Amorphisation of Free Acid Ibuprofen and Other Profens in Mixtures with Nanocellulose: Dry Powder Formulation Strategy for Enhanced Solubility
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Mixture Preparation
2.2.1. Physical Mixtures Preparation
2.2.2. Heated Mixtures Preparation
2.3. Scanning Electron Microscopy (SEM)
2.4. Differential Scanning Calorimetry (DSC)
2.5. X-ray Diffraction (XRD)
2.6. Fourier-Transform Infrared Spectroscopy (FTIR)
2.7. In Vitro Drug Release—Dissolution Test in Biorelevant Media
2.8. HPLC Analysis
2.9. In Vivo Drug Release—Administration in Animals
2.10. Analysis of Plasma Samples
2.11. Plasma Sample Preparation
2.12. Pharmacokinetic Data Evaluation
- -
- AUC0–t (area under the curve from 0 h to the time point of the last quantifiable concentration) was calculated according to the log linear trapezoidal method, μg mL−1;
- -
- AUC0–∞ (area under the curve from time 0 to infinity) was calculated as the sum of AUC0–t and AUCt–∞, where AUCt–∞ = Ct/λz (the measured concentration at the last time point with quantifiable data divided by the elimination rate constant), μg mL−1;
- -
- Mean residence time (MRT), min;
- -
- Non-compartmental t½ (terminal half-life), min.
3. Results
3.1. Ibuprofen Mixtures
3.2. Ketoprofen Mixtures
3.3. Flurbiprofen Mixtures
3.4. Naproxen Mixtures
- -
- It involves a minimal number of processing steps;
- -
- Profens are used in their free acidic form;
- -
- There is no need for organic solvents for drug loading;
- -
- There is no need for salt conjugates or soft gel liquid capsules.
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
IBU | ibuprofen |
MCC | microcrystalline cellulose |
CLAD | Cladophora cellulose |
DSC | differential scanning calorimetry |
SGF | simulated gastric fluid |
FaSIF | fasted simulated intestinal fluid |
FeSIF | fed simulated intestinal fluid |
KET | ketoprofen |
XRD | X-ray diffraction |
FTIR | Fourier-transform infrared spectroscopy |
FLB | flurbiprofen |
NAP | naproxen |
Appendix A
Component | Concentration mM | ||
---|---|---|---|
SGF | FaSIF | FeSIF | |
Taurocholate | 0.08 | 3 | 15 |
Phospholipids | 0.02 | 0.75 | 3.75 |
Sodium | 34 | 148 | 319 |
Chloride | 59 | 106 | 209 |
Phosphate | - | 29 | - |
Acetic acid | - | - | 144 |
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Drug | Structure | IUPAC Name | Mol. Mass, g/mol | Tm, °C | pKa | logP |
---|---|---|---|---|---|---|
IBU | | Iso-butylphenylpropionic acid | 206 | 78 | 4.9 | 4.0 |
KET | | 2-(3-benzoylphenyl)-propanoic acid | 254 | 94 | 3.9 | 3.1 |
FLB | | 2-(3-fluoro-4-phenylphenyl)-propanoic acid | 244 | 111 | 4.4 | 4.2 |
NAP | | (2S)-2-(6-methoxynaphthalen-2-yl)-propanoic acid | 230 | 155 | 4.2 | 3.3 |
Cellulose | BET Surface Area, m²/g | Pore Volume, cm³/g | DFT Pore Mode, nm |
---|---|---|---|
MCC | 0.9 | 0.002 a | - |
CLAD | 98.8 | 0.553 b | 37 |
Drugs Samples | Ton, °C | Tm, °C | ΔH, J/g drug | CrI, % |
---|---|---|---|---|
IBU | 74.9 | 75.7 | 197.6 | 100 |
IBU-MCC-P | 71.5 | 74.4 | 196.9 | 99.6 |
IBU-MCC-H | 72.2 | 73.1 | 149.9 | 75.8 |
IBU-CLAD-P | 71.5 | 73.1 | 154.7 | 78.3 |
IBU-CLAD-H | 62.6 | 67.6 | 1.7 | 0.9 |
KET | 92.4 | 94.4 | 149.3 | 100 |
KET-CLAD-P | 92.4 | 94.4 | 137.8 | 92.3 |
KET-CLAD-H | - | - | 0.3 | 0.2 |
FLB | 112.0 | 114.2 | 131.8 | 100 |
FLB-CLAD-P | 112.0 | 114.2 | 52.6 | 39.9 |
FLB-CLAD-H | 103.0 | 105.5 | 3.2 | 2.4 |
NAP | 153.0 | 155.1 | 174.4 | 100 |
NAP-CLAD-P | 155.9 | 156.3 | 98.3 | 56.4 |
NAP-CLAD-H | 128.1 | 132.2 | 1.0 | 0.6 |
Samples | AUC0–t min (µg mL−1) | AUC0–∞ min (µg mL−1) | MRT, min | T1/2, min |
---|---|---|---|---|
IBU-MCC-P | 197.0 ± 20.8 | 419.9 ± 328.3 | 192 ± 202 | 133 ± 140 |
IBU-CLAD-H | 2323.7 ± 170.1 | 3026.0 ± 186.4 | 85 ± 11 | 59 ± 8 |
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Mantas, A.; Labbe, V.; Loryan, I.; Mihranyan, A. Amorphisation of Free Acid Ibuprofen and Other Profens in Mixtures with Nanocellulose: Dry Powder Formulation Strategy for Enhanced Solubility. Pharmaceutics 2019, 11, 68. https://doi.org/10.3390/pharmaceutics11020068
Mantas A, Labbe V, Loryan I, Mihranyan A. Amorphisation of Free Acid Ibuprofen and Other Profens in Mixtures with Nanocellulose: Dry Powder Formulation Strategy for Enhanced Solubility. Pharmaceutics. 2019; 11(2):68. https://doi.org/10.3390/pharmaceutics11020068
Chicago/Turabian StyleMantas, Athanasios, Valentine Labbe, Irena Loryan, and Albert Mihranyan. 2019. "Amorphisation of Free Acid Ibuprofen and Other Profens in Mixtures with Nanocellulose: Dry Powder Formulation Strategy for Enhanced Solubility" Pharmaceutics 11, no. 2: 68. https://doi.org/10.3390/pharmaceutics11020068
APA StyleMantas, A., Labbe, V., Loryan, I., & Mihranyan, A. (2019). Amorphisation of Free Acid Ibuprofen and Other Profens in Mixtures with Nanocellulose: Dry Powder Formulation Strategy for Enhanced Solubility. Pharmaceutics, 11(2), 68. https://doi.org/10.3390/pharmaceutics11020068