title: Preparation and Physicochemical Characterization of an Inclusion Complex Between Dimethylated β-Cyclodextrin and a Drug Lead From a New Class of Orally Active Antimalarial 3,5-Diaryl-2-Aminopyridines.
abstract: Cyclodextrins (CDs) were used to increase the aqueous solubility of a recently discovered orally active 3,5-diaryl-2-aminopyridine antimalarial drug lead (MMP). Phase-solubility studies using β-CD, hydroxypropyl-β-CD, and heptakis(2,6-di-O-methyl)-β-CD (DIMEB) as potential solubilizers for MMP yielded solubility enhancement factors of 17, 49, and 65, respectively, at 25°C with CD concentrations ∼20 mM. A crystalline complex, DIMEB⋅MMP⋅2H2O, was prepared and characterized by thermal and single-crystal X-ray analyses. The latter technique revealed preferential encapsulation of the hydrophobic methylsulfonylphenyl moiety of MMP within the CD cavity and protrusion of the more polar methoxypyridinyl and aminopyridine residues from the cavity. This inclusion mode results in a DIMEB complex with a new packing arrangement and an intricate network of intermolecular hydrogen bonds linking guest residues that protrude from 21-related host cavities. A summary of the results of the performance of the inclusion complex in preliminary pharmacokinetic and efficacy tests in mouse models is provided.
authors.affiliation: Department of Chemistry, Centre for Supramolecular Chemistry Research, University of Cape Town, Rondebosch, South Africa.
authors.forename: Laurelle M
authors.initials: LM
authors.lastname: Joseph
authors.affiliation: Department of Chemistry, South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.affiliation: Department of Chemistry, Centre for Supramolecular Chemistry Research, University of Cape Town, Rondebosch, South Africa. Electronic address: mino.caira@uct.ac.za.
authors.forename: Mino R
authors.initials: MR
authors.lastname: Caira
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D055598:Chemical Phenomena / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003505:Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014961:X-Ray Diffraction / Q000379:methods; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D000962:Antimalarials; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; C487419:heptakis(2,6-di-O-methyl)cyclomaltoheptaose; C031215:betadex
keywords: X-ray diffractometry; complexation; crystal structure; crystallization; cyclodextrins; hydrates/solvates; oral drug delivery; physical characterization; solubility; thermal analysis