Stability Study of Parenteral N-Acetylcysteine, and Chemical Inhibition of Its Dimerization
Abstract
:1. Introduction
2. Results
2.1. N-acetylcysteine Dosing Method Validation
2.2. Forced Degradation Studies
2.3. Stability Study
3. Discussion
4. Materials and Methods
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Samples | Repeatability (% RSD within-Day) | Intermediate Precision (% RSD between-Day) | Accuracy (Bias in %) |
---|---|---|---|
NAC 450 µg·mL−1 | 0.640% | 2.458% | −1.827% |
NAC 500 µg·mL−1 | 0.287% | 1.909% | −1.656% |
NAC 550 µg·mL−1 | 0.319% | 0.910% | −2.081% |
Conditions | %RSD 1 | |
---|---|---|
pH of mobile phase | 2.7 | 0.887 |
3.0 | 0.347 | |
3.3 | 2.757 | |
Composition of mobile phase | 98:2 | 0.501 |
97:3 | 0.347 | |
96:4 | 0.281 | |
Flow | 1.8 mL·min−1 | 0.216 |
2.0 mL·min−1 | 0.347 | |
2.2 mL·min−1 | 0.244 | |
Column | C18 Kromasil®, 4.6 × 250 mm, 5 µm | 0.089 |
C18 XTerra®, 4.6 × 250 mm, 5 µm | 0.347 | |
C18 Lichrospher®, 4.6 × 250 mm, 5 µm | 4.404 | |
Wavelength | 198 nm | 1.502 |
200 nm | 0.347 | |
202 nm | 0.588 |
Experimental Conditions | API Degradation | Degradation Products’ Retention Times |
---|---|---|
Heat (80 °C, 3 h) | 24% | 1.3 min, 1.5 min, 1.8 min, 2.2 min, 5.3 min, 7.2–7.7 min |
Light (sunlamp, 28 days) | 3% | 7.2–7.7 min |
Oxidation (H2O2 0.3%, 3 h) | 6% | 1.6 min, 2.0 min, 7.2–7.7 min |
Acid (HCl 0.5 M, 1 min) | 15% | 1.5 min, 1.7 min, 7.2–7.7 min |
Alkaline (NaOH 0.1 M, 10 min) | 23% | 1.9 min, 2.0 min, 7.2–7.7 min |
T0 | 6 h | 1 Day | 2 Days | 3 Days | 4 Days | 7 Days | 8 Days | R 2,4 | p Value 5 | |
---|---|---|---|---|---|---|---|---|---|---|
NAC content ± S.D. 1 | 22.82 ± 1.99 | 22.28 ± 0.18 | 22.09 ± 0.04 | 22.41 ± 0.41 | 22.22 ± 0.35 | 21.56 ± 0.23 | 21.88 ± 0.21 | 21.42 ± 0.50 | 0.65 | <0.02 |
% NAC dimer ± S.D. 2 | 0.20 ± 0.03 | 0.29 ± 0.01 | 0.32 ± 0.01 | 0.34 ± 0.02 | 0.37 ± 0.01 | 0.42 ± 0.01 | 0.53 ± 0.02 | 0.54 ± 0.04 | 0.94 | <0.001 |
Osmolality 3 | 511 | 500 | 510 | 508 | 524 | 510 | 515 | 512 | 0.15 | NS 6 |
pH | 6.26 | 6.24 | 6.24 | 6.21 | 6.24 | 6.15 | 6.10 | 6.12 | 0.87 | <0.001 |
Visible particles | none | none | none | none | none | none | none | none |
T0 | 6 h | 1 Day | 2 Days | 3 Days | 4 Days | 7 Days | 8 Days | R 2,4 | p Value 5 | |
---|---|---|---|---|---|---|---|---|---|---|
NAC content ± S.D. 1 | 22.82 ± 1.99 | 22.15 ± 0.17 | 21.78 ± 0.26 | 22.03 ± 0.43 | 21.52 ± 0.29 | 21.95 ± 0.25 | 21.61 ± 0.42 | 21.27 ± 0.20 | 0.58 | <0.05 |
% NAC dimer ± S.D. 2 | 0.20 ± 0.03 | 0.29 ± 0.01 | 0.39 ± 0.02 | 0.52 ± 0.01 | 0.61 ± 0.01 | 0.71 ± 0.02 | 1.09 ± 0.10 | 1.13 ± 0.18 | 0.99 | <0.001 |
Osmolality 3 | 511 | 508 | 507 | 507 | 505 | 521 | 515 | 520 | 0.48 | NS 6 |
pH | 6.26 | 6.13 | 6.11 | 6.04 | 6.05 | 6.04 | 6.04 | 5.95 | 0.65 | <0.02 |
Visible particles | none | none | none | none | none | none | none | none |
T0 | 4 Days | 8 Days | ||
---|---|---|---|---|
Control | % NAC dimer | 0.20 | 0.42 | 0.54 |
variation from baseline | ×2.1 | ×2.7 | ||
ascorbic acid 12.5 mg·mL−1 | % NAC dimer | 0.27 | 2.08 | 3.68 |
variation from baseline | ×7.7 | ×13.6 | ||
Sodium edetate 2 mg·mL−1 | % NAC dimer | 0.39 | 0.50 | 0.64 |
variation from baseline | ×1.3 | ×1.6 | ||
