Cocrystallization of Febuxostat with Pyridine Coformers: Crystal Structural and Physicochemical Properties Analysis

Lei Gao,Xianrui Zhang,Franc Perdih

doi:10.1155/2021/3834368

Abstract

Drug cocrystals and salts have promising applications for modulating the physicochemical properties and solubility of pharmaceuticals. In this study, a cocrystal and two salts of febuxostat (FEB) with pyridine nitrogen coformers, including 4, 4′-bipyridine (BIP), 3-aminopyridine (3AP) and 4-hydroxypyridine (4HP), were designed to improve the solubility of FEB. The single-crystal structures were elucidated, and their physical and chemical properties were investigated by IR, PXRD, and DSC. In addition, drug-related properties, including the solubility and powder dissolution rate were assessed. The solubility and powder dissolution studies showed that the FEB-BIP cocrystal and FEB-3AP salt have superior dissolution compared to FEB.

Highlights

Over the past decades, drug cocrystals and salts screening has been an important tool for optimizing the drug-forming properties [1–8]
FEB is classified as a biopharmaceutical classification system (BCS) II compound with a low water solubility and high penetrability
Two febuxostat molecules are connected by O2–H1· · ·N3 hydrogen bonds to form a parallel chain (Figure 2). e parallel chains are held together via C18–H18· · ·N2 and C20–H20· · ·N2 hydrogen bonds to produce a two-dimensional sheet framework (Figure 3)

Summary

Introduction

Drug cocrystals and salts screening has been an important tool for optimizing the drug-forming properties [1–8]. Due to the diversity of cocrystal formers (CCFs), researchers can design drug cocrystal and salt forms in a targeted manner to optimize their solubility, mechanical properties, hygroscopicity, stability, and bioavailability [9–14]. We designed new cocrystal or salt forms of febuxostat to modulate its solubility and dissolution rate. Based on the structural analysis of previous-reported cocrystals and salts of febuxostat, we identified those cocrystal coformers containing pyridine nitrogen with the potential to form hydrogen bonds with FEB. Us, a series of cocrystal coformers containing pyridine nitrogen was employed to screen the cocrystals and salts of FEB (Supplementary Materials, Figure S1). A novel cocrystal of FEB and 4, 4′-bipyridine (BIP) and two salts of 3-aminopyridine (3AP) and 4-hydroxypyridine (4HP) were successfully designed, synthesized, and characterized (Figure 1)

Materials and Methods

Results and Discussion

Conclusions