Pharmaceutical Systems as a Strategy to Enhance the Stability of Oxytetracycline Hydrochloride Polymorphs in Solution
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Equipment
2.2. Obtaining the Solid Forms of Oxytetracycline Hydrochloride
2.3. Preparation of Binary Systems
2.4. Determination of Association Constants from UV-Visible Spectroscopy
2.4.1. Scott’s Plot Method
2.4.2. Statistical Treatment of Data
2.5. Stability Study Design
2.5.1. Chemical Stability Study
2.5.2. Chromatographic Conditions
2.5.3. Validation of Chromatographic Method
2.6. Nuclear Magnetic Resonance Spectroscopy Study
3. Results and Discussion
3.1. Determination of the Apparent Binding Constants
3.2. Stability Studies
3.2.1. Validation of Chromatographic Method
3.2.2. Degradation Studies
3.3. Nuclear Magnetic Resonance Spectroscopy
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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Polymorph | Ligands | |||
---|---|---|---|---|
β-CD | ASP | HIS | NAC | |
OxyCl-I | 3761 | 34,645 | 224 | 2042 |
OxyCl-II | 15,425 | 3063 | 323 | 4582 |
OxyCl-III | 3607 | 1771 | 8247 | 3897 |
Parameters | Results | |
---|---|---|
Linearity | Regression equation a | Y = 14.544 X − 2.603 |
Correlation coefficient (r2) | 0.994 | |
Linear range (μg/mL) | 5.0–40.0 | |
Detection limit | 0.38 (μg/mL) | |
Quantification limit | 1.15 (μg/mL) |
Nominal Concentration (μg/mL) | Measured Concentration (μg/mL) | Accuracy (% Recovery) | Precision (% R.S.D.) |
---|---|---|---|
Intra-day (repeatability) | |||
20 | 20.1 ± 0.2 | 100.36 | 1.26 |
25.2 | 25.2 ± 0.4 | 100.22 | 1.73 |
30.2 | 30.2 ± 0.1 | 99.86 | 0.32 |
Inter-day (intermediate precision) | |||
20.2 | 20.5 ± 0.1 | 101.38 | 0.55 |
25.5 | 26.0 ± 0.3 | 101.93 | 1.33 |
29.9 | 30.5 ± 0.1 | 101.96 | 0.42 |
Solids | k0 (h−1) | kobs (h−1) | t50 (h) | t90 (h) | k0/kobs |
---|---|---|---|---|---|
OxyCl-I | 0.0102 | 68 | 10 | ||
OxyCl-I:β-CD | 0.0134 | 52 | 8 | 0.76 | |
OxyCl-I:ASP | 0.0143 | 48 | 7 | 0.71 | |
OxyCl-I: NAC | 0.0093 | 74 | 11 | 1.10 | |
OxyCl-II | 0.0121 | 57 | 9 | ||
OxyCl-II:β-CD | 0.0132 | 53 | 8 | 0.92 | |
OxyCl-II:ASP | 0.0142 | 49 | 7 | 0.85 | |
OxyCl-II:NAC | 0.0079 | 73 | 11 | 1.53 | |
OxyCl-III | 0.0116 | 60 | 9 | ||
OxyCl-III:β-CD | 0.0087 | 80 | 12 | 1.33 | |
OxyCl-III:ASP | 0.0300 | 23 | 4 | 0.39 | |
OxyCl-III:NAC | 0.0095 | 87 | 13 | 1.22 |
Solids | k0 (h−1) | kobs (h−1) | t50 (h) | t90 (h) | k0/kobs |
OxyCl-I | 0.009 | 81 | 12 | ||
OxyCl-I:NAC | 0.012 | 58 | 9 | 0.75 | |
OxyCl-II | 0.005 | 139 | 21 | ||
OxyCl-II:NAC | 0.022 | 32 | 5 | 0.22 | |
OxyCl-III | 0.007 | 102 | 15 | ||
OxyCl-III:NAC | 0.013 | 53 | 8 | 0.54 |
