Quality by Design Methodology Applied to Process Optimization and Scale up of Curcumin Nanoemulsions Produced by Catastrophic Phase Inversion
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Curcumin Solubility in Oils and Surfactants
2.3. Design of Experiments and Multiple Linear Regression Modeling
2.4. Dynamic Light Scattering
2.5. Nanoemulsion Stability Testing
2.5.1. Centrifugal Force Stability
2.5.2. Serum Stability
2.5.3. Thermal Stability
2.6. Drug Free Nanoemulsion Production
2.7. Manufacture and Scale-up of CUR-Loaded Nanoemulsion
2.8. CUR Drug Content by High Performance Liquid Chromatography (HPLC)
2.9. Cell Viability
2.10. Rheology
3. Results
3.1. Excipient Selection and Formulation Development
3.2. Initial Process Screening
3.3. Selection of Critical Quality Attributes and Design of Experiments
3.4. Manufacture and Scale-up of CUR Nanoemulsion
3.5. Cell Viability Assays
3.6. Rheological Behavior of Curcumin Nanoemulsions
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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DOE Runs | MCT Oil (g) | Tween 80 (g) | Water (g) | Temperature (°C) | Titration Rate (g/min) | Stir Rate (rpm) |
---|---|---|---|---|---|---|
1 | 10 | 10 | 80 | 25 | 3 | 100 |
2 | 10 | 10 | 80 | 45 | 9 | 500 |
3 | 10 | 10 | 80 | 25 | 9 | 500 |
4 | 10 | 10 | 80 | 35 | 6 | 300 |
5 | 10 | 10 | 80 | 25 | 9 | 100 |
6 | 10 | 10 | 80 | 45 | 3 | 100 |
7 | 10 | 10 | 80 | 45 | 9 | 100 |
8 | 10 | 10 | 80 | 25 | 3 | 500 |
9 | 10 | 10 | 80 | 35 | 6 | 300 |
10 | 10 | 10 | 80 | 45 | 3 | 500 |
11 | 10 | 10 | 80 | 35 | 6 | 300 |
CQA (Specification) | |||||||||
---|---|---|---|---|---|---|---|---|---|
Run | Appearance | Diameter (≤250 nm) | PDI (≤0.25) | Centrifugation Diameter Change (≤10%) | Centrifugation PDI (≤0.25) | 1 W 50 °C Diameter Change (≤10%) | 1 W 50 °C PDI (≤0.25) | Cell Culture Diameter Change (≤10%) | Cell Culture PDI (≤0.30) |
1 | Homogenous | 145.03 | 0.200 | 0.712 | 0.183 | 6.160 | 0.152 | 9.400 | 0.212 |
2 | Homogenous | 166.97 | 0.247 | 2.815 | 0.228 | 0.299 | 0.229 | 1.717 | 0.251 |
3 | Homogenous | 156.37 | 0.278 | 3.176 | 0.259 | 2.558 | 0.224 | 3.667 | 0.316 |
4 * | Homogenous | 163.30 | 0.235 | 6.144 | 0.238 | 2.633 | 0.182 | 2.082 | 0.264 |
5 | Homogenous | 142.80 | 0.250 | 4.552 | 0.220 | 3.151 | 0.190 | 3.058 | 0.265 |
6 | Homogenous | 186.00 | 0.263 | 4.767 | 0.233 | 1.918 | 0.249 | 0.197 | 0.245 |
7 | Homogenous | 170.27 | 0.236 | 4.150 | 0.220 | 3.426 | 0.219 | 0.078 | 0.240 |
8 | Homogenous | 197.90 | 0.225 | 3.672 | 0.191 | 0.421 | 0.170 | 5.087 | 0.221 |
9 * | Homogenous | 166.33 | 0.247 | 3.146 | 0.226 | 1.303 | 0.171 | 1.202 | 0.264 |
10 | Homogenous | 216.70 | 0.245 | 4.507 | 0.313 | 0.108 | 0.237 | 1.615 | 0.232 |
