Determining Relative Response Factors of Impurities by NMR & Developing GMP NMR Methods – Expanding the Role of NMR beyond Structure Identification

Life Sciences, Pharmaceutical, Drug Discovery & Development, Preclinical, Laboratory Technology,
  • Friday, October 18, 2013

Nuclear magnetic resonance (NMR) spectroscopy is widely recognized as an extremely information-rich analytical technique. In the pharmaceutical industry, the utility of NMR is expanding beyond its traditional role as a tool for studying molecular structures and dynamics. The use of NMR to determine relative response factors of impurities in active pharmaceutical ingredients (APIs) is one example of a new application for NMR (Webster, Marsden et al. 2009; Iqbal, Rao et al. 2011).  Quantitative NMR methods and the use of NMR in a GMP environment are also gaining greater acceptance. In this presentation, the advantages and challenges of applying NMR in these new areas will be discussed.

Regulatory agencies dictate that impurities in APIs, and drug products present above certain levels must be monitored and controlled, and at higher levels, fully structurally characterized. Impurity levels are commonly monitored by HPLC/UV. While HPLC/UV methods are robust and sensitive, UV detection suffers from the flaw that not all compounds absorb UV light equally. Late in the drug manufacturing process, it becomes critical to determine the relative response factors of impurities in order to accurately assess their levels in APIs and formulated drug products. Determining these relative response factors can be time consuming and may require hundreds of milligrams of the isolated or synthesized impurity. Under the proper experimental conditions, NMR does not suffer from the same flaw as UV detection and can serve as a universal detector for compounds containing hydrogen. Integrated areas in the 1H NMR spectrum can be used to determine the exact molar ratios of species in solution, which can then be used in concert with HPLC data to calculate relative response factors with potential savings in time and resources.  Recent literature and experiences will be discussed.

NMR is used routinely in GMP environments for tasks such as the release of starting materials, qualification of reference standards and structural identification of impurities. However, the performance of modern NMR spectrometers is characterized by high reproducibility and extensive dynamic range, allowing the development and validation of GMP NMR methods that can meet linearity, robustness, precision and accuracy criteria analogous to HPLC/UV methods.  A case study describing a validated NMR method developed when other analytical methods were not feasible (ie. no chromophores) will be presented.


Iqbal, M. Y., K. M. V. N. Rao, et al. (2011). “Characterization and relative response factor determination of process related impurity in Naproxen by nuclear magnetic resonance spectroscopy.” Journal of Pharmaceutical and Biomedical Analysis 56(3): 484-490.

Webster, G. K., I. Marsden, et al. (2009). “Determination of relative response factors for chromatographic investigations using NMR spectrometry.” Journal of Pharmaceutical and Biomedical Analysis 49(5): 1261-1265.




Darryl A. LeBlanc, Ph.D., NMR Spectroscopist, Manager - Analytical Services, SCYNEXIS, Inc.

Dr. Darryl A. LeBlanc joined SCYNEXIS, Inc in 2001 as a Research Scientist. In this role, Dr. LeBlanc was responsible for all nuclear magnetic resonance (NMR) resources utilized to support medicinal and process chemists at SCYNEXIS. He implemented an open access NMR service and began providing custom NMR support for all company projects. Dr. LeBlanc was responsible for implementing NMR services under Good Manufacturing Practices (GMP) at SCYNEXIS and has more than a decade of GMP NMR experience. Dr. LeBlanc now serves as Manager of Analytical Services and oversees a team responsible for all structural analyses and open-access analytical services at SCYNEXIS. The Analytical Services team also provides impurity identification, physical properties characterization and high throughput purification services for both internal and external customers.

Prior to joining SCYNEXIS, Dr. LeBlanc was employed for 3 years by BASF. Dr. LeBlanc received his Ph.D. in Biochemistry from Louisiana State University in 1994, he was awarded an Intramural Research and Training Fellowship by the National Institute of Environmental Health Sciences, NIH. He spent 4 years as a Post-Doctoral Fellow in the laboratory of Dr. Robert E. London at NIEHS using advanced NMR methods to study protein structure and chemical modifications on the surfaces of proteins. Dr. LeBlanc has more than 15 years of professional NMR experience, more than 12 years in the Pharmaceutical industry, and is a co-author on 5 peer-reviewed publications.

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Allan R. Moorman , Ph.D., Founder, Alta Vetta Pharmaceutical Consulting

Before founding Alta Vetta Pharmaceutical Consulting, Dr. Allan R. Moorman was Senior Director of Medicinal Chemistry for King Pharmaceuticals. In this role, Dr. Moorman was responsible for all discovery and development activities related to drug substance, including discovery chemistry, analytical development, process development, and regulatory submissions, as well as bioanalytical methodologies. He was directly responsible for the discovery of novel candidate molecules for the treatment of neuropathic pain, inflammatory pain, chronic obstructive pulmonary disease (COPD), Parkinson disease, and asthma. He established and led multinational teams to optimize the in vitro and in vivo activities of the compounds in the neuropathic pain, Parkinson disease, and asthma programs, as well as directed the chemical process development required to advance these programs into clinical trials. During his tenure at King, Dr. Moorman was also instrumental in designing and implementing the optimized chemical and analytical processes for the manufacture of the clinical candidates binodenoson, sonodenoson, and T-62. His improvements to the manufacture for sonodenoson, which increased overall yield 20-fold, reduced costs 12-fold, and shortened the manufacturing process from eight steps to three, were notably recognized when he was named the 2006 recipient of the King Pharmaceuticals Employee Award for Innovation.

Prior to joining King, Dr. Moorman held a number of positions of increasing responsibility at Diamond Shamrock Corporation, Burroughs Wellcome Company, and the Institute for Diabetes Discovery. He received his Ph.D. in Medicinal Chemistry from the University of Kansas, followed by an NIH funded postdoctoral fellowship in Mechanistic Enzymology at Brandeis University. With more than 28 years of experience in the Pharmaceutical industry, Dr. Moorman is a named inventor on 31 U.S. patents or patent applications and a co-author of more than 50 peer-reviewed publications.

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Who Should Attend?

Directors of Analytical Research and Development, CMC and/or Process chemistry and formulation development from mid-sized pharma and bio-tech companies

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SCYNEXIS, Inc. is a premier drug discovery and development company headquartered in Research Triangle Park, North Carolina. SCYNEXIS delivers innovative solutions to solve the toughest problems in drug discovery and development for our Pharmaceutical, global health and life science partners. Our contract research and development services include Discovery Research, Integrated Pharmaceutical Solutions and Integrated Parasitology. The SCYNEXIS Integrated Pharmaceutical Solutions drives our clients’ success by rapidly solving the toughest drug development problems through integrated analytical and synthetic chemistry in combination with regulatory expertise.

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