title: Bioavailability enhancement of poorly water soluble and weakly acidic new chemical entity with 2-hydroxy propyl-beta-cyclodextrin: selection of meglumine, a polyhydroxy base, as a novel ternary component.
abstract: The purpose of the present study was to investigate the influence of a polyhydroxy base, N-acetyl glucamine (also know as Meglumine), as a ternary component on the complexation of DRF-4367, a poorly water-soluble and weakly acidic anti-inflammatory molecule, with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). The molecular inclusion of DRF-4367 with HPbetaCD alone and in combination with ternary component was aimed at improvement in solubility and, subsequently, dissolution rate-limited oral bioavailability. The solid complexes of DRF-4367 and HPbetaCD with or without meglumine (binary and ternary systems, respectively) were prepared as coevaporated product in different stoichiometric ratios and compared against physical mixture. The formation of inclusion complexes was confirmed by using classical instrumental techniques. Phase solubility studies suggested that meglumine was responsible for solubility improvement via multiple factors rather than just providing a favorable pH. Mechanisms and factors governing solubility enhancement were investigated by using phase solubility and thermodynamic parameters. The complexation of DRF-4367 with HPbetaCD is thermodynamically favored because the Gibbs free energies of transfer of the drug to the cyclodextrin cavity are negative. The solubilization efficiency and stability were further improved while retaining the favorable Gibbs free energies of transfer with the addition of meglumine. Inclusion ternary complex of DRF-4367 with HPbetaCD and meglumine showed significant improvement in dissolution compared with uncomplexed drug and binary system. Moreover, the phenomena of reprecipitation observed with binary system during dissolution could be avoided with meglumine as an enabling ternary component. This improved physicochemical behavior of ternary complex with the novel inclusion of a polyhydroxy base translated into an enhanced oral bioavailability of DRF-4367 compared with either uncomplexed drug or nanosuspension.
authors.affiliation: Formulation Research Department, Discovery Research, Dr Reddy's Laboratories Ltd, Hyderabad, India.
authors.forename: S
authors.initials: S
authors.lastname: Basavaraj
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Sihorkar
authors.forename: T R
authors.initials: TR
authors.lastname: Shantha Kumar
authors.forename: Prakash
authors.initials: P
authors.lastname: Sundaramurthi
authors.forename: Nuggehally R
authors.initials: NR
authors.lastname: Srinivas
authors.forename: P
authors.initials: P
authors.lastname: Venkatesh
authors.forename: Mullangi
authors.initials: M
authors.lastname: Ramesh
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar Singh
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000143:Acids; D001682:Biological Availability; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D008536:Meglumine / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012995:Solubility; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013816:Thermodynamics; D014867:Water; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000493:pharmacokinetics*; D000096926:Benzenesulfonamides
chemical_list: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000143:Acids; D004337:Drug Carriers; D008536:Meglumine; D011720:Pyrazoles; D013449:Sulfonamides; D014867:Water; D047392:beta-Cyclodextrins; C482791:2-hydroxymethyl-4-(5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl)-1-benzenesulfonamide; D000096926:Benzenesulfonamides