title: Screening method to identify preclinical liquid and semi-solid formulations for low solubility compounds: miniaturization and automation of solvent casting and dissolution testing.
abstract: We have developed an efficient screening method to identify liquid and semisolid formulations for low-solubility compounds. The method is most suitable for identifying dosing vehicles for compounds in lead optimization, where compound supply is limited and long-term stability is not a requirement. Dilute compound and excipient stock solutions are prepared in organic solvent and then dispensed and mixed in 96-well plates. The solvent is removed in a vacuum centrifuge evaporator, leaving neat formulation (e.g., 10-40 microg compound, 0.4 mg excipient) at the bottom of each well. After an aging step, an aqueous dilution medium is added and the plates are incubated (agitation by orbital shaking). The diluted formulations are then filtered and analyzed by ultraviolet (UV) absorbance or high-performance liquid chromatography (HPLC). To illustrate the method, two compounds (aqueous solubility </=1 microg/mL) were combined with eight solubilizing excipients, at four drug-loading levels (25, 50, 75, and 100 mg/g) and three incubation times (0.5, 2, and 24 h). This allowed identification of the excipients and loading levels, which generated the highest and most stable kinetic solubility upon dilution. The peak kinetic solubility was strongly correlated with the equilibrium solubility. Application of the method to screening compound/surfactant/oil formulations is also presented.
authors.affiliation: ALZA Corporation, 1010 Joaquin Road, Mountain View, California 94043, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Mansky
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Dai
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.forename: Crystal
authors.initials: C
authors.lastname: Pollock-Dove
authors.forename: Klaus
authors.initials: K
authors.lastname: Daehne
authors.forename: Liang
authors.initials: L
authors.lastname: Dong
authors.forename: Gary
authors.initials: G
authors.lastname: Eichenbaum
mesh_terms: D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D005079:Excipients / Q000008:administration & dosage*; D012995:Solubility; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet
chemical_list: D005079:Excipients; D012997:Solvents