ASSAY OF 4 STEREOISOMERS OF DESACETYL DILTIAZEM HYDROCHLORIDE - APPLICATION TO IN-VITRO CHIRAL INVERSION STUDIES

Direct resolution of four stereoisomers of the related compound of dil tiazem hydrochloride, namely desacetyl diltiazem hydrochloride, was st udied by both normal and reversed-phase chiral HPLC. The four stereois omers were completely resolved on a Chiralcel OF column. The technique developed was applied to a chiral inversion study of desacetyl diltia zem hydrochloride. This inversion was observed neither in the solid st ate, in aqueous solution at 100 degrees C for 3 h nor under visible li ght for 10 h, but was observed in aqueous solution under UV irradiatio n. The (+)-(2S, 3S)-cis-desacetyl diltiazem hydrochloride degraded wit h a half-life of 1.9 h in aqueous solution under UV and epimerized to (+)-(2R, 3S)-trans-desacetyl diltiazem hydrochloride. Similarly, (+)-( 2S, 3S)-cis-desacetyl diltiazem hydrochloride degraded about three tim es faster than diltiazem hydrochloride. Reverse epimerization of (+)-( 2R, 3S)-trans-desacetyl diltiazem hydrochloride to (+)-(2S, 3S)-cis-de sacetyl diltiazem hydrochloride was not observed. The overall degradat ion was the result of two competitive processes, the epimerization and the decomposition of the benzothiazepin ring. The degradation and epi merization rate of (+)-(2S, 3S)-cis-desacetyl diltiazem hydrochloride in solution under UV depended upon the solvent, the aqueous pH, and co ncentration.