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NMR Spectroscopy in Pharmacy – European Regulatory Dossier, International Pharmacopoeias and Related Applications

The development of nuclear magnetic resonance (NMR) spectroscopy since its inception in the 1950s has been remarkable in demonstrating its power and versatility in the field of chemistry, biochemistry, biology, pharmacy and medicine. NMR spectroscopy in the pharmacy has been used primarily in a classical, organic framework. Typical studies include the structure elucidation of compounds, investigating chirality of drug substances, the determination of cellular metabolism as well as protein studies. The pharmaceutical industry has employed various aspects of NMR techniques during development of drug substances and new medicinal products. Thus, NMR spectroscopy has attained an established role in the regulation of medicinal products. In the European Union (EU) there are various routes by which the sale of a medicinal products can be authorised. Some applications are made to the European Medicinal Evaluation Agency (EMEA) and are dealt with by the Committee for Proprietary Medicinal Products (CPMP) through the ‘ centralised procedure’ , whilst others are made directly to the national or ‘ competent’ authorities of the EU member states. The original legal basis of applications for marketing authorisations in the EU was set out in Council Directive 65/65/EEC together with a brief description of the documents which should accompany such applications in order to establish the quality, safety and efficacy of the product. The basic requirements for the contents of the dossier of information accompanying the application are the same whatever the route and are laid out in detail in Directive 75/318/EEC and its subsequent amendments. The Directive are presented into fourth parts: Part I (the form of a summary of the information presented), Part II (The quality of the product with details of its chemical, pharmaceutical and biological testing), Part III (The toxicological and pharmacological tests, pre-clinical tests) and Part IV (The clinical documentation). NMR methods are most likely to appear in Part II (IIC, II E and II F) which describes respectively the control of starting materials, control of finished product and stability of active ingredient and finished product. Sections of the dossier other than Part II may also feature NMR spectroscopy, for example, reports on clinical studies using in vivo NMR imaging as a diagnostic tool or on product which is itself an NMR imaging agent. NMR spectroscopy is also used to identify drug metabolites isolated during animal and human pharmacokinetic studies, an area where hyphenated techniques are increasingly being used (e.g. LC-NMR, etc). International pharmacopoeias also apply NMR methods in their monographs for testing starting materials, excipients, as well as for identification and control of active ingredients and impurities. Thus, where a pharmacopoeial monograph for an active substance or pharmaceutical excipient employs NMR spectroscopy in a test method, the substance must comply with this test. NMR methods are particularly useful for identifying new organic impurities (if they can be isolated in sufficient quantities), which result from differences in the synthesis route. Whereas the European pharmacopoeias describe the method of NMR spectroscopy only in principle, the United States Pharmacopoeia 23 gives detailed information about the procedure of qualitative and quantitative applications. Even thought the reproducibility of NMR spectroscopic methods in terms of qualitative and quantitative analysis is proved to be very high, the European pharmacopoeias use NMR spectroscopy mostly for the identification of drugs and reagents (e.g. adenine, adenosine, aesculin, butoxycaine, chamazulene, guaiazulene, etc.). From a development perspective, NMR is traditionally used for structure elucidation, but also for analytical applications. In each case, solution-phase NMR studies are the norm. It seems ironic that although about 90% of the pharmaceutical products on the market exist in the solid form, solid-state NMR (CP-MAS) is in its infancy concerning its application to pharmaceutical problem solving and methods development. During the course of developing pharmaceutical compounds, it is becoming increasingly important to characterize the drug in its dispensed form, which is frequently solid. It has long been known that drugs may exist in more than one polymorphyc form. These forms sometimes display significant differences in solubility, bioavailability, processability, and physical/chemical stability. The study of the solid state of a pharmaceutical compound must not only take place at the bulk level, but also with the dosage form. Sometimes the extreme conditions of processing the formulation into the dosage form can alter the solid, or increase its interaction with excipients. Therefore, solid-state analytical techniques are important to characterize pharmaceutical solids. With recent advances in NMR hardware and sofware development, the acquisition of high resolution, multinuclear NMR data of pharmaceutical solids is now more achieviable.

NMR spectroscopy; pharmacy application

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