Pharmaceutical Characterization with NMR

Spectroscopy recently interviewed Editorial Advisory Board member Gary McGeorge, Principal Scientist at Bristol-Myers Squibb, on his research in nuclear magnetic resonance (NMR) and solid-state NMR.

You did your doctoral thesis and postdoctoral research on using nuclear magnetic resonance (NMR) to study polymorphs. How applicable did you find the technique once you started working in industry?

Solid-state nuclear magnetic resonance (ssNMR) was, and continues to be, a very powerful technique for differentiating polymorphs and for allowing one to identify key areas on the molecule where there may be conformational changes. For the most part my PhD training made it possible for me to continue to demonstrate the utility of ssNMR; however, it quickly became apparent to me that my industrial colleagues had a lot to teach me about breaking down polymorphism problems in a systematic, multidisciplinary manner and that ssNMR wasn’t an independent tool. This is why I enjoy using powder X-ray diffraction (pXRD), near-infrared (NIR) spectroscopy, IR, Raman, and ssNMR in a holistic manner — each tool provides different information.

How are you currently applying NMR in your work?

ssNMR is being used extensively within Bristol-Myers Squibb (BMS) for a variety of development challenges. These include characterization of polymorphic active pharmaceutical ingredients (APIs) as already discussed, but also for solvates analysis. This is really an area where ssNMR shines, because it can actually pinpoint how the solvent molecule or molecules are incorporated into the crystal lattice. Many scientists have studied the fragility of solvates using ssNMR. The amorphous phase is one area for which ssNMR has shown significant promise and provides data unavailable with most other techniques; namely, the ssNMR spectra can be inherently related to the local and global molecular mobility of the material being analyzed. These could be single or multicomponent amorphous systems, helping one predict the physical stability of amorphous systems (often used to improve the drug bioavailability for poorly soluble compounds).

ssNMR is also getting more sensitive, with higher field spectrometers, and is fundamentally quantitative. For the analysis of solid samples this means that low-level polymorphic impurities can be quantified both in API and drug product.

Do you have any tips or tricks on using NMR for characterizing pharmaceutical products that might be helpful to analysts just starting to use the technique?

One of the biggest factors in the application of ssNMR is to make sure that you can link your NMR data to the other physical measurements taken for the same sample (for example, differential scanning calorimetry [DSC], thermogravimetric analysis [TGA], pXRD, and more). This is particularly important for solvates because the process of collecting a high-resolution ssNMR spectrum induces a bit of heating that can drive off the solvent if it is weakly held within the crystal lattice. One key consideration for carbon-13 ssMR spectra is that the spectrum is derived from the contents of the asymmetric unit (the basic building block that can be replicated/transformed to generate a crystal) and as such there will be discrete peaks for each and every carbon atom in the asymmetric unit. This is different from solution where the molecule represents the basic building block.

Does NMR have an important role to play in the pharmaceutical industry, such as for the characterization of polymorphs or for other applications?

ssNMR is becoming even more important and its role will continue to increase as its utility and accessibility increases. Most major pharmaceutical companies have ssNMR spectrometers and there are several contract laboratories that have the capabilities to collect ssNMR spectra. I may be biased, but ssNMR can play a pivotal role in the identification and characterization of crystalline forms during early crystal form studies. Selecting the correct crystal form may be critical to the performance of the drug product and the drug’s physical and chemical stability is often dependent upon its crystal structure. ssNMR is one of the most powerful tools to establish that a sample represents a pure phase without any other secondary data when a single crystal structure is unavailable.

Recent innovations in NMR have involved the study of protein structures. Do you think that is a promising area for NMR?

Absolutely! ssNMR analysis of “small” molecules underwent significant growth and development from the early 1990s. The current trends and advances are now in the area of macromolecular systems and there is significant interest in the academic field. ssNMR tools have been developed by groups such as Chad Rienstra’s at the University of Illinois that probe with atomic level resolution the molecular structure of biological materials. Such tools have been applied, not just to the solution of protein structures, but to characterize membrane bound proteins in the binding pocket. One can obtain binding constants and also explore the local structure of how the target interacts with a protein. ssNMR has also been applied to characterize the supramolecular organization of amyloid fibrils that are associated with Parkinson’s and Alzheimer’s diseases. This is really exciting because these systems are typically noncrystalline, affording ssNMR a unique opportunity, where other tools are incapable of going.

Where do you see industrial applications of NMR going in the future?

There have been a collection of recent papers that really nicely demonstrate the concept of NMR crystallography in addition to a book by Harris, Wasylishen, and Duer. This is where ssNMR spectra can be interrogated in a manner that enables one to construct a crystal structure based either purely by the NMR spectrum or in concert with other characterization data; for example, pX-ray diffraction. Ab-initio quantum mechanical calculations are now routinely used with sufficient accuracy to predict the chemical shifts in the crystalline state. Linking ssNMR spectra to these calculations allows one to make inference to the structure in cases where crystal structures are unknown. This is a significant advance because there are occasions whereby one may not be able to obtain a crystal structure from the traditional single crystal approaches.