Polymorphism of griseofulvin: concomitant crystallization from the melt and a single crystal structure of a metastable polymorph with anomalously large thermal expansion

Abstract

Griseofulvin (GSF) is a classic antifungal drug that has been in clinical use for over 50 years, but its polymorphism was recognized only recently via melt crystallization. Here we report the structure of a single crystal of GSF form II which was unusually harvested from the supercooled melt. GSF form II exhibits an anomalously large thermal expansion coefficient.

Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

“…Polarized light microscope combined with hot stage can also be used to obtain highquality single crystals [35,36]. For instance, high-quality single crystals of the metastable form II of griseofulvin, was obtained from the melt under a polarized light microscope equipped with a hot stage [35].…”

“…Polarized light microscope combined with hot stage can also be used to obtain highquality single crystals [35,36]. For instance, high-quality single crystals of the metastable form II of griseofulvin, was obtained from the melt under a polarized light microscope equipped with a hot stage [35]. Large and faceted single crystals of griseofulvin form II were observed after a rapid growth at 200 • C in the presence of 10% w/w PEO, which is reported to effectively accelerate the crystal growth [35].…”

“…For instance, high-quality single crystals of the metastable form II of griseofulvin, was obtained from the melt under a polarized light microscope equipped with a hot stage [35]. Large and faceted single crystals of griseofulvin form II were observed after a rapid growth at 200 • C in the presence of 10% w/w PEO, which is reported to effectively accelerate the crystal growth [35]. Single-crystal X-ray diffraction analysis as a function of temperature revealed that griseofulvin form II exhibited an anomalously large coefficient of thermal expansion [35].…”

The solid-state conformation of the topical antifungal agent O-naphthalen-2-yl N-methyl-N-(3-methylphenyl)carbamothioate

“…Crystallographically, griseofulvin, clotrimazole, miconazole nitrate, and the hydrochloride salts of terbinafine and butenafine have all been structurally characterized. For example, the Cambridge Structural Database (CSD; Groom et al, 2016) lists 13 entries for griseofulvin alone, with the two most recent studies having been published earlier this year (Mahieu et al, 2018;Su et al, 2018). However, the crystal structure of tolnaftate, an equally classic compound as griseofulvin in the antifungal arena, is nowhere to be found in the CSD or the scientific literature.…”

Ambient l-lactic acid crystal polymorphism

“…Melt crystallization has been an effective method of late for discovering new polymorphs. [18][19][20][21][22][23][24] LLA, however, when melted in sealed glass tubes and then quenched at 25°C…”