Factors affecting solubilization of a poorly soluble novel tubulin-binding agent.
JCA112 is a novel tubulin-binding agent with limited aqueous solubility and high hydrophobicity. Three strategies; cyclodextrin inclusion complexation, solid dispersion (SD) formation, and liposome incorporation were evaluated to enhance the solubility of JCA112. Phase-solubility studies were carried out with hydroxypropyl β-cyclodextrin (HPβCD), SDs were prepared by solvent evaporation method and liposomes were prepared by thin-film hydration method. Saturation solubility of the prepared formulations resulted in a significant increase in the solubility of JCA112 by all three methods. Cyclodextrin complexation resulted in a higher order complex formation increasing the aqueous solubility by 30-fold up to 105 μg/mL. Amongst the selected polymers, Poloxamer 188 (Pluronic(®) F68) was the most effective polymer in enhancing the aqueous solubility via SD, resulting in an equilibrium solubility of 50 μg/mL, independent of the drug loading. Liposomes were the most effective amongst all three techniques, with a saturation solubility of 1.8 mg/mL contributing to greater than 500-fold increase in the solubility of JCA112. The solubility enhancement by liposome was directly proportional to the drug loading. All the three strategies were successful in enhancing the solubility of the drug. Solubility enhancement by the three techniques can be attributed to the geometry/structure and the lipophilicity of the drug.
Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, Oxford, MS, USA. ashah11@gmail.com
Amit K
AK
Shah
Christy M
CM
Wyandt
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005079:Excipients / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry; D020442:Poloxamer / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D014404:Tubulin / Q000737:chemistry*; D014867:Water / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry*
D005079:Excipients; C581525:JCA112; D008081:Liposomes; D011108:Polymers; D012997:Solvents; D014404:Tubulin; D047392:beta-Cyclodextrins; D014867:Water; D020442:Poloxamer; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D017239:Paclitaxel