Development and Characterization of Pharmaceutical Systems Containing Rifampicin
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Phase Solubility Studies
2.3. Molecular Modeling
2.3.1. Modeling of Compounds
2.3.2. Molecular Docking Studies
2.3.3. Molecular Dynamics Simulations
2.3.4. Selection of Target Temperature for MD Simulations
2.4. Proton Nuclear Magnetic Resonance Spectroscopy
2.5. Preparation of Inclusion Complexes in Solid State
2.6. Fourier Transform-Infrared Spectroscopy and Powder X-ray Diffraction
2.7. Scanning Electron Microscopy
2.8. Dissolution Studies
2.9. Microbiological Studies
2.9.1. Bacterial Strain and Growth Conditions
2.9.2. Determination of the Minimum Inhibitory Concentration of RIF
2.9.3. In Vitro Antimicrobial Study
2.9.4. Evaluation of the Metabolic Activity of the Biofilm
Biofilm Formation and Treatment
XTT Assay
2.9.5. Biofilm Analysis by Scanning Electron Microscopy
Biofilm Preparation
Sample Preparation for SEM
2.10. Antileishmanial Activity
2.10.1. Promastigotes Culture
2.10.2. Antipromastigote Assay
Antipromastigote Assay
2.11. Stability Studies
2.11.1. Chromatographic Conditions
2.11.2. Degradation Studies
2.11.3. Validation Method
Linearity
Accuracy
Precision
Detection and Quantification Limits
Stability Evaluation
3. Results and Discussion
3.1. Phase Solubility Studies
3.2. Molecular Modeling of Binary Complexes
3.2.1. Molecular Modeling of Binary Complexes
3.2.2. Molecular Modeling of Multicomponent Complexes
3.2.3. Interaction between RIF and ARG
3.3. Proton Nuclear Magnetic Resonance Spectroscopy
3.4. Characterization of Systems in the Solid State by Fourier Transform-Infrared Spectroscopy, Powder X-ray Diffraction, Thermal Analysis and Scanning Electron Microscopy
3.5. Dissolution Studies
3.6. Microbiological Studies
3.6.1. In Vitro Antimicrobial Study
3.6.2. Evaluation of the Metabolic Activity of the Biofilm
3.6.3. Biofilm Analysis by SEM
3.7. Antileishmanial Activity
3.8. Stability Studies
3.8.1. Method Validation
3.8.2. Stability Evaluation
4. 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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Mode | VDW | ELE | PolSolv | NPolSolv | GAS | Total |
---|---|---|---|---|---|---|
mode-1 | −25.46 | 35.33 | 43.41 | −2.40 | −60.79 | −19.78 |
mode-2 | −40.58 | −33.90 | 47.88 | −4.26 | −74.49 | 30.87 |
mode-3 | −42.09 | −33.12 | 48.73 | −4.99 | −75.22 | −31.47 |
mode-4 | −15.17 | −25.42 | 32.19 | −1.32 | −40.59 | −9.72 |
mode-5 | −47.91 | −40.29 | 62.92 | −5.02 | −88.20 | −30.30 |
mode-6 | −32.87 | −28.61 | 46.24 | −3.78 | −61.49 | −19.03 |
Mode | VDW | ELE | PolSolv | NPolSolv | GAS | Total |
---|---|---|---|---|---|---|
mode-1 | −6.87 | −39.70 | 38.84 | −1.15 | −46.57 | −8.89 |
mode-2 | −5.96 | −38.95 | 37.88 | −1.00 | −44.92 | −8.03 |
Mode | VDW | ELE | PolSolv | NPolSolv | GAS | Total |
---|---|---|---|---|---|---|
mode-3.3.4 | −46.43 | −25.98 | 44.90 | −5.38 | −72.41 | −32.89 |
VDW | ELE | PolSolv | NPolSolv | GAS | Total | |
---|---|---|---|---|---|---|
RIF:ARG | −11.10 | −38.02 | 42.45 | −1.58 | −49.13 | −8.26 |
1H-NMR Signals | |||
---|---|---|---|
RIF Protons | RIF:ARG | RIF:γ-CD | RIF:γ-CD:ARG |
H33 | −0.0400 | −0.0470 | −0.0535 |
H31 | −0.0265 | −0.0255 | −0.0645 |
H32 | −0.0290 | −0.0310 | −0.0670 |
H26 | −0.0240 | −0.0405 | −0.0670 |
H24 | −0.0360 | −0.0455 | −0.0645 |
