Metronidazole Cocrystal Polymorphs with Gallic and Gentisic Acid Accessed through Slurry, Atomization Techniques, and Thermal Methods

Aleksandra J Dyba; Ewa Wiącek; Maciej Nowak; Jan Janczak; Karol P Nartowski; Doris E Braun

doi:10.1021/acs.cgd.3c00951

Metronidazole Cocrystal Polymorphs with Gallic and Gentisic Acid Accessed through Slurry, Atomization Techniques, and Thermal Methods

Cryst Growth Des. 2023 Oct 12;23(11):8241-8260. doi: 10.1021/acs.cgd.3c00951. eCollection 2023 Nov 1.

Authors

Aleksandra J Dyba^{1

2}, Ewa Wiącek², Maciej Nowak², Jan Janczak³, Karol P Nartowski^{2

4}, Doris E Braun¹

Affiliations

¹ Institute of Pharmacy, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.
² Department of Drug Form Technology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland.
³ Institute of Low Temperature and Structure Research, Polish Academy of Sciences, P.O. Box 1410, Okolna 2, 50-950 Wroclaw, Poland.
⁴ School of Pharmacy, University of East Anglia, Norwich Research Park, NR4 7TJ Norwich, U.K.

Abstract

In this study, key features of metronidazole (MNZ) cocrystal polymorphs with gallic acid (GAL) and gentisic acid (GNT) were elucidated. Solvent-mediated phase transformation experiments in 30 solvents with varying properties were employed to control the polymorphic behavior of the MNZ cocrystal with GAL. Solvents with relative polarity (RP) values above 0.35 led to cocrystal I°, the thermodynamically stable form. Conversely, solvents with RP values below 0.35 produced cocrystal II, which was found to be only 0.3 kJ mol^-1 less stable in enthalpy. The feasibility of electrospraying, including solvent properties and process conditions required, and spray drying techniques to control cocrystal polymorphism was also investigated, and these techniques were found to facilitate exclusive formation of the metastable MNZ-GAL cocrystal II. Additionally, the screening approach resulted in a new, high-temperature polymorph I of the MNZ-GNT cocrystal system, which is enantiotropically related to the already known form II°. The intermolecular energy calculations, as well as the 2D similarity between the MNZ-GAL polymorphs and the 3D similarity between MNZ-GNT polymorphs, rationalized the observed transition behaviors. Furthermore, the evaluation of virtual cocrystal screening techniques identified molecular electrostatic potential calculations as a supportive tool for coformer selection.