title: Dissolution-modulating mechanism of alkalizers and polymers in a nanoemulsifying solid dispersion containing ionizable and poorly water-soluble drug.
abstract: We investigated the dissolution-modulating mechanism of alkalizers and polymers in nanoemulsifying Gelucire 44/14 (GUC)-based solid dispersions (SDs) for controlled release. Aceclofenac (AFC), an ionizable and poorly water-soluble drug, was chosen because of its extremely low solubility at low pH. Nanoemulsifying SD systems containing alkalizers and/or polymers were prepared by the melting method. Drug crystallinity, microenvironmental pH (pH(M)), dissolution rate, and droplet size in the media from nanoemulsifying SD were then characterized. Ternary SD containing alkalizers, mainly Na(2)CO(3) and NaHCO(3), enhanced the initial release rate of AFC in simulated gastric fluid (pH 1.2), but resulted in spring-like precipitation. However, adding a secondary polymer, Poloxamer 407, prevented precipitation in the quaternary SD system. Poloxamer 407 and alkalizer (Na(2)CO(3)) facilitated nanoemulsion formation (80-140 nm) with a smaller droplet size in a medium of pH 1.2 as visualized by TEM. The surface and inner pH(M) were also modulated by the alkalizers, but not by the polymers. The drug's crystalline structure was further changed to partially or almost amorphous form by the alkalizers and polymers in SD as characterized by instrumental analysis. The synergistic effects of alkalizers and secondary polymers in SD on reduction of drug crystallinity and modulation of pH(M) via molecular interactions could modulate dissolution rates of ionizable and poorly water-soluble model drug without spring-like precipitation by providing more favorable nanoemulsion-forming environment.
authors.affiliation: National Research Laboratory for Bioavailability Control, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: Thao Truong-Dinh
authors.initials: TT
authors.lastname: Tran
authors.forename: Phuong Ha-Lien
authors.initials: PH
authors.lastname: Tran
authors.forename: Beom-Jin
authors.initials: BJ
authors.lastname: Lee
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D016503:Drug Delivery Systems; D004655:Emulsions; D006863:Hydrogen-Ion Concentration; D007477:Ions; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods*; D010316:Particle Size; D020442:Poloxamer / Q000737:chemistry; D012995:Solubility; D013696:Temperature; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D004655:Emulsions; D007477:Ions; D014867:Water; D020442:Poloxamer