Quercetin/L-proline cocrystals with additives production through the GAS antisolvent (GAS) method

Quercetin/L-proline cocrystals (QUE/PRO) are crystalline materials composed by these two compounds in the same lattice. This configuration provides improved physicochemical properties to the material compared with the pure substances. This cocrystal has been successfully produced using the gas antisolvent (GAS) method, which employs CO₂ as an antisolvent to induce the precipitation of the parent mixture as a cocrystal. This work aimed to study for the first time, the role of polymeric additives on the morphology, particle size and dissolution performance of GAS-produced QUE/PRO cocrystal. In brief, QUE/PRO were produced as follow: 1:2 mmol ratio, 80 bar, 35°C, with 2% (w/w) of the polymers polyvinylpyrrolidone K30 (PVP-K30), poly(ethylene glycol) (PEG-6000), Pluronic® F127 (PLU), and ethylcellulose (ECL). The formation was confirmed by Powder X-ray (PXRD) and Scanning Electron Microscopy (SEM) was used to evaluate morphology and particle size. Dissolution studies were performed at pH 1.2 and 6.8 (180 min), to evaluate the QUE concentration vs time. Cocrystals yields (57.7-67.9%) were not affected by the additives. The particle size of polymer-produced samples decreased (21.9 to 10.8 µm) compared to the additive-free samples. It was evidenced sample agglomeration with distinct shapes, needle-like for PVP, dandelion like for samples supplemented with PEG and ECL. Also, PVP provided an enhanced and stable dissolution of QUE at pH 1.2, maintaining the high concentration levels for 180 min.; the other samples showed a similar behavior in the same medium. At pH 6.8, the addition of PLU and ECL caused high levels of supersaturation, displaying a dissolution profile consistent with spring and parachute effect; samples with PVP and PEG were similar to pure quercetin and additive-free cocrystal. The addition of PVP, PLU, and ECL had a positive effect in the QUE/PRO cocrystal, paving the way for future studies varying polymer concentration.