Trends in Analytical Chemistry, Vol. 25, No. 3, 2006 Trends Electrospray ionization source geometry for mass spectrometry: past, present, and future Irina Manisali, David D.Y. Chen, Bradley B. Schneider The geometry of an electrospray ion source plays important roles in the The technique involves a number of steps, processes of analyte desolvation, ionization, transportation, and detection in including the formation of charged drop- a mass spectrometer. We provide a brief account of the scientific principles lets, desolvation, ion generation, declus- involved in developing an electrospray ion source, and in the various geo- tering, and ion sampling. As the name metries used to improve the sensitivity of mass spectrometry. We also pre- suggests, the basis of this technique lies in sent some popular configurations currently available and outline future using a strong electric field to create an trends in this research area. excess of charge at the tip of a capillary ª 2005 Elsevier Ltd. All rights reserved. containing the analyte solution. Charged droplets exit the capillary as a spray and Keywords: Atmospheric pressure ionization; Commercial ion source design; Electro- travel at atmospheric pressure down an spray ionization; Ion source; Ion source geometry; Mass spectrometry electrical gradient to the gas conductance- 1. Brief introduction to electrospray limiting orifice or tube. Gas phase ions are Irina Manisali, then transported through different vac- David D.Y. Chen* Electrospray ionization (ESI) is a soft ioni- uum stages to the mass analyzer and Department of Chemistry, zation method, allowing the formation of ultimately the detector. ESI has success- University of British Columbia, fully been coupled with a variety of mass 2036 Main Mall, Vancouver, gas phase ions through a gentle process BC, Canada V6T 1Z1 that makes possible the sensitive analysis analyzers. Each analyzer has different of non-volatile and thermolabile com- advantages and the choice of which to use Bradley B. Schneider pounds. Consequently, the use of the ESI is based on the requirements of the appli- MDS SCIEX, 71 Four Valley Dr., cation. Comprehensive information about Concord, ON, Canada L4K 4V8 source in the field of mass spectrometry (MS) has greatly facilitated the study of the coupling of ESI with various mass large biomolecules, as well as pharma- analyzers can be found in Cole’s 1997 ceutical drugs and their metabolites. Thus, compilation of review articles on the topic the ESI source has evolved with the [2]. growth of proteomics and drug discovery research [1]. The analysis of carbohy- drates, nucleotides, and small polar mole- 2. Milestones in the evolution of cules comprises a few of the many other electrospray applications in which ESI-MS is currently used. Together with matrix assisted laser Since 1968, when Dole used ESI and a desorption ionization (MALDI), another nozzle-skimmer system to produce soft ionization technique, ESI has revolu- charged gas-phase polystyrene [3], the ESI tionized biomedical analysis. In 2002, half source has continued to undergo various the Nobel Prize for Chemistry was awar- changes in its size, material, and geome- ded to ESI developer John Fenn, who try. These transformations were made to shared it with Koichi Tanaka, who made optimize both the ionization efficiency and an outstanding contribution to the devel- the efficiency of transferring gas phase opment of MALDI. ions into the mass analyzer. * Corresponding author. The concept of the ESI source is The evolution of the electrospray-source Tel.: +1 604 822 0887; Fax: +1 604 822 2847; deceivably simple, as some aspects of its design has also reflected the coupling of E-mail: [email protected] functioning are still not well understood. the ion source to separation systems, such 0165-9936/$ - see front matter ª 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.trac.2005.07.007 243 Trends Trends in Analytical Chemistry, Vol. 25, No. 3, 2006 as high performance liquid chromatography (HPLC) and electrode can be either the curtain plate of the mass capillary electrophoresis (CE). This has brought new spectrometer or a transport capillary, which will be challenges in generating ions at different flow rates, discussed later. The optimal potential difference between minimizing contamination of the interface, and opti- the sprayer and the principal counter electrode depends mizing overall efficiency. Leading instrument manufac- on experimental parameters, such as the charge state of turers are directly involved in providing innovative the analyte, the solution flow rate, the solvent compo- solutions to the industry’s demand for more sensitive, sition, and the distance between the tip and the counter reliable mass spectrometers. electrode. While different mass spectrometers may re- The purpose of this review is to present some mile- quire different applied voltages on the sprayer and the stones in the evolution of the ESI source to achieve the counter electrode, the potential difference between them