Ionization, lipophilicity and solubility properties of repaglinide.
Potentiometric and spectrophotometric titrations were used for the determination of ionization behaviour, lipophilicity and solubility profile of repaglinide. Acid-base equilibria were characterized by means of protonation macro- and microconstants using Target Factor Analysis of spectrophotometric data. Lipophilicity profiles were evaluated by determination of partition coefficients of neutral and ionized forms of repaglinide in biphasic octanol/water system. The intrinsic solubilities of repaglinide were determined from the solubility data and temperature dependence of intrinsic solubilities were evaluated using van't Hoff equation. Repaglinide possesses two protonation sites and in aqueous solutions exhibits ampholitic properties. At isoelectric pH the zwitterionic form of the molecule predominates over the uncharged form with the tautomeric ratio, logKz=1.9. The difference between calculated and measured logP values, as well as the difference between logP values of uncharged form of repaglinide, HR0, and either one of mono-charged forms indicated the significant partition of zwitterion into octanol. Temperature dependence of solubility data revealed exothermic dissolution process with DeltasolH=-36 kJmol-1 and negative entropy of solution of DeltasolS=-0.19 kJK-1mol-1.
Mandić
Zoran
Z
Department of Electrochemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, P.O. Box 177, HR-10000 Zagreb, Croatia. zoran.mandic@fkit.hr
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D002219:Carbamates / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000737:chemistry*; D007526:Isoelectric Point; D008055:Lipids / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet
D002219:Carbamates; D007004:Hypoglycemic Agents; D008055:Lipids; D010880:Piperidines; C072379:repaglinide