Crystal Structure, Solubility, and Pharmacokinetic Study on a Hesperetin Cocrystal with Piperine as Coformer.

Yanjie Liu,Xiaoxue Zhang,Xiuhua Zhao,Siying Wang,Qilei Yang,Fan Yang

doi:10.3390/pharmaceutics14010094

Abstract

Hesperetin (HES) is a key biological active ingredient in citrus peels, and is one of the natural flavonoids that attract the attention of researchers due to its numerous therapeutic bioactivities that have been identified in vitro. As a bioenhancer, piperine (PIP) can effectively improve the absorption of insoluble drugs in vivo. In the present study, a cocrystal of HES and PIP was successfully obtained through solution crystallization. The single-crystal structure was illustrated and comprehensive characterization of the cocrystal was conducted. The cocrystal was formed by two drug molecules at a molar ratio of 1:1, which contained O–H–O hydrogen bonds between the carbonyl and ether oxygen of PIP and the phenolic hydroxyl group of HES. In addition, a solubility experiment was performed on powder cocrystal in simulated gastrointestinal fluid, and the result revealed that the cocrystal improves the dissolution behavior of HES compared with that of the pure substance. Furthermore, HES’s bioavailability in the cocrystal was six times higher than that of pristine drugs. These results may provide an efficient oral formulation for HES.

Highlights

Numerous drugs are widely known to have polymorphism which leads to differences in bioavailability and activity indicators
Considering the relationship between a physical mixture’s thermal behavior and cocrystal formation, an exothermic peak associated with cocrystal formation was detected immediately after the occurrence of an endothermic peak when the physical mixture consisting of two components capable of cocrystal formation was heated via Differential Scanning Calorimetry (DSC) [46,47]
The TG image showed that HES, PIP, and the HES–PIP cocrystal were free from crystalline water or solvents in the lattice and begin to decompose at approximately 252.5 ◦ C, 267.4 ◦ C, and 254.9 ◦ C, respectively

Summary

Introduction

Numerous drugs are widely known to have polymorphism which leads to differences in bioavailability and activity indicators. Numerous studies on the fundamental aspects and applications of cocrystallization have been published, and several cocrystals are currently on the market or under clinical trial phases, e.g., sacubitril-disodium valsartan-water (EntrestoTM ), escitalopram oxalate-oxalic acid (Lexapro® ), ertuglifozin-L-pyroglutamic acid and tramadol-celecoxib [9,10,11,12,13]. These indicated that cocrystal formation is an effective method for improving drug’s solubility and oral bioavailability

Methods

Results

Conclusion