designs and the capabilities currently offered by com- is similar (typically 2–5 kV) [8]. In the presence of an mercial manufacturers. We discuss some important electric field, liquid emerges from the tip of the capillary developments achieved by research groups with respect in the shape of a cone, also known as the ‘‘Taylor cone’’ to ESI design. We also present a basic theoretical back- (Fig. 1) [9]. When the electrostatic repulsion between ground on droplet formation and current theories of gas charged molecules at the surface of the Taylor cone phase ion creation in order to provide the reader with a approaches the surface tension of the solution – known better understanding of the reasoning behind the modi- as reaching the Rayleigh limit – charged droplets are fications in source design. While other atmospheric expelled from the tip. The droplets containing excess pressure ion sources use similar geometries, this review positive charge generally follow the electric field lines at will focus on only electrospray ionization. atmospheric pressure toward the counter electrode. However, trajectories will also be affected by space charge and gas flow. 3. Theory The mechanism of forming the Taylor cone is not entirely understood, but it is known that, under certain A number of publications have presented details of the conditions, the morphology of the spray emitted from the electrochemical nature of the electrospray process [4–6]. capillary tip can change [10]. The various spray modes When a large potential difference is applied between an strongly depend on the capillary voltage and are related electrode shaped as a wire and a counter electrode, a to pulsation phenomena observed in the capillary cur- strong electric field is created at the tip. In the case of ESI, rent [10]. Juraschek and Ro¨llgen showed that liquid flow a high voltage is applied to a capillary containing the rate, capillary diameter, and electrolyte concentration analyte solution. For simplicity, we consider the appli- can all impact the spray mode. Controlling the spray cation of positive potential only. Due to the electric field mode is thus crucial in achieving a stable spray and gradient at the tip, charge separation occurs in the an optimal signal. However, this becomes particularly solution as anions migrate towards the capillary walls, difficult when the mobile phase composition changes and cations travel towards the meniscus of the droplet during gradient elution conditions necessary in many formed at the tip (Fig. 1) [7]. LC-MS applications. To address this problem, Valaskovic In order to direct charged species into the mass spec- and Murphy have developed an orthogonal optoelec- trometer, a series of counter electrodes is used in order of tronic system capable of identifying many spray modes decreasing potential. Typically, the principal counter under different conditions [11]. The system automati- cally optimizes the ESI potential in response to changes in flow rate and solvent composition. The size of the spray droplets released from the Taylor cone, highly dependent on flow rate and capillary diameter, is critical to the efficient ionization of the HV evaporation analyte. _ _ _ _ _ _ _ _ _ _ Taylor + + Since a small droplet contains less solvent, desolvation + + ions + + + cone + sample + + ++ + + _ + + + and ionization can be more efficient. Because less fission _ _ _ _ + and __+ + ++ + + solution + _ + + neutrals + + + +_ is required to produce ions, the salt concentration in the _ _ _ _ _ _ _ _ _ + + final offspring droplets may be lower compared to a offspring droplet that has undergone more evaporation-fission droplets cycles. As a result, the background noise in the mass spectrum may be reduced [12]. In addition, with smaller E droplets, analytes that are not surface active will have a counter electrode greater chance of being transferred to the gas phase rather than being lost in the bulk of the parent droplet Figure 1. Schematic diagram of the electrospray process. residue [12]. 244 http://www.elsevier.com/locate/trac Trends in Analytical Chemistry, Vol. 25, No. 3, 2006 Trends The solvent is typically a combination of acidified [21,22]. In addition, counter current nitrogen gas flow water and an organic modifier. The role of the organic (Curtain Gase, further illustrated in Fig. 5) emanating solvent is to lower the surface tension of the liquid, from in front of the gas conductance limiting orifice facilitating the formation of gas phase ions. As the sol- provided additional desolvation [8]. The advantage of vent evaporates, the droplet shrinks and the electrostatic the Curtain Gas is that neutral molecules, such as sol- repulsion between charges within the droplet increases. vent, are carried away from the sampling orifice by the When the Rayleigh limit is approached, offspring drop- nitrogen flow, while charged molecules are directed lets begin to break away unevenly in a process also through the gas flow under the influence of the electric known as ‘‘coulombic fission’’ [7].