Mass spectrometry in pharmaceutical analysis

The mass spectrometer is now widely accepted as a crucial analytical tool for organic molecules in the pharmaceutical industry. Although usually treated as a spectroscopic technique, it does not rely on the interaction with electromagnetic radiation (light, infrared, etc.) for the analysis. Rather it is a micro-chemical technique relying on the production of characteristic ions in the gas phase, followed by the separation and acquisition of those ions. By its operation, it destroys the sample unlike other techniques, such as nuclear magnetic resonance (NMR), infrared (IR) and Raman/UV spectroscopies. Nonetheless, mass spectrometry is so sensitive that molecular weight and structural information can be provided on very small samples (attomolar (10 molar) quantities). 

There is a variety of mass spectrometers available to the analyst. Each type has unique attributes which make it more suitable for certain operations. This review will briefly cover the major types of mass analysers suitable for applications in the Chemical Development Eaboratory and their mode of operation. 

1953 Invention of the quadnq ole mass spectrometer Paul Steinwedel, 4 

1955 Time of flight mass spectrometer Wiley McLaren, 7 

1967 On-line computerised data processing systems Bowen, 10 

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Goodlett, D.R. Gale, D.C. Guiles, S. Crowther, J.B. Mass spectrometry in pharmaceutical analysis. In Encyclopedia... 

Goodlett, D.R. Gale, D.C. Guiles, S. Crowther, J.B. Mass spectrometry in pharmaceutical analysis. In Encyclopedia of Analytical Chemistry Applications, Theory and Instrumentation, Meyers, R.A. Ed. John Wiley Sons Chichester, England, 2000 Vol. 8, 7209-7278. 

The large numbers of compounds synthesized by HTOS and purified by HTP require high throughput analysis and quality assessment. Mass spectrometry is commonly used for this purpose. Research and development in the analysis of libraries have been focused primarily on the improvement of throughput and automation in the analysis, interpretation, and reporting of data. Morand et al. have recently reviewed development of high throughput mass spectrometry in pharmaceutical research [20] for the analysis of chemical library compounds. Also, the use of one or more auxiliary detection techniques, such as UV or ELSD in addition to mass spectrometry, allows for better assessment of the purity of library compounds. 

J. Huang, X. Hu, J. Zhang, K. Li, Y. Yan, and X. Xu. The application of inductively coupled plasma mass spectrometry in pharmaceutical and biomedical analysis. Journal of Pharmaceutical and Biomedical Analysis 40 227-234, 2006. 

Simultaneous analysis of neutral and acidic pharmaceuticals as well as related compounds by gas chromatography-tandem mass spectrometry in wastewater. Talanta 73 314-320... 

Petrovic M, Hernando MD, Diaz-Cruz MS, Barcelo D (2005) Liquid chromatography-tandem mass spectrometry for the analysis of pharmaceutical residues in environmental samples a review. J Chromatogr A 1067 1-14... 

Modern spectroscopy plays an important role in pharmaceutical analysis. Historically, spectroscopic techniques such as infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS) were used primarily for characterization of drug substances and structure elucidation of synthetic impurities and degradation products. Because of the limitation in specificity (spectral and chemical interference) and sensitivity, spectroscopy alone has assumed a much less important role than chromatographic techniques in quantitative analytical applications. However, spectroscopy offers the significant advantages of simple sample preparation and expeditious operation. 

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. 

Erny, G. L., and Cifuentes, A. (2006). Liquid separation techniques coupled with mass spectrometry for chiral analysis of pharmaceuticals compounds and their metabolites in biological fluids. ]. Pharm. Biomed. Anal. 40, 509—515. 

The marriage of HPLC to mass spectrometry (MS), now developed into a mature instrumentation, continues to greatly impact many of the separation sciences, especially in pharmaceutical analysis where it has been used in new drug discovery [23,24] and in drug metabolite identification [25-27]. HPLC-MS has also made an impact on lipid research, providing a convenient approach to the analysis of phospholipids and fatty acids [28,29]. It has also greatly benefited the field of proteomics [30-34], especially analysis of protein structure and function. 

With the availability of less expensive and more dependable commercial instruments, liquid chromatography coupled to mass spectrometry is quickly becoming the industry standard. However, the role of electrochemistry in pharmaceutical analysis has been well defined, and will likely continue to be preferentially employed in applications where low analyte concentrations, small sample volumes, or complex sample matrices requiring high specificity challenge the analytical method. 

RS Plumb, GJ Dear, D Mallett, IJ Fraser, J Ayrton, C loannou. The application of fast gradient capillary liquid chromatography/mass spectrometry to the analysis of Pharmaceuticals in biofluids. Rapid Commun Mass Spectrom 13(10) 865-872,1999. 

Now that we know what some of the tools are, the following will illustrate the utility of mass spectrometry in the arena of impurity/degradant identification using these tools. Recognize that we have left out a large variety of very valuable and interesting areas and aspects of mass spectrometry to focus on the analysis of pharmaceutically important compounds. 

Plumb, R.S. Dear, G.J. Mallett, D. Fraser, LJ. Ayrton, J. loannou, C. TheApplication of Fast Gradient Capillary Liquid Chromatography/Mass Spectrometry to the Analysis of Pharmaceuticals in Biofluids, Rapid Commun. Mass Spectrom. 13, 865-872 (1999). 

Ramanathan, R. et al., Early assessment of metabolites in clinical studies Potential applications of NanoSpray ionization mass spectrometry, in 10th Annual Symposium on Chemical and Pharmaceutical Structure Analysis, Langhome, PA, 2007. 

Today, MS is one of the most powerful analytical techniques particularly in pharmaceutical analysis where good selectivity and high sensitivity are often needed. Liquid chromatography-mass spectrometry (LC-MS) has become a highly developed tool for the determination of dmgs in... 

Belanger J, Pare JRJ. Fast atom bombardment mass spectrometry in the pharmaceutical analysis of drugs. J Pharm Biomed Anal. 1986 4 415 1. 

Huerta-Fontela M, Galceran MT, Ventura F. Fast liquid chromatography—quadrupole-linear ion trap mass spectrometry for the analysis of pharmaceuticals and hormones in water resources. J Chromatogr A 2010 1217(25) 4212—22. 

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