From Microsolvation to Cell Permeation: Novel Separation Science for Drug Discovery

The development of new drugs requires extensive analysis of their physiochemical properties. Chemical analysis will include an accurate definition of the mass and structure of the target compound. It also necessitates considerable effort to determine the solubility of a given drug candidate, along with a robust assessment of how it will behave in a variety of biological environments. Of critical importance is the ease with which it will cross permeable membranes, for example, the barrier between blood and the brain. This battery of required analyses comes at significant cost, and is both timeand compoundconsuming. A challenge for analytical scientists is to develop a “one stop shop analysis” providing physiochemical properties on a single platform which would in turn drive down the costs of development. Liu et al. have done just this with a technique called differential mobility spectrometry coupled to mass spectrometry (DMS–MS) (Figure 1). This method, originated by Gruvemont and Purves, has more recently been commercialized by several companies, including Sciex, who have coauthored ref 1 along with researchers from Pfizer and the University of Waterloo Canada. Differential mobility spectrometry records the movement of ions in the presence of modulated applied electric field against a counter flow of nitrogen gas. The ions pass between a pair of electrodes, which may be parallel or in an annular geometry; one electrode is maintained at ground potential while the other has an asymmetric waveform applied to it, composed of a high-voltage component which lasts for a short period of time and a longer low voltage component, of opposite polarity. Separation of ions in DMS occurs under atmospheric pressure and room temperature conditions; as a consequence, the ions commonly cluster with neutral solvent molecules, and the mobility is therefore dependent on the action of the applied electric field on a desolvated, or partially solvated, ion. The output of a DMS measurement provides the voltage necessary to separate an ion (SV) coupled with the optimum voltage applied to compensate for this (CV) allowing good transmission of a given species. The compensation voltage can be thought of as a separation parameter superposed on the asymmetric waveform to equilibrate a given species, enabling it to pass through the electrodes. The voltages applied to the electrodes can be tuned to allow a single moiety to pass through to a detector (usually a mass spectrometer) or can be scanned providing a spectrum of all of the species present in a mixture. One of the distinct advantages of all forms of ion mobility mass spectrometry over mass spectrometry alone is its ability to distinguish isobaric and isometric species or even species that are very close in mass, thus simplifying the resultant mass spectrum, akin to gas or solution chromatography. The orthogonal separation of DMS compared with MS means that, when combined, the revolving power is significantly enhanced, and hence DMS− MS has been successfully applied to the measurement of many different analytes, including peptides, proteins, metabolites, and as in this work drug-like molecules. What sets this study aside from much of what has gone before is that the authors have related the gas phase measurement to solution phase properties.