API Powder Property Control During Crystallization, Wet Milling, and Drying

Powder properties for an active pharmaceutical ingredient (API) are traditionally controlled during the final crystallization and drying unit operations.  These unit operations, however, are often scale dependent and difficult to study in a laboratory setting.  Consequently, the identification of a design space to control powder properties can prove challenging. This paper describes work at scales greater than 100 kg to study particle size and API saturation during cooling crystallization with simultaneous wet milling. Multiple parameters such as cooling rate, seed age, and turnover frequency were studied to determine their corresponding impact on final PSD and crystallization supersaturation profile.  Further studies monitored form conversion, residual solvent, amorphous material production, and particle attrition during drying.  The impact of dryer temperature, size, and agitation was assessed.  Overall, these studies provided a wide breadth of knowledge that has been used to set process parameter ranges on both crystallization and drying operations to establish adequate ranges to control the physical attributes of the API.