Identification of Polymorphic Forms of Active Pharmaceutical Ingredient in Low-Concentration Dry Powder Formulations by Synchrotron X-Ray Powder Diffraction

Kenji Egusa, Fumiaki Okazaki, Joerg Schiewe, Ulrike Werthmann, Markus Wolkenhauer

The identification of different (pseudo) polymorphs of an active pharmaceutical ingredient in dry powder formulations is of importance during development and entire product lifecycle, e.g., quality control. Whereas determination of polymorphic differences of pure substances is rather easy, in dry powder formulations, it is generally difficult and the difficulties increase particularly, if the substance of interest is present only in low concentrations in the formulation. Such a formulation is SpirivaR inhalation powder (Boehringer Ingelheim), which contains only 0.4 w/w% of the active pharmaceutical ingredient tiotropium bromide monohydrate in a matrix of α-lactose monohydrate as excipient. In this study, identification of 0.4 w/w% tiotropium bromide in the dry powder formulation was examined by X-ray powder diffraction (XRPD) using a synchrotron radiation source and the results were compared with the conventional laboratory XRPD measurements. The detection limit of tiotropium bromide by the laboratory XRPD was around 2-5 w/w%, and hence, detection of 0.4 w/w% tiotropium bromide was impossible. The synchrotron XRPD was capable to detect significantly lower level of tiotropium bromide by at least an order of magnitude. Four different polymorphic forms of tiotropium bromide present at 0.4 w/w% concentration in lactose powder blends were unambiguously identified by the synchrotron XRPD method.