A Novel Strategy for Pharmaceutical Cocrystal Generation Without Knowledge of Stoichiometric Ratio: Myricetin Cocrystals and a Ternary Phase Diagram

To develop a streamlined strategy for pharmaceutical cocrystal preparation without knowledge of the stoichiometric ratio by preparing and characterizing the cocrystals of myricetin (MYR) with four cocrystal coformers (CCF). An approach based on the phase solubility diagram (PSD) was used for MYR cocrystals preparation and the solid-state properties were characterized by differential scanning calorimetry (DSC), fourier transform-infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The ternary phase diagram (TPD) was constructed by combining the PSD and nuclear magnetic resonance (NMR) data. After that, the TPD was verified by traditional methods. The dissolution of MYR in the four cocrystals and pure MYR within three different media were also evaluated. A simple research method for MYR cocrystal preparation was obtained as follows: first, the PSD of MYR and CCF was constructed and analyzed; second, by transforming the curve in the PSD to a TPD, a region of pure cocrystals formation was exhibited, and then MYR cocrystals were prepared and identified by DSC, FT-IR, PXRD, and SEM; third, with the composition of the prepared cocrystal from NMR, the TPD of the MYR-CCF-Solvent system was constructed. The powder dissolution data showed that the solubility and dissolution rate of MYR was significantly enhanced by the cocrystals. A novel strategy for pharmaceutical cocrystals preparation without knowledge of the stoichiometric ratio based on the TPD was established and MYR cocrystals were successfully prepared. The present study provides a systematic approach for pharmaceutical cocrystal generation, which benefits the development and application of cocrystal technology in drug delivery.