Exploring Coformer Substitution in Cocrystallization: Griseofulvin and Phenol Derivatives

Abstract

This study investigates the cocrystallization of griseofulvin with phenolic coformers, highlighting its feasibility and variability. In addition to the previously reported cocrystal of griseofulvin with 4-t-butylphenol (1:1), the experimental screening identified three new cocrystals: with phenol (2:5), 4-t-amylphenol (1:1), and 2,4,6-trichlorophenol (2:3). Phenols with carbon substituents in the ortho or meta positions failed to form cocrystals, likely due to steric hindrance and electron-donating effects. In contrast, phenols with chlorine substituents, particularly in the ortho and para positions, demonstrated enhanced cocrystallization potential, driven by the electron-withdrawing effects that promote hydrogen bonding. The 2:5 phenol cocrystal required optimized conditions for isolation and exhibited instability under ambient conditions due to coformer sublimation, a tendency also observed for the other cocrystals. While challenging, sublimation facilitated the determination of stoichiometric ratios, which varied from 1:1 to 2:3 and 2:5. Furthermore, this study provides a data set of cocrystal-forming and noncocrystal-forming combinations as a rigorous test case for virtual cocrystal prediction. Among the tested methods, crystal structure prediction proved the most reliable, identifying all observed cocrystal combinations and, together with powder X-ray diffraction, offering insights into the experimental coformer and cocrystal structures. Future integration of CSP with machine learning could accelerate prediction speed and accommodate a broader range of stoichiometric ratios. Overall, this work highlights the complexity and potential of cocrystallization.