(366c) Development of a High Shear Crystallization Process for a Pharmaceutical Intermediate

Batch crystallization processes for pharmaceutical intermediates are generally design to maximize the removal of impurities and to minimize yield losses. Crystallization performance is dependent on the ability to control several mass transport mechanisms such as growth, nucleation, impurity deposition etc. These mechanisms, in turn, can be impacted by controlling the amount of shear during the crystallization. Wet milling via rotor-stator devices is commonly employed in batch crystallization to control shear.  While wet milling is mostly used as a particle size reduction technique, it can be used to control the purity of the isolated solids and to improve yield.

This talk will highlight the use of wet milling in a pharmaceutical intermediate crystallization to improve quality, purity and cycle time.  The crystallization involves an initial mass nucleation followed by a solid-solid form conversion.  Upon initial scale-up the process suffered from inconsistent yields and impurity rejection. These inconsistencies appeared to correlate with final product particle size.  Wet milling achieved consistently smaller crystals and enabled faster desaturation leading to consistently higher yields.  Additionally, wet milling improved the purity of the crystallized material by mitigating impurity inclusion.  The use of a DoE study to determine the main parameters affecting desaturation and impurity removal will be highlighted. Scale up results from a pliot plant campaign will also be presented.