Process chemistry determination. For more than a decade, the traditional approach to high throughput analyses for the assessment of compound purity and structure confirmation has been to apply fast liquid chromatography-mass spectrometry (LC-MS) methods with very steep gradients, high flow rates, high temperature, short columns, and acidic volatile mobile phases. Despite the popularity and quite acceptable separation performance of this approach, which is supported by sound theoretical explanations [3-5], only so-called "quick-and-dirty" types of method development could be handled. This approach trades selectivity and resolution for high speed with the use of MS for highly selective analysis. The downside of this approach is experienced with the analysis of focused libraries that contain structurally related impurities with small differences in polarity, lipophilicity, or any other physicochemical property from the compound of interest. As a result, sample components that closely elute are observed. These components can compromise resolution during the preparative scale-up stage.

The third concept is to generate as much useful information as possible from a single analysis (e.g., to obtain both structural and quantitative information from a single run without tedious external or internal calibrations) [39].

Finally, one of the most difficult bottlenecks to overcome in drug discovery is the purification process. The successful introduction of an automated preparative LC-MS (prepLC-MS)-based high throughput purification (HTP) platform in the late 1990s [6,7] has enabled purification to be achieved quickly and easily. The introduction of this technology, however, only moves the bottleneck to the next step of the process [8]. The biggest bottleneck still remains with the tedious postpurification process that involves multiple steps (e.g., transferring fractions, solvent evaporation, purity assessment, weighing, and reformatting the fractions for HTS) to achieve the final products. Under the traditional model, laboratories focus on improvements with the purification or solvent-evaporation technologies per se instead of the entire purification platform. Therefore, the overall efficiency of HTP platforms has yet to be realized. A new concept is required to develop the next generation of purification infrastructure. This approach aims to integrate all fragmented purification-related platforms, such as open-access, HTP, large-scale, and specialized purification, into one highly efficient and functional process based upon a stage-appropriate analysis concept.

Was this article helpful?

0 0

Post a comment