Carbon dioxide has been extensively used as a green solvent medium for the crystallization of active pharmaceutical ingredients (APIs) by replacing harmful organic solvents. This work explores the mechanisms underlying a novel recrystallization methodcocrystallization with supercritical solvent (CSS)which enables APIs cocrystallization by suspending powders in pure CO 2 . Six well-known APIs that form cocrystals with saccharin (SAC) were processed by CSS, namely, theophylline (TPL), indomethacin (IND), carbamazepine (CBZ), caffeine (CAF), sulfamethazine (SFZ), and acetylsalicylic acid (ASA). Pure cocrystals were obtained for TPL, IND, and CBZ (with SAC) after 2 h of CSS processing. Convection was revealed to be a determining parameter for successful cocrystallization with high-yield levels. TPL− SAC was selected as a model system to study the cocrystallization kinetics in the gas, supercritical, and liquid phases under different conditions of pressure (8−20 MPa), temperature (30 to 70°C), and convection regimes. The solubility of each substance in CO 2 was measured at the selected working conditions. TPL−SAC showed a cocrystallization rate of 2.9% min −1 , two times higher than that of IND−SAC, due to the higher solubility of TPL in CO 2 . The cocrystallization kinetics was also improved by increasing the CO 2 density, showing that cocrystallization was limited by the dissolution of cocrystal formers. Overall, the CSS process has a potential for scale-up as a novel, simple, solvent-free batch process whenever the cocrystal phase is formed in the CO 2 media.

Supercritical carbon dioxide (scCO 2 ) induces polymorphism in pharmaceutical drugs. However, it is unclear whether polymorphism is induced by the CO 2 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. Polymorphs were obtained by supercritical enhanced atomization (SEA) using either CO 2 or N 2 revealing that polymorphism was induced by atomization in all cases except for TPL, which was very sensitive to the CO 2 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 CO 2 -tetrahydrofuran and its high sensitivity to the antisolvent precipitation mechanism limit the purity of this polymorph to a narrow range of process conditions.

This work evaluates the feasibility of the supercritical enhanced atomization (SEA) process to improve stability and delivery of active pharmaceutical ingredients (APIs). This process was used to generate distinct microcomposites of pure theophylline (TPL), an API model, the theophylline-saccharin (TPL-SAC) cocrystal, and dispersions of each crystalline form in hydrogenated palm oil (HPO), TPL-HPO and TPL-SAC-HPO. The formation of the TPL-SAC cocrystal within the HPO suggests that the cocrystallization step anticipates the lipid dispersion during the formation of the microcomposites. The TPL-SAC cocrystal extended the TPL stability at 92% relative humidity by over 6 months, contrary to that of raw TPL, which converted into a monohydrate after a few days only, even when dispersed into HPO. The TPL-SAC cocrystal slowed the TPL release from the lipid particles, which is explained by its higher stability toward hydration. The feasibility of the cocrystal microcomposites for therapeutic application was evaluated by estimating the plasmatic concentration of TPL using a pharmacokinetic model (one compartment approach). This model revealed that the small therapeutic concentration window and high elimination rate of TPL raises serious limitations to control the TPL release. The microcomposites were able to attenuate the TPL burst effect and improve stability toward hydration but could not extend significantly its delivery.

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This work describes a new crystalline structure of minocycline and evidences the ability of ethanol-CO2 system in removing water molecules from the crystalline structure of this API, at modest pressure, temperature and relatively short time (2 h), while controlling the crystal habit. This process has therefore the potential to become a consistent alternative towards the control of the solid form of APIs.