NIR diffuse reflectance for on-scale monitoring of the polymorphic form transformation of pazopanib hydrochloride (GW786034); model development and method transfer

[摘要] We report the successful application of in situ diffuse reflectance near-infrared (NIR) spectroscopy for characterization of the solvent mediated polymorphic form transformation of pazopanib hydrochloride. Crystal form is a critical quality attribute (CQA) for this active pharmaceutical ingredient (API) to ensure appropriate levels of exposure in patients. NIR spectroscopy was implemented to monitor this final stage unit operation in real-time on manufacturing scale. This technique provided an automated in situ method to replace labour intensive off-line qualitative testing and manual sampling. A partial least squares (PLS) model was created using NIR data collected during an early manufacturing campaign and a novel strategy based on interval-PLS was used to select and optimize the model parameters. The model was subsequently implemented on plant scale and used to monitor clinical manufacturing campaigns. The PLS method clearly differentiated between the monohydrate and the desired anhydrous form allowing determination of the transformation end point in real-time. Utilisation of PLS diagnostics such as Mahalanobis distance and spectral residuals provided additional capability to signal any unexpected behaviour in the process and/or indicate the presence of an undesired solvate polymorph also seen during process development...

[学科分类] 分析化学