Quantitative determination of two polymorphic forms of imatinib mesylate in a drug substance and tablet formulation by X-ray powder diffraction, differential scanning calorimetry and attenuated total reflectance Fourier transform infrared spectroscopy

摘要

Imatinib has been identified as a tyrosine kinase inhibitor that selectively inhibits the Abl tyrosine kinases, including Bcr-Abl. The active substance used in drug product is the mesylate salt form of imatinib, a phenylaminopyrimidine derivative and chemically named as N-(3-(4-(pyridin-3-yl) pyrimidin-2-ylamino)-4-methylphenyl)-4-(4-methylpiperazin-1-yl) methyl)-benzamide methanesulfonic acid salt. It exhibits many polymorphic forms and most stable and commercialized polymorphs are known as alpha and beta forms. Molecules in alpha and beta polymorphic forms exhibit significant conformational differences due to their different intra- and intermolecular interactions, which stabilize their molecular conformations and affect their physicochemical properties such as bulk density, melting point, solubility, stability, and processability. The manufacturing process of a drug tablet included granulation, compression, coating, and drying may cause polymorphic conversions. Therefore, polymorphic content of the drug substance should be controlled during quality control and stability testing. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) methods were evaluated for determination of the polymorphic content of the drug substance and drug product; and PXRD was the most accurate technique and selected as preferred method and validated. Prior to development of a quantification method, pure alpha and beta polymorphs were characterized and used throughout the method development and validation studies. Mixtures with different ratios of alpha and beta forms were scanned using X-ray diffractometer with a scan rate of 0.250 degrees/min over an angular range of 19.5-21.0 degrees 2 theta and the peak heights for characteristic peak of beta form at 20.5 +/- 0.2 degrees 2 theta diffraction angle were used to generate a calibration curve. The detection limit of beta polymorph in alpha form imatinib mesylate tablets was found as 4% and the linear regression analysis data for the calibration plots showed good linear relationship with correlation coefficient of 0.992 with respect to relative peak height in the concentration range of 12-75 wt% beta form containing tablet mixtures. The obtained results at each stage of the validation study proved that the method is specific, repeatable, precise and accurate, and could be used for determination of beta polymorph content in tablets produced by using alpha polymorph of imatinib mesylate. The developed PXRD quantification method was used to monitor the polymorphic purity of alpha form drug substance and corresponding drug products during the quality control analyses and stability studies, and the results indicated that a form was stable and not converted to beta form during the manufacturing process and stability period. (C) 2015 Elsevier B.V. All rights reserved.