From Drying Kinetics, Solvate Structure, Particle Morphology, and Modeling to Optimal Drying Protocol

The mechanistic understanding of three key active pharmaceutical ingredient (API) drying elements: drying kinetics, physical property control, and stability control, is critical for downstream formulation development and manufacture. The objective of this study was to collect drying kinetic data through the use of a laboratory integrated sorption chamber to elucidate the drying mechanism and thereby establish a drying model. In addition, the collection of drying kinetic data would provide a greater understanding of the solvent to API ratio as well as the API stability to help develop a large-scale drying protocol. The study material is an ethanol solvate (ethanolate) of the API. There is no fundamental crystal structure change upon drying of the solvate in the temperature range from 50 to 90 °C, and the drying kinetic data show that the molar ratio of ethanol to API is 1:1. This is confirmed by X-ray crystallography. An analysis of the drying kinetics showed that the diffusion of ethanol through the crystal lattice provided the primary mass transfer resistance, which can be simulated using the Fickian principle of diffusion through a slab. The diffusion coefficients from 50 to 90 °C at 20 mmHg were found to be strongly temperature-dependent and fit well using an Arrhenius type relationship. The activation energy for diffusion was then determined from this relationship. By using these diffusion parameters, the drying curves at various temperatures were generated to predict the drying time to meet the final ethanol specification. The predicted drying time was in good agreement with experimental drying data at high temperatures (80 and 90 °C) but shorter than that observed when drying at lower temperatures (between 50 and 70 °C). Thermal stability data showed that the compound is stable at drying temperatures equal or below 70 °C. Drying data from this study are generated from a static balance. Hence, the effect of shear forces imposed from cake depth and dryer agitation on particle morphology, physical stability of the desolvated API, and drying time needs to be studied to generate the optimal drying protocol for large-scale operation.