Quantitation of Pharmaceutical Compounds

The use of high-repetition lasers has facilitated its coupling to analyzers other than TOFs, and has also driven the real-time analysis of three or more samples 

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Kovarik P, Grivet C, Bourgogne E, Hopfgartner G. Method development aspects for the quantitation of pharmaceutical compounds in human plasma with a matrix-assisted laser desorption/ionization source in the multiple reaction monitoring mode. Rapid Commun Mass Spectrom 2007 21(6) 911—919. 

Many research groups have studied the potential applicability of CEC for the separation of different types of pharmaceutical compounds. However, an important issue to be addressed before CEC will be accepted as a method for routine analysis is the repeatability of the experiment to provide quantitative results. 

Leuthold, L. A., Grivet, C., Allen, M., Baumert, M., and Hopfgartner, G. (2004). Simultaneous selected reaction monitoring, MS /MS and MS3 quantitation for the analysis of pharmaceutical compounds in human plasma using chip-based infusion. Rapid Commun. Mass Spectrom. 18 1995-2000. 

The UV-vis spectrophotometric methods require validation of the method for the analysis of pharmaceutical compounds. Once the method is developed, data regarding precision, accuracy, linear response behavior, limit of quantitation, limit of detection, selectivity, and ruggedness are generated. These terms are very well-defined in many compendial monographs and in ICH, USP, and FDA guidelines. These are not addressed further. However, it should be emphasized that without appropriate validation data and reasonable understanding of how the method results will be affected by minor day-to-day variation of experimental parameters, routine generation of acceptable data may be difficult. 

Corkery, L.J. et al., Automated nanospray using chip-based emitters for the quantitative analysis of pharmaceutical compounds, J. Am. Soc. Mass Spectrom., 16(3), 363, 2005. 

This chapter will look at the use of CE for pharmaceutical analysis and will include descriptions of the various modes of CE and their suitability for quantitative and qualitative analysis of pharmaceutical compounds. Practical applications of CE for the analysis of pharmaceuticals will be covered, these applications include drug assay, impurity determination, physicochemical measurements, chiral separations, and the analysis of small molecules. A section covering the approach to CE method development for pharmaeeutical analysis will include guidelines to selecting the best mode of CE for an intended separation. Extensive data will be provided on successful pharmaceutical separations with references to extra source material for the interested reader. This chapter will provide a comprehensive and up to date view of the role and importance of CE for the analysis of pharmaceuticals and will provide the reader with practical information and real data that will help them to decide if CE is suitable for an intended separation. 

Corkery, LJ., Pang, H., Schneider, B.B., Covey, T.R., Siu, K.W.M. (2005) Automated Nanospray Using Chip-based Emitters for the Quantitative Analysis of Pharmaceutical Compounds. J. Am. Soc. Mass Spectrom. 16 363-369. 

CP-MAS NMR spectra are influenced by the local environment of the observed nucleus rather than by the long-range molecular order, and useful information can be extracted from the spectra of pharmaceutical compounds whether they are powdered microcrystals or amorphous preparations. Unlike diffraction techniques, for example, CP-MAS NMR can access information on local dynamics with appropriate relaxation measurements and line shape analyses. Moreover, with appropriate calibration, it is possible to gain quantitative information from heterogeneous samples, such as drug-excipient formulations and co-crystals. A comprehensive description of CP-MAS NMR methods and their applications to small organic molecules is beyond the scope of this chapter, and the reader is referred to several excellent reviews for more extensive perspectives in this regard. 

A challenging task in material science as well as in pharmaceutical research is to custom tailor a compound s properties. George S. Hammond stated that the most fundamental and lasting objective of synthesis is not production of new compounds, but production of properties (Norris Award Lecture, 1968). The molecular structure of an organic or inorganic compound determines its properties. Nevertheless, methods for the direct prediction of a compound s properties based on its molecular structure are usually not available (Figure 8-1). Therefore, the establishment of Quantitative Structure-Property Relationships (QSPRs) and Quantitative Structure-Activity Relationships (QSARs) uses an indirect approach in order to tackle this problem. In the first step, numerical descriptors encoding information about the molecular structure are calculated for a set of compounds. Secondly, statistical and artificial neural network models are used to predict the property or activity of interest based on these descriptors or a suitable subset. 

The application areas for LC-MS, as will be illustrated later, are diverse, encompassing both qualitative and quantitative determinations of both high-and low-molecular-weight materials, including synthetic polymers, biopolymers, environmental pollutants, pharmaceutical compounds (drugs and their metabolites) and natural products. In essence, it is used for any compounds which are found in complex matrices for which HPLC is the separation method of choice and where the mass spectrometer provides the necessary selectivity and sensitivity to provide quantitative information and/or it provides structural information that cannot be obtained by using other detectors. 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

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