title: Parallel screening approach to identify solubility-enhancing formulations for improved bioavailability of a poorly water-soluble compound using milligram quantities of material.
abstract: In this article, we present a parallel experimentation approach to rapidly identify a solubility-enhancing formulation that improved the bioavailability of a poorly water-soluble compound using milligrams of material. The lead compound and a panel of excipients were dissolved in n-propanol and dispensed into the wells of a 96-well microtiter plate by a TECAN robot. Following solvent evaporation, the neat formulations were diluted with an aqueous buffer, and incubated for 24h. The solubilization capacity of the excipients for the compound at 24h (SC(24h)), was determined by HPLC, and compared with its solubility in the corresponding neat formulations determined by a bench-scale method. The ranking order of solubilization capacity of the five tested formulations for this compound by this microscreening assay is same as the ranking order of the compound solubility in the neat formulations. Several formulations that achieved the target aqueous solubility were identified using the screening method. One of the top formulations, an aqueous solution of the compound containing 20% Tween 80 by weight, increased the compound solubility from less than 2 microg/mL to at least 10mg/mL. In a rat pharmacokinetic (PK) study, the Tween 80 formulation achieved 26.6% of bioavailability, a significant improvement over 3.4% of bioavailability for the aqueous Methocel formulation (p<0.01). The results in the study suggest that this parallel screening assay can be potentially used to rapidly identify solubility-enhancing formulations for an improved bioavailability of poorly water-soluble compounds using milligram quantities of material.
authors.affiliation: ALZA Corporation, 1900 Charleston Road, Mountain View, CA 94039, USA. wdai2@alzus.jnj.com
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Dai
authors.forename: Liang C
authors.initials: LC
authors.lastname: Dong
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.forename: Crystal
authors.initials: C
authors.lastname: Pollock-Dove
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Paul
authors.initials: P
authors.lastname: Mansky
authors.forename: Gary
authors.initials: G
authors.lastname: Eichenbaum
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D005079:Excipients / Q000737:chemistry; D005260:Female; D006863:Hydrogen-Ion Concentration; D007189:Indans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008970:Molecular Weight; D010539:Permeability; D019999:Pharmaceutical Solutions / Q000737:chemistry; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry*; D044366:Transition Temperature; D014867:Water / Q000737:chemistry
chemical_list: C505208:(6,7-dimethoxy-2,4-dihydroindeno(1,2-c)pyrazol-3-yl)(3-fluorophenyl)amine; D005079:Excipients; D007189:Indans; D019999:Pharmaceutical Solutions; D011720:Pyrazoles; D013501:Surface-Active Agents; D014867:Water; D017479:Receptors, Platelet-Derived Growth Factor