H13 | −0.0300 | −0.0640 | −0.1330 |
H22 | 0.0175 | −0.0060 | 0.0845 |
H14 | −0.0290 | −0.0190 | −0.0430 |
H30 | −0.0130 | −0.0440 | −0.0440 |
H36 | −0.0310 | −0.0360 | −0.0630 |
H20 | −0.0255 | −0.0245 | −0.0695 |
H4’ | 0.0360 | 0.1280 | −0.3325 |
H37 | −0.0320 | −0.0335 | −0.0550 |
H3’–H5’ | −0.0015 | −0.0220 | −0.0685 |
H2’–H6’ | −0.0750 | −0.0800 | −0.0315 |
H27 | −0.0295 | −0.0335 | −0.0725 |
H21 | −0.0310 | 0.0060 | −0.0260 |
H28 | −0.0175 | 0.0055 | −0.0795 |
H19 | 0.0000 | −0.0065 | −0.0845 |
H29 | 0.0905 | −0.0265 | −0.0720 |
H17 | 0.0205 | −0.0125 | −0.0715 |
H18 | 0.0035 | 0.0650 | −0.0830 |
H1′ | −0.0180 | 0.0170 | −0.4670 |
γ-CD protons | |||
H4 | - | 0.0020 | −0.0235 |
H2 | - | −0.0015 | −0.0380 |
H5–H6 | - | −0.0140 | −0.0760 |
H3 | - | −0.0040 | −0.0360 |
H1 | - | −0.0060 | −0.0470 |
ARG protons | |||
H4–H3 | 0.0345 | - | 0.0395 |
H5 | 0.0015 | - | −0.0410 |
H2 | −0.0250 | - | −0.0785 |
RIF Dissolved (%) at Each Sampling Time | f2 Values | ||||
---|---|---|---|---|---|
15 min | 30 min | 60 min | 120 min | ||
Pure RIF | 14 ± 2% | 30 ± 2% | 46 ± 3% | 63 ± 1% | |
RIF:ARG | 15 min | 30 min | 60 min | 120 min | f2 |
PM | 45 ± 2% | 71 ± 3% | 91 ± 2% | 94.3 ± 0.4% | 23 |
KN | 51 ± 4% | 70 ± 2% | 84 ± 3% | 94 ± 1% | 24 |
FD | 63 ± 3% | 73 ± 1% | 79 ± 1% | 78 ± 1% | 24 |
RIF:γ-CD | 15 min | 30 min | 60 min | 120 min | f2 |
PM | 31 ± 1% | 52 ± 3% | 71 ± 2% | 80 ± 1% | 35 |
KN | 68 ± 1% | 80 ± 1% | 80 ± 2% | 82 ± 3% | 22 |
FD | 35 ± 2% | 50 ± 3% | 61 ± 2% | 74 ± 2% | 41 |
RIF:γ-CD:ARG | 15 min | 30 min | 60 min | 120 min | f2 |
PM | 43 ± 1% | 58 ± 3% | 68 ± 2% | 71 ± 3% | 34 |
KN | 67 ± 2% | 67 ± 5% | 68 ± 2% | 68 ± 1% | 26 |
FD | 42 ± 1% | 63 ± 2% | 83 ± 7% | 93 ± 3% | 26 |
Parameter | Acceptance Criteria | Calculated Values |
---|---|---|
Linearity | r2 > 0.998 | Range = 50–150 µg/mL Area = 29.627 × C (µg/mL) − 42.365 r2 = 0.9996 |
Accuracy | Recovery 98–102% | n = 9 RIF (µg/mL) = 50, 100, 150 Average recovery (%) = 100, 100, 99 |
Repeatability | CV < 2% | n = 9 RIF (µg/mL) = 50, 100, 150 CV (%) = 0.01, 0.38, 0.88 |
Intermediate precision | CV < 3% | n = 9 RIF (µg/mL) = 50, 100, 150 CV (%) = 0.01, 1.19, 0.33 |
DL | DL << 0.05% | DL = 0.001% (0.002 µg/mL) |
QL | QL ≤ 0.05% | QL = 0.004% (0.006 µg/mL) |
Solutions | kc × 10−3 (h−1) | t90 (h) |
---|---|---|
RIF | 30 ± 1 | 3.5 ± 0.1 |
RIF:ARG | 32.0 ± 0.4 | 3.28 ± 0.04 |
RIF:γ-CD | 37.1 ± 0.4 | 2.88 ± 0.03 |
RIF:γ-CD:ARG | 31.9 ± 0.1 | 3.29 ± 0.01 |
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Dan Córdoba, A.V.; Aiassa, V.; Dimmer, J.A.; Barrionuevo, C.N.; Quevedo, M.A.; Longhi, M.R.; Zoppi, A. Development and Characterization of Pharmaceutical Systems Containing Rifampicin. Pharmaceutics 2023, 15, 198. https://doi.org/10.3390/pharmaceutics15010198
Dan Córdoba AV, Aiassa V, Dimmer JA, Barrionuevo CN, Quevedo MA, Longhi MR, Zoppi A. Development and Characterization of Pharmaceutical Systems Containing Rifampicin. Pharmaceutics. 2023; 15(1):198. https://doi.org/10.3390/pharmaceutics15010198
Chicago/Turabian StyleDan Córdoba, Antonella V., Virginia Aiassa, Jesica A. Dimmer, Camila N. Barrionuevo, Mario A. Quevedo, Marcela R. Longhi, and Ariana Zoppi. 2023. "Development and Characterization of Pharmaceutical Systems Containing Rifampicin" Pharmaceutics 15, no. 1: 198. https://doi.org/10.3390/pharmaceutics15010198