Simulated Moving Beds Aid Chiral Chromatography
The evolution of chiral pharmaceutical chemistry been shadowing progress in achiral or racemic organic transformations, about twenty years behind. Steady improvement in organic synthetic techniques during the 1970s through today is just now being imitated by chiral chemistry. In 1998 pharmaceutical engineers can boast of a versatile tool chest of asymmetric organic processes that work on tons as well as milligrams. One area still in need of improvement, however, is separations, where chiral chromatography remains something of a bottleneck.
At the Pharmaceutical Ingredients U.S.A. show in Philadelphia (May 11-13, 1998), two Daicel Chemical subsidiaries demonstrated a significant improvement in large scale chiral separations, namely the chiral simulated moving bed (SMB).
Daicel Chemical Industries' SMB chiral separation pilot plant uses between 4 and 24 chiral high-pressure columns connected in series, plus rotary valves to switch inlet and outlet ports, extract and raffinate (Figure 1). The valves are switched intelligently to maximize recovery of the desired enantiomer through individual columns and the system as a whole (Figure 2).
Figure 2. Schematic of SMB Separation Strategy
Daicel installed the pilot-scale SMB unit in March, 1997 to supply chiral compounds in quantities up to about fifty kg per batch. To demonstrate the immense advantages of SMB vs. batch chromatography, Daicel has provided data for separation of enantiomers of propranalol, a cardiovascular medication, using a Chiracel OD column and n-hexane/2-propanol (80-20 v/v%) at 40°C.
Figure 3. Productivity of SMB vs. Batch Chromatography
Using the same quantities of media, the batch system is capable of producing about 100 kg/year of propranolol at 98% optical purity and a cost of about $2100 per kg of active. The pilot plant described above offers about the same annual production and slightly higher optical purity for about one-third the cost. An SMB production-scale plant (Figure 4) will produce 10,000 kg of propranolol per year at 99% optical purity for just $30 per kg, a cost savings of more than 98% compared with batch chromatography.
Figure 4. Production scale SMB Chiral Chromatography System
When Does Chiral Chromatography Make Sense?
Chiral chromatography is one of four important techniques for obtaining enantiomerically pure chemicals in large quantities. The other three methods are: finding the desired compounds in nature; chemical synthesis (including enzymatic transformation), and chiral resolution. For synthetic drugs of course "nature" is not an option.
The burning question is: Should chiral drugs be synthesized as single-isomer entities or produced as racemates and separated through chiral resolution or chromatography?
Of the three non-natural methods, all work well on compounds with one chiral center, although chiral resolution has a reputation for being labor-intensive. Enzymatic resolution has improved efficiency somewhat, but for compounds with multiple chiral centers resolving diastereomers is not always possible. For isomers arising from multiple chiral centers chiral chromatography has the advantage of separating, in one process, diastereomers on the basis of their different chemical affinities for the stationary phase, and the individual enantiomers based on their chiral affinity.
Ultimately engineers and chemists together must decide on a process based on cost (reagents, stationary phases, time), available chiral chemistry (how easily is an asymmetric process carried out vs. a chiral chromatography step?), scaleup issues (synthesis or chromatography may demonstrate a scaleup advantage), and required product purity.
By Angelo DePalma
For more information: James Cochran, Director of Business Development, Chiral Technologies, Inc., 730 Springdale Dr., Exton, PA 19341. Tel: 610-594-2100.