Spectrometric Analysis of Dantrolene Sodium

Abstract

Dantrolene sodium is a direct-acting skeletal muscle relaxant. Dantrolene sodium for injection is indicated, along with suitable supportive measures, for the management of sudden, severe hypermetabolism of skeletal muscle typical of malignant hyperthermia crises in patients of any age. The formulation scanned in this work was designed to be injected intravenously. Intra-lot and inter-lot variability in the spectra of REVONTO^™ (dantrolene sodium) was measured in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). Spectra of 69 vials from lot 20REV01A contained two groups (n₁=56 vials, n₂=13 vials) when scanned with an FTNIR. The two groups of spectra in lot 20REV01A were found to be 66.7 SDs apart using a subcluster detection test, suggesting that the two groups were manufactured differently. As a result, all available samples of dantrolene were examined. A library of spectra of 141 vials of dantrolene from 4 lots were found to contain 3 separate groups, also suggesting that different vials contain different materials.

Figure 1.

Vials of dantrolene sodium for injection. These vials are from lot 20REV01A.

Figure 2.

The figure shows Fourier transform near-infrared (FTNIR) spectra of 69 vials from lot 20REV01A in the range of 5000–6800 cm⁻¹. The labeled peaks are indicative of major differences within one lot of the drug. The variation in their intensity suggests that there is some variation in the drug’s composition between the vials.

Figure 3.

FTNIR spectra of 69 vials from lot 20REV01A from 5000–4100 cm⁻¹. The peaks with the most variation are labeled according to their wavenumber.

Figure 4.

A principal component (PC) scatterplot of 69 vials from Lot 20REV01A shows two distinct groups. The blue line indicates that the outliers in the group on the right are dispersed throughout the 69 samples taken from the lot. These three PCs account for 62% of the total spectral variation.

Figure 5.

The QQ plot of Lot 20REV01A of dantrolene. The distance between the two groups highlights that the groups likely are not exactly the same material.

Figure 6.

PC scatterplot of the 141 vials in the dantrolene library on PCs 1, 2, and 3. In this plot, three separate groups are apparent. These three groups might have also been present in Figure 4, but only represented by vials 35 and 41. Group 1 is the group farthest to the left, and is the blue line in Figure 8. Group 2 is just to the right of group 1, in between groups 1 and 3. Group 2 is the red line in Figure 8. Group 3 on the right forms the yellow line in Figure 8. These three PCs account for 61% of the total spectral variation.

Figure 7.

PC scatterplot of the 141 vials in the dantrolene library on PCs 4, 5, and 6. In this plot using smaller PCs than Figure 6, the three separate groups are not visible.

Figure 8.

The spectrum of each of the centers of the three groups in Figure 6 (the groups can be identified as 1, 2, and 3, numbering from from left to right in Figure 6). Group 1 (blue line) contains 50 vials, group 2 (red line) contains 78 vials, and group 3 (yellow line) contains 13 vials.

Figure 9.

Loadings for PC1 of the spectra in the dantrolene library containing lots19REV07A, 19REV08A, and 19REV12A and 20REV01A. This loadings spectrum shows the effects of baseline variation following multiplicative scatter correction. Major peaks are marked at 4264, 4389, 4555, 5932, 8277, 8493, and 9721 cm⁻¹.

Figure 10.

Loadings for PC2 of the spectra in the dantrolene library containing lots 19REV07A, 19REV08A, and 19REV12A and 20REV01A. Major peaks are marked at 4391, 4972, 5269, 6587, 8180, and 8984 cm⁻¹.

Figure 11.

Loadings for PC3 of the spectra in the dantrolene library containing lots 19REV07A, 19REV08A, and 19REV12A and 20REV01A. Major peaks are marked at 4197, 4733, 6565, and 7138 cm⁻¹.