Behaviour of Tetrabenazine in Acid Medium: Reassessment and Impact on Formulation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Reagents and Solvents
2.2. Forced Acid Degradation Studies
2.3. Instrumentation and Chromatographic Separation Conditions
2.3.1. LC-MS Analyses
2.4. Syntheses and Structural Characterization of [1,1-di-2H,3-2H]-Tetrabenazine([1,1-di-2H,3-2H]-TBZ)
2.4.1. Materials and Methods
2.4.2. Synthesis of [1,1-di-2H,3-2H]-Tetrabenazine
2.5. Characterization of TBZ Integrity in ODF
2.5.1. Extraction of TBZ
2.5.2. Condition of Stability Study
3. Results
3.1. Acid-Forced Degradation Studies and LC-MS Analyses
3.2. NMR Studies of TBZ in Acid Medium
3.3. LC-MS Analyses of TBZ Contained in ODF
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Stress Condition | Solvent | Time | Temp. (°C) | Visual Observation | tr TBZ (min) | tr Unknown (min) | Ratio (%) |
---|---|---|---|---|---|---|---|
No | ACN | One week | 4 | limpid colorless | 1.847 | - | - |
No | ACN + H2O | 70 h | 70 | light yellow | 1.853 | 2.336 | 79:21 |
Acid | HCl 0.1 M | 70 h | 70 | dark yellow-orange | 1.837 | 2.314 | 77:23 |
Acid | HCl 1 M | 16 h | 70 | dark orange | 1.977 | 2.562 | 84:16 |
Acid | HCl 1 M | 70 h | 70 | dark brown | 1.850 | 2.332 | 78:22 |
Acid | Citric acid 1.5 M | 70 h | 70 | light yellow | 1.852 | 2.334 | 79:21 |
Formulation | Polymer Matrix (%) | TBZ (%) | Citric Acid (%) | Glycerol (%) | Sorbitol (%) |
---|---|---|---|---|---|
HPMC-ODF (F1) | 50.00 | 15.00 | 15.00 | 12.00 | 8.00 |
PVP-ODF (F2) | 54.35 | 16.30 | 16.30 | 13.05 | - |
PUL-ODF (F3) | 54.35 | 16.30 | 16.30 | 13.05 | - |
HEC-ODF (F4) | 56.80 | 17.05 | 17.05 | - | 9.10 |
Sample | Visual Observation | TBZ (%) | Unknown (%) |
---|---|---|---|
ODF at T = 0, ambient temperature (n = 3) | |||
F1 | Homogeneous, transparent, slightly yellow | 78.4 ± 0.9 | 17.4 ± 0.3 |
F2 | Homogeneous, transparent, no colour | 83.2 ± 2.3 | 14.2 ± 2.2 |
F3 | Homogeneous, transparent, no colour | 81.2 ± 0.5 | 17.2 ± 0.3 |
F4 | Homogeneous, transparent, no colour | 82.3 ± 0.9 | 14.6 ± 0.2 |
ODF stored at 40 °C, 75% HR after 3 months (n = 3) | |||
F1 | Homogeneous, transparent, yellow | 74.2 ± 0.7 | 17.2 ± 0.4 |
F2 | Homogeneous, opaque area, slightly yellow | 91.2 ± 0.6 | 4.4 ± 0.5 |
F3 | Homogenenous, transparent, slightly yellow | 79.7 ± 0.3 | 15.7 ± 0.1 |
F4 | Heterogeneous, opaque area, slightly yellow | 81.0 ± 0.3 | 14.2 ± 0.3 |
ODF stored at 40 °C, 75% HR after 6 months (n = 3) | |||
F1 | Homogeneous, transparent, yellow | 80.1 ± 0.1 | 16.3 ± 0.1 |
F2 | Homogeneous, opaque area, slightly yellow | 89.5 ± 0.7 | 6.5 ± 0.6 |
F3 | Homogenenous, transparent, slightly yellow | 84.3 ± 0.1 | 14.1 ± 0.6 |
F4 | Heterogeneous, opaque area, slightly yellow | 92.65 ±0.7 | 6.0 ± 0.7 |
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Ettouati, L.; Senta-Loys, Z.; Bourgeois, S.; Fenet, B.; Le Borgne, M.; Fessi, H. Behaviour of Tetrabenazine in Acid Medium: Reassessment and Impact on Formulation. Pharmaceutics 2019, 11, 44. https://doi.org/10.3390/pharmaceutics11010044
Ettouati L, Senta-Loys Z, Bourgeois S, Fenet B, Le Borgne M, Fessi H. Behaviour of Tetrabenazine in Acid Medium: Reassessment and Impact on Formulation. Pharmaceutics. 2019; 11(1):44. https://doi.org/10.3390/pharmaceutics11010044
Chicago/Turabian StyleEttouati, Laurent, Zoé Senta-Loys, Sandrine Bourgeois, Bernard Fenet, Marc Le Borgne, and Hatem Fessi. 2019. "Behaviour of Tetrabenazine in Acid Medium: Reassessment and Impact on Formulation" Pharmaceutics 11, no. 1: 44. https://doi.org/10.3390/pharmaceutics11010044
APA StyleEttouati, L., Senta-Loys, Z., Bourgeois, S., Fenet, B., Le Borgne, M., & Fessi, H. (2019). Behaviour of Tetrabenazine in Acid Medium: Reassessment and Impact on Formulation. Pharmaceutics, 11(1), 44. https://doi.org/10.3390/pharmaceutics11010044