(355c) Scale-up of a Synchronous Wet-Milling & Crystallization Operation to Obtain API with Small, Unimodal Particle Size Distribution.

Achieving small unimodal distributions in active pharmaceutical ingredient (API) crystallizations is a challenging target in development but it is often required for low dose drug substances, where crystal size has a high impact on content uniformity and compound bioavailability of the final drug product. Wet milling is a unit operation used to reduce crystal size before isolation. However, scaling up such processes is not always straightforward given the competing breakage and kinetic mechanisms at play. This presentation will describe the development work done to obtain small unimodal particle size distribution (PSD) by modifying the crystallization and wet-milling parameters of a process based on a predictive model. Small unimodal distributions were previously obtained in development batches (25-30g) by extending the milling time. However, longer milling time was not a feasible scale-up strategy given the corrosive nature of the process stream – prolonged exposure at elevated temperatures presented a risk of corrosion and potential elevated metal levels in the product. Matching the number of turnovers alone did not produce consistent PSD across scales either. A synchronous wet milling/crystallization model was developed and applied to this reactive crystallization. The model was able to predict a set of operating conditions that would result in the desired PSD using reasonable processing times. The conditions from the model were tested at 25g and 100g scales and the desired small, unimodal distribution was consistently achieved.