Radiant energy – Ionic separation or analysis – With sample supply means
Reexamination Certificate
1998-07-03
2001-10-02
Nguyen, Kiet T. (Department: 2881)
Radiant energy
Ionic separation or analysis
With sample supply means
Reexamination Certificate
active
06297499
ABSTRACT:
TECHNICAL FIELD
This invention provides for improvements in mass spectrometric analysis of chemical compounds. In particular it is concerned with providing more effective means of interfacing mass spectrometric detection with separation techniques such as liquid chromatography and electrophoresis. The main problem in such interfacing is to obtain effective transformation of compounds present as solutes in solution to intact gas phase ions and to introduce those ions to a mass analyzer in a vacuum system. Over the past decade so-called Electrospray Ionization (ESI) has emerged as one of the most effective techniques for achieving that transformation. It has emerged that stable and effective operation of conventional ESI sources is readily achieved only when the flow rate, electrical conductivity and surface tension of the sample solution are all relatively low. Unfortunately, separation techniques such as liquid chromatography and electroporesis often work much better with solutions in which these properties have higher values than ESI can very well accommodate. In particular, flow rates for the mobile phase in the most: widely used liquid chromatography protocols are close to one milliliter per minute (mL/min). ESI works best at flow rates below one or two microliters per minute (uL/min). Various techniques have been developed to overcome this incompatibility of flow rates but none of them is very satisfactory. The present invention seems to provide the best yet solution method of overcoming this flow rate incompatibility. It also relieves some of the constraints on surface tension and electrical conductivity.
BACKGROUND OF THE INVENTION
Electrospray Ionization (ESI) of solute species in a volatile liquid solvent is carried out by dispersing the liquid as a fine spray of highly charged droplets in a bath gas. As solvent evaporation shrinks the droplets they pass through a somewhat intricate sequence of steps that leads ultimately to the transformation of polar solute species in the droplet liquid to free ions in the ambient bath gas. Some of the resulting ion-gas mixture can be admitted into a vacuum system where the ions can be “weighed” by a mass analyzer. This combination of ESI with mass analysis in so-called Electrospray Ionization Mass Spectrometry (ESIMS) can produce and weigh intact ions from simple polar molecules as well as from complex and fragile species with molecular weights up to many millions. The ESIM ions of large molecules are multiply charged so their mass/charge (m/z) ratios are low enough for weighing by relatively inexpensive instruments such as quadrupole mass filters and ion traps. Sensitivity is so high that a complete analysis may require only attomols of analyte. These features of the ESIMS technique have brought about an explosive expansion in its use. In the archival journals of 1984 there were only two papers on the subject [M. Yamashita and J. B. Fenn, Journal of Physical Chemistry 88, 4451 and 4471 (1984)]. In 1996 alone there were around 800 papers relating to the mechanisms, procedures and applications of ESIMS. The world population of ESIMS systems, now around 5000, is expected to grow rapidly as they increasingly become the detector of choice for liquid chromatographs of which around 12,000 are sold annually.
To provide some background perspective for the present invention we present a brief operational description of the ESIMS method along with some examples of results.
FIG. 1
shows a schematic diagram of an ESIMS apparatus similar to that described in US patents of Labowsky et al (4,531,056) and Yamashita et al (4,542,293). It also resembles the systems described in US Patent of Henion et al (4,861,988) and Smith et al, (4,842,701 and 4,885,706) as well as in review articles [Fenn et al, Science 246, 64 (1989); Fenn et al, Mass Spectrometry Reviews 6, 37 (1990); Smith et al, Analytical Chemistry 2, 882 (1990)]. It will be useful to set forth the essential features of the technique with reference to FIG.
1
. Sample solution at a few microliters/minute (uL/min) is injected through hypodermic needle
1
into an opposing flow of bath or drying gas
2
(e.g. a few L/min of warm dry nitrogen) in electrospray chamber
3
whose walls serve as a cylindrical electrode and whose pressure is typically maintained at or near one atmosphere. In the end wall of chamber
3
is glass capillary tube
4
with typical dimensions in mm of: L=180, OD=6, and ID=0.6. The front face of glass capillary tube
4
is metalized and held at a few kV “below” the potential of injection needle
1
which can be at any desired potential including ground. Cylindrical electrode (spray chamber
3
) is at a potential intermediate between that of injection needle
1
and metallized face of glass tube
4
. The resulting electric field at the tip of needle
1
disperses the emerging liquid into a fine spray of charged droplets. Driven by the field the droplets drift toward the inlet of tube
4
, shrinking as they evaporate solvent into the opposing flow of drying gas
2
. This shrinking increases each droplet's surface charge density until the so-called Rayleigh limit is reached at which electrostatic repulsion overcomes surface tension and a “Coulomb explosion” disperses the droplet into a plurality of smaller droplets which repeat the sequence of evaporation and explosion. Then the droplets become small enough a charge density below the Rayleigh limit can produce an electric field normal to the droplet surface that is strong enough to evaporate or desorb solute surface ions into the ambient bath gas. This Ion Desorption Mechanism, proposed by Iribarne and Thomson [J. Chem. Phys. 64, 2287 (1976) and 71, 4451 (1979)] is now accepted by many investigators. Others favor a Charged Residue Mechanism (CRM) proposed by Malcolm Dole and his colleagues [J. Chem. Phys. 49, 2240 (1968) and 52, 4977 (1970)]. It assumes that the evaporation-explosion sequence leads to ultimate droplets so small that each one contains only a single solute molecule that becomes an ion by retaining some of that ultimate droplet's charge as the last solvent evaporates.
By whatever mechanism they may be formed, the ions along with the evaporating droplets drift down the field, counter-current to the flow of drying gas to arrive at the entrance of glass tube
4
where some are entrained in dry bath gas that emerges into first stage
5
of a vacuum system as a supersonic free jet. A core portion of that jet passes through skimmer
6
and electrostatic lens stack:
7
delivering ions to mass analyzer
8
in second vacuum stage
9
. The ions entering glass tube
4
are in a potential well whose depth is the difference in voltage between needle
1
and the entrance of the glass tube
4
. The flow of gas through the glass tube drags the ions up out of said well to any desired potential at the tube exit, even many KV above ground! By this arrangement all external parts of the apparatus are at ground potential, posing no hazard to an operator.
In the system of
FIG. 1
just described the counter-current flow of warm bath gas achieves evaporation of droplet solvent and desolvation of the resulting ions before they enter the glass tube leading into the vacuum system containing a mass analyzer. However, there are some variations on this general approach which can also deliver desolvated ES ions to the mass analyzer. Some systems avoid the need for counter-current gas flow and achieve most of the desolvation of droplets and ions by raising the temperature of the mixture of droplets, ions, and bath gas, or a portion thereof, before it enters the vacuum system. One such system passes a portion of said mixture of ions and solvent-containing bath gas through a heated metal tube instead of glass tube
4
of FIG.
1
. The metal tube walls are sufficiently hot to raise the gas temperature enough to avoid resolvation of the ions due to adiabatic cooling during the free jet expansion of the ion-bearing bath gas at the exit of the tube by which the ions and
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