(123f) A Molecular Dynamics Simulation Approach Towards Designing of Drug Formulations: Case Study of Anti-Cancer Drug (Taxol)

An effective drug formulation shall contain the correct amount of drug in the right form and maintain its chemical and biological integrity for delivery at or over the proper time, at the proper rate, and at the desired location. Most of the new drugs under development fall into the category of Class IV compounds – low solubility and permeability. Poor solubility leads to significant hurdles in the oral absorption and bioavailability of the drug candidate by decreasing its dissolution rate and membrane permeation. A well known example of a Class IV drug is Paclitaxel (Taxol) which was first found as a natural product from the Western yew tree, Taxus brevifolia. It has been recognized as one of the most promising antineoplastic drugs for treatment of a wide spectrum of cancers such as breast, ovarian, colon, and lung cancer as well as melanoma and lymphoma.

The current commercial formulation of Taxol contains Cremophor-EL as solvent, which often causes serious side effects like hypersensitivity reactions, nephrotoxicity, and neurotoxicity. The search for an alternative solvent is therefore imperative. Considering the cost associated with the trial and error experimentation to arrive at possible solvent combinations, it will be beneficial to develop a molecular simulation based screening protocol to identify promising formulations for further experimental testing. On one hand, they can reduce trial and error experimentation; on the other hand, they provide insightful information at molecular as well as micro length scales which are often not extracted from experiments. The interactions computed at molecular levels can be gainfully applied to find the optimum combination for a given drug.

In this current work, a total of 8 solvent combinations were studied using molecular dynamics (MD) simulations comprising of ethanol, water, PEG 400, glycerol and Tween 80 in binary and ternary ratio (1:1 and 1:1:1). The relative solubility and relative diffusivity of Taxol in these solvent combinations is studied to find the best solvent combination. Based on solubility and diffusivity values Ethanol-Water and Ethanol-Water-Tween 80 were found to be the best solvent combinations for Taxol. The diffusivity of Taxol in Triacetin solvent, which is used for commercial formulation, was also computed and compared. The simulated properties were compared with the experimental solubility of Taxol reported in the literature.