By Dr. David J. Lamberto, Merck

The crystallization of an active pharmaceutical ingredient (API) from ethanol and water exhibited non-typical behavior relative to the formation of the desired three-dimensional “blocky” crystal morphology. For other compounds, relatively low levels of supersaturation are used to enhance particle growth and avoid undesired nucleation. However, for the compound of interest here, commonly used seeded antisolvent crystallizations have promoted particle growth in one dimension leading to the formation of needles resulting in solids with prohibitively low bulk density. To improve upon this, a reverse addition process was developed. However, formation of undesired needles was still observed in laboratory experiments following procedures used successfully at larger scale. Initial studies suggested that the process may be mixing sensitive, or perhaps that the morphology generated was related to a critical water activity. It was also speculated that the different morphologies observed could be related to different crystalline forms. However, this was found not to be the case. Further investigation showed that generation of high supersaturation is required to drive three-dimensional growth and achieve higher bulk density solids. A design of experiments (DOE) was performed to manipulate the supersaturation trajectory during the crystallization and assess the impact on the particles formed. This presentation describes the crystallization experiments performed, the process analytical technology (PAT) used, and provides the boundaries of the operating space required for consistently generating particles with the desired physical attributes. The DOE methodology and experiments performed to further derisk the process to ensure successful scale-up will be discussed. Finally, the results of a range finding study performed to determine critical API attributes needed to ensure successful drug product formulation will be presented.