Two Crystal Forms of a Hydrated 2:1 β-Cyclodextrin Fluconazole Complex: Single Crystal X-ray Structures, Dehydration Profiles, and Conditions for Their Individual Isolation

Andrea Sala,Alessia Bacchi,Mino R Caira,Zakiena Hoossen

doi:10.3390/molecules26154427

Andrea Sala, Alessia Bacchi + Show 2 more

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https://doi.org/10.3390/molecules26154427

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Journal: Molecules	Publication Date: Jul 22, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: University of Parma, University of Cape Town

Abstract

Inclusion complexes between cyclodextrins (CDs) and active pharmaceutical ingredients (APIs) have potential for pharmaceutical formulation. Since crystallization of a given complex may result in the isolation of multiple crystal forms, it is essential to characterize these forms with respect to their structures and physicochemical properties to optimize pharmaceutical candidate selection. Here, we report the preparation and characterization of two crystallographically distinct hydrated forms of an inclusion complex between β-cyclodextrin (β-CD) and the antifungal API fluconazole (FLU) as well as temperature–concentration conditions required for their individual isolation. Determination of crystal water contents was achieved using thermoanalytical methods. X-ray analyses revealed distinct structural differences between the triclinic (TBCDFLU, space group P1) and monoclinic (MBCDFLU, space group C2) crystal forms. Removal of the crystals from their mother liquors led to rapid dehydration of the MBCDFLU crystal, while the TBCDFLU crystal was stable, a result that could be reconciled with the distinct packing arrangements in the respective crystals. This study highlights (a) the importance of identifying possible multiple forms of a cyclodextrin API complex and controlling the crystallization conditions, and (b) the need to characterize such crystal forms to determine the extent to which their physicochemical properties may differ.

Highlights

Extending the solid-state landscape of active pharmaceutical ingredients (APIs) and promising drug candidates via the generation of new forms continues to be a vibrant pursuit in both academia and in the pharmaceutical industry [1,2,3]
Since the corresponding isostructural β-CD complexes with matching reference powder X-ray diffraction (PXRD) patterns are known to be based on dimeric host units with distinct dimer complex packing arrangements, it could be deduced that the MBCDFLU complex crystallizes in channel (CH)-type packing while TBCDFLU is based on the “intermediate” (IM)-type packing scheme
It was established that maintaining the initial solution temperature of 60 ◦C led to the monoclinic form MBCDFLU (M) exclusively, whereas if the procedure commenced with the solution at 45 ◦C, only crystals of TBCDFLU (T) were obtained

Summary

Introduction

Extending the solid-state landscape of active pharmaceutical ingredients (APIs) and promising drug candidates via the generation of new forms (e.g., polymorphs and multicomponent species such as solvates, inclusion complexes, salts, co-crystals, and eutectics) continues to be a vibrant pursuit in both academia and in the pharmaceutical industry [1,2,3]. These types of ‘supramolecular derivatives’ contain the API intact, with retention of its bioactivity since no covalent bonds are created or broken during their synthesis.

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