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Purpose: Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated., Methods: Self-association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables., Results: Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data., Conclusions: Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation.

The condensation of a chiral primary alkyl amine, (1 S ,2 S )-2-amino-1-(4-nitrophenyl)propane-1,3-diol ( 1 ) as a model compound with dl -glyceraldehyde dimer ( 2 ), 1,3-dihydroxyacetone dimer ( 3 ), and pyruvaldehyde ( 4 ), respectively, forms the same diastereomeric dl -alanine derivatives ( 6 and 7 ) as major products. A plausible mechanism is proposed to elaborate such non-enzymatic transformation. [ABSTRACT FROM AUTHOR]

Abstract: Two degradants observed in a drug formulation of the hepatitis B drug entecavir (Baraclude®), 1 were shown to be identical to the products resulting from the condensation between glyceraldehyde and the guanine nucleoside. The reaction products, 2a and 2b were identified by the analysis of comprehensive NMR data to be two diastereomeric derivatives of alanine implying a novel rearrangement in the reaction between glyceraldehyde and 1. [Copyright &y& Elsevier]