title: Solubilization and dissolution of insoluble weak acid, ketoprofen: effects of pH combined with surfactant.
abstract: This study investigated the combined effect of pH and surfactant on the solubility and dissolution of ketoprofen (KP), a highly permeable and an ionizable and water-poorly soluble drug in gastrointestinal tract. The equilibrium solubility of KP was determined in buffers at the pH range from 4.0 to 6.8 and sodium lauryl sulfate (SLS) concentrations from 0% to 2.0%. Its intrinsic dissolution rate was measured in the same media using a rotating disk apparatus. A simple additive model accounting for the free unionized KP and ionized KP(-) forms, and their corresponding micellar forms was employed to study the in vitro solubility and dissolution behavior. Non-linear regression analysis showed that the proposed model agreed well with the experimental data, with R(sq)=0.96 (P<0.0001) for the solubility study, and R(sq)=0.98 (P<0.0001) for the intrinsic dissolution rate measurement. The pK(a) and c(KP) values are estimated as 4.76+/-0.00 and 0.253+/-0.05 mg/mL, respectively, in good agreement with literature reports. The micellar solubilization coefficient k(*) for the unionized [KP](micelle) is 757+/-165 L/mol, whereas the value k(**) for the ionized [KP(-)](micelle) is 9.88+/-6.70 L/mol. The diffusion coefficients of various species: KP, KP(-), [KP](micelle), and [KP(-)](micelle), are 7.68 x 10(-6), 1.54 x 10(-6), 2.32 x 10(-7), and 2.13 x 10(-20)cm(2)/s, respectively. The maximum enhancement of solubilization is approximately 232-fold, while the maximum dissolution amplification is only 54-fold because of the smaller diffusivity of micellar species. The dramatic enhancement of in vitro solubility/dissolution attributable to an increase of pH and presence of SLS mimics the in vivo solubilization/dissolution behavior of KP along the gastrointestinal tract, when the pH increases from 1-2 in the stomach to 5-6 in the duodenum. The results suggest that the KP dissolves very rapidly in small intestine, implying that its absorption will be predominantly controlled by gastric emptying, and only minimally limited by the subsequent dissolution processes. This behavior is very similar to BCS I drugs, thus KP may be considered for possible waivers of bioequivalence.
authors.affiliation: College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, United States.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Sheng
authors.forename: Nehal A
authors.initials: NA
authors.lastname: Kasim
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Chandrasekharan
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
mesh_terms: D006863:Hydrogen-Ion Concentration; D007660:Ketoprofen / Q000737:chemistry*; D012995:Solubility; D013501:Surface-Active Agents / Q000494:pharmacology*; D013810:Therapeutic Equivalency
chemical_list: D013501:Surface-Active Agents; D007660:Ketoprofen