Laboratory operations chromatographic optimization

The purification of value-added pharmaceuticals in the past required multiple chromatographic steps for batch purification processes. The design and optimization of these processes were often cumbersome and the operations were fundamentally complex. Individual batch processes requires optimization between chromatographic efficiency and enantioselectivity, which results in major economic ramifications. An additional problem was the extremely short time for development of the purification process. Commercial constraints demand that the time interval between non-optimized laboratory bench purification and the first process-scale production for clinical trials are kept to a minimum. Therefore, rapid process design and optimization methods based on computer aided simulation of an SMB process will assist at this stage. 

Differences between the simulated and physical distillation procedures lie in the imperfect nature of each. The most frequently used D86 and D1160 methods are relatively fast single-plate distillations that closely approximate the refinery processes. The large scale of the refinery processes are of necessity imprecise. Thus the compromise between analysis time and the need for information of adequate precision for process control was met by the single-plate laboratory distillations. The introduction and use of simulated distillations from chromatographic data paralleled the need for more precise and detailed data to optimize the refinery process. Refinery operations have become more cosfly wifh fhe rise in energy cosfs and fhe increased value of refinery producfs. 

Because of the uncertainty of sample delivery times, rapid/fast IPC chromatographic methods are needed to maintain an efficient analytical laboratory and plant operation.Since many samples can be generated during the process development, IPC methods should be developed and optimized for the shortest analysis time possible. The need for a fast IPC method was demonstrated by Wu et al. who redeveloped an in-process method to shorten the run time for a reaction conversion HPLC analysis from 30 to 10 min using a monolithic HPLC column.The newly developed method could also be used to determine mother liquor concentrations and perform impurity profiles for the crude product. This optimized method reduced the process cycle time for lab instrumentation. The dual purpose for an IPC method (i.e., COR, impurity profiling, and/or concentration analysis) is another opportunity to improve the process and lab efficiency. Another example of a dual-purpose method use was demonstrated by Nageswara Rao et al. who developed a 15-min RP-HPLC method that could determine the COR and impurity profile (isolated product) for two different processes for production of 4-methoxyphenyl acetic acid." The dual-purpose method is a common theme for in-process analyses. It is also important to remember that a reduction in the analysis time and overall manufacturing time can reduce the cost of the API. 

From this standard solution, one optimizes the chromatographic separation (injection mode, choice of capillary column, and programming of oven temperature), generally in El because this non-selective ionization mode guarantees the detection of all compounds of interest. Remember, it is not necessary for all the compounds to be perfectly separated since detection operates only on certain characteristic ions. Nevertheless, the better the separation, the less likely the risks of interference. The point therefore is to find a compromise between the best analyte separation possible and an analysis time that is compatible with the specifications of the laboratory. 

---