Production of Resveratrol/L-Proline Cocrystals with Additives Using the GAS Antisolvent Method

Resveratrol/L-proline cocrystals (RES/PRO) are crystalline materials composed of these two compounds in the same crystal lattice, seeking enhance properties. This cocrystal has been produced by gas antisolvent (GAS), an eco-friendly method that uses CO₂ as an antisolvent to trigger the precipitation of the parent mixture as a cocrystal. In this work, GAS process was applied to produce RES:PRO (1:2 mmol, 90 bar, 35°C, 30 mL ethanol) cocrystals with the addition of 2% of polyvinylpyrrolidone K30 (PVP), poly(ethylene glycol) 6000 (PEG), Pluronic® F127 (PLU), and ethylcellulose (ECL) for the first time, aiming to investigate their role in modifications in particle size, morphology and dissolution profile on this cocrystallization. Cocrystal formation was confirmed by powder X-ray diffraction (PXRD). Particle morphology and size were analyzed by scanning electron microscopy (SEM), and dissolution studies were conducted for 180 min at pH 1.2 and pH 6.8 to evaluate the stability and RES concentration. Cocrystals yields (57.5-72.5%) were not affected by the additives, and the PXRD diffractograms confirmed successful cocrystallization. An increase in average particle size (from 6.4 to 27.8 µm) was observed in all polymer-containing samples. Regarding to morphology, the addition of PVP and ECL maintained the needle-like shape of the cocrystals, and the addition of PLU and PEG formed agglomerates. The dissolution profile was not improved by the additives. At pH 6.8, all samples had worse dissolution when compared to RES and the pure cocrystal. In pH 1.2, the addition of PVP was capable of stabilizing the RES concentration through 180 min, without decreasing, but did not improve the solubility. Therefore, it was possible to form cocrystals with additives, which affected the particle size and morphology but poorly affected the dissolution profile. PVP had the best results and may be used in further studies, with variation in the amount added.