Polymorphism of active pharmaceutical ingredients is becoming an increasingly important issue in the contemporary drug development. Polymorphic form of an active pharmaceutical ingredient (API) might influence it’s kinetics of solubilization and thus affect the release of API from the finished dose of a drug. This is especially in a case for solid dosages like tablets. The release process of API from dosage form is crucial for drug bioavailability and therapeutic function. Due to the higher activity of new generation of API’s and lower doses of API in drugs (from former 200 – 600 mg down to sometimes submilligram level) the studies of polymorphic forms of API’s in finished doses have become recently a tough task. Therefore, there is a need for analytical methods to determine the polymorphic form of API not only in a plain crystalline substance but also in its finished dose. The later is to make sure that selected polymorphic form of API is preserved in a number of mechanical and thermal processes like wet granulation, fluid bed drying, grinding, mixing, sieving and tableting, in the manufacturing of a finished dose of a drug. When single crystal diffractogram for API can not be obtained a combination of several other method is to be used, as there is still no single method replacement for this analysis. In order to define a polymorphic form of API in such a quite common case standards of all existing polymorphs are to be prepared and methods developed for defining of their identity and content in mixtures of polymorphs.

In this presentation a number of examples will be discussed of determination of polymorphic forms of API’s in crystalline substances and in finished doses, carried out at Pharmaceutical Research Institute in Warsaw over the last several years. To define the polymorph of API a set of diffractometric, spectroscopic and thermal methods are used at this laboratory. First and second order spectra in FT-IR spectroscopy were used to develop a method for identification and quantitative determination of contaminating polymorph II in an API that should be present in a tablet exclusively as a polymorph I. Due to the overlapping of signals originated from API with that from excipients (placebo), selection of diagnostic regions in XRPD profiles is usually very much limited and it was successful in a very few cases that will be shown. In our examination of differences between polymorphs and pseudopolimorphs (solvates) of API the most supportive results were obtained by thermal analyses. For a number of solvates studied the additional endothermic peak in differential scaning calorimetry (DSC) is usually recorded at lower temperatures, as compared with the non-solvated substance. Combination of DSC and termogravimetric (TG) techniques allows to discriminate between a signal originated from a solvent and a signal originated from a phase transition in a DSC thermograms.

References:

[1] W. Szczepek, D. Samson-Łazińska, R. Modzelewski, U. Frączek, M. Ławecka, M. Glice, P. Cmoch, Ł. Kaczmarek, W. Szelejewski: Method of preparation of crystalline α-form of imatinib, PCT/PL2004/000024.

[2] J. Piechaczek, J. Serafin, W. Maruszak, R. Balicki, W. Szelejewski, M. Cybulski, G. Maciejewski, M. Wysoczyńska, M. Glice, K. Korczak: Method of preparation of crystalline form I of clopidogrel, PCT/PL2003/00130.

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