Application of Near-Infrared Spectroscopy for Screening of Chlorothiazide Sodium Vials

Abstract

Chlorothiazide sodium for injection, USP, is a diuretic and antihypertensive medication in the form of a white or practically white, sterile, lyophilized powder. Each vial contains 500 mg of chlorothiazide sodium, equivalent to 500 mg of chlorothiazide, and 250 mg of mannitol as an inactive ingredient. The pH is adjusted with sodium hydroxide. Chlorothiazide sodium has a molecular weight of 317.71 amu. Since 2020 there have been multiple national shortages of chlorothiazide. Recent studies target chlorothiazide's low bioavailability, aiming to enhance it through nanoparticle production via a supercritical method. The drug's solubility in supercritical carbon dioxide (scCO₂) is vital, with measurements ranging from 0.417×10^-5 to 1.012×10^-5 mole fraction under specific conditions. Adding co-solvents, like ethanol, DMSO, and acetone, to scCO₂ boosts solubility, with ethanol proving most effective, enhancing solubility by 2.02-11.75 times. Intra-lot variability was discovered in a sample of a lot of chlorothiazide sodium by the University of Kentucky Drug Quality Task Force. Two vials of six screened in one lot were displaced from the center of the lot by 4.0 and 4.2 SDs, respectively. Inter-lot variability was confirmed in the near-IR spectra of 204 vials obtained from 28 different lots of chlorothiazide sodium. Using full spectrum BEST analysis 13 vials (6.4%) were outliers.

Figure 1.

Vials of chlorothiazide sodium from lot G2590039.

Figure 2.

Spectra obtained from 6 vials of Sagent chlorothiazide sodium from lot 230111.The yellow line represents vial 3 in the set and is 4.2 SDs from the remaining vials in the set of 6.

Figure 3.

Principal components scores of the near-IR spectra shown in Figure 2. Vial numbers 3 and 6 appear to be outliers when measured back to the center of the other five vials.

Figure 4.

Spectra of 204 vials of chlorothiazide sodium obtained from 28 different lots. Thirteen spectra are outliers using a full spectrum BEST from the library of 28 lots.

Figure 5.

Principal component scores of the 204 vial spectra shown in Figure 4. At least one small subcluster appears to the left of the majority of the library.

Figure 6.

Another rotated view of the principal component scores of the 204 vial spectra shown in Figure 4. At least one small subcluster appears to the right of the majority of the library.

Figure 7.

Another rotated view of the principal component scores of the 204 vial spectra shown in Figure 4. One small subcluster appears to the right of the majority of the library and another slightly larger subcluster to the left. The two different subclusters derive from different lots.

Figure 8.

Another rotation of the principal component scores of the 204 vial spectra shown in Figure 4. At least one small subcluster appears to the left of the majority of the library.

Figure 9.

Principal component scores (PCs 4, 5, and 6) of the 204 vial spectra shown in Figure 4. At least one small subcluster appears above and to the right of the majority of the library.

Figure 10.

Principal component scores (PCs 7, 8, and 9) of the 204 vial spectra shown in Figure 9.

Figure 11.

Loadings spectrum of PC 1 for the spectral library from 204 vials of chlorothiazide sodium. Important peaks are marked with arrows.

Figure 12.

Loadings spectrum of PC 2 of the spectral library.

Figure 13.

Loadings spectrum of PC 3 of the spectral library.

Figure 14.

Loadings spectrum of PC 4 of the spectral library.

Figure 15.

Loadings spectrum of PC 5 of the spectral library.

Figure 16.

Loadings spectrum of PC 6 of the spectral library.

Figure 17.

Loadings spectrum of PC 7 of the spectral library.

Figure 18.

Loadings spectrum of PC 8 of the spectral library.

Figure 19.

Loadings spectrum of PC 9 of the spectral library.