Transport models : Permeability , solubility , charge state amd the ph partition hypothesis

this topic is all about influence of ph on drug solubilty and permeability , henderson hasselbalch equation , PH partition hypothesis and its deviations

1. TRANSPORT MODELS : PERMEABILITY , SOLUBILITY – CHARGE STATE AND THE PH PARTITION HYPOTHESIS PRESENTED BY : Nisha N . M .Pharm 2 nd Sem Dept . Of Pharmaceutics SUBMITTED TO : Prof . H . S . Keerthy Dept . Of Pharmaceutics Mallige College of Pharmacy 1/23

2. CONTENTS : Permeability - solubility charge state Ph partition theory Henderson hasselbalch equation Influence of drug pka on drug absorption Drug solubility and PH Lipophilicity and drug absorption Deviation from Ph partition theory 2/23

3. According to Ficks first law passive diffusion of a solute is the product of diffusivity and concentration gradient of the solute inside the membrane. The membrane/water apparent partition coefficient relates the latter internal gradient to the external bulk water concentration difference between the two solutions separated by the membrane For an ionizable molecule to permeate by passive diffusion most efficiently, the molecule needs to be in its uncharged form at the membrane surface. The amount of the uncharged form present at a given pH, which directly contributes to the flux, depends on several important factors, such as pH, binding to proteins and bile acids, self-binding, and solubility Permeability -Solubility charge state 3/23

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5. Consider a vessel is divided into 2 chambers separated by lipid membrane ,left side is the donor compartment and right side is the acceptor compartment. Fick’s first law applied to homogeneous membranes at steady state is a transport equation, J= Dm dCm/dx = Dm [ Cm0 - Cmh ] / h J = flux Cm0 – Cmh = uncharged form of solute within the membrane at two membrane boundaries h = thickness of the membrane Dm = diffusivity of the solute within the membrane At steady state, the concentration gradient, dCm/dx, within the membrane is linear 5/23

6. The limitation of eq. 1 is that measurement of concentrations of solute within different parts of the membrane is very inconvenient. So we can estimate the distribution coefficients between bulk water and the membrane, log Kd (the pH dependent apparent partition coefficient), we can convert eq. 1 into a more accessible form, J = Dm Kd (CD - CA)/h ……... (2) where the substitution of Kd allows us to use bulk water concentrations in the donor and acceptor compartments, CD and CA, respectively. ( for ionizable molecules, CA and CD refer to the concentrations of the solute summed over all forms of charge state.) 6/23

7. Eq. 2 is still not sufficiently convenient, since we need to estimate Dm and Kd. It is a common practice to lump these parameters and the thickness of the membrane into a composite parameter, called “effective permeability,” Pe, Pe = Dm Kd / h ……… (3) The relevance of eq. 2 (which predicts how quickly molecules pass through simple membranes) to solubility comes in the concentration terms. Consider “sink” conditions, where CA is essentially zero. Eq. 2 reduces to the following flux equation J = Pe C ………(4) 7/23

8. Flux depends on the product of effective permeability of the solute times the concentration of the solute (summed over all charge state forms) at the water-side of the donor surface of the membrane. This concentration ideally may be equal to the dose of the drug, unless the dose exceeds the solubility limit, in which case it is equal to the solubility. Since the uncharged molecular species is the permeant, eq. 4 may be restated as J = Po Co<Po So ……… (5) 8/23

9. Where, Po = the intrinsic permeability Co= concentration of the uncharged species, respectively. The intrinsic permeability does not depend on pH, but its cofactor in the flux equation, Co, does. The concentration of the uncharged species is always equal to or less than the intrinsic solubility of the species, So. Note that for the uncharged species, eq. 3 takes on the form Po = Dm Kp/h ………..(6) where Kp = Cm(0) / CDo; also, Kp = Cm(h) / CAO; CDo and CAo are the aqueous solution concentrations of the uncharged species in the donor and acceptor sides, respectively. 9/23

10. PH PARTITION THEORY It explain drug absorption from GIT and its distribution across bio-membranes. 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. For a drug to be absorbed, it should be unionized and the unionized portion should be lipid soluble. 10/23

11. 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 unionized drug Higher the lipophilicity of the unionized degree, better the absorption 11/23

12. 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 pro-drugs have been developed which are lipid soluble to overcome poor oral absorption of their parent compounds. HENDERSON HASSELBALCH EQUATION 12/23

13. 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 %) 13/23

14. Influence of drug pKa and GI pH on drug absorption 14/23

15. 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) Drug Solubility and pH 15/23

16. 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. 16/23

17. Lipophilicity and Drug absorption The gastrointestinal 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 17/23

18. 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. 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 18/23

19. 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. 19/23

20. 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 20/23

21. REFERENCES : www.slideshare.net https://www.slideshare.net/SujithaMary1/transport-models-biopharamaceutics https://www.slideshare.net/DrxShubhamBadhe/seminar-advance-biopharmaceutics . 21/23

22. QUESTIONS : Explain Ph partition hypothesis and its limitations ? ( Jan 2020 ) Discuss the Ph partition theory of drug absorption ? ( June 2019 ) 22/23

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