Isomorphous Crystals Formed by the Similar Supramolecular Motifs in Sorafenib Hydrochloride and Regorafenib Hydrochloride Salts

Chi Uyen Phan,Jie Shen,Jiyong Liu,Guping Tang,Jianming Mao,Xiurong Hu

doi:10.3390/cryst9120649

Chi Uyen Phan, Jie Shen + Show 4 more

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https://doi.org/10.3390/cryst9120649

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Journal: Crystals	Publication Date: Dec 6, 2019
Citations: 9	License type: CC BY 4.0

Affiliation: Zhejiang University, University of Da Nang

Abstract

Sorafenib and regorafenib (or fluoro-sorafenib) are multikinase inhibitors active in the treatment of various human cancers, but their solubilities are very poor. To improve their solubilities, in this study, sorafenib hydrochloride (Sor·HCl, I) and regorafenib hydrochloride (Reg·HCl, II) have been prepared and their crystal structures were characterized. Their solubility properties in water were evaluated. Intriguingly, they are isomorphous crystal structures with the same space group and the similar unit cell dimensions, which were caused by the similar supramolecular patterns resulted by the formation of N–H···Cl− hydrogen bond instead of hydrogen bond between the protonated pyridinium cation and counterion. Moreover, the solubility properties displayed identical profiles. It may be concluded that a similar crystal structure leads to a comparable solubility profile.

Highlights

Low solubility is considered to be one of the most challenging issues in drug development
Sorafenib and regorafenib dissolved very slowly in water. These results showed that hydrochloride salt of sorafenib and regorafenib have improved their solubility, which might enhance their bioavailability
Sorafenib hydrochloride and regorafenib hydrochloride salts were recrystallized from methanol, the experimental and calculated Powder X-Ray Diffraction (PXRD) patterns showed that the structures of the two salts were not changed (Figure S3)

Summary

Introduction

Low solubility is considered to be one of the most challenging issues in drug development. Improving the solubility of drugs with poor water solubility is critical in terms of enhancing their pharmacokinetic and pharmacodynamic properties in order to increase bioavailability [2]. There are many approaches to improve solubility, such as salt or cocrystal formation. Solubility improvement of insoluble drugs can be typically achieved by salt formation in pharmaceutical therapy [4] such as hydrochloride, sulfonate, sulfate, maleate, fumarate, etc. Among these salts, hydrochloride of drugs is preferred and the most commonly used salt form clinically for its low toxicity and high biocompatibility [5]

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