title: Further development of a robust workup process for solution-phase high-throughput library synthesis to address environmental and sample tracking issues.
abstract: During further improvement of a high-throughput, solution-phase synthesis system, new workup tools and apparatus for parallel liquid-liquid extraction and evaporation have been developed. A combination of in-house design and collaboration with external manufacturers has been used to address (1) environmental issues concerning solvent emissions and (2) sample tracking errors arising from manual intervention. A parallel liquid-liquid extraction unit, containing miniature high-speed magnetic stirrers for efficient mixing of organic and aqueous phases, has been developed for use on a multichannel liquid handler. Separation of the phases is achieved by dispensing them into a newly patented filter tube containing a vertical hydrophobic porous membrane, which allows only the organic phase to pass into collection vials positioned below. The vertical positioning of the membrane overcomes the hitherto dependence on the use of heavier-than-water, bottom-phase, organic solvents such as dichloromethane, which are restricted due to environmental concerns. Both small (6-mL) and large (60-mL) filter tubes were developed for parallel phase separation in library and template synthesis, respectively. In addition, an apparatus for parallel solvent evaporation was developed to (1) remove solvent from the above samples with highly efficient recovery and (2) avoid the movement of individual samples between their collection on a liquid handler and registration to prevent sample identification errors. The apparatus uses a diaphragm pump to achieve a dynamic circulating closed system with a heating block for the rack of 96 sample vials and an efficient condenser to trap the solvents. Solvent recovery is typically >98%, and convenient operation and monitoring has made the apparatus the first choice for removal of volatile solvents.
authors.affiliation: Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 17-85 Jusohonmachi 2-chome, Osaka 532-8686, Japan. Kuroda_Noritaka@takeda.co.jp
authors.forename: Noritaka
authors.initials: N
authors.lastname: Kuroda
authors.forename: Nick
authors.initials: N
authors.lastname: Hird
authors.forename: David G
authors.initials: DG
authors.lastname: Cork
mesh_terms: D000577:Amides / Q000138:chemical synthesis*; D002853:Chromatography, Liquid / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D005374:Filtration; D008956:Models, Chemical; D010421:Pentanoic Acids / Q000138:chemical synthesis*; D011136:Polysorbates / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D013997:Time Factors; D014835:Volatilization
chemical_list: D000577:Amides; D010421:Pentanoic Acids; D011136:Polysorbates; D012997:Solvents; D013501:Surface-Active Agents