Pressure-induced phase behaviour and compressibility of the racemic and chiral solid forms, ofloxacin and levofloxacin

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Gasol-Cardona, Julia and Ward, Martin R. and Comboni, Davide and Hanfland, Michael and Scatena, Rebecca and Warren, Mark R. and Maloney, Andrew G.P. and Oswald, Iain D. H. (2025) Pressure-induced phase behaviour and compressibility of the racemic and chiral solid forms, ofloxacin and levofloxacin. CrystEngComm, 27 (47). pp. 7662-7676. ISSN 1466-8033 (https://doi.org/10.1039/D5CE00855G)

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Abstract

We report a comparative high-pressure crystallographic study of the RS- and S- forms of 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid, encompassing ofloxacin (O), γ-levofloxacin (Lγ), and levofloxacin hemihydrate (LH). Single-crystal and X-ray powder diffraction experiments reveal all three compounds are relatively soft and compressible due to dominant dispersive intermolecular interactions via parallel molecular packing of the main bodies. Each form undergoes distinct pressure-induced phase transitions, with Lγ exhibiting a low transition pressure at 1.14 GPa, while LH displays a unique sensitivity to the water content of the pressure-transmitting medium. Under inert conditions, LH remains stable up to ~5.1 GPa before a transition to a lower-symmetry polymorph but using certain media it can undergo a phase transition to a new unidentified phase. O shows subtle structural changes above 4.65 GPa in methanol–ethanol medium, though no definitive phase transition was observed in the single-crystal form. These findings provide critical insights into the pressure-dependent behaviour of fluoroquinolone antibiotics, with implications for solid form selection, formulation design, and mechanical stability during pharmaceutical processing.

ORCID iDs

Gasol-Cardona, Julia ORCID logoORCID: https://orcid.org/0009-0006-1249-3609, Ward, Martin R. ORCID logoORCID: https://orcid.org/0000-0003-0013-5004, Comboni, Davide, Hanfland, Michael, Scatena, Rebecca, Warren, Mark R., Maloney, Andrew G.P. and Oswald, Iain D. H. ORCID logoORCID: https://orcid.org/0000-0003-4339-9392;
CORE (COnnecting REpositories)