Development and validation of an analytical method for the simultaneous quantitation of posaconazole Form I and Form-S in oral suspensions

Abstract

Any polymorphic conversion of an active pharmaceutical ingredient (API), even if partial, is likely to lead to changes in its efficiency and safety. Posaconazole, an antifungal drug, is detected as Form-S in the commercially available oral suspensions. However, a mixture of Form-S and the initial Form I is likely to coexist depending either on the manufacturing process of the suspensions and/or to the storage conditions of the suspension. The simultaneous quantitation of these crystal forms in suspensions is challenging because of the dose inhomogeneity and the instability of Form-S at ambient conditions. Although X-ray Powder Diffraction (XRPD) was initially employed, preferred orientation issues in the suspension inhibited the successful quantitative determination of the polymorphs. In order to circumvent the problem Raman spectroscopy was selected for addressing this challenge, while the additional application of a home-made rotation system reduced the inhomogeneity problems. A separate calibration curve was generated for each polymorph using a conventional linear regression. The combination of these two relations led to the formation of a comprehensive equation relating the characteristic Raman peak intensities of posaconazole Form-S and Form I with the concentrations thereof. The method was validated and the results were confirmed through a partial least square regression (PLSR). The detection limits for Form-S and Form I were determined equal to 1.9 mg/mL and 2.2 mg/mL, respectively.