T.H. Kalantar, M. Ladika, J. Zhao, K. Harris, C. Tucker, M. Tulchinsky, T.C. Kuo, B. Bell, J. Kiefer, S. Chen, R. Krystosek, K. Stoneburner, J. Penny
Keywords: BCS class II, drug solubilization, amorphous drug
Summary:Forty percent of new chemical entities suffer from poor aqueous solubility and/or slow dissolution, reducing their bioavailability and efficacy, and limiting their widespread use. This study explored a solubilization approach using alkyl polyoxyalkylene block copolymers to enhance drug solubility and dissolution rate, wherein the insoluble drug was combined with the polymeric excipient to form an amorphous solid dispersion. High throughput (HT) methods were used to prepare libraries of novel excipient polymers, form the drug-excipient mixtures, and characterize the degree of drug solubilization, the retention of drug supersaturation over time in aqueous solution, and the stability of the amorphous form of the drugs over time, all important factors in drug bioavailability. In this study, a novel class of alkylated polyols was synthesized in a high throughput polymer synthesis reactor system using alkoxylate initiators. The alcohols were first alkoxylated with butylene oxide (BO), then further ethoxylated with ethylene oxide (EO), yielding a library of 24 polymers. The effect on drug solubilization of these copolymers was studied using model insoluble drugs. Drug-excipient samples were prepared via HT liquid handling methods. HT Raman spectroscopy was used to characterize the crystallinity of the drug in the drug-excipient blend. Dissolution rate in water, aqueous solubility and the stability of the dissolved drug against precipitation in solution was studied via optical microscopy, HT nephelometry and HPLC. Solubility enhancement relative to the milled, unprocessed drug was evaluated by nephelometry. Low scattering values indicate a clear solution, suggestive of complete or almost complete dissolution of the drug. HT Raman spectroscopy suggested that several Alkyl-BO-EO polymer excipients were effective in stabilizing the drugs in their amorphous form in the solid state over the four week study period. Under accelerated aging conditions, the observed increases in probucol solubility were significant (ca. 8,000-fold). HT methods of studying drug solubilization correlate well with traditional bench-top approaches but offer the benefit of a very high rate of synthesis, sample preparation, and characterization of solubilization. This study demonstrated that many polyoxyalkylene copolymers can be used as solubilization-excipients for poorly soluble drugs.