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Prediction of stability in pharmaceutical preparations XVIII: application of high-pressure liquid chromatographic assays to study of nafronyl stability and bioanalysis.

Specific, sensitive, reversed-phase high-pressure liquid chromatographic assays of nafronyl (I) and its acidic metabolite and hydrolysis product (II) were developed in aqueous solutions and in biological fluids with sensitivities of 100 ng/ml using butacaine as the internal standard and spectrophotometric detection of 224 nm. Heparinized plasma can be analyzed easily in the organic phase immediately after acetonitrile denaturation. Both I and II can be extracted with haloalkane solvents, and the extracts are evaporated, reconstituted, and assayed in a minimal amount of acetonitrile. Conditions are presented that minimize the interference of II and extracted plasma components. The assay was used to determine the stability of nafronyl in aqueous solutions, to establish its log k-pH profiles at various temperatures, and to evaluate the Arrhenius parameters. Nafronyl is hydrolyzed by specific hydrogen-ion (15.2 kcal/mole) and hydroxide-ion (7.72 kcal/mole) catalysis of the neutral species and specific hydroxide-ion catalysis (5.91 kcal/mole) of the protonated species. The pH of maximum stability is 3.0, and pH 5.4 is the maximum that can be tolerated at 30 degrees, with a 10% solvolysis in 3 years. The half-life of nafronyl at 30 degrees was 7 days at pH 7, 12 hr at pH 10, and 21 min in 0.5 N NaOH. Since nafronyl has a half-life of 3.2 hr in heparinized dog plasma at 25 degrees, blood samples for pharmacokinetic studies of nafronyl must be assayed immediately after sampling. The partition coefficients of I and II determined as functions of pH permit the extraction of both compounds at pH 4.5, but only I can be extracted at pH values above 9.5.