Spectrometry in Identification of Impurities

Mass spectrometry is, however, a destructive technique—it consumes sample, albeit very small amounts. It is not a universal detector. There are entire classes of compounds that respond differentially in the mass spectrometer under varied conditions, poorly in general, or not at all. The inference of structure from mass spectra is also highly empirical. Regardless of effort, the theoretical prediction of the mass spectrum from a given structure has not been 

The most important concept to remember when evaluating the value of mass spectrometry—or of any analytical technique—is what the technique cannot tell one about the problem. This is just as important as what the technique can tell one about the problem. It is vital not to mislead oneself by thinking that the technique under consideration can address the problem when it really cannot. 

When nonsimple differences are observed, the art of structure elucidation becomes more important. Simple differences can lead to very sensible, detailed procedures. The more difficult the work, the simpler the process map, because the activities have to become more creative and are often ill defined. 

The technique of mass spectrometry has been around for almost 100 years. Most practitioners target J. J. Thomson s 1910-1912 reports on his work with the parabola mass spectrograph as the origin. The field has evolved into a number of techniques— tools —that had significant utility initially, then either proved their worth over the long term as general purpose tools, settled into a particular niche application area, or faded entirely from view. 

FIGURE I I Mass spectrometry process flow chart for identification of impurities. 

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The technique of mass spectrometry (MS) is itself of no help in the detection of impurities, but in combination with gas chromatography (the GC-MS technique) it would be the method of choice for the identification of impurities. 

A laser-induced ToF mass spectrometer (LIMA-2A) was manufactured by Cambridge Mass Spectrometry Ltd., Cambridge, UK, for micro local analysis and was used to analyze thin sections of biological samples in the transmission mode or bulk material in the reflection mode.150,151 Typical LIMA applications in microelectronics include identification of impurities in dielectrics, microlocal analysis, depth profiling, thick film analysis and investigations on hybrid circuits. 

As already emphasized, the process of identification of impurities and/or degradants begins early in drug development. Early brainstorming sessions should involve the analytical chemist, process chemist, formulator, and degradation chemist, as well as the mass spectrometry and NMR experts. It is imperative to involve all that are familiar with the project of interest. The... 

Furthermore, LC-MS is used in a wide variety of other identification studies, e.g., in the identification of impurities and by-products in bulk chemicals used in industry, in the characterization of frequently applied fluorescent derivatives for LC in combination with fluorescence detection, for studying simulated biochemical processes via online electrochemical conversion units, and mass spectrometry via an LC-MS interface. 

H. Kramer, S. Semel J.E. Abel, Trace Elemental Survey Analysis of Trinitrotoluene , PATR 4767 (1975) (An evaluation of the applicability of spark source mass spectrometry and thermal neutron activation for the detn of origin-related trace elemental impurities in TNT) 10) C. Ribando J. Haber-man, Origin-Identification of Explosives Via Their Composite Impurity Profiles I. The... 

Quite often a normal electron ionization mass spectrum appears insufficient for reliable analyte identification. In this case additional mass spectral possibilities may be engaged. For example, the absence of the molecular ion peak in the electron ionization spectrum may require recording another type of mass spectrum of this analyte by means of soft ionization (chemical ionization, field ionization). The problem of impurities interfering with the spectra recorded via a direct inlet system may be resolved using GC/MS techniques. The value of high resolution mass spectrometry is obvious as the information on the elemental composition of the molecular and fragment ions is of primary importance. 

Traditional methodologies for structural identification of trace level impurities in drng substances/products usually involve fractionation of each impurities using a scaled-np analytical chromatographic method, followed by off-line spectroscopic analysis. Coupling of HPLC separation and electrospray mass spectrometry allows on-line acquisition of full scan mass spectra and generation of tandem mass spectrometric data. LC/ESI MS has revolntionized trace analysis for qnalitative and quantitative studies in pharmaceutical analysis. 

C. Eckers,N. Haskins and J. Langridge.The use of liquid chromatography combined with a quadrupole time-of-flight analyzer for the identification of trace impurities in drug substance. Rapid Communications in Mass Spectrometry, 1997,11(17), 1916-1922. 

The best method for getting rapid identification of trace impurities, which should ideally be carried out using chromatographic separation in conjunction with high resolution mass spectrometry so that elemental compositions can be determined... 

The more advanced instrumental methods of analysis, including GC, for the detection and identification of expls are presented (Ref 90) Pyrolysis of expls in tandem with GC/MS was used for the identification of contaminant expls in the environment (Ref 108). Isomer vapor impurities of TNT were characterized by GC-electron capture detector and mass spectrometry (Ref 61). Volatile impurities in TNT and Comp B were analyzed using a GC/MS the GC was equipped with electron capture and flame ionization detectors (Ref 79). The vapors evolved from mines, TNT, acetone, toluene, cyclohexanone and an organosilicon, were analyzed by GC/MS (Ref 78). Red water produced by the sellite purification of crude TNT was analyzed by GC/MS for potentially useful organic compds, 2,4-dinitrotoluene, 3- and 4-sulfonic acids (Ref 124). Various reports were surveyed to determine which methods, including GC/MS, are potential candidates for detection of traces of TNT vapors emitted from land mines factors influencing transportability of TNT vapors thru soil to soil/air interface are dis-... 

Mak, M., Czira, G., Brlik, J. Mass spectrometry in impurity profiling. In Gorog, S. (ed.) Identification and Determination of Impurities in Drugs. Elsevier, Amsterdam (2000)... 

G. J. Lehr, T. L. Barry, G. Petzinger, G. M. Hanna, S. W. Zito, Isolation and identification of process impurities in trimethoprim drug substance by high-performance liquid chromatography, atmospheric pressure chemical ionization liquid chro-matography/mass spectrometry and nuclear magnetic resonance spectroscopy, J. Pharm. Biomed. Anal. 19 (1999), 373-389. 

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