Manufacture and Control of a Hygroscopic Anhydrous API

Control of the desired polymorphic form of an API is necessary to ensure consistent drug product manufacture and performance of the final drug product.  In this paper an API crystallized as a di-Ethanolate solvate is dried and isolated as crystalline anhydrous API.  We show how the form conversion may be monitored from the thermal profile of the pilot plant agitated drier which correlates strongly to the polymorphic state of the drying material.  Once isolated, the anhydrous API may undergo conversion to a hydrate at relative humidity in excess of 30%.  Hydration has a potential impact on the formulation of the drug product and requires control in the packaged material.  Moisture uptake rates of the API were measured and the effective diffusivity of water vapor was used to estimate the risk for form conversion as a function of processing scale and define a control strategy to minimize the impact on the drug product manufacture.