Radiant energy – Ionic separation or analysis – With sample supply means
Reexamination Certificate
2002-05-24
2004-06-01
Lee, John R. (Department: 2887)
Radiant energy
Ionic separation or analysis
With sample supply means
C250S287000, C250S42300F, C239S003000, C239S704000
Reexamination Certificate
active
06744046
ABSTRACT:
This invention pertains to a novel method and apparatus for the feedback control of electrospray processes through opt-electronic feedback.
The novel method and apparatus is applicable to the field of analytical chemistry, specifically, the area of chemical analysis by the technique of electrospray ionization coupled to mass spectrometry. By the inventive method and apparatus, opto-electronic feedback is used to create an electrospray system that is self-controlling and obtains optimal signal under varying experimental conditions. The inventive method and apparatus is particularly useful in electrospray ionization mass spectrometry (LC-MS), sample preparation for matrix assisted laser desorption ionization mass spectrometry (MALDI MS), and general sample preparation by electrospray.
BACKGROUND OF THE INVENTION
Since the original works of Zeleny (Zeleny, J., Phys. Rev., 1914, 3, 69-91; Zeleny, J., Phys. Rev., 1917, 10, 1-6) and Taylor (Taylor, G., Pro. R. Soc. A, 1964, A280, 383-397), it has been known that the application of a high electric field to a liquid will cause the liquid to become unstable and to break up into many smaller daughter droplets. It is known that if a liquid effluent is pumped though a capillary nozzle, and the exit of the nozzle is placed in a high electric field relative to the surroundings, the liquid exiting the nozzle will break-up into a continuous stream of charged droplets, as shown in FIG.
1
. This process of electrohydrodynamic atomization is commonly referred to as electrospray (Cloupeau, M. and Prunet-Foch, B., J. Aerosol Sci., 1994, 25, 1021-1036).
Electrospray has many practical applications. It has been utilized in the application of thin film coatings, thick film coatings such as electrostatic painting, and powder deposition. Importantly, it is also a practical source of ionization, in which ions present in the liquid are transformed to gas phase ions, through the process of atmospheric pressure ionization. In this configuration, electrospray is often used in combination with the analytical technique of mass spectrometry. Electrospray ionization-mass spectrometry is a method of nearly universal application for chemical analysis, finding wide use in chemical manufacturing, analytical chemistry, environmental chemistry, and perhaps most importantly in the life sciences. Electrospray is currently the method of choice to interface high performance liquid chromatographic (HPLC) separations to mass spectrometry, referred to here, as LC-MS. HPLC is a key tool in separation science, whereby a mixture of components in a liquid phase are seperated, with the mass spectrometry providing high specificity chemical identification. LC-MS plays a central role in pharmaceutical drug discovery and development. Thus practical improvements to the stability, and/or sensitivity, of the electrospray method are of considerable importance.
It is known to those skilled in the art that the stability of an electrospray process is a function of several interdependent parameters, such as:
(1). Nozzle (tip) geometry,
(2) Electric field strength, which is in turn a function of:
(A) Applied voltage and
(B) Distance to Counter electrode,
(3) Mobile phase flow rate,
(4) Mobile phase chemical composition.
Because of the interdependency of these variables, a certain amount of empirical work is required to tune each particular electrospray system for optimal results in each particular application. In most systems, one or more of the foregoing parameters are either fixed or difficult to adjust. In most systems, therefore, the tuning that is required to obtain electrospray stability is generally accomplished by varying and adjusting the electric field strength at the nozzle. This, in turn, requires adjusting either the applied voltage or the distance between the nozzle and counter electrode or mass spectrometer inlet system.
Electrospray systems are generally tuned by one of two different methods. In the first method, the electrospray nozzle is visualized through, for example, a microscope, video camera, etc. and then an operator manually adjusts experimental parameters, such as voltage, distance or both, until a satisfactory spray pattern is achieved. In a second method, the ion current generated by the electrospray process is monitored while the voltage, distance (between the nozzle and counter electrode or mass spectrometer inlet) or both are adjusted. The parameters are adjusted until an ion current of satisfactory magnitude or stability is obtained. Adjustments may be carried out under manual control by an operator, or under electronic (i.e., computer) control for an automatic tuning process. The ion current tuning method is most often employed when an electrospray system is being used as an ionization source in communication with a mass spectrometer.
Both of the foregoing methods have serious limitations. The manual method using visualization of the electrospray nozzle requires constant operator attention and adjustment, and does not respond to varying conditions unless the operator observes and reacts to such changing conditions. Ion current, as used in the second method, on the other hand, is not a completely satisfactory choice upon which to base control, because it is dependent on the chemical nature of the liquid exiting the electrospray nozzle. A change in the chemical composition will change-the ion current. This-results in a system that must be re-tuned when the chemical composition of the liquid changes.
It has been well established (Cloupeau, M. and Prunet-Foch, B., J. Aerosol Sci., 1994, 25, 1021-1036; Jaworek, A. and Krupa, A., J. Aerosol Sci., 1999, 30, 873-893) that the liquid effluent (the mobile phase) and subsequent spray exiting the nozzle may take on a wide variety of physical forms, or spray modes. Jaworek and Krupa (Jaworek, A. and Krupa, A., J. Aerosol Sci., 1999, 30, 873-893) identified ten distinct spray modes, each with definable time-dependant morphological characteristics. The specific spray mode obtained depends strongly upon the geometry of the nozzle, the strength and shape of the electric field, and the mobile phase chemical composition. The spray modes are particularly sensitive to the mobile phase surface tension, viscosity, and electrical conductivity (Grace, J. M. and Marijnissen, J. C. M., J. Aerosol Sci., 1994, 25, 1005-1019).
FIG. 2
shows the basic relationship of the electrical potential and flow rate for the most common electrospray modes for an aqueous based mobile phase. The most commonly encountered modes are shown in FIGS.
3
through
8
and are referred to as: dripping mode, spindle mode, pulsed cone-jet mode, cone-jet mode, and multi-jet mode. Each mode will generate a given distribution of droplet sizes, with each droplet carrying a distribution of electrical charge. The dripping mode typically generates the largest observable droplets, producing drops that can be millimeters in diameter. These droplets can be larger in diameter than the nozzle itself. The cone-jet and multi-jet modes produce the smallest droplets having the highest charge-to-mass ratio. The cone-jet and multi-jet modes are capable of producing nearly monodisperse droplets, having a narrow distribution in both diameter and charge state. Droplet diameters for these modes can be sub-micrometer, much smaller than the diameter of the nozzle itself. Some modes, such as the spindle mode and pulsed cone-jet mode, generate droplets of a large distribution in size and charge, which is not desirable for many applications. These modes also exhibit a pulsing or oscillatory behavior, which can range in frequencies from tens of Hertz to hundreds of Kilohertz. The combination of a wide size distribution along with pulsing behavior is undesirable for many applications. In mass spectrometry, for example, spray pulsing can create poor reproducibility in signal measurement and waste sample, since ion current is not being generated 100% of the time. Large droplets are also known to contribute a significantly to the total ion current yielding a high degree of non-specific “chem
Lee Mike S.
Valaskovic Gary A.
Fernandez Kalimah
Lee John R.
New Objective Inc.
Norris & McLaughlin & Marcus
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