Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Quantification by HPLC Analysis
2.3. Preparation of Powders, Study Design, and Optimization
2.4. Particle Size and Size Distribution by Laser Light Diffraction
2.5. Crystallinity by X-ray Powder Diffraction (XRPD)
2.6. Residual Solvent Content by Thermogravimetric Analysis (TGA)
2.7. Phase Transition by Differential Scanning Calorimetry (DSC)
2.8. Powder Density and Flow Property
2.9. Particle Morphology by Scanning Electron Microscopy (SEM)
2.10. In Vitro Aerosolization Performance by Next-Generation Impactor (NGI)
2.11. Stability Studies
2.12. Effect of Inhaler Device and Flow Rate on Aerosolization
2.13. Cytotoxicity Studies by MTT Assay
2.14. Statistical Analysis
3. Results and Discussions
3.1. Powder Production and Optimization
3.2. Process Yield, Particle Size, and Drug Content of the Optimized Powder
3.3. Crystallinity
3.4. Moisture Content
3.5. Differential Scanning Calorimetry (DSC)
3.6. Powder Density
3.7. Surface Morphology
3.8. In Vitro Aerosolization Performance
3.9. Stability Studies
3.10. Effects of Device and Flow Rate on In Vitro Aerosolization
3.11. Cytotoxicity
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Factors | Levels | ||
---|---|---|---|
Low (1) | Medium (2) | High (3) | |
A: Feed concentration (% w/v) | 0.25 | 0.50 | 0.75 |
B: Spray-gas flow rate (L/h) | 601 | 670 | 742 |
Formulation | Level of Factor in the Experiment | |
---|---|---|
A | B | |
F1 | 1 | 1 |
F2 | 2 | 1 |
F3 | 2 | 2 |
F4 | 2 | 3 |
F5 | 3 | 1 |
F6 | 3 | 2 |
F7 | 1 | 2 |
F8 | 3 | 3 |
F9 | 1 | 3 |
Formulation | Process Yield (%) | Volumetric Particle Diameter | |||
---|---|---|---|---|---|
D10 (µm) | D50 (µm) | D90 (µm) | Span | ||
F1 | 21.9 | 4.8 | 7.9 | 13.7 | 1.1 |
F2 | 56.7 | 7.2 | 8.7 | 10.4 | 0.4 |
F3 | 34.0 | 3.3 | 7.3 | 13.3 | 1.4 |
F4 | 62.0 | 5.3 | 8.5 | 13.2 | 0.9 |
F5 | 57.9 | 1.9 | 4.3 | 8.9 | 1.6 |
F6 | 48.8 | 4.2 | 6.7 | 10.1 | 0.9 |
F7 | 8.0 | 3.4 | 7.8 | 12.6 | 1.2 |
F8 | 39.6 | 5.5 | 6.5 | 7.6 | 0.3 |
F9 | 18.0 | 6.5 | 11.8 | 18 | 1.0 |
Formulation | Yield (%) | Particle Size (D50) | Moisture Content (%) | Bulk Density (g/mL) | Tapped Density (g/mL) | Carr’s Index (%) |
---|---|---|---|---|---|---|
SD roflumilast-only | 47.7 | 5.5 ± 0.4 | 1.1 ± 0.2 | 0.363 | 0.539 | 32.7 |
CoSD powder-Batch 1 | 62.3 | 4.9 ± 0.3 | 1.9 ± 0.7 | 0.345 | 0.489 | 29.6 |
CoSD powder-Batch 2 | 62.5 | 5.4 ± 0.2 | 1.4 ± 0.1 | 0.356 | 0.495 | 28.1 |
CoSD powder-Batch 3 | 64.7 | 5.2 ± 0.1 | 1.4 ± 0.1 | 0.352 | 0.514 | 31.5 |
Formulation | ED (%) | FPF (%) | MMAD (µm) | GSD |
---|---|---|---|---|
SD roflumilast-only | 58.3 ± 2.7 | 25.5 ± 5.3 | 5.3 ± 0.7 | 2.0 ± 0.0 |
CoSD powder—Batch 1 | 89.6 ± 1.1 | 52.0 ± 5.4 | 3.5 ± 0.2 | 2.0 ± 0.3 |
CoSD powder—Batch 2 | 88.1 ± 2.0 | 53.5 ± 4.5 | 3.6 ± 0.2 | 1.7 ± 0.0 |
CoSD powder—Batch 3 | 88.2 ± 1.8 | 52.7 ± 5.3 | 3.7 ± 0.3 | 1.6 ± 0.1 |
Formulation | ED (%) | FPF (%) | ||||
---|---|---|---|---|---|---|
Initial | 15% RH | 75% RH | Initial | 15% RH | 75% RH | |
SD roflumilast-only | 58.3 ± 2.7 | 89.5 ± 0.8 * | 85.8 ± 1.1 * | 25.5 ± 5.3 | 23.3 ± 0.3 | 14.1 ± 0.4 * |
CoSD powder | 88.1 ± 2.0 | 87.9 ± 2.1 | 85.1 ± 1.2 | 53.5 ± 4.5 | 59.0 ± 1.2 | 31.3 ± 1.5 * |
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Momin, M.A.M.; Adhikari, B.R.; Sinha, S.; Larson, I.; Das, S.C. Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization. Pharmaceutics 2021, 13, 1254. https://doi.org/10.3390/pharmaceutics13081254
Momin MAM, Adhikari BR, Sinha S, Larson I, Das SC. Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization. Pharmaceutics. 2021; 13(8):1254. https://doi.org/10.3390/pharmaceutics13081254
Chicago/Turabian StyleMomin, Mohammad A. M., Bishal Raj Adhikari, Shubhra Sinha, Ian Larson, and Shyamal C. Das. 2021. "Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization" Pharmaceutics 13, no. 8: 1254. https://doi.org/10.3390/pharmaceutics13081254
APA StyleMomin, M. A. M., Adhikari, B. R., Sinha, S., Larson, I., & Das, S. C. (2021). Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization. Pharmaceutics, 13(8), 1254. https://doi.org/10.3390/pharmaceutics13081254