Directing crystallization outcomes of conformationally flexible molecules: polymorphs, solvates and desolvation pathways of fluconazole

Nowak, Maciej, Dyba, Aleksandra, Janczak, Jan, Morritt, Alexander, Fabian, Laszlo, Karolewicz, Bożena, Khimyak, Yaroslav Z. ORCID:, Braun, Doris E. and Nartowski, Karol P. (2022) Directing crystallization outcomes of conformationally flexible molecules: polymorphs, solvates and desolvation pathways of fluconazole. Molecular Pharmaceutics, 19 (2). pp. 456-471. ISSN 1543-8384

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Control over polymorphism and solvatomorphism in API assisted by structural information, e.g., molecular conformation or associations via hydrogen bonds, is crucial for the industrial development of new drugs, as the crystallization products differ in solubility, dissolution profile, compressibility, or melting temperature. The stability of the final formulation and technological factors of the pharmaceutical powders further emphasize the importance of precise crystallization protocols. This is particularly important when working with highly flexible molecules with considerable conformational freedom and a large number of hydrogen bond donors or acceptors (e.g., fluconazole, FLU). Here, cooling and suspension crystallization were applied to access polymorphs and solvates of FLU, a widely used azole antifungal agent with high molecular flexibility and several reported polymorphs. Each of four polymorphic forms, FLU I, II, III, or IV, can be obtained from the same set of alcohols (MeOH, EtOH, isPrOH) and DMF via careful control of the crystallization conditions. For the first time, two types of isostructural channel solvates of FLU were obtained (nine new structures). Type I solvates were prepared by cooling crystallization in Tol, ACN, DMSO, BuOH, and BuON. Type II solvates formed in DCM, ACN, nPrOH, and BuOH during suspension experiments. We propose desolvation pathways for both types of solvates based on the structural analysis of the newly obtained solvates and their desolvation products. Type I solvates desolvate to FLU form I by hydrogen-bonded chain rearrangements. Type II solvates desolvation leads first to an isomorphic desolvate, followed by a phase transition to FLU form II through hydrogen-bonded dimer rearrangement. Combining solvent-mediated phase transformations with structural analysis and solid-state NMR, supported by periodic electronic structure calculations, allowed us to elucidate the interrelations and transformation pathways of FLU.

Item Type: Article
Additional Information: Funding Information: This project was funded by the National Science Centre in Poland via research grant UMO-2020/01/Y/ST4/00101 (AJD Ph.D. scholarship and MN funding). This research was funded with national funds for scientific research by the Ministry of Science and Higher Education, Poland (SUB.D190.21.098).
Uncontrolled Keywords: crystal structure,desolvation,fluconazole,polymorphism,solvates,molecular medicine,pharmaceutical science,drug discovery ,/dk/atira/pure/subjectarea/asjc/1300/1313
Faculty \ School: Faculty of Science > School of Pharmacy
UEA Research Groups: Faculty of Science > Research Groups > Pharmaceutical Materials and Soft Matter
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Depositing User: LivePure Connector
Date Deposited: 16 Feb 2022 09:30
Last Modified: 10 Aug 2023 22:30
DOI: 10.1021/acs.molpharmaceut.1c00752


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