Two Novel Palbociclib-Resorcinol and Palbociclib-Orcinol Cocrystals with Enhanced Solubility and Dissolution Rate.

Chenxin Duan,Feifei Liang,Wenwen Liu,Chao Hao,Guisen Zhang,Yanming Chen,Yin Chen,Xinyi Xiao,Yunwen Tao

doi:10.3390/pharmaceutics14010023

Abstract

Palbociclib (PAL) is an effective anti-breast cancer drug, but its use has been partly restricted due to poor bioavailability (resulting from extremely low water solubility) and serious adverse reactions. In this study, two cocrystals of PAL with resorcinol (RES) or orcinol (ORC) were prepared by evaporation crystallization to enhance their solubility. The cocrystals were characterized by single crystal X-ray diffraction, Hirshfeld surface analysis, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared and scanning electron microscopy. The intrinsic dissolution rates of the PAL cocrystals were determined in three different dissolution media (pH 1.0, pH 4.5 and pH 6.8), and both cocrystals showed improved dissolution rates at pH 1.0 and pH 6.8 in comparison to the parent drug. In addition, the cocrystals increased the solubility of PAL at pH 6.8 by 2–3 times and showed good stabilities in both the accelerated stability testing and stress testing. The PAL-RES cocrystal also exhibited an improved relative bioavailability (1.24 times) than PAL in vivo pharmacokinetics in rats. Moreover, the in vitro cytotoxicity assay of PAL-RES showed an increased IC50 value for normal cells, suggesting a better biosafety profile than PAL. Co-crystallization may represent a promising strategy for improving the physicochemical properties of PAL with better pharmacokinetics.

Highlights

Publisher’s Note: MDPI stays neutralImproving the solubility of poorly water-soluble drugs is one of the current challenges facing the pharmaceutical industry [1]
Drug cocrystals refer to crystalline substances composed of two or more different molecules, usually with active pharmaceutical ingredients (API) and cocrystal formations (“coformers”) in the same crystal lattice [9,10]
The cocrystal data were collected by Single Crystal X-ray Diffraction (SCXRD) to obtain the three-dimensional (3D) structure and the intermolecular interactions of the cocrystals

Summary

Introduction

Improving the solubility of poorly water-soluble drugs is one of the current challenges facing the pharmaceutical industry [1]. The core of this endeavor underlies the exploitation of different forms of APIs, such as cocrystals, amorphous solids [2], polymorphs [3], salts [4], hydrates [5], and solvent compounds [6]. Different coformers can be selected according to the different properties of drugs to prepare cocrystals, which provides a broader space for the development of pharmaceutical preparations [25,26,27,28]

Methods

Results

Conclusion