ABSTRACT
High-throughput screening and purification are critical in the strategy of a company for finding drug-like compounds [15,16]. During the exploratory stage, pharmaceutical companies can screen a million or more compounds by employing combinatorial and parallel synthesis. Successful isolation is a priority during all stages of a project, and instrument reliability is essential. As the chemistry becomes more focused, fewer compounds are produced and high purity becomes critical for cell biology and pharmacokinetic studies. 2.2.1 Chromatographic Technologies
Utilizing complementary chromatographic screening and purification technologies is necessary in high-throughput environments to maximize the output of pure compounds [17,18]. Reversed-phase liquid chromatography (RPLC) is often the technique of choice as many drug-like compounds can be effectively screened and purified with appropriate reversed-phase methods. More recently, ultra-high-performance liquid chromatography (UHPLC) and the use of small particle (<2 µm) columns have allowed for rapid 1-2 min analytical-scale separations at higher efficiencies and a wider range of flow rates but at much higher ~1200 bar back pressures [19]. Supercritical fluid chromatography (SFC) has also experienced a
growing acceptance in pharmaceutical laboratories this past decade because of significant savings in operation costs and improved efficiency at low ~120 bar back pressures [20]. Implementing these high-throughput technologies is essential in the drug discovery sciences to maximize the rate of success in finding lead compounds from diverse sets of projects with short turnaround time. 2.2.2 Laboratory WorkflowThe Research Analytical Group at Theravance operates a dedicated, highly automated facility with a multi-step process (Fig. 2.1) set up for rapid compound library screening and purification support for Medicinal Chemistry. Implementing a specific workflow has significantly improved efficiency and reduced the turnaround time of sample purification. By employing rational drug design by using structural information of validated targets, potential leads across several chemical classes can be quickly identified from focused libraries on the scale of hundreds to thousands of compounds.
