When it comes to controlling the quality of a final active pharmaceutical ingredient, high-performance liquid chromatography
(HPLC) is one of the techniques used by quality control departments to analyze the final product. HPLC has gained popularity
because of its efficient separation performance. Unfortunately, this separating power is rarely considered as a potential
purification process at the commercial scale. The reason is that chromatography is always perceived as an expensive technique
because of poor throughput and high solvent consumption. Although production-scale HPLC may have been expensive in the past
because of glass columns, it is not today, thanks to major improvements in the technology.
Highly efficient packing materials, also called stationary phases, with narrow particle-size distribution are available and can be used at high pressure. As a result, high throughput can
be achieved with high purity and high recovery compared with traditional "column" chromatography. Furthermore, additional
improvements to the technique allow for counter-current continuous operation that further reduces the need for solvent and
significantly improves process throughput. This technique, called simulated moving bed (SMB), is currently in use in many industrial applications at large scales (see Figure 1). For example, the purification
of sugar is conducted using large diameter SMB units with a throughput of several tons of purified fructose or glucose per
Figure 1: Commercial-scale simulated moving bed unit, 5 columns of 1 m in diameter. This unit can process several hundred
tons of racemic solution per year. (PHOTO: AMPAC FINE CHEMICALS)
Description of the process
SMB has been presented in many different ways in the scientific literature. Using a merry-go-round of 5–8 columns and a set
of valves per column, a simple batch separation process can be converted into a continuous operation. This is achieved by
changing the relative velocities of each compound in the columns. By "moving" the columns at a constant speed against the
eluent flow, the most-retained component appears to move with the columns while the less-retained component flows with the
eluent. As a result, a gap between the two fractions is created and can be filled continuously. To avoid accumulation, outlet
streams must be collected on either side of the point of entry of the feed. This is truly a counter-current process and the
packing material is used more efficiently. The only limitations are that SMB separations are conducted in an isocratic mode
and that only two product streams can be isolated. This makes SMB an excellent candidate for binary separations such as the
separation of enantiomers.
Method development and chiral applications
The number of drugs entering the market that have one or more chiral centers has grown significantly in the past decade. Knowing
that one enantiomer can potentially carry side effects has brought regulatory authorities such as the US Food and Drug Administration
to favor the single enantiomer version of a drug whenever possible. Specific crystallization, enzymatic or chemical resolution,
or chromatography can be added as a unit operation to the existing synthesis route to obtain the single enantiomer. Or a completely
new asymmetric route can be designed to obtain the desired single enantiomer. As a result, pharmaceutical companies have invested
substantial resources in trying to find the right chiral catalyst or the right enzyme that will provide the single enantiomer
at a satisfactory enantiomeric purity.
The development of a chromatographic chiral separation is a straightforward process that requires a few steps, described as
Find a separation.
There are a handful of chiral stationary phases (CSP) that provide greater than 80% probabilities of finding a good separation.
If these phases are not working, there are a few more that may be suitable. The selection of solvents for the separation traditionally
has been limited to acetonitrile, alcohols, and mixtures of alcohols with heptane. However, with the development of more robust
CSPs that can handle solvents such as acetone, MTBE, toluene, and ethers, more possibilities exist. These solvents allow for
high solubility and low viscosities, which are key elements to achieve high throughput. The screening process typically takes
1–2 weeks. From this study a handful of conditions can be identified as potential candidates.