δ (ppm) | ||||||
---|---|---|---|---|---|---|
Assignment | Polymorph | Assignment | Ligand | |||
OxyCl-I | OxyCl-II | OxyCl-III | NAC | β-CD | ||
H4 | 4.167 | 4.280 | 4.167 | H2 | 2.992 | |
H13-14 | 3.054 | 3.054 | 3.061 | H3 | 4.569 | |
H4a | 2.843 | 2.939 | 2.843 | H9 | 2.099 | |
H5 | 3.961 | 3.949 | 3.964 | |||
H5a | 2.927 | 2.968 | 2.927 | H1 | 5.068 | |
H16 | 1.814 | 1.803 | 1.821 | H2 | 3.647 | |
H7 | 7.254 | 7.246 | 7.261 | H3 | 3.965 | |
H8 | 7.624 | 7.617 | 7.631 | H4 | 3.582 | |
H9 | 7.037 | 7.026 | 7.044 | H5 | 3.870 | |
NH2 | 8.352 | 8.254 | 8.360 | H6 | 3.908 |
Δδ = δsystem − δfree | ||||||
---|---|---|---|---|---|---|
Assignment | OxyCl-I:β-CD | OxyCl-II:β-CD | OxyCl-III:β-CD | OxyCl-I:NAC | OxyCl-II:NAC | OxyCl-III:NAC |
H4 | 0.152 | 0.044 | 0.179 | 0.172 | 0.06 | 0.178 |
H13-14 | 0.005 | 0.009 | 0.009 | −0.007 | −0.004 | 0.002 |
H4a | 0.095 | 0.045 | 0.187 | 0.143 | 0.049 | 0.147 |
H5 | 0.015 | 0.032 | 0.016 | −0.007 | 0.008 | 0.011 |
H5a | 0.071 | 0.035 | 0.085 | 0.076 | 0.037 | 0.078 |
H16 | 0.001 | 0.046 | 0.027 | −0.005 | 0.008 | 0.007 |
H7 | 0.008 | 0.021 | 0.009 | −0.005 | 0.005 | 0.005 |
H8 | 0.011 | 0.022 | 0.012 | −0.007 | 0.003 | 0.005 |
H9 | 0.004 | 0.018 | 0.005 | −0.006 | −0.003 | 0.014 |
Ligands | ||||||
β-CD | ||||||
H1 | 0.002 | 0.007 | 0.007 | |||
H2 | 0.009 | 0.014 | 0.019 | |||
H3 | −0.05 | −0.045 | −0.04 | |||
H4 | 0.001 | 0.006 | 0.006 | |||
H5 | −0.036 | −0.024 | −0.027 | |||
H6 | 0.007 | 0.012 | 0.005 | |||
NAC | ||||||
H2 | −0.012 | −0.006 | −0.016 | |||
H3 | 0.047 | 0.05 | 0.054 | |||
H9 | −0.012 | −0.009 | −0.009 |
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Bueno, M.S.; Longhi, M.R.; Garnero, C. Pharmaceutical Systems as a Strategy to Enhance the Stability of Oxytetracycline Hydrochloride Polymorphs in Solution. Pharmaceutics 2023, 15, 192. https://doi.org/10.3390/pharmaceutics15010192
Bueno MS, Longhi MR, Garnero C. Pharmaceutical Systems as a Strategy to Enhance the Stability of Oxytetracycline Hydrochloride Polymorphs in Solution. Pharmaceutics. 2023; 15(1):192. https://doi.org/10.3390/pharmaceutics15010192
Chicago/Turabian StyleBueno, Maria S., Marcela R. Longhi, and Claudia Garnero. 2023. "Pharmaceutical Systems as a Strategy to Enhance the Stability of Oxytetracycline Hydrochloride Polymorphs in Solution" Pharmaceutics 15, no. 1: 192. https://doi.org/10.3390/pharmaceutics15010192
APA StyleBueno, M. S., Longhi, M. R., & Garnero, C. (2023). Pharmaceutical Systems as a Strategy to Enhance the Stability of Oxytetracycline Hydrochloride Polymorphs in Solution. Pharmaceutics, 15(1), 192. https://doi.org/10.3390/pharmaceutics15010192