In search of chiral purity
The US Food and Drug Administration and other regulatory agencies encourage the pharmaceutical industry to develop drugs with fewer side effects for the benefit of the end user. Better understanding of the mode of action of an active pharmaceutical ingredient (API), as well as tragedies such as the thalidomide-related birth defects in the 1960s, drove the need to achieve chiral purity. Enantiomeric purity can be achieved in two ways. The desired enantiomer can be synthesized directly by using either naturally occurring chiral building blocks as starting materials or by asymmetric synthesis through chemocatalytic or biocatalytic methods. Asymmetric synthesis is often considered the most elegant solution by chemists (4). It is an attractive option, but it may require large development efforts and associated costs.Another method is to prepare the racemate and separate the desired enantiomer from the unwanted enantiomer. This approach has the advantage of producing both enantiomers during early development, which allows each enantiomer to be analyzed in toxicology studies and to be used to generate reference standards for analytical purposes. The chiral separation can be achieved either by salt resolution, enzymatic resolution, or chiral chromatography. Salt resolution is common, but it involves a three-step process: salt formation, resolution, and product recovery. This process requires large amounts of solvents and generates the equivalent amount of waste. Enzymatic resolution can be efficient, but its success relies on the identification of the best enzyme for the process. Sometimes several generations of enzymes need to be engineered before an optimal biocatalytic route can be developed. Chiral chromatography quickly provides a solution that can be cost effective. In two to three weeks, several chiral stationary phases (CSPs) can be screened with various mobile-phase compositions to identify separation conditions. At this point, either a batch or a continuous chromatographic method can be used. Typically, for small quantities, a batch preparative column (1–8 cm in diameter) is easy to set up and can provide the desired amount of product in a short period of time with a minimum investment in CSPs and solvents. When quantity requirements are larger, a continuous process such an SMB can be considered. Only a few more data points are usually required to develop the SMB process. Ultimately, a demonstration can be performed on a benchtop unit equipped with small columns to obtain the actual productivity of the separation and generate data for the scale-up. The total development time for a SMB process is approximately six weeks. After this initial work, the process can be demonstrated at any scale without additional development.