Determination of polymorph conversion of an active pharmaceutical ingredient in wet granulation using NIR calibration models generated from the premix blends.

Near infrared (NIR) spectroscopy was used for quantitatively monitoring polymorph conversion of an active pharmaceutical ingredient (API) in wet granulation. The API under pharmaceutical development has two different polymorphs. Polymorph A is the stable form for drug development and polymorph B is the undesired form produced at elevated temperature and humidity. Because a reference method was not available for quantitation of polymorph B, a calibration set was not readily available for NIR method development. Analysis of NIR spectra of different polymorphs of the API, the premix blend and wet granulation samples revealed narrow spectral regions, which were unique to polymorph B and insensitive to differences in physical properties between the premix blend and wet granulation. Therefore, the premix blend samples spiked with polymorph B were used as the calibration set. The final univariate NIR method can be used for off-line or on-line monitoring of polymorph conversion in the wet granulation process.