The effects of pH, surfactant, ion concentration, coformer, and molecular arrangement on the solubility behavior of myricetin cocrystals

Shuzhen Ren; Mingyu Liu; Chao Hong; Guowen Li; Jiabin Sun; Jianying Wang; Lei Zhang; Yan Xie

doi:10.1016/j.apsb.2018.09.008

The effects of pH, surfactant, ion concentration, coformer, and molecular arrangement on the solubility behavior of myricetin cocrystals

Acta Pharm Sin B. 2019 Jan;9(1):59-73. doi: 10.1016/j.apsb.2018.09.008. Epub 2018 Sep 19.

Authors

Shuzhen Ren¹, Mingyu Liu^{1

2}, Chao Hong¹, Guowen Li³, Jiabin Sun¹, Jianying Wang⁴, Lei Zhang⁴, Yan Xie¹

Affiliations

¹ Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
² Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
³ Pharmacy Department, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China.
⁴ Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Abstract

Pharmaceutical cocrystals are a promising technology that can be used to improve the solubility of poor aqueous compounds. The objective of this study was to systematically investigate the solubility of myricetin (MYR) cocrystals, including their kinetic solubility, thermodynamic solubility, and intrinsic dissolution rate (IDR). The effects of pH, surfactant, ion concentration, and coformers on the cocrystal solubility were evaluated. Furthermore, single crystal structures of MYR, myricetin-isonicotinamide (MYR-INM) and myricetin-caffeine (MYR-CAF) cocrystals were analyzed to discuss the possible reasons for the enhancement of cocrystal solubility from the perspective of the spatial structure. The results indicated that the kinetic solubility of MYR cocrystals was modulated by pH and cocrystal coformer (CCF) ionization in buffer solution, while it primarily depended on the CCF solubility in pure water. In addition, the solubility of MYR cocrystals was increased in a concentration dependent fashion by the surfactant or ion concentration. The thermodynamic solubility of MYR-INM (1:3) cocrystals decreased with the increases of the pH value of the dissolution media. The IDR of MYR cocrystals was faster than that of MYR in the same medium and extremely fast in pH 4.5 buffer. The improved solubility of MYR cocrystals was probably related to the alternate arrangements of MYR and INM/CAF molecules and increased intermolecular distance. The present study provides some references to investigate the solubility behavior of pharmaceutical cocrystals.

Keywords: API, active pharmaceutical ingredient; CAF, caffeine; CCF, cocrystal coformer; CCF, coformer; CSC, critical stabilization concentration; Cocrystal solubility; Coformer; Crystal structure; Ctr, transition concentration; FDA, Food and Drug Administration; IDR, intrinsic dissolution rate; INM, isonicotinamide; Ksp, solubility product; MYR, myricetin; MYR–CAF, myricetin–caffeine; MYR–INM, myricetin–isonicotinamide; Myricetin; NIC, nicotinamide; PRO, proline; PXRD, powder X-ray diffraction; pH.