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Phase transition and solubility of levofloxacin crystal forms: anhydrates versus hydrates

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Abstract

Levofloxacin (LF), a pure levo-isomer of ofloxacin, is a quinolone-class antibiotic marketed in its hemihydrate (LF-½H) crystal form. Another LF hydrate is known as monohydrate (LF-1H), and LF-½H and LF-1H dehydration results in a pair of anhydrous polymorphs: LF-γ (from LF-½H) and LF-α (from LF-1H). Herein, a pure crystalline material of each of these four LF crystal forms has been successfully produced and systematically characterized by X-ray powder diffraction (PXRD), infrared attenuated total reflectance spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analyses. Coupling cyclic DSC and ex-situ PXRD analyses allowed probing dehydration, melting, crystallization and polymorphic phase transitions involving LF-½H, LF-1H, LF-α, LF-γ, and LF-δ (an enantiotropic polymorph of LF-γ). Furthermore, for the first time, the LF-½H, LF-1H, LF-γ and LF-α equilibrium solubilities were individually measured in five different aqueous media (pH from 1.0 to 7.2). The general solubility order is: LF-γ > LF-½H = LF-α > LF-1H. The crystal phases identified in the residual solid materials separated from equilibrium solutions show that LF-½H and LF-α forms in converted to LF-1H. The information provided herein about stability and solubility of known LF crystal forms proved to be essential to control the hydration/dehydration/rehydration process between the LF crystalline phases and ensure safe drugs with low toxicity or design LF solids with properties improved physical chemistry.

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Acknowledgements

This work received financial support and fellowships from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (308893/2019-0 and 312433/2023-9), Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG) (APQ-01835-18, RED-00116-23, APQ-00544-23 and APQ-05218-23), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (post-doctoral (C.C.M.) and post-graduate (J.T.J.F. and M.B.) grants – Finance Code 001), and PRPPG-UNIFAL-MG (RI grant). We also thanks the facilities for X-ray diffraction, thermal and spectroscopic analysis at UNIFAL-MG.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas, MG, 37130-001, Brazil

    Jennifer T. J. Freitas, Olimpia M. M. S. Viana, Cristiane C. de Melo, Monalisa Bitencourt, Magali B. de Araújo & Antonio C. Doriguetto

  2. LabcrystAL, Chemistry Institute, Federal University of Alfenas, Alfenas, MG, 37130-001, Brazil

    Cristiane C. de Melo & Antonio C. Doriguetto

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  1. Jennifer T. J. Freitas
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Jennifer T. J. Freitas involved in conceptualization, methodology, synthesis, characterization, and writing – original draft, review and editing; Olimpia M. M. S. Viana involved in equilibrium solubility assays and writing – original draft; Cristiane C. de Melo involved in supervision, writing – original draft and review; Monalisa Bitencourt involved in HPLC quantification assays and writing – original draft; Magali B. de Araújo involved in supervision and funding acquisition; Antônio Carlos Doriguetto involved in preparation of the published work, project administration, supervision, formal analysis and funding acquisition.

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Correspondence to Antonio C. Doriguetto.

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Freitas, J.T.J., Viana, O.M.M.S., de Melo, C.C. et al. Phase transition and solubility of levofloxacin crystal forms: anhydrates versus hydrates. J Therm Anal Calorim (2024). https://doi.org/10.1007/s10973-024-13252-y

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