Influence of solvent selection and RESS processing conditions on formation of a praziquantel-malonic acid cocrystal in supercritical CO2

Praziquantel (PZQ) is an anthelmintic drug with low solubility, therefore cocrystallization and particle size reduction is desirable to improve bioavailability. In this study, a PZQ-malonic acid cocrystal was micronized by rapid expansion of supercritical solution (RESS). Due to low solubility in scCO 2 , four cosolvents were screened as RESS modifiers. While addition of acetone or THF yielded mixtures of PZQ and its cocrystal, MeOH and EtOH produced pure cocrystal. Impact of pressure (15–30 MPa), temperature (35–55 °C), and cosolvent loading (3–10 volumes) on phase-purity, yield, and particle size were investigated. Adding cosolvent to RESS facilitated dissolution of cocrystal formers in scCO 2 and crystallization of the cocrystal with yields up to 68.5 wt% and particle size as low as 600 nm. Results show that for APIs with low solubility in scCO 2 , cosolvent-modified RESS is a suitable approach for simultaneous crystallization and micronization. • A praziquantel-malonic acid cocrystal was made by RESS and reactive crystallization. • The API solubility in pure scCO 2 was too low for using the RESS process. • Four cosolvents with different properties were screened for RESS. • Effect of pressure, temperature, solvent amount was studied with MeOH cosolvent. • Yields up to 69 % were obtained from RESS with MeOH cosolvent.