[ionised drug conc.] / [Unionised drug conc.] {1} pH = pKa + Log [A-] / [HA] % drug Ionised = 10 to the power of (pH -pka)/1 + 10 to the power of (pH-pKa)* 100 {1} For weak bases : pH = pKa + Log [unionised drug conc.] / [ionised drug conc.] {1} pH = pKa + Log [B] / [BH+] % drug Ionised =10 to the power of (pKa-pH) / 1 + 10 to the power of (pKa-pH)*100 {1} According to Shore et al, if there is a membrane barrier between the aqueous solutions of different Ph such as GIT and the plasma, then the theoretical ratio R of drug concentration on either side of the membrane is given by: For weak acids: R ACID : CGIT /CPlasma = 1+ 10 to the power of (pHGIT-pKa) / 1+10 to the power of (pHplasma-pKa) {1} For weak bases: R BASE :CGIT / CPlasma = 1+ 10 to the power of (pKa-pHGIT) / 1+10 to the power of (pKa-pHplasma) {1} Generalizations regarding Ionisation & Absorption of drugs can be made, as predicted from the pH-Partition Theory: [pH GIT: 1-8] Stomach: 1.5-3; S.Intestine: 5-7.5; L.Intestine: 6-8. {1} For Acidic drugs : 1. pKa >8: Very weak acids. Ex:- Phenytoin, Ethosuximide, Several Barbiturates exists in unchanged form at all pH ranges. Absorption is rapid and independent of pH. {1} 2. pKa 2.5 - 7.5: Greatly affected by pH changes. Absorption mainly depends on GIT pH. Ex:- NSAIDS, Penicillin analogs, Ibuprofen, Phenylbutazones etc.., these have better absorption at acidic environment (pH11: Ex:- Mecamylamine & Guanithidine. Ionised at all pH ranges hence poorly absorbed. {1} Limitations of pH - Partition Hypothesis:{1} 1. Presence of Virtual Membrane. 2. Absorption of Ionised Drugs. 3. Influence of GI Surface Area & Residence time of the drug. 4. Presence of Aqueous unstirred diffusion layer. CONCLUSION: Down the years, there has been unacceptance of the pH-partition hypothesis. By going through lot of literature works on drug absorption infers that the acidic drugs are best absorbed from the acidic gastric fluids and basic drugs are best absorbed from the alkaline environment. So this concept favours the absorption of unchanged drug than the ionised form. However the conditions of GIT is not same all through so unchanged, ionised acid or base are best absorbed from the small intestine as a result of large surface area and more contact time. More over, we have to focus not only the pH and pKa but a prominent role is played by the solubility and permeability of the drug molecule. References: 1.Biopharmaceutics and Pharmacokinetics a Treatise by D.M.Brahmankar and Sunil B.Jaiswal, Vallabh Prakashan Publications,[Reprint in 2008] Page no: 32 to 37 2. Biopharmaceutics and Pharmacokinetics. V.Venkateswarulu, Pharma Book Syndicate. Reprint 2006 Page no : 28 "This blog does not contain any plagiarized material"

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