| Abstract |
Supercritical carbon dioxide (scCO(2)) induces polymorphism in pharmaceutical drugs. However, it is unclear whether polymorphism is induced by the CO2 antisolvent effect or simply by the spray-drying step involved in the scCO(2) antisolvent processes. Herein, this effect is clarified by using supercritical enhanced atomization techniques assisted with scCO(2) and scN(2) and three drugs (indomethacin (IND), carbamazepine (CBZ), and theophylline (TPL)) that have already exhibited polymorphism when processed by classical supercritical antisolvent (SAS) processing. Polyrnorphs were obtained by supercritical enhanced atomization (SEA) using either CO2 or N-2 revealing that polymorphism was induced by atomization in all cases except for TPL, which was very sensitive to the CO2 antisolvent action. The TPL polymorph was produced by the atomization of supercritical antisolvent induced suspensions (ASAIS) process, which enables SAS to be performed in standard (atmospheric pressure) spray dryers. A computational fluid dynamics (CFD) model was developed to understand the antisolvent-driven supersaturation of TPL inside the ASAIS nozzle. The significant solubility of TPL in CO2-tetrahydrofuran and its high sensitivity to the antisolvent precipitation mechanism limit the purity of this polymorph to a narrow range of process conditions. |