11 * | Homogenous | 169.60 | 0.243 | 4.363 | 0.223 | 0.432 | 0.184 | 0.649 | 0.266 |
Source | Estimate | Standard Error | p-Value |
---|---|---|---|
Intercept | 137.93 | 12.02 | <0.0001 |
Titration rate (g/min) | −4.5508 | 0.9136 | 0.0025 |
Temp (°C) | 1.2230 | 0.2740 | 0.0043 |
Stir Rate (rpm) | 0.0587 | 0.0137 | 0.0052 |
Titration rate (g/min) * Stir Rate (rpm) | −0.0153 | 0.0046 | 0.0156 |
Formulation Composition | DoE Scale-100 g | Scale-up-500 g |
MCT Oil (g) | 10.0 | 50.0 |
Tween 80 (g) | 10.0 | 50.0 |
Curcumin (g) | 0.1 | 0.5 |
Water (g) | 79.9 | 399.5 |
Processing Parameters | DoE Scale-100 g | Scale-up-500 g |
Temperature (°C) | 25 | 25 |
Titration Rate (g/min) | 9 | 45 |
Stir Rate (rpm) | 100 | 300 |
CQA (Specification) | |||||||||
---|---|---|---|---|---|---|---|---|---|
Scale (g) | Diameter (≤250 nm) | PDI (≤0.25) | CUR Loading (≥90%) | Centrifugation Diameter Change (≤10%) | Centrifugation PDI (≤0.25) | 1 W 50 °C Diameter Change (≤10%) | 1 W 50 °C PDI (≤0.25) | Cell Culture Diameter Change (≤10%) | Cell Culture PDI (≤0.30) |
100 | 148.73 | 0.22 | 96.29 ± 0.76% | 3.78 | 0.21 | 1.30 | 0.25 | 3.91 | 0.23 |
500 | 155.10 | 0.25 | 95.60 ± 0.88% | 4.89 | 0.23 | 0.33 | 0.27 | 4.85 | 0.26 |
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Adena, S.K.R.; Herneisey, M.; Pierce, E.; Hartmeier, P.R.; Adlakha, S.; Hosfeld, M.A.I.; Drennen, J.K.; Janjic, J.M. Quality by Design Methodology Applied to Process Optimization and Scale up of Curcumin Nanoemulsions Produced by Catastrophic Phase Inversion. Pharmaceutics 2021, 13, 880. https://doi.org/10.3390/pharmaceutics13060880
Adena SKR, Herneisey M, Pierce E, Hartmeier PR, Adlakha S, Hosfeld MAI, Drennen JK, Janjic JM. Quality by Design Methodology Applied to Process Optimization and Scale up of Curcumin Nanoemulsions Produced by Catastrophic Phase Inversion. Pharmaceutics. 2021; 13(6):880. https://doi.org/10.3390/pharmaceutics13060880
Chicago/Turabian StyleAdena, Sandeep Kumar Reddy, Michele Herneisey, Eric Pierce, Paul R. Hartmeier, Suneera Adlakha, Marco A. I. Hosfeld, James K. Drennen, and Jelena M. Janjic. 2021. "Quality by Design Methodology Applied to Process Optimization and Scale up of Curcumin Nanoemulsions Produced by Catastrophic Phase Inversion" Pharmaceutics 13, no. 6: 880. https://doi.org/10.3390/pharmaceutics13060880
APA StyleAdena, S. K. R., Herneisey, M., Pierce, E., Hartmeier, P. R., Adlakha, S., Hosfeld, M. A. I., Drennen, J. K., & Janjic, J. M. (2021). Quality by Design Methodology Applied to Process Optimization and Scale up of Curcumin Nanoemulsions Produced by Catastrophic Phase Inversion. Pharmaceutics, 13(6), 880. https://doi.org/10.3390/pharmaceutics13060880