Clarification of the USP compendial procedure for phenoxybenzamine hydrochloride via updating impurity profiles.

Abstract The current United States Pharmacopeia–National Formulary (USP–NF) and the British Pharmacopoeia phenoxybenzamine (PBA) hydrochloride drug substance and drug product monographs describe an HPLC procedure for the determination of a specified impurity “tertiary amine phenoxybenzamine” and use the resolution of an “unknown related substance” from PBA as a system suitability criterion; however, neither structural information of the “unknown related substance” is provided nor reference standards of the two impurities are available. The ambiguity in pharmacopeias poses difficulties in implementing the procedure for quality control. To clarify the degradation pathways, and incorporate the impurity profile of PBA into the USP monographs, the degradation of PBA was revisited. PBA undergoes rapid degradation in neutral or basic aqueous solution to generate the “tertiary amine phenoxybenzamine” as the predominant degradation product, which was confirmed as phenoxybenzamine hydroxide (PBA-OH). In addition, the “unknown related substance” was proposed as the phenoxybenzamine nitrile (PBA-CN) on the basis of LC–MS studies. The identity of PBA-CN was unambiguously verified via chemical synthesis, HPLC and NMR analyses. A stability-indicating method was developed and validated for the determination of PBA and its impurities, and was used to support USP monograph modernization.