(664f) Minimizing Process Development Costs in Industry By Computational Molecular Modeling Screening: Separation of Enantiomers for Pharmaceutical Applications

The overall goal of this project is to develop an efficient (time and cost) and reliable computational molecular modeling for screening conditions for effective separation of enantiomers using chiral stationery phases. More than half of all pharmaceuticals are chiral compounds. The potential market for enantiomer separation is $1.2 billion. Although enantiomers of chiral compounds have the same chemical structure, they can exhibit marked differences in physiological activity; therefore, it is important to remove the undesirable enantiomer. Chromatographic separation of chiral enantiomers is one of the best available methods to obtain enantio-pure substances, but the optimization of the experimental conditions can be very time-consuming. Generally, there are several chiral stationary phases to choose from; the most commonly used ones are polymers that have an amylose or cellulose backbone, with various sidechains, coated or covalently bonded to a solid support. Then there is the choice of the solvent system that constitutes the mobile phase. Furthermore, modifiers (acids or bases or buffers) may be added to the solvent in order to change or protect some functional groups on the drug to effect a better separation between the enantiomers. One could try different CSPs and mobile phases using educated guesses, but the number of possible combinations is huge, and could easily run into hundreds of combinations. This has stymied progress for developing new drugs especially orphan drugs. To overcome these problems, we have used molecular dynamics simulations to screen for these choices. Chromatographic enantiomer separation is a dynamic process, with the interactions between the drug and the chiral stationary phase mediated by the solvent, thus, no single interacting structure, such as could be found by finding low-energy structures via MD or quantum calculations, could possibly describe and account for the ratio of residence times in the chromatographic column for the enantiomeric pair. Atomistic molecular dynamics simulations permit us to develop an approach to predict which enantiomer elutes first and also provide an estimate of the separation factor.