Advancing USP compendial methods for fixed dose combinations: A case study of metoprolol tartrate and hydrochlorothiazide tablets / 药物分析学报

ABSTRACT

The current United States Pharmacopeia–National Formulary (USP–NF) includes more than 250 mono-graphs of fixed dose combinations (FDCs), and some of them need to be updated due to incompleteness of impurity profiles and obsolescence of analytical methodologies. A case study of metoprolol tartrate and hydrochlorothiazide tablets is presented to summarize challenges encountered during the USP monograph modernization initiative of FDCs and to highlight an "adoption and adaptation" approach employed for method development. To this end, a single stability-indicating HPLC method was devel-oped to separate the two drug substances and eight related compounds with resolution 2.0 or higher between all critical pairs. Chromatographic separations were achieved on a Symmetry column (C18, 100 mm × 4.6 mm, 3.5 μm) using sodium phosphate buffer (pH 3.0; 34 mM) and acetonitrile as mobile phase in a gradient elution mode. The stability-indicating capability of this method has been demon-strated by analyzing stressed samples of the two drug substances. The developed HPLC method was validated for simultaneous determination of metoprolol tartrate and hydrochlorothiazide and relevant impurities in the tablets. Moreover, the developed method was successfully applied to the analysis of commercial tablet dosage forms and proved to be suitable for routine quality control use. The case study could be used to streamline USP's monograph modernization process of FDCs and strengthen compendial procedures.