Binary mixtures of flufenamic acid and its chloro, difluoromethyl and fluoromethyl analogues; incorporation and distribution in flufenamic acid crystals

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dc.contributor.authorBourke, Timothy
dc.contributor.authorChiarella, Renato A.
dc.contributor.authorMoynihan, Humphrey A.
dc.contributor.funderAlkermes
dc.contributor.funderIrish Research Council, EPSPG/2016/179
dc.contributor.funderScience Foundation Ireland, SFI, SFI 12/RC/2275_P2
dc.date.accessioned2026-07-23T15:50:02Z
dc.date.available2026-07-23T15:50:02Z
dc.date.issued2026-08-10
dc.description.abstractImpurities are a common feature of pharmaceutical process chemistry. For example, fluorine-containing drug substances are often found to have the corresponding desfluoro compounds as impurities which are difficult to remove by crystallization. Analogues of flufenamic acid in which the trifluoromethyl group was replaced by difluoromethyl, fluoromethyl or chloro groups were synthesized and examined as examples of such impurities. Investigation of the extent of incorporation and behaviour by PXRD and DSC were consistent with crystal lattice level substitution of flufenamic acid molecules with analogous impurities. Use of methanol or acetonitrile as crystallization solvent resulted in efficient incorporation of the impurities into flufenamic acid crystals. Examination of the distribution of the impurities within flufenamic acid crystals by partial dissolution methods showed that impurity inclusion was occurring throughout the crystal growth process. In each of the impurities studied, the trifluoromethyl group of flufenamic acid was replaced by a group with similar electronic and steric properties. Consideration of the crystal structure of the flufenamic acid polymorph obtained, i.e., form III, suggested that replacement of flufenamic acid molecules by those impurities could be accommodated within the flufenamic acid form III crystal lattice.en
dc.description.sponsorshipWe are grateful to Alkermes Pharma Ireland Ltd and the Irish Research Council, now Research Ireland, for provision of support under grant number EPSPG/2016/179 and to Science Foundation Ireland, now Research Ireland, under grant number SFI 12/RC/2275_P2.
dc.description.versionPublished Version
dc.format.extent12
dc.format.mimetypeapplication/pdfen
dc.identifier.authororcidBourke, Timothy
dc.identifier.authororcidChiarella, Renato A.
dc.identifier.authororcidMoynihan, Humphrey A.§0000-0003-2700-2746
dc.identifier.citationBourke, T, Chiarella, R A & Moynihan, H A 2026, 'Binary mixtures of flufenamic acid and its chloro, difluoromethyl and fluoromethyl analogues; incorporation and distribution in flufenamic acid crystals', CrystEngComm, vol. 28, no. 31, pp. 4516-4527. https://doi.org/10.1039/d6ce00346j
dc.identifier.doi10.1039/d6ce00346j
dc.identifier.endpage4527
dc.identifier.issn1466-8033
dc.identifier.issued31
dc.identifier.journaltitleCrystEngComm
dc.identifier.startpage4516
dc.identifier.urihttps://hdl.handle.net/10468/19092
dc.identifier.volume28
dc.language.isoen
dc.publisherRoyal Society of Chemistry
dc.relation.urihttps://www.scopus.com/pages/publications/105043794282
dc.rights© 2026, The Author(s). Published by the Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution 4.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.
dc.rights.accessrightsopen access
dc.rights.licensenameAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.statusPeer reviewed
dc.subjectBinary mixtures
dc.subjectFlufenamic acid
dc.subject[Chemistry]
dc.titleBinary mixtures of flufenamic acid and its chloro, difluoromethyl and fluoromethyl analogues; incorporation and distribution in flufenamic acid crystalsen
dc.typeArticle (peer-reviewed)
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