How to Use Solid-state NMR for Pharmaceutical Analysis

Understanding the properties of pharmaceuticals in solid form is critical for drug development and efficacy. Over recent years, advances in solid-state nuclear magnetic resonance (NMR) spectroscopy have made the high-resolution analysis of these products a central method in the pharmaceutical industry.

The Challenges of Pharmaceutical Polymorphs

The majority of pharmaceuticals are produced in solid form but they can vary significantly in their efficacy due to the occurrence of polymorphic forms – the existence of more than one structure. These can arise for a number of reasons, including differences in the way the drug has been formulated or stored. Whether the solid-state form of the active pharmaceutical ingredient (API) is a crystalline material, an amorphous solid, or solvate can have a major impact on its properties, including its dissolution rate, solubility and bioavailability.

A lack of understanding of the solid-state properties of a drug can lead to major setbacks, for example, being unable to reliably produce the optimal form of a drug during clinical trials. Furthermore, better knowledge in this area can lead to improvements to properties of the drug, to make them better for patients, and can be advantageous to pharmaceutical companies by allowing them to extend or broaden patents.

However, studying polymorphs in solid-state pharmaceuticals is challenging. Traditional techniques are not able to characterize all of the components within a formulation. Many polymorphs, hydrates and solvates cannot be obtained as a single crystal suitable for solving their crystal structure, meaning single crystal x-ray diffraction is not effective. For example, the technique cannot be used to characterize amorphous solid dispersions, which are of increasing interest to the pharmaceutical industry. Fortunately, solid-state NMR has many characteristics which help to overcome these obstacles and meet the challenge of understanding the solid forms of pharmaceuticals.

Why Use Solid-State NMR?

Over the past few decades solid-state NMR has come to the fore as a means to study the properties of solid pharmaceutical forms, and is now an integral technique for the pharmaceutical industry. Solid-state NMR is able to provide us with a wealth of information on the physical and chemical state of pharmaceutical products at every stage of drug development.

It is a highly sensitive technique, able to identify crystalline and amorphous forms of drugs and excipients, as well as solvates and hydrates. Furthermore, the API and excipients can be analysed simultaneously, as well as selectively due to the ability to remove components from the spectrum. As a quantitative technique, solid-state NMR can also reveal the proportion of solid forms, for example crystalline and amorphous material, within a sample.

Solid-state NMR can also be used to examine the interactions between drugs and excipients and changes that can occur during formulation, such as crystallization. It can provide detailed information about molecular geometry, bonding and packing.

Solid-state NMR also offers a number of practical advantages. It can be used without sample preparation and applied to whole samples. Additionally, it is non-destructive, which can allow the same sample to be re-analyzed using other techniques.

How We Can Use Solid-State NMR

Solid-state NMR spectra of pharmaceutical solids are primarily acquired using magic-angle spinning with cross-polarization, most often with ¹³C detection. The method has been applied in a number of situations within the pharmaceutical industry.

For example, a study by Agrawal et al (2004) used solid-state NMR to explore why rifampicin, a drug to treat tuberculosis, has variable bioavailability in solid oral dosage forms. The difficulty in producing robust dosage forms was seen as a major obstacle in the treatment of the disease. Using solid-state NMR, the researchers found that commercially available samples of the drug existed in various combinations of three different forms. They found that the dissolution of samples was influenced both by particle size (when greater than 100 μm) and by pH, due to differences in hydrogen-bonding exhibited by the polymorphs. Thus, the research was able to shed light on clinical and regulatory-relevant aspects of rifampicin’s characteristics in its solid form.

Bruker provide hardware and software that is ideal for performing solid-state NMR experiments at the highest possible level.

Bruker TopSolids software combines automated spectrometer adjustment with a comprehensive range of pre-defined protocols to ensure robust spectrometer and probe set-up and guarantee optimal spectral quality.  As such, it offers the most sophisticated solid-state NMR to the broadest range of users, from non-specialists to experts.

Bruker TopSolids is the ideal companion to Bruker’s industry-leading hardware, like the Bruker Avance III NMR spectrometer. The Bruker Avance is the fastest, best-performing research spectrometer on the market, delivering an unsurpassed RF performance. It is able to handle even the most demanding solid-state experiments, thanks to extremely fast phase, frequency and amplitude switching.

References:

• Agrawal S, Ashokraj Y, Bharatam PV, et al. Solid-state characterization of rifampicin samples and its biopharmaceutic relevance. European Journal of Pharmaceutical Sciences 2004; 22: 127-144. doi: 10.1016/j.ejps.2004.02.011.
• Mingyue Li, Wei Xu, Youngchao Su. Solid-state NMR spectroscopy in pharmaceutical sciences. TrAC Trends in Analytical Chemistry 2021. doi:10.1016/j.trac.2020.116152.
• Yong Du, Youngchao Su. 19F Solid-state NMR characterization of pharmaceutical solids. Solid State Nuclear Magnetic Resonance 2022. doi:10.1016/ j.ssnmr.2022.101796
• Berendt RT, Sperger DM, Munson EJ, et al. Solid-state NMR spectroscopy in pharmaceutical research and analysis. Trends in Analytical Chemistry 2006; 25: 977-984. doi: 10.1016/j.trac.2006.07.006.
• Brown SP. Applications of high-resolution ¹H solid-state NMR. Solid State Nuclear Magnetic Resonance 2012; 41: 1-27. doi: 10.1016/j.ssnmr.2011.11.006.
• Hilfiker R (ed.). Polymorphism in the Pharmaceutical Industry. Weinheim: Wiley, 2006.
• Holzgrabe U, Wawer I, Diehl B (eds.) NMR Spectroscopy in Pharmaceutical Analysis. Oxford: Elsevier, 2008.