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PREFACE
Nuclear magnetic resonance (NMR) was discovered in 1945/1946 by two groups of physicists, and it is still a technique with rapid progress with regard to both method development and new fields of application. It has spread from Physics to Chemistry, Biochemistry, Pharmacy, Physiology, Food Science, Veterinary and Medicine. Mostly used by chemists as a tool for structure elucidation and confirmation of synthesized and natural compounds, it has also moved into the emerging field of magnetic resonance imaging (MRI). MRI has proven to be indispensable for clinicians in diagnosis and monitoring of pathology. Moreover, for more than one decade, people started to use NMR spectroscopy for quantitative purposes. Whereas the determination of the enantiomeric excess of a chiral compound has a long-standing tradition in the organic chemistry area of asymmetric synthesis, the evaluation of drugs and agrochemicals by means of NMR spectroscopy has not yet been established from the point of view of licensing authorities all over the world even though the methods have been proved to be applicable. NMR spectroscopy in medicine also attempts to use the quantitative approaches to the biochemical characterization of disease, investigating biopsies, tissue extracts or body fluids. The book deals with quantitative NMR spectroscopy by demonstrating the possibilities of the technique and by training the people who have not yet used NMR spectroscopy for assessment of drugs, natural products, plant extracts, agrochemicals or food. The book is divided into three parts: Part I gives the fundamentals of solution and solid-state NMR spectroscopy and its quantitative application as well as the basics of hyphenated techniques. In Part II, principal application fields are presented and modi operandi discussed: drug evaluation, polymer characterization, natural compound assessment in mixtures, investigation of drug formulations, metabolic profiling, DOSY (diffusion-ordered spectroscopy) for faked drugs and quality control of agrochemicals. Finally, in Part III, special applications from various fields are described, e.g. vaccine evaluation, metabolic studies using 19F and 32P NMR, 2D techniques for glycosaminoglycan analysis, assessment of the inhibitory potency of antibiotics by MRI or hypernation of LC–UV–NMR–MS and its application in industries. This increasing significance of qNMR is currently emphasized by the quality evaluation of heparine contaminated with anaphylactoid oversulfated chrondroitin sulfate. Chapter 2 in Part II and Chapter 4 in Part III give corresponding information. Taken together, we tried to collect all possible applications of NMR spectroscopy in the field of quantitative pharmaceutical analysis. The book is written for both students in chemistry, pharmacy or related disciplines who are already familiar with NMR spectroscopy and application chemists in pharmaceutical, agrochemical and food industries. We are sure that many stimulating ideas may emerge when reading the book. Ulrike Holzgrabe, Bernd Diehl and Iwona Wawer Wu¨rzburg, Cologne and Warsaw, 2008 xv
LIST oF CONTRIBUTORS
S. Balayssac Groupe de RMN Biome´dicale, Laboratoire SPCMIB, Universite´ Paul Sabatier, Toulouse cedex, France M. Bernstein AstraZeneca R&D Charnwood, Loughborough, Leics., Great Britain T. Beyer Institute of Pharmacy and Food Chemistry, University of Wu¨rzburg, Germany J. Cheung Bob Wells and Associates, Killara, New South Wales, Australia M.-A. Delsuc Centre de Biochimie Structurale, CNRS, Universite´ Montpellier I, Montpellier, France B. Diehl Spectral Service, Ko¨ln, Germany C. Faber Institute of Physics, University of Wu¨rzburg, Germany F. Fang Department of Chemistry, University of California, Physical Sciences I, Riverside, CA, USA V. Gilard Groupe de RMN Biome´dicale, Laboratoire SPCMIB, Universite´ Paul Sabatier, Toulouse cedex, France T. Gostan N