(T1530-11-63) Development of the USP Chapter < 1762 > for Solid-State Nuclear Magnetic Resonance Spectroscopy

Purpose: While the use of ssNMR to characterize critical quality attributes (CQAs) of pharmaceutical substances, products and excipients has been demonstrated in literature, its integration into routine quality control remains limited. Data acquired highlights the theory and best practices for solid-state NMR data collection for drug substance and drug product. Solid state NMR spectroscopy is a powerful, nondestructive technique that is being widely adapted by pharmaceutical scientist to better identify changes in the solid state. The goal of the work is to provide relevant information to the pharmaceutical community on the benefits and best practices of solid-state NMR spectroscopy for non-experts.

Methods: USP reference standard ibuprofen was obtained from USP. Samples were packed into either 4 mm (52 µL) or 7 mm (300µL) rotors for analysis by solid-state NMR spectroscopy. Three commercially available drug product samples of tablets containing ibuprofen were purchased and analyzed by ¹³C solid-state NMR spectroscopy using the 7 mm 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 18.5^oC. Magic angle spinning (MAS) speeds for the 4 mm rotor were static, and 1 – 15 kHz in 1 kHz steps. MAS speeds for the 7 mm were 5 kHz. Prior to data collection, the ¹H T₁ values were determined for each sample to ensure proper recycle delays for data collection. Data was acquired using the cross polarization (CP) experiment on the 4 mm rotor. Both Cross Polarization with Total Sideband Suppression (CPTOSS) experiments were performed with the 7 mm rotor. Typical parameters included one dummy scan, 2048 acquisitions, a 2 ms contact time, ~50 ms acquisition time, and ¹H decoupling (SPINAL64) of either ~55 kHz (7 mm rotor) or ~100 kHz (4 mm rotor). Additionally, 2D ¹H/¹³C HETCOR experiments were performed with Ibuprofen with two different mixing times for correlation experiments. The 2D HETCORs were acquired with homonuclear decoupling in the indirect dimension to achieve a high resolution ¹H NMR spectrum, 224 indirect dimension points in 64 µs steps, States-TPPI acquisition, 128 (0.1 ms CP contact time) to 256 scans (1.5 ms CP contact time). Sample preparation was the following. For ibuprofen, one sample was packed into the rotor as is, without modification. For the drug product samples, a tablet was gently broken up into smaller pieces and packed into the rotor.

Results: Ibuprofen: 1 dimensional (1D) and 2 dimensional (2D) Experiments: One dimensional experiments were used to highlight the effect of MAS speed on data collection, highlighted in Figure 1. Spinning the sample about the magic angle (15 kHz) compared to static resulted in a wealth of information being obtained by improved resolution and signal to noise ratios. Two-dimensional correlation experiments were performed and are highlighted in Figure 2. The short CP contact time (0.1 ms) shows ¹H-¹³C correlations that in close spatial proximity and the long CP contact time (1.5 ms) shows correlations between all the NMR signals due to ¹H spin diffusion. Ibuprofen Drug Product Formulations: 1D spectra acquired for the commercially available drug product formulations containing ibuprofen. Three different samples were acquired with the CPTOSS experiment. Identification of the ibuprofen API peaks are distinguishable from the excipient peaks. While the API peaks for ibuprofen are consistent with the USP reference standard peaks for the different commercial products, different manufacturers use different excipient blends, as observed in the ¹³C spectra in Figure 3.

Conclusion: Solid-state NMR spectroscopy is a powerful, non-destructive tool for analysis of drug substance and drug product formations. Solid-state NMR is becoming widely utilized for form identification in drug substance and formulations, quantitation, and form changes to name a few applications. The work presented here and the USP chapter aims to educate the non-experts on the potential applications of solid-state NMR in the pharmaceutical industry.

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

Figure 1: Static vs. 15 kHz magic angle spinning (MAS) for Ibuprofen using a 4 mm rotor and spinning module.

Figure 2: 2D HETCOR correlation experiments with (A) 0.1 ms and (B) 1.5 ms contact times for ibuprofen and DUMBO homonuclear decoupling, highlighting the entire 13C chemical shift region.

Figure 3: 13C CPTOSS spectra for Ibuprofen API and commercially available drug product formulations.