title: Are fluorine-rich pharmaceuticals lost by partition into fluorous phases?
abstract: The recently developed technology of droplet microfluidics has demonstrated great potential for many applications such as biochemical assay, high throughput screening, cell culture, directed evolution, and chemical synthesis. Intrigued by its capabilities for miniaturization, flexible manipulation, rapid reagent mixing and high throughput experimentation and analysis, the pharmaceutical industry has begun to investigate droplet microfluidic implementation in medicinal and process chemistry. Segmented by an immiscible secondary phase, usually perfluorinated oil, aqueous or organic droplets serve as individual micro-reactors without suffering cross-contamination. As many drug molecules contain fluorines, it is necessary to investigate whether such compounds will be preferentially extracted into the fluorous phase via fluorophilic solvation, which could lead to erroneous analytical results. In this work, we chose drugs with up to 10 fluorines to probe their partition into perfluorodecalin (PFD) from a variety of organic solvents. A fast and straightforward MISER (Multiple Injections in a Single Experimental Run) LC-MS method was applied to measure the loss of drug after mixing with PFD. We found that no significant partition occurred, with the concentration of drugs in the 'experimental' group measured as ±10% of the 'control' group. The RSD% of multiple injections is <5%. The finding was further validated by the conventional LC-MS approach.
authors.affiliation: Department of Process & Analytical Chemistry, Merck Research Laboratories, Rahway, NJ, United States. Electronic address: sunsw921@gmail.com.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Process & Analytical Chemistry, Merck Research Laboratories, Rahway, NJ, United States.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Zawatzky
authors.affiliation: Department of Process & Analytical Chemistry, Merck Research Laboratories, Rahway, NJ, United States.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Regalado
authors.affiliation: Department of Process & Analytical Chemistry, Merck Research Laboratories, Rahway, NJ, United States.
authors.forename: Ian K
authors.initials: IK
authors.lastname: Mangion
authors.affiliation: Department of Process & Analytical Chemistry, Merck Research Laboratories, Rahway, NJ, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Welch
mesh_terms: D002853:Chromatography, Liquid / Q000379:methods; D005461:Fluorine / Q000737:chemistry*; D005466:Fluorocarbons / Q000737:chemistry; D013058:Mass Spectrometry / Q000379:methods; D046210:Microfluidic Analytical Techniques; D044085:Microfluidics / Q000379:methods; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D005466:Fluorocarbons; D004364:Pharmaceutical Preparations; D012997:Solvents; D014867:Water; D005461:Fluorine; C008805:perfluorodecalin
keywords: Droplet microfluidics; Fluorine-rich pharmaceuticals; Fluorous phase partition; Multiple injections in a single experimental run