Improvement of the Solubility and Evaluation of the Physical Properties of an Inclusion Complex Formed by a New Ferulic Acid Derivative and γ-Cyclodextrin

Nao Ikeda; Yutaka Inoue; Yuka Ogata; Isamu Murata; Xuan Meiyan; Jun Takayama; Takeshi Sakamoto; Mari Okazaki; Ikuo Kanamoto

doi:10.1021/acsomega.0c00277

Improvement of the Solubility and Evaluation of the Physical Properties of an Inclusion Complex Formed by a New Ferulic Acid Derivative and γ-Cyclodextrin

ACS Omega. 2020 May 18;5(21):12073-12080. doi: 10.1021/acsomega.0c00277. eCollection 2020 Jun 2.

Authors

Nao Ikeda¹, Yutaka Inoue¹, Yuka Ogata¹, Isamu Murata¹, Xuan Meiyan², Jun Takayama², Takeshi Sakamoto², Mari Okazaki³, Ikuo Kanamoto¹

Affiliations

¹ Laboratory of Drug Safety Management, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado-shi, Saitama 3500295, Japan.
² Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado-shi, Saitama 3500295, Japan.
³ Laboratory of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado-shi, Saitama 3500295, Japan.

Abstract

Ferulic acid derivative 012 (FAD012) is a ferulic acid (FA) derivative. The current study prepared a solid dispersion of FAD012 and γ-cyclodextrin (γCD) and ground it using a three-dimensional ball mill (3DGM) to prepare an inclusion complex. This study also assessed the physicochemical properties such as solubility of that complex. A Job's plot indicated that FAD012 and γCD formed an inclusion complex at a molar ratio of 1:1. Phase solubility diagrams revealed that FAD012 produced a B_S diagram. According to PXRD, FAD012 produced a diffraction peak at 2θ = 7.0° and γCD produced a diffraction peak at 2θ = 9.1°. Those two peaks were not produced by the 3DGM, but new peaks (2θ = 7.3 and 16.5°) were evident. DSC patterns revealed an endothermic peak due to the melting of FAD012 at 190 °C, but no endothermic peaks were evident with the 3DGM. NIR spectra of the 3DGM indicated that the methyl group of FAD012 produced a higher peak and that the OH groups of γCD produced a higher peak. ¹H-¹H ROESY NMR spectra (D₂O) revealed cross peaks for protons of the methyl group of FAD012 and a proton (H-3) in the cavity of γCD, so FAD012 presumably interacts with the wide opening of the γCD torus. A solubility test (25 °C) indicated that solubility improved about 5-fold for the 3DGM in comparison to the solubility of FAD012 alone (about 140 μg/mL). Based on these findings, an FAD012/γCD complex was formed by cogrinding, and its solubility improved. These observations are expected to expand the usefulness of cogrinding of FAD012 with γCD using a 3D ball mill.