Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal
Abstract
:1. Introduction
2. Materials, Preparative Methods, and Characterization Techniques
2.1. Materials
2.2. Methods
2.2.1. Preparation of Cocrystal CTD-CAF
2.2.2. Solid-State Stability Tests
2.2.3. Solubility Studies
2.2.4. Polymer Selection
2.2.5. Powder Dissolution under Non-Sink Conditions and Phase Stability
2.2.6. Induced Precipitation Experiments
2.2.7. Preparation of Capsule Formulations
2.2.8. Dissolution Experiments under Sink Conditions
2.3. Characterization Techniques
2.3.1. Powder X-ray Diffraction Analysis (PXRD)
2.3.2. Single-Crystal X-ray Diffraction Analysis (SCXRD)
2.3.3. Infrared Spectroscopy Analysis (IR)
2.3.4. Thermogravimetric Analysis and Differential Scanning Calorimetry (TGA-DSC)
2.3.5. High-Performance Liquid Chromatography (HPLC)
2.4. Statistical Analysis
3. Results
3.1. Preparation of Cocrystal CTD-CAF
3.2. Crystallographic Analysis
3.3. Analysis by IR Spectroscopy
3.4. TG-DSC Analysis
3.5. Solid-State Stability Tests
3.6. Solubility Studies
3.7. Polymer Selection for Dissolution Studies
3.8. Powder Dissolution Studies under Non-Sink Conditions
3.9. Induced Precipitation Experiments
3.10. Dissolution Studies under Sink Conditions
4. Discussion
4.1. Solubility of CTD-CAF Cocrystal and Performance under Non-Sink Conditions
4.2. Study of the Solution-Mediated Phase Transformation (SMPT) Mechanism
4.3. Performance of CTD-CAF Cocrystal Pre-Formulations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Formulation | 1 | 2 | 3 | 4 |
---|---|---|---|---|
CTD-CAF a | 64.3 | 64.3 | 64.3 | 64.3 |
HPMC 80–120 cPs b | - | 2.8 | 7.1 | 14.2 |
Parameter | Value |
---|---|
Formula | C36H32Cl2N8O10S2 |
MW (g mol−1) | 871.71 |
T (K) | 298 |
Crystal system | triclinic |
Space group | P-1 |
a (Å) | 8.3218(5) |
b (Å) | 14.6139(9) |
c (Å) | 16.2923(10) |
α (deg) | 72.529(3) |
β (deg) | 81.128(3) |
γ (deg) | 86.070(3) |
Volume (Å3) | 1866.8(2) |
Z | 2 |
ρcalc (g cm−3) | 1.551 |
μ (mm−1) | 3.225 |
R1 (I ≥ 2σ(I)) | 0.0550 |
wR2 (all data) | 0.1568 |
GOF | 1.029 |
Compound | Motif | ||||
---|---|---|---|---|---|
I | II | III | IV | Reference | |
CTD-CAF | ✓ | ✓ | ✓ | ✓ | This work |
CTD polymorph I | ✓ | ✓ | ✓ | ✓ | [23] |
CTD polymorph II | ✓ | - | - | - | [24] |
CTD polymorph III | ✓ | - | ✓ | - | [23] |
CTD chloroform solvate | - | ✓ | - | - | [25] |
Dissolution Medium | Sdrug [mM] | SCC [mM] | Keu | SA | D0D | D0CC |
---|---|---|---|---|---|---|
HCl pH 1.2 | 0.687 ± 0.005 | 2.00 ± 0.03 | 12.3 ± 0.6 | 2.91 ± 0.05 | 0.859 ± 0.006 | 0.295 ± 0.004 |
PBS pH 6.8 | 0.643 ± 0.007 | 2.05 ± 0.05 | 16 ± 1 | 3.19 ± 0.09 | 0.92 ± 0.01 | 0.288 ± 0.007 |
Solid Form (Dissolution Media) a | AUC0–45 b | AUC45–180 b | AUCTotal b | (AUCTotal, PM or CC/AUCTotal, CTD) |
---|---|---|---|---|
CTD (1.2) | 28.0 | 88.6 | 116.6 | - |
CTD (6.8) | 28.2 | 86.2 | 114.4 | - |
CTD (1.2, HPMC) | 27.5 | 91.0 | 118.5 | - |
CTD (6.8, HPMC) | 28.9 | 94.0 | 122.9 | - |
PM (1.2) | 32.9 | 98.8 | 131.7 | 1.12 |
PM (6.8) | 32.3 | 99.3 | 131.6 | 1.15 |
PM (1.2, HPMC) | 34.4 | 98.5 | 132.9 | 1.12 |
PM (6.8, HPMC) | 31.5 | 108.6 | 140.1 | 1.13 |
CC (1.2) | 55.1 | 114.7 | 169.8 | 1.45 |
CC (6.8) | 57.2 | 151.0 | 208.2 | 1.81 |
CC (1.2, HPMC) | 49.4 | 196.0 | 245.4 | 2.07 |
CC (6.8, HPMC) | 55.3 | 198.2 | 253.5 | 2.06 |
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Rodríguez-Ruiz, C.; Montes-Tolentino, P.; Domínguez-Chávez, J.G.; Morales-Rojas, H.; Höpfl, H.; Herrera-Ruiz, D. Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal. Pharmaceutics 2022, 14, 334. https://doi.org/10.3390/pharmaceutics14020334
Rodríguez-Ruiz C, Montes-Tolentino P, Domínguez-Chávez JG, Morales-Rojas H, Höpfl H, Herrera-Ruiz D. Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal. Pharmaceutics. 2022; 14(2):334. https://doi.org/10.3390/pharmaceutics14020334
Chicago/Turabian StyleRodríguez-Ruiz, Christian, Pedro Montes-Tolentino, Jorge Guillermo Domínguez-Chávez, Hugo Morales-Rojas, Herbert Höpfl, and Dea Herrera-Ruiz. 2022. "Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal" Pharmaceutics 14, no. 2: 334. https://doi.org/10.3390/pharmaceutics14020334
APA StyleRodríguez-Ruiz, C., Montes-Tolentino, P., Domínguez-Chávez, J. G., Morales-Rojas, H., Höpfl, H., & Herrera-Ruiz, D. (2022). Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal. Pharmaceutics, 14(2), 334. https://doi.org/10.3390/pharmaceutics14020334