Elusive Seed Formation via Electrical Confinement: Control of a Novel Cocrystal in Cooling Crystallization

Pharmaceutical cocrystals are multicomponent materials formed to enhance the properties of active pharmaceutical ingredients (APIs) and are commercially used to increase the number of drug candidates that successfully make it through the drug discovery pipeline. Nevertheless, the industrial production of cocrystals and other elusive solid forms remains a challenge. The main limitations are due to challenges related to the scale-up, solid-form control, and undesirable parameters needed for the preparation method. This study leverages the features of electrospray crystallization to generate elusive cocrystal forms that contain the API acetaminophen (paracetamol) and its regioisomer metacetamol. We report the formation of a new cocrystal, which is held together by van der Waals interactions, and the use of the newly electrosprayed cocrystals as seeds to tune the performance of cooling crystallization, allowing this commonly used crystallization method to produce the elusive cocrystal. The electrosprayed cocrystal displays a previously unseen sponge-like surface topology and a fourfold solubility enhancement over those found for single-component APIs. This new technology expands the accessibility to new solid forms that were previously inaccessible by other crystallization methods.