Pharmaceuticals impurities

In the characterization of low-level pharmaceutical impurities. Prudent decision-making is necessary to select the most advantageous technologies and capabilities specific for each project. Such selections are made to overcome extreme limitations in sensitivity or resolution, or both, that standard techniques would afford. The following two case studies covers show how new NMR technologies and techniques were employed to solve real pharmaceutical challenges. 

As liquid chromatography plays a dominant role in chemical separations, advancements in the field of LC-NMR and the availability of commercial LC-NMR instrumentation in several formats has contributed to the widespread acceptance of hyphenated NMR techniques. The different methods for sampling and data acquisition, as well as selected applications will be discussed in this section. LC-NMR has found a wide range of applications including structure elucidation of natural products, studies of drug metabolism, transformation of environmental contaminants, structure determination of pharmaceutical impurities, and analysis of biofiuids such as urine and blood plasma. Readers interested in an in-depth treatment of this topic are referred to the recent book on this subject [25]. 

Any comprehensive discussion of chromatographic methods is well beyond the scope of both this chapter and the author s area of expertise, but the importance of high-quality isolates nevertheless warrants comment. There are a number of published reviews dealing with various aspects of preparative chromatography in relation to pharmaceutical impurities to which the interested reader is referred [25-30], as well as to Chapter 7. 

Any comprehensive survey of impurities in pharmaceuticals is completely beyond the scope of this contribution. A SciFinder search using the terminology pharmaceutical impurities uncovered 1933 citations. Sorting those citations by year gave a rather interesting picmre of the importance of this area of investigation. 

Sharman GJ, Jones IC. Critical investigation of coupled liquid chromatogra-phy-NMR spectroscopy in pharmaceutical impurity identification. Magn Reson Chem 2003 41 448-454. 

Pharmaceutical impurities are those chemical entities other than the APIs themselves and known formulation... 

Supercritical fluids are widely used in manufacturing operations, however analytical-scale SFE has had a relatively modest impact on the isolation of pharmaceutical impurities. Pharmaceutical samples usually consist of complex matrices with polar target analytes, which lead to difficult method development and optimization steps for SFE. Nevertheless, novel laboratory research has successfully used supercritical fluids for the isolation of active pharmaceutical ingredients (API) and pharmaceuticals products. 

How can one be assured that all the samples components are resolved This is particularly important in critical assays such as pharmaceutical impurity testing to ensure that no impurity peaks are co-eluting with other components or hidden under the active ingredient peak. The standard practice is the use of an orthogonal separation technique or method to demonstrate that all impurities are accounted for. An orthogonal method is one based on different separation mechanism from the primary method. 

This chapter provides an overview of modern HPLC method development and discusses approaches for initial method development (column, detector, and mobile phase selection), method optimization to improve resolution, and emerging method development trends. The focus is on reversed-phase methods for quantitative analysis of small organic molecules since RPLC accounts for 60-80% of these applications. Several case studies on pharmaceutical impurity testing are presented to illustrate the method development process. For a detailed treatment of this subject and examples of other sample types, the reader is referred to the classic book on general HPLC method development by L. Snyder et al.1 and book chapters2,3 on pharmaceutical method development by H. Rasmussen et al. Other resources include computer-based training4 and training courses.5... 

S., Patel, Hasmukh B., Powers, Roslyn F., and Yu, Lawrence, Pharmaceutical impurities regulatory perspective for abbreviated new drug apphcations. Advanced Drug Delivery Reviews, 59, 64—72, 2007. Guidance issued by the EMEA (European Medicines Agency, Evaluation of Medicines for Human Use, London, June 23, 2004. See also Reference 6. 

Pharmaceutical Impurities in synthetic drugs Stability tests of synthetic drugs Content uniformity Pharmacokinetic studies and drug monitoring Assay Enantiomeric purity... 

Dobo KL, Greene N, Ered C, et al. In silico methods combined with expert knowledge rule out mutagenic potential of pharmaceutical impurities An industry survey. Regul Toxicol Pharmacol 2012 62 449-455. 

R636 K. Kawaguchi, T. Nakano and K. Kimura, How Do You Use Liquid Chromatography-Nuclear Magnetic Resonance (LC-NMR) Effectively for Structural Determinations of Pharmaceutical Impurities and Metabolites ,... 

Roy, J. Pharmaceutical impurities—A mini-review. AAPS PharmSciTech 2002, 3 (2), article 6. 

Jiben, R. Pharmaceutical impurities-A mini-review. AAPS PharmSciTech 3(2), 2002. http www. aapspharscitech.org, 2002. (article (6)). 

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