High-Throughput Purification of Single Compounds and Libraries

Abstract

The need for increasing productivity in medicinal chemistry and associated improvements in automated synthesis technologies for compound library production during the past few years have resulted in a major challenge for compound purification technology and its organization. To meet this challenge, we have recently set up three full-service chromatography units with the aid of in-house engineers, different HPLC suppliers, and several companies specializing in custom laboratory automation technologies. Our goal was to combine high-throughput purification with the high attention to detail which would be afforded by a dedicated purification service. The resulting final purification laboratory can purify up to 1000 compounds/week in amounts ranging from 5 to 300 mg, whereas the two service intermediate purification units take 100 samples per week from 0.3 to 100 g. The technologies consist of normal-phase and reversed-phase chromatography, robotic fraction pooling and reformatting, a bottling system, an automated external solvent supply and removal system, and a customized, high-capacity freeze-dryer. All work processes are linked by an electronic sample registration and tracking system.

Role of Chemistry in Lead Discovery

“…Schaffrath and coworkers describe purification strategies in different stages of drug discovery chemistry, pointing out that methodologies used depend on amounts of compound and number of samples under investigation. For large-scale intermediates (1-100 g), normal-phase chromatography is considered most suitable, whereas advanced intermediates (0.2-20 g) and target compounds for first evaluation (5-300 mg) are purified via reversed-phase chromatography [37].…”

Purification of flavonoids and triterpene saponins from the licorice extract using preparative HPLC under RP and HILIC mode

“…Currently the essential properties of commercially available parallel preparative HPLC systems are composed of multi-channel parallel separation modules, automated sampling and accurate fraction tracking, which can fully meet the requirement for separation reproducibility and selectivity. Now parallel preparative HPLC has become one of the important techniques in isolation and purification of compounds of interest with high purity and efficiency [15,16].…”

Novel Approach to Optimization of a High-Throughput Semipreparative LC/MS System

“…Automated semipreparative LC/MS systems are now well-established commercially and commonly used for purification of early stage drug discovery compounds. − A number of vendors − have instruments on the market that are capable of reliably purifying compounds with good water/acetonitrile solubility. However, these systems often fail when the sample has poor solubility, extreme polarity, and/or poor ionization.…”