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

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.

A study to discover novel pharmaceutical cocrystals of pelubiprofen with a machine learning approach compared

“…In addition, subsequent annealing may induce a transformation from a residual supercooled amorphous phase to a cocrystal phase. 69 During our rotary evaporation-based cocrystallization experiments, some of the products occurred as translucent amorphous or paste-like sticky solids. This semi-solid-like morphology did not substantially change, regardless of exposure to vacuum drying for a few days.…”

Discovery of new cocrystals beyond serendipity: lessons learned from successes and failures

“…186 Many odd-numbered acids exhibit subzero theoretical T g values, owing to their inability to adopt an in-plane orientation of both carboxylic groups with respect to the hydrocarbon chain. 187 Hence, the use of these low T g coformers may disfavor the recrystallization of the coamorphous glassy phase. Similar trends have also been observed in unsaturated derivatives of succinic acid 187 (Fig.…”

“…187 Hence, the use of these low T g coformers may disfavor the recrystallization of the coamorphous glassy phase. Similar trends have also been observed in unsaturated derivatives of succinic acid 187 (Fig. 7).…”

Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline

“…The CI was calculated from the raw PXRD data, which is the ratio of the area of all crystalline peaks to the total area comprising the crystalline and amorphous content [67,[98][99][100]. High-angle Bragg peaks (>20 • ) were excluded in this analysis as poorer counting statistics could be resulted from high-angle data, due to the combined effects of a decrease in the scattering coefficient with increasing sin θ/λ, Lorentzpolarization factor and thermal vibrations [101,102]. CIs of the 11 formulations ranged from 57 to 75% (Table 4).…”