Effects of the Glass-Forming Ability and Annealing Conditions on Cocrystallization Behaviors via Rapid Solvent Removal: A Case Study of Voriconazole.

Si Nga Wong,Henry H Y Tong,Shing Fung Chow,Susan Wing Sze Chan,Bianfei Xuan,Xuexin Peng,Hok Wai Lee

doi:10.3390/pharmaceutics12121209

Si Nga Wong, Henry H Y Tong + Show 5 more

Open Access

https://doi.org/10.3390/pharmaceutics12121209

Copy DOI

Abstract

The kinetic entrapment of molecules in an amorphous phase is a common obstacle to cocrystal screening using rapid solvent removal, especially for drugs with a moderate or high glass-forming ability (GFA). The aim of this study was to elucidate the effects of the coformer’s GFA and annealing conditions on the nature of amorphous phase transformation to the cocrystal counterpart. Attempts were made to cocrystallize voriconazole (VRC) with four structural analogues, namely fumaric acid (FUM), tartaric acid (TAR), malic acid (MAL), and maleic acid (MAE). The overall GFA of VRC binary systems increased with decreasing glass transition temperatures (Tgs) of these diacids, which appeared as a critical parameter for predicting the cocrystallization propensity such that a high-Tg coformer is more desirable. A new 1:1 VRC-TAR cocrystal was successfully produced via a supercooled-mediated re-cocrystallization process, and characterized by PXRD, DSC, and FTIR. The cocrystal purity against the annealing temperature displayed a bell-shaped curve, with a threshold at 40 °C. The isothermal phase purity improved with annealing and adhered to the Kolmogorov–Johnson–Mehl–Avrami kinetics. The superior dissolution behavior of the VRC-TAR cocrystal could minimize VRC precipitation upon gastric emptying. This study offers a simple but useful guide for efficient cocrystal screening based on the Tg of structurally similar coformers, annealing temperature, and time.

Highlights

The application of rapid solvent removal via rotary evaporation has gained increasing popularity for screening kinetically stable pharmaceutical cocrystals, which cannot be obtained by neat grinding, slow evaporation, slurry conversion, etc
Despite no conclusion having been drawn about whether cocrystal formation is favored over coamorphous systems at present [9], it should be noted that a cocrystal retains its distinct value in oral dosage form production and storage in light of its capability to simultaneously improve the dissolution rate, and the tableting behavior and hygroscopicity, etc. [14]
This study aims to provide deeper understandings regarding the phase transitions between supercooled amorphous and cocrystal states

Summary

Introduction

The application of rapid solvent removal via rotary evaporation has gained increasing popularity for screening kinetically stable pharmaceutical cocrystals, which cannot be obtained by neat grinding, slow evaporation, slurry conversion, etc It is deemed an efficient and easy-to-use approach for circumventing the inherent cocrystal metastability through creating a sufficiently high degree of solute supersaturation in solution [1,2]. At the same time, it is not uncommon to encounter amorphization during rotary evaporation [3,4,5] since the rapid elimination of solvent can kinetically entrap the drug and coformer in amorphous content and prevent these solute molecules from rearranging into a long-range order structure of crystals Such an effect is more pronounced for metastable systems, where the phase purity of cocrystals correlates to the solvent evaporation rate [6]. Despite no conclusion having been drawn about whether cocrystal formation is favored over coamorphous systems at present [9], it should be noted that a cocrystal retains its distinct value in oral dosage form production and storage in light of its capability to simultaneously improve the dissolution rate, and the tableting behavior and hygroscopicity, etc. [14]

Objectives

Methods

Results

Conclusion