International Journal of Mass Spectrometry 277 (2008) 305–308 Contents lists available at ScienceDirect International Journal of Mass Spectrometry journal homepage: www.elsevier.com/locate/ijms Transferring pharmaceuticals into the gas phase Wolfgang Christen ∗ , Tim Krause, Klaus Rademann Humboldt-Universit¨ at zu Berlin, Institut f¨ ur Chemie, Brook-Taylor-Str. 2, 12489 Berlin, Germany article info Article history: Received 1 April 2008 Received in revised form 30 April 2008 Accepted 30 April 2008 Available online 8 May 2008 PACS: 37.20.+j 64.75.Bc 87.15. -v Keywords: Biomolecule Solubility Supercritical fluid Supersonic beam abstract The dissolution of molecules of biological interest in supercritical carbon dioxide is investigated using pulsed molecular beam mass spectrometry. Due to the mild processing temperatures of most supercritical fluids, their adiabatic expansion into vacuum permits to transfer even thermally very sensitive substances into the gas phase, which is particularly attractive for pharmaceutical and biomedical applications. In addition, supercritical CO 2 constitutes a chemically inert solvent that is compatible with hydrocarbon-free ultrahigh vacuum conditions. Here, we report on the dissolution and pulsed supersonic jet expansion of caffeine (C 8 H 10 N 4 O 2 ), the provitamin menadione (C 11 H 8 O 2 ), and the amino acid derivative l-phenylalanine tert-butyl ester hydrochloride (C 6 H 5 CH 2 CH(NH 2 )COOC(CH 3 ) 3 ·HCl), into vacuum. An on-axis residual gas analyzer is used to monitor the relative amounts of solute and solvent in the molecular beam as a function of solvent density. The excellent selectivity and sensitivity provided by mass spectrometry permits to probe even trace amounts of solutes. The strong density variation of CO 2 close to the critical point results in a pronounced pressure dependence of the relative ion currents of solute and solvent molecules, reflecting a substantial change in solubility. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Many scientific and technical applications rely on the experi- mental ability to transfer molecules intact into the gas phase. This is, however, particularly challenging for larger organic molecules, where, in general, the vapor pressure decreases and the ther- mal fragmentation probability increases with the size of the molecule. Most substances relevant in biochemistry and pharmaceutics belong to this class of nonvolatile or thermally sensitive molecules, and thus tremendous efforts are devoted to this topic. Established approaches to bypass some of the difficulties encountered with the vaporization of drugs and other complex materials include electro- spray ionization (ESI [1,2]), laser desorption, and matrix-assisted laser desorption and ionization (MALDI [3–8]). Common to ESI and MALDI is the quest for a suitable solvent. The use of liquefied gases as reaction media and solvents is well established [9]. Similarly, compressed gases, i.e., supercritical fluids, most notably supercritical CO 2 , have evolved as a possible alternative to conventional organic solvents. They feature liquid- like densities combined with higher diffusivity, lower viscosity, ∗ Corresponding author. E-mail address: christen@wolfgang-christen.net. URL: http://wolfgang-christen.net/home.php. and lower surface tension than in the liquid phase, accelerating mass transfer, and facilitating penetration into a solid. Due to their low processing temperatures and the virtually contaminant- free separation of the solute from the solvent, they are widely used in food, pharmaceutical [10], polymer and textile indus- tries, for the production of micron and submicron particles with controllable morphology and narrow size distribution [11], and in environmental technologies [12]. Well-known applications are the decaffeination of green coffee beans and the extraction and enrichment of spices, aromatic substances, fragrances, and phar- maceuticals. Therefore, the supersonic expansion of a solid substance, dis- solved in a supercritical fluid, can be a novel route for generating molecular beams of nonvolatile or thermally sensitive, biologi- cally relevant molecules [13–19]. This approach provides the strong cooling of adiabatic jet expansions [20], and electrically neutral particles, features not readily available otherwise. In this method pulsed beams are indispensable to bridge the huge pressure gap between compressed gases (of the order of 10MPa) and vacuum or ultrahigh vacuum applications at rea- sonable effort [18]. Time-resolved measurements of the beam composition permit to probe the process of dissolution, or the influ- ence of density on solubility. Due to the high compressibility of supercritical fluids along near-critical temperatures, their densities, transport properties, and, in particular, their solvent strengths can be continuously adjusted between gas-like and liquid-like values 1387-3806/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ijms.2008.04.029