Zinc gluconate 12.5 µg·mL−1 | % NAC dimer | 0.36 | 0.48 | 0.58 |
variation from baseline | ×1.3 | ×1.6 | ||
Zinc gluconate 62.5 µg·mL−1 | % NAC dimer | 0.28 | 0.33 | 0.36 |
variation from baseline | ×1.2 | ×1.3 | ||
Zinc gluconate 125 µg·mL−1 | % NAC dimer | 0.31 | 0.29 | 0.25 |
variation from baseline | ×0.9 | ×0.8 | ||
Tocopherol 1.25 mg·mL−1 | % NAC dimer | 0.28 | 0.46 | 0.63 |
variation from baseline | ×1.6 | ×2.3 |
T0 | 1 Day | 2 Days | 3 Days | 4 Days | 7 Days | 8 Days | R 2,4 | p Value 5 | |
---|---|---|---|---|---|---|---|---|---|
NAC content ± S.D. 1 | 21.78 ± 0.20 | 21.97 ± 0.43 | 22.33 ± 0.60 | 22.42 ± 0.61 | 22.17 ± 0.10 | 22.57 ± 0.13 | 23.25 ± 0.05 | 0.80 | <0.01 |
% NAC dimer ± S.D. 2 | 0.28 ± 0.03 | 0.28 ± 0.03 | 0.30 ± 0.04 | 0.32 ± 0.03 | 0.34 ± 0.01 | 0.36 ± 0.01 | 0.36 ± 0.01 | 0.92 | <0.001 |
Osmolality 3 | 499 | 512 | 505 | 502 | 526 | 522 | 484 | 0.01 | NS 6 |
pH | 5.22 | 5.14 | 5.19 | 5.19 | 5.21 | 5.14 | 5.20 | 0.03 | NS 6 |
Sterility | Sterile | ND | ND | ND | Sterile | ND | Sterile | ||
Endotoxins 4 | 0.1< | ND | ND | ND | 0.1< | ND | 0.1< | ||
Visible particles | none | none | none | none | none | none | none |
T0 | 1 Day | 2 Days | 3 Days | 4 Days | 7 Days | 8 Days | R 2,4 | p Value 5 | |
---|---|---|---|---|---|---|---|---|---|
NAC content ± S.D. 1 | 22.10 ± 0.20 | 21.93 ± 0.18 | 21.40 ± 0.15 | 21.58 ± 0.08 | 21.65 ± 0.10 | 21.17 ± 0.08 | 21.23 ± 0.18 | 0.75 | <0.02 |
% NAC dimer ± S.D. 2 | 0.27 ± 0.03 | 0.29 ± 0.03 | 0.34 ± 0.03 | 0.38 ± 0.04 | 0.42 ± 0.05 | 0.50 ± 0.04 | 0.53 ± 0.04 | 0.99 | <0.001 |
Osmolality 3 | 541 | 540 | 580 | 584 | 569 | 540 | 538 | 0.06 | NS 6 |
pH | 5.29 | 5.29 | 5.31 | 5.32 | 5.33 | 5.41 | 5.43 | 0.96 | <0.001 |
Sterility | Sterile | ND | ND | ND | Sterile | ND | Sterile | ||
Endotoxins 4 | 0.1< | ND | ND | ND | 0.1< | ND | 0.1< | ||
Visible particles | none | none | none | none | none | none | none |
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Primas, N.; Lano, G.; Brun, D.; Curti, C.; Sallée, M.; Sampol-Manos, E.; Lamy, E.; Bornet, C.; Burtey, S.; Vanelle, P. Stability Study of Parenteral N-Acetylcysteine, and Chemical Inhibition of Its Dimerization. Pharmaceuticals 2023, 16, 72. https://doi.org/10.3390/ph16010072
Primas N, Lano G, Brun D, Curti C, Sallée M, Sampol-Manos E, Lamy E, Bornet C, Burtey S, Vanelle P. Stability Study of Parenteral N-Acetylcysteine, and Chemical Inhibition of Its Dimerization. Pharmaceuticals. 2023; 16(1):72. https://doi.org/10.3390/ph16010072
Chicago/Turabian StylePrimas, Nicolas, Guillaume Lano, Damien Brun, Christophe Curti, Marion Sallée, Emmanuelle Sampol-Manos, Edouard Lamy, Charleric Bornet, Stéphane Burtey, and Patrice Vanelle. 2023. "Stability Study of Parenteral N-Acetylcysteine, and Chemical Inhibition of Its Dimerization" Pharmaceuticals 16, no. 1: 72. https://doi.org/10.3390/ph16010072
APA StylePrimas, N., Lano, G., Brun, D., Curti, C., Sallée, M., Sampol-Manos, E., Lamy, E., Bornet, C., Burtey, S., & Vanelle, P. (2023). Stability Study of Parenteral N-Acetylcysteine, and Chemical Inhibition of Its Dimerization. Pharmaceuticals, 16(1), 72. https://doi.org/10.3390/ph16010072