Preface

In late-stage pharmaceutical and biopharmaceutical drug development, the comprehensive characterisation of drug substances and drug products is paramount to ensure their safety, efficacy, and regulatory approval before their ‘on-market’ deployment. Among the numerous analytical techniques available to research scientists, nuclear magnetic resonance (NMR), as spectroscopy and imaging, is perhaps the most versatile and informative analytical tool for the characterisation of pharmaceutical/biopharmaceutical materials. This forward provides a brief synopsis of the various chapters which describe the applications and advancements of magnetic resonance techniques in the pharmaceutical and biopharmaceutical industry and highlights their significance in drug substance and drug product development, authentication of pharmaceuticals, structural analysis, and quality control.

Chapter 1, by Silva-Elipe, focusses on the role of NMR spectroscopy in drug substance development; topics covered include the elucidation of drug substance structures and related materials, monitoring of reactions during process development, quantification of drug substances, and the characterisation of drug substances using solid-state nuclear magnetic resonance. Silva-Elipe’s contribution draws upon recent literature examples and showcases the valuable insights NMR offers at the different stages of drug substance and drug product development.

Chapter 2, authored by McCudden and Embrey, presents a comprehensive account of how counterfeit, falsified, and substandard medicines continue to pose a significant threat to public health worldwide. The first part of this chapter gives a thorough generic overview of counterfeit, falsified, and substandard medicines and the impact they have on patients around the globe. The second and third parts of this contribution describe how multidimensional NMR techniques can be used as a powerful weapon against this illegal and deadly trade. The authors explain how various 1D, 2D, and 3D NMR techniques (along with complimentary analytical techniques) have emerged as valuable tools in the authentication, forensic analysis, and compositional characterisation of suspect pharmaceutical/biopharmaceutical products.

Chapter 3, written by Wren and Szell, describes a more niche application of magnetic resonance in the form of nuclear quadrupole resonance (NQR) spectroscopy. NQR is a radio-frequency-based technique that does not require an external magnetic field but can extract vital information about the structure of pharmaceutical solids. The chapter contains examples where NQR has been used to investigate polymorphism and crystal structures and analyse tablet compaction and counterfeits.

Chapter 4, by Hughes et al., introduces the concept of NMR crystallography and shows how solid-state NMR techniques have revolutionised the characterisation of active pharmaceutical ingredients (APIs) and their formulations. Moreover, Hughes et al. illustrate how the combination of experimental solid-state NMR and density-functional theory (DFT) calculations can provide complementary, synergistic insights into polymorphism, solvates, hydrates, salt and co-crystal formation, and amorphous solid dispersions. Key magic-angle spinning (MAS) NMR experiments, such as cross-polarization (CP)MAS coupled with two-dimensional heteronuclear correlation experiments are described, and the authors highlight their importance for unravelling the complex structures of pharmaceutical materials.

Chapter 5, by Briggs et al. describes how low-field (LF) water proton nuclear magnetic resonance (wNMR) is emerging as an innovative, non-invasive, and inexpensive analytical technology that offers unique opportunities for pharmaceutical and biopharmaceutical manufacturing and product inspection. A particular focus of this chapter is the application of wNMR to characterise aluminium-adjuvanted vaccines highlighting its ability to assess the physicochemical status of solutes in water. Through specific examples, Briggs et al. demonstrate the power of wNMR to detect freeze/thaw variability, monitor vaccine sedimentation kinetics, and ensure the quality of finished drug products.

Chapter 6, by Grimes and Mantle, discusses the application of NMR spectroscopic and magnetic resonance imaging (MRI) techniques to the area of biopharmaceuticals and bioprocessing, thus giving valuable insights for optimising bioprocesses and maximizing cell culture productivity. The advantages of the non-invasiveness of NMR spectroscopy and MRI in studying cell cultures and bioreactors are described and show how it is possible to provide real-time data and quantitative flow information within operating bioreactors, thus offering valuable insights for the optimisation of bioprocesses and maximizing cell culture productivity.

In Chapter 7, Mantle gives a comprehensive overview of the pulsed field gradient nuclear magnetic resonance (PFG-NMR) experiment for studying molecular self-diffusion. PFG-NMR, mainly in the form of diffusion ordered spectroscopy (DOSY), is extensively utilised in late-stage pharmaceutical and biopharmaceutical research. This chapter describes the fundamental origins of the PFG-NMR experiment and goes on to discuss in some detail the theory and physical interpretation behind non-linearity (curvature) that may be present in experimental data. Selected examples of the use of PFG-NMR in late-stage small molecule pharmaceutical and biopharmaceutical research are highlighted.

Chapter 8, authored by Kulinowski and Dorożyński, focusses on the application of magnetic resonance imaging in pharmaceutical technology to solve technological issues in drug development, manufacturing, and formulation. Kulinowski and Dorożyński highlight the importance of MRI in controlled drug release devices and formulations and go on to show how this type of data can be used to explain dissolution mechanisms as well as serving as an additional discriminatory test for in vitro dissolution studies.

Chapter 9, by Newling, introduces the reader to specialist MRI techniques specifically designed for imaging short-lifetime (broad-line) materials in the pharmaceutical industry. While these methods are not widely employed in industrial research, Newling shows how short-lifetime, single point imaging (SPI) magnetic resonance methods provide unique and complementary physical insights into materials imaging in pharmaceutical research.

In summary, this compilation offers a comprehensive overview of the recent advances and applications of nuclear magnetic resonance techniques to enhance our understanding of pharmaceutical and biopharmaceutical development. From drug substance development and authentication to the characterization of pharmaceutical solids and the optimization of bioprocesses, NMR techniques continue to play a pivotal role in advancing pharmaceutical research and ensuring the quality and safety of drug products. The diverse applications summarised in this preface exemplify the vast potential of NMR in the ever-evolving landscape of pharmaceutical and biopharmaceutical research. The editors thank Dr Patrick Szell for the cover art.

Michael D. Mantle and Leslie P. Hughes