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Ph partion hypotesis

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Ph partion hypotesis

  1. 1. COPS DSU DEPARTMENT OF PHARMACEUTICS PRESENTED BY: SAGAR.G M. PHARM, 2nd SEM DEPARTMENT OF PHARMACEUTICS SUBMITTED TO : Dr. JOSEPHINE LENO JENITHA ASST. PROFESSOR DEPARTMENT OF PHARMACEUTICS PH PARTITION HYPOTHESIS
  2. 2. COPS DSU DEPARTMENT OF PHARMACEUTICS It explain drug absorption from GIT and its distribution across biomembranes. 
 Drug (>100 daltons) transported by passive diffusion depend upon: dissociation constant, pKa of the drug lipid solubility, K o/w pH at absorption site. Most drugs are either weak acids or weak bases whose degree of ionization is depend upon pH of biological fluid. 
 PH PARTITION THEORY
  3. 3. COPS DSU DEPARTMENT OF PHARMACEUTICS For a drug to be absorbed, it should be unionised and the unionised portion should be lipid soluble. The fraction of drug remaining unionised is a function of both Dissociation constant (pKa) and pH of solution. The pH partition theory is based on following assumption: GIT acts as a lipoidal barrier to the transport of the drug The rate of absorption of drug is directly proportional to its fraction of unionised drug Higher the lipophilicity of the unionised degree, better the absorption.
  4. 4. COPS DSU DEPARTMENT OF PHARMACEUTICS Henderson Hasselbach equation For acid, pKa -pH= log [Cu/Ci] For base, 
 pKa–pH= log [Ci/Cu] Ex: Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have > 99%of unionised form so gets absorbed in stomach Weak base quinine (pKa=8.5) will have very negligible unionisation in gastric pH so negligible absorption Several prodrugs have been developed which are lipid soluble to overcome poor oral absorption of their parent compounds. 

  5. 5. COPS DSU DEPARTMENT OF PHARMACEUTICS EX: Pivampicilin, the pivaloyloxy-methyl ester of ampicilin is more lipid soluble than ampicilin. Lipid solubility is provided to a drug by its partition coefficient between An organic solvent and water or an aq. Buffer (same pH of ab. Site) Ex: Barbital has a p.c. of 0.7 its absorption is 12 % Phenobarbital ( p.c = 4.8 absorption= 12 %) Secobarbital (p.c =50.7 absorption= 40 %)
  6. 6. COPS DSU DEPARTMENT OF PHARMACEUTICS Influence of Drug pKa and GI pH on drug absorption
  7. 7. COPS DSU DEPARTMENT OF PHARMACEUTICS Drug Solubility and pH Drug Solubility The absorption of drug requires that molecule be in solution at absorption site. Dissolution, an important step, depends upon solubility of drug substance. • pH solubility profile:
 pH environment of GIT varies from Acidic in stomach to slightly Alkaline in a small intestine. soluble 1)Basic drug 1) Acidic medium( stomach) 2)Acidic drug 2) basic medium( intestine)
  8. 8. COPS DSU DEPARTMENT OF PHARMACEUTICS Improvement of solubility: Addition of acidic or basic excipient
 • Ex: Solubility of Aspirin (weak acid) increased by addition of basic excipient. For formulation of CRD , buffering agents may be added to slow or modify the release rate of a fast dissolving drug.
  9. 9. COPS DSU DEPARTMENT OF PHARMACEUTICS LIPOPHILICITY AND DRUG ABSORPTION: • The gastro intestinal cell membrane are essentially lipoidal. Highly lipid soluble drugs are generally absorbed while decidedly lipid insoluble drugs are in general poorly absorbed. • Certain drugs are poorly absorbed after oral administration even though they are largely unionised in the small intestine, low lipid solubility of the uncharged molecule may be the reason. • A guide to the lipophilic nature of a drug is its partition coefficient between a fat like solvent and water or an aqueous buffer. • The critical role of lipid solubility in drug absorption is a guiding principle in drug development. Polar molecules such as gentamicin, ceftriaxone, heparin and streptokinase are poorly absorbed after oral administration and must be given by injection. • Lipid soluble drugs with favorable partition coefficient are usually well absorbed after oral administration. The selection of a more lipid soluble compound from a series of research compounds often result in improved pharmacologic activity.
  10. 10. COPS DSU DEPARTMENT OF PHARMACEUTICS • Occasionally the structure of an existing drug can be modified to develop a similar compound with improved absorption.Eg: The development of clindamycin, which differs from lincomycin by the single substitution of chloride for a hydroxyl group. Even slight molecular modification, however runs the risk of also changing the efficacy and safety profile of the drug. For this reason, medicinal chemists prefer the development of lipid soluble prodrugs of a drug with poor oral absorption characteristics. example: cefuroxime (cefuroxime axetil - acetoxy ethyl ester) • The lipid solubility of a drug is determined from its oil/water partition coefficient (ko/w) value. • This value is a measure of the degree of distribution of drug between one of the several organic, water immiscible, lipophilic solvents and an aqueous phase. • In general, the octonal /pH 7.4 buffer partition coefficient value in the range of 1 to 2 of a drug is sufficient for passive absorption across lipoidal membranes.
  11. 11. COPS DSU DEPARTMENT OF PHARMACEUTICS DEVIATIONS FROM pH-PARTITION THEORY • The pH-partition theory provides a basic frame work for understanding drug absorption, but it is an over simplification of a more complex process. • The theory indicates that the relationship between pH and permeation or absorption rate is described by an S- shaped curve corresponding to the dissociation curve of the drug. • For a simple acid or base, the inflection point of the pH- absorption curve should occur at a pH equal to the pka of the drug. This is rarely observed experimentally. In general pH absorption curves are less steep then expected and are shifted to higher pH values for acids and to lower pH values for bases. The conditions for deviations of the pH-absorption curve from the course predicted by the simple pH-partition theory are investigated theoretically. The deviations are an elevation of the asymptotic section usually approaching zero and/or a shift of the intermediate section, more exactly of the inflection point, in the direction of the abscissa and/ or the ordinate. In the absence of a special pH at the surface of the barrier (microclimate pH), the elevation of the asymptotic section can be attributed to a permeability of the barrier to the ionized form of the permeating substance.
  12. 12. COPS DSU DEPARTMENT OF PHARMACEUTICS REFERENCES 1. Milo Gibaldi, biopharmaceutics and clinical pharmacokinetics, fourth edition, 2005, pg:40-45. 2. Leon shargel, Susanna WV-Pong and Andrew B.C.Yu, Applied biopharmaceutics and pharmacokinetics, fifth edition, 2005, pg:375-379. 3. Alfred Martin, physical pharmacy, fourth edition, 2005, pg:342-346. 4. D.M.Brahmankar, Sunil B Jaiswal, biopharmaceutics and pharmacokinetics a treatise, first edition, 1995, pg:32-39. 5. G.R. chatwal, biopharmaceutics and pharmacokinetics,first edition ,2003, pg: 22-24. 6. Leon Lachman, Herbert A.Lieberman, Joseph L. kanig, The theory and practice of industrial pharmacy, third edition, pg; 222 7. M.E.Aulton, pharmaceutics,The science of dosage form design, second edition, pg:241-244. 8. Ansels pharmaceutical dosage forms and drug delivery systems, eighth edition by Loyd V.Allen, Jr. Nichollas G. popovich, Howard C.Ansel.pg:144-147 9. www.boomer.com
  13. 13. COPS DSU DEPARTMENT OF PHARMACEUTICS THANK YOU

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