title: Identification and proportion of the enantiomers of the antihypertensive drug chlortalidone in its Form II by high quality single-crystal X-ray diffraction data.
abstract: Chlortalidone (CTD) is a diuretic drug largely used as part of antihypertensive therapies. It is marketed as an equimolar mixture of its enantiomers in the racemic crystal phase named Form I, despite of the higher aqueous solubility of another crystal form. The latter, named Form II, was thought to contain both enantiomers as a racemic conglomerate, i.e., in the form of a mixture of crystals, half of which consists solely of the (R)-enantiomer, the other half the (S)-enantiomer. The occurrence of both enantiomers in individual crystals of CTD Form II was demonstrated in this study. Spontaneous resolution does really occur upon crystallization, as presumed previously even without physical evidence of the (S)-enantiomer. Both (R) and (S)-enantiomers were successfully identified as two domains of a twinned by inversion single crystal of CTD Form II. A reliable Flack parameter of 0.14(4) allowed to determine the proportion of the enantiomers in the crystal, which is formed with 86% of the (R)-enantiomer and 14% of the (S)-enantiomer.
authors.affiliation: Instituto de Química, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva 700, 37130-000 Alfenas, MG, Brazil; Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva 700, 37130-000 Alfenas, MG, Brazil.
authors.forename: Leandro M
authors.initials: LM
authors.lastname: Santos
authors.affiliation: Instituto de Química, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva 700, 37130-000 Alfenas, MG, Brazil.
authors.forename: Olimpia M M
authors.initials: OMM
authors.lastname: Santos
authors.affiliation: Instituto de Química, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva 700, 37130-000 Alfenas, MG, Brazil.
authors.forename: Paula Freire
authors.initials: PF
authors.lastname: Mendes
authors.affiliation: Instituto de Química, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva 700, 37130-000 Alfenas, MG, Brazil.
authors.forename: Iara Maria Landre
authors.initials: IML
authors.lastname: Rosa
authors.affiliation: Instituto de Química, Universidade Federal de Goiás, Campus Samambaia, CP 131, 74001-970 Goiânia, GO, Brazil.
authors.forename: Cameron Capeletti da
authors.initials: CCD
authors.lastname: Silva
authors.affiliation: Instituto de Ciências da Saúde, Universidade Federal de Mato Grosso (UFMT), CEP 78557-267, Campus Universitário de Sinop, Sinop, MT, Brazil.
authors.forename: Rudy
authors.initials: R
authors.lastname: Bonfilio
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva 700, 37130-000 Alfenas, MG, Brazil.
authors.forename: Magali B
authors.initials: MB
authors.lastname: de Araujo
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva 700, 37130-000 Alfenas, MG, Brazil.
authors.forename: Vanessa B
authors.initials: VB
authors.lastname: Boralli
authors.affiliation: Instituto de Química, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva 700, 37130-000 Alfenas, MG, Brazil. Electronic address: doriguetto@unifal-mg.edu.br.
authors.forename: Antônio C
authors.initials: AC
authors.lastname: Doriguetto
authors.affiliation: Instituto de Química, Universidade Federal de Goiás, Campus Samambaia, CP 131, 74001-970 Goiânia, GO, Brazil. Electronic address: felipe@ufg.br.
authors.forename: Felipe T
authors.initials: FT
authors.lastname: Martins
mesh_terms: D000959:Antihypertensive Agents / Q000032:analysis / Q000737:chemistry*; D002752:Chlorthalidone / Q000032:analysis / Q000737:chemistry*; D018360:Crystallography, X-Ray / Q000379:methods; D013237:Stereoisomerism; D014961:X-Ray Diffraction / Q000379:methods*
chemical_list: D000959:Antihypertensive Agents; D002752:Chlorthalidone
keywords: Chlortalidone; Conglomerate; Enantiomers; Flack parameter; Pharmaceutical solids; Single-crystal X-ray diffraction data