Effect of Seed Type on the Resistance of API Agglomerates to Agitated Drying

Control of the Active Pharmaceutical Ingredient’s (API) powder properties is often necessary to ensure successful drug product development and manufacture.  This is, in part, accomplished by designing a crystallization process that can deliver consistent batch-to-batch powder properties.  When an API forms agglomerates during the crystallization, the resulting powder often exhibits enhanced flow properties and bulk density, which are of benefit to the formulation.  However, development of a crystallization to consistently produce agglomerates that can withstand downstream processing, particularly agitated drying, represents a significant challenge.   Weak agglomerates that are prone to break during agitated drying increase the risk of batch-to-batch powder property variability and scale dependence. 

This presentation describes the development of a crystallization process that consistently yields API agglomerates which are robust to agitated drying.  During development, the impact of several factors on agglomerate formation and strength was evaluated, and a mechanism of agglomeration was proposed.  These studies showed that seed type has a strong impact on agglomerate properties and, subsequently, on the extent of agglomerate breakage during drying.  Seeds with varying properties were generated via wet milling, jet milling, and hammer milling, and evaluated in the crystallization on laboratory and pilot scale.  Filter, conical, and helical dryers were used on pilot and manufacturing scale to investigate the propensity of agglomerates made from the different seed types to withstand agitation.  Results from the studies enabled definition of a robust manufacturing process and powder property control.