Preparation of pharmaceutical co-crystals through sustainable processes using supercritical carbon dioxide: a review

Abstract

The preparation of pharmaceutical co-crystals using supercritical CO₂ (scCO₂) is reviewed. Co-crystallization is an emerging and powerful technique to improve the physicochemical properties of an active pharmaceutical ingredient (API). The solid-state and solution co-crystallization methods usually employed present several disadvantages that may be overcome using the supercritical methods. All the methods employing scCO₂ have low environmental impact and operate at relatively low temperature avoiding API degradation and producing solvent-free pharmaceuticals. The role of the fluid varies from one method to another. In the rapid expansion of supercritical solutions (RESS) the API and the coformer are dissolved in scCO₂. In the co-crystallization with supercritical solvents (CSS), the fluid also acts as a solvent that facilitates molecular interactions in a suspension of the API and coformer powders. However, in the supercritical antisolvent (SAS) and the gas antisolvent (GAS) crystallizations scCO₂ acts as an antisolvent that induces precipitation of the API and the coformer previously dissolved in an organic solvent. In the atomization and antisolvent (AAS) technique and supercritical fluid enhanced atomization (SEA) the fluid may act either as a spray enhancer or an antisolvent depending on the process conditions. Each method is described and its application, advantages and disadvantages are discussed. Future perspectives and areas to be investigated are outlined.