Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Chemical analysis
Reexamination Certificate
2000-07-31
2003-06-17
Barlow, John (Department: 2863)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Chemical analysis
C702S022000, C702S023000, C702S031000
Reexamination Certificate
active
06581013
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to Mass Spectrographic analysis, and more specifically to the identification of organic compounds in complex mixtures of organic compounds.
Mass spectrometry (MS) is a widely used technique for the identification of molecules, both in organic and inorganic chemistry. MS may be thought of as a weighing machine for molecules. The weight of a molecule is a crucial piece of information in the identification of unknown molecules, or in the identification of a known molecule in a unknown mixture of molecules. Examples of situations in which MS analysis may be used include drug development and manufacture, pollution control analysis, and chemical quality control.
MS is frequently used in conjunction with other analysis tools such as gas chromatography (GC) and liquid chromatography (LC), which help to simplify the analysis of MS spectra by essentially spreading out the timing of the arrival of the individual components of a chemical mixture to the MS system. Thus, the number of different molecular species in the mass spectrometer at any one time is reduced, and separation of mass spectrum peaks is simplified. This procedure works well for chemical samples that contain on the order of 10 to 20 different molecular species, but is inadequate for analyzing samples that contain thousands of different species.
Mass spectrometry operates by first ionizing the chemical material of interest in an ionization source. There are many well known ionization sources in the art, such as electrospray ionization (ESI) and atmospheric pressure chemical ionization (ApCI). The above mentioned ionization methods generally produce what is known in the art as a protonated molecule, meaning the addition of a proton or a hydrogen nucleus, [M+H]
+,
where M signifies the molecule of interest, and H signifies the hydrogen ion, which is the same as a proton.
Some ionization methods will also produce analogous ions. Analogous ions may arise by the addition of an alkaline metal cation, rather than the proton discussed above. A typical species might be [M+Na]
+
or [M+K]
+
. The analysis of the ionized molecules is similar irrespective of whether one is concerned with a protonated ion as discussed above or dealing with an added alkaline metal cation. The major difference is that the addition of a proton adds one mass unit (typically called one Dalton), for the case of the hydrogen ion (i.e., proton), 23 Daltons in the case of sodium, or 39 Daltons in the case of potassium. These additional weights or masses are simply added to the molecular weight of the molecule of interest and the MS peak occurs at the point for the molecular weight of the molecule of interest plus the weight of the ion that has been added.
These ionization methods can also produce negative ions. The most common molecular signal is the deprotonated molecule [M−H]
−
, in this case the mass is one Dalton lower than the molecular weight of the molecule of interest. In addition, some ionization methods will produce multiply charged ions. These are of the general identification type of [M+nH]
n+
, where small n identifies the number of additional protons that have been added.
The ions produced in any of the ionization methods discussed above are passed through a mass separator, typically a magnetic field, a quadrupole electromagnet, or a time-of-flight mass separator, so that the mass of the ions may be distinguished, as well as the number of ions at each mass level. These mass separated ions go into a detector and the number of ions is recorded. The mass spectrum is usually shown as a chart such as
FIG. 1
, which illustrates the case of ionized carbon. Note that in this case there are two significant peaks, each representing a different atomic isotope of carbon. In the figure the normalized intensity, or number of ions detected, is displayed on the vertical scale, and the mass to charge ratio (m/z, sometimes also known as Da/e) of the ion is recorded on the horizontal axis. In cases where the charge on the ion of interest is equal to one, as in the case of the singly protonated molecular ions, this mass to charge ratio (m/z) is exactly equal to the mass of the ion of interest plus the mass of the proton.
The situation is not always as simple as that shown in FIG.
1
.
FIGS. 17
a-c
show spectra for a single moderate sized organic molecular species containing 1-3 bromine atoms. Even though there is only a single molecular species represented in the spectrum, there are many significant large ion peaks. For example, the peaks at mass 553 indicate the base molecule of interest with all of the carbon atoms being C-12, and all of the bromine atoms being Br-79. The peak at 555 has one Br-79 replaced with the isotope Br-81, and the smaller peak between 553 and 555 is due to one C-12 being replaced by a C-13. The peaks at m/z 556 represent one Br-81 substitution and one C-13 substitution, and so on. In general there will also be lower m/z peaks that represent fragments of the original molecule and various isotope substitutions. Thus any molecule that contains carbon, bromine or a number of other well known elements having isotopes, will always have multiple peaks, making spectrum analysis difficult.
It is often possible to identify the specific molecular species generating, a MS signal by discerning its molecular weight, since different chemicals typically have different molecular weights. MS is a powerful tool in the analysis of unknown pure organic compounds because it can identify the molecular weight or mass of the compound, thus helping to identify the specific compound by limiting the number of possible compounds. MS is a useful tool, but as just demonstrated there are many ways to incorrectly identify a peak, and the analysis can be time consuming and expensive. Furthermore, if the sample of interest contains more than one compound (i.e., it is a mixture of different materials), then the mass spectrum may become even more difficult to interpret. It may not be easy to identify which particular peak in the spectrum corresponds to a specific compound in the sample introduced. Therefore, as was previously noted, to help analyze complex mixtures it is known in the prior art to do some preliminary separation of the mixture prior to introduction into the mass spectrometer by the use of gas chromatography (GC) or liquid chromatography (LC). For example LC/MS (meaning liquid chromatography/mass spectrometry), is frequently. employed in the analysis of drug metabolites in drug discovery laboratories, where it is used to identify which compound has a specific action in living creatures. It is also known to use GC/MS in environmental pollution analysis. This is typically done in cases involving volatile materials, for example dioxins or polychloronated biphenyls. It is possible to identify a specific material of interest, such as dioxin, by looking for the known mass spectrographic characteristic of a dioxin, i.e., its weight, its isotope distribution, and chromatograph retention time. In the above noted examples, the LC and GC methods are used to allow the sample of the unknown mixture of chemicals to enter the mass spectrometer in a known sequence. Preferably only one compound will enter the MS system at a time. By knowing how long it takes the material of interest to move through a gas chromatograph, it is then possible to know at what time the material will enter the mass spectrometer. Looking at the mass spectrometer output during the expected time for dioxin gives a fairly good chance of identifying the dioxin signature without having the signal cluttered by other materials whose mass spectrum may overlap that of dioxin. Thus, it is known in the art to use MS for analyzing sets of chemical compounds with the addition of gas chromatographic or liquid chromatographic separation at the beginning of the Mass Spectrometer. Such systems produce what are known as total ion chromatograms (TICs) which sho
Annis D. Allen
Birnbaum Mark
Birnbaum Seth N.
Tyler Andrew N.
Barlow John
Fish & Richardson P.C.
Neogenesis Pharmaceuticals, Inc.
Vo Hien
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