Structural Characterization of Active Pharmaceutical Ingredients and Commercial Drug Products by Multi-Nuclear Magnetic Resonance Spectroscopy

Iowa State University, Ames IA

Investigators

Abstract

With the support of the Chemical Measurement and Imaging Program in the Division of Chemistry, Professor Aaron Rossini at Iowa State University is developing solid-state nuclear magnetic resonance (SSNMR) spectroscopy approaches to enable the atomic-level structural characterization of formulated pharmaceuticals. A persistent challenge in the pharmaceutical industry is the successful design of formulations for the administration of active pharmaceutical ingredients (APIs). The performance of pharmaceutical formulations is ultimately determined by the atomic-level structure of the APIs. However, atomic-level structure determination of formulated APIs is challenging because of the low API loading within formulations that is often 10 weight percent or less and molecular interactions between the APIs and other components of the formulation. This project will enable the atomic-level characterization of formulated pharmaceuticals and solid APIs by first developing methods that improve SSNMR sensitivity and resolution. Second, these methods will be used to perform SSNMR spectroscopy experiments with isotopes such as 14N, 17O, 19F and 119Sn to access novel structural information that cannot be obtained by conventional spectroscopic methods or diffraction techniques. Graduate and undergraduate students participating in the research will learn how to perform NMR spectroscopy experiments, prepare pharmaceuticals and computationally model the atomic structures of APIs. The proposed research will be executed in collaboration with scientists at Genentech, Boehringer-Ingelheim and Colgate-Palmolive, ensuring its relevance to the pharmaceutical industry. Students will collaborate with industrial scientists, enhancing their training and giving them insight into potential industrial career paths. 1H and 13C SSNMR spectroscopy are now routine methods for the structural characterization of pure and formulated solid APIs. However, structure determination by 1H or 13C NMR spectroscopy requires known reference structures obtained from X-ray diffraction or model structures obtained by computational methods. To overcome these limitations, 1D and 2D NMR experiments will be performed with exotic and unreceptive NMR isotopes such as 14N, 17O, 19F and 119Sn. 1D and 2D NMR experiments with these isotopes will directly reveal the molecular and macroscopic structure within solid drug forms and formulated drug products. For example, analysis of complementary 2D 1H-17O and 1H-14N SSNMR spectra can be used to directly reveal the structure and hydrogen bonding patterns within solid APIs. 2D 119Sn-17O NMR experiments can be used to directly determine the interactions between tin ions and oxygen atoms present in different ingredients within formulated toothpastes. The proposed research will include demonstrating facile techniques for 17O isotope enrichment to enable 17O SSNMR experiments on multi-component solid APIs, solid solutions and formulated APIs. Instrumentation such as ultra-high magnetic fields, dynamic nuclear polarization (DNP) and fast magic angle spinning (MAS) combined with indirect detection will be used to enhance the sensitivity and resolution of SSNMR spectroscopy. Sensitivity enhancement by these techniques is crucial to extend SSNMR experiments to systems which feature low API loading such as commercial drug formulations or solid solutions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.