(717f) Polyalkoxylated Alcohols As Excipients for Poorly Soluble Drugs

Thomas H. Kalantar¹, Jin Zhao², Mladen Ladika¹, Keith Harris¹, Chris Tucker¹, Michael Tulchinsky¹, TC Kuo¹, Joe Kiefer¹, Xiaoyun Chen¹, Robert Krystosek¹

(1) The Dow Chemical Company, Herbert D. Doan R&D Center, Midland, Michigan, 48674, USA

(2) Pharmaceutical Excipients R&D, Dow Food, Pharma & Medical Films, Midland, MI 48674

There has been a steady increase in the number of active pharmaceutical ingredients (APIs) that are characterized with low aqueous solubility. It has been estimated that 40 to 80% of new drug candidates suffer from poor aqueous solubility and/or slow dissolution, reducing their bioavailability and efficacy, and even preventing their general use ¹. This study explored a solubilization approach using low-T_g alkylated polyoxyalkylene copolymers to enhance drug solubility and dissolution rate², where the drug was combined with the polymeric excipient to form an amorphous solid dispersion at the molecular level. Such low-T_g excipients yield liquid or semi-solid drug/excipient formulations.

In this study, a novel class of alkylated polyols was synthesized using renewably sourced alkyl initiators, with a specific emphasis on terpene alcohol precursors. These alcohols were first alkoxylated with butylene oxide then further ethoxylated with ethylene oxide. The effect of solubilization by these copolymers was studied using four model drugs (ketoprofen, danazol, griseofulvin, and probucol). Raman spectroscopy suggested that several copolymers from this study were effective in stabilizing ketoprofen in its amorphous form. The aqueous solubility and dissolution rate of drugs in presence of these excipients were studied using nephelometry and optical microscopy. Several drug/excipient samples showed a dramatic reduction in turbidity relative to the turbidity of drugs alone in water. Optical microscopy of those drug/excipient samples in water also indicated an increase in drug dissolution. Drug solubility was also measured by an HPLC method in which a capsule filled with probucol/excipient mixture was placed in phosphate buffer solution for 30 minutes after capsules were disintegrated.

Medium to high enhancement of solubility were observed with blends of common commercial polymeric excipients with three drugs: phenytoin, griseofulvin, and probucol. Probucol solubility was significantly enhanced when mixed with excipient polymers at a molecular level. When mixtures of probucol and novel alkyl-BO-EO excipients were loaded into capsules and subjected to ambient conditions for one week and accelerated aging at 40 ^oC and 75% RH for 4 months, the observed increases in probucol solubility were significant (up to 8,000-fold) under both sets of storage condition.

Many polyoxyalkylene copolymers can be used as solubilization-excipients for poorly soluble drugs; however the structure of alkyl-BO-EO copolymers can be optimized to specific drug structures to enable otpimization of solubilization.

References

 

1. Benet, L. Z., The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development. J Pharm Sci. 2013, 102 (1), 34-42.

2. (a) Tang, J.-L.; Sun, J.; He, Z.-G., Current Drug Therapy 2007, 2, 85-93; (b) Nielsen, F. S.; Petersen, K. B.; Mullertz, A., Eur. J. Pharm. Biopharm. 2008, 69, 553-562; (c) Kohli, K.; Chopra, S.; Dhar, D.; Arora, S.; Khar, R. K., Drug Dicsovery Today 2010, 15, 958-965; (d) Holm, R.; Jorgensen, E. B.; Harborg, M.; Larsen, R.; Holm, P.; Mullertz, A.; Jacobsen, J., Eur. J. Pharm. Sci. 2011, 42, 416-422.