(M1530-11-63) Safe and Effective Analysis of High Potency Compounds Using Solid-State NMR Spectroscopy

Purpose: Solid-state NMR of certain pharmaceuticals can present substantial experimental and environmental challenges. Among the most significant of these challenges is the characterization of high potency compounds. Occupation Exposure Band (OEB) band 4 and band 5 compounds present serious hazards for human safety at very low levels of environmental concentration. Many important pharmaceutical compounds including estrogens and a wide range of oncology drugs fall into the band 4 and 5 category. We have fully validated a solid-state NMR containment system and protocols for the safe handling and analysis of these compounds as a part of our existing good manufacturing processes (GMP) system. Data acquired highlights the containment system developed where in the event of a solid-state NMR rotor failure the high potency compound remains contained in the inner rotor and limits the possibility of exposing the operator to the material. In addition, we show data acquired on a tablet of a commercially available drug highlighting the utility of solid-state NMR on high potency compounds.

Methods: Blue chalk was used to validate the performance of the containment system. The blue chalk material was packed into the high potency sample containment system and the ibuprofen was packed into a 7 mm rotor (300 µL) and the  high potency sample containment system (36 µL) which were both analyzed by ¹³C solid-state NMR spectroscopy. Ibuprofen was used to demonstrate NMR performance. Ibuprofen tablets were gently broken up into smaller pieces and packed into the NMR rotor. Data was acquired on a Bruker NEO spectrometer (400 MHz) using the Topspin 4.0.8 software package for data processing. Data was acquired at a nominal sample temperature of 18.5ºC. Magic angle spinning (MAS) was 5 kHz for NMR data acquisition. Prior to data collection, the ¹H T₁ values were determined for each sample to ensure proper recycle delays for data collection. Data was acquired with the Cross Polarization with Total Sideband Suppression (CPTOSS) experiments for both the 7 mm rotor and the high potency containment system (7.5 mm rotor). Typical parameters included one dummy scan, 6 second recycle delay, 2048 acquisitions, a 3 ms contact time, ~50 ms acquisition time, and ¹H decoupling (SPINAL64) of ~55 kHz.

Results: High Potency Sample Containment Failure Testing: Blue chalk was packed into the high potency sample containment system rotor, which consists of a 3.2 mm rotor sleeve placed inside a plastic flak jacket inside of a 7.5 mm NMR rotor. The rotor was spun beyond the manufacturer specification to cause a rotor failure and prove that in the event of a rotor failure the high potency material remains contained in the inner rotor. Figure 1 shows the module after intentional rotor failure, where the lack of blue chalk in the NMR module highlights that the containment system developed prevents exposure from a high potency compound. Ibuprofen Drug Product Formulations: 1D NMR spectra were acquired for a commercially available drug product formulation containing ibuprofen using both a 7 mm rotor and the high potency compound containment system. The NMR spectra collected from the two different rotor systems shows nearly identical ¹³C solid-state NMR spectra. The main difference between the two spectra is the reduced signal to noise ratio and lower filing factor on the high potency rotor setup due to the smaller sample volume. These results highlight the ability to acquire solid-state NMR data on high potency samples in a safe and effective manner, which otherwise is not achievable by conventional solid-state NMR methods.

Conclusion: Characterization of high potency drugs and drug substances which carry a high hazard to the human operator and thus are challenging to safely characterize. With the high potency sample containment system developed, these hazards are minimized, making the drug formulation characterization of high potency samples by solid-state NMR feasible.

References: 1. Farnan, I., Cho, H., Weber, W.J., Scheele, R.D., Johnson, N.R., and Kozelisky, A.E., High-resolution solid-state nuclear magnetic resonance experiments on highly radioactive ceramics. Review of Scientific Instruments, 2004. 75(12): p. 5232-5236.

Acknowledgements: Eric Munson is a partial owner in Kansas Analytical Services, LLC which provides solid-state NMR services to the pharmaceutical industry.

Figure 1: Pictures of the frontside (A) and backside (B) of the 7.5 mm module after the rotor explosion test with Kel-F rotor and flak jacket. (C) Picture of the containment system after the rotor explosion.

Figure 2: 13C solid-state NMR comparison of a commercial ibuprofen tablet using a 7 mm NMR rotor (top trace) and the high potency containment system (bottom trace). The highlighted regions show the NMR signals attributed to the different parts of the tablet.