Development and metrological characterization of quantitative X-ray diffraction phase analysis for the mixtures of clopidogrel bisulphate polymorphs.

Clopidogrel bisulphate (CLP) is a pharmaceutical compound with a novel mechanism of action for the reduction of atherosclerotic events. Only two crystalline forms (CLP I and CLP II) among the six known polymorphs of CLP have therapeutic activity. The structure of the CLP I polymorph is unknown and the structure of the CLP II polymorph is known only partially. Two techniques of X-ray diffraction quantitative phase analysis have been developed in this work for the quantification of CLP I and CLP II in their mixtures. The first technique is based on use of the whole powder pattern decomposition method (WPDM). WPDM was realized through Powder Cell for Windows v.2.4 (PCW) freeware. The second technique is based on the classical direct method. Metrological characterization and comparison of methods have been performed on the mixtures with known phase composition as well as on the real samples with varying phase content. Quantitative phase analyses of 120 specimens containing mixtures of forms I and II of CLP were performed using both developed techniques. Absolute and relative errors and reproducibility of both methods were found to be very similar. The statistical analysis of obtained results revealed that the WPDM gives higher accuracy. We found that the limit of quantification using both methods is 1.0-1.5wt.% of phase content in the mix.