Metformin-NSAIDs Molecular Salts: A Path towards Enhanced Oral Bioavailability and Stability
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Salt Syntheses
2.2.1. Metformin Hydrochloride Neutralization
2.2.2. Mechanochemical Synthesis
2.2.3. Preparation of Single Crystals
2.3. X-ray Diffraction Analysis
2.4. Differential Scanning Calorimetry
2.5. Stability Studies
2.6. Solubility Studies
3. Results and Discussion
3.1. Salt Synthesis
3.2. Salt Screening
3.3. Crystal Structure Analysis of Molecular Salts
3.3.1. MTF–MEF and MTF–TLF Salts
3.3.2. MTF–NIF Salts and MTF–NIF·2H2O Hydrate Salt
3.3.3. MTF–DIF Salt
3.3.4. MTF–FLP Salt
3.4. Thermal Analysis
3.5. Stability Studies
3.6. Solubility Studies
Compound | MTF Solubility in the Salts [mg/mL] | NSAID Solubility in the Salts [mg/mL] | Solubility Enhancement over MTF·HCl/NSAID | NSAID Solubility [mg/mL] | Ref. |
---|---|---|---|---|---|
MTF–NIF·2H2O | 5.290 | 11.493 | 0.0212x/574x | <0.02 | [66] |
MTF–FLP | 4.775 | 5.552 | 0.0191x/1110x | <0.005 | [67] |
MTF–MEF | 3.185 | 5.950 | 0.0127x/119x | <0.05 | [68,69] |
MTF–TLF | 2.740 | 10.397 | 0.0110x/208x | <0.05 | [68] |
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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APIs | Reported pKa Values | References | Calculated pKa Values * | Calculated MTF-NSAID ΔpKa |
---|---|---|---|---|
Metformin | 12.4 | [47] | 12.30 | - |
Mefenamic Acid | 3.93 | [48] | 3.89 | 8.41 |
Tolfenamic Acid | 4.3 | [49] | 3.88 | 8.42 |
Niflumic acid | 1.88 | [50] | 1.88 | 10.42 |
Diflunisal | 2.69 | [50] | 2.69 | 9.61 |
Flurbiprofen | 4.2 | [51] | 4.42 | 7.88 |
Compound Name | MFT–MEF | MFT–TLF | MFT–NIF | MFT–NIF·2H2O | MTF–DIF | MFT–FLP |
---|---|---|---|---|---|---|
Formula | C19H26N6O2 | C18H23ClN6O2 | C17H20F3N7O2 | C17H24F3N7O4 | C17H19F2N5O3 | C19H24FN5O2 |
Formula weight | 370.46 | 390.87 | 411.40 | 447.43 | 379.37 | 373.43 |
Crystal system | Monoclinic | Monoclinic | Monoclinic | Monoclinic | Monoclinic | Triclinic |
Space group | P21/c | P21/c | P21/n | P21/c | C2/c | P-1 |
a/Å | 15.5701(19) | 15.5584(15) | 6.2011(16) | 19.9296(15) | 36.998(2) | 8.7587(5) |
b/Å | 8.7141(11) | 8.7072(8) | 32.216(8) | 7.9245(6) | 6.7220(5) | 10.5391(7) |
c/Å | 16.239(2) | 16.3668(16) | 9.846(3) | 14.6836(11) | 15.0427(9) | 10.5990(6) |
α/° | 90 | 90 | 90 | 90 | 90 | 90.265(2) |
β/° | 116.408(4) | 117.919(4) | 101.051(13) | 109.362(4) | 104.981(3) | 96.217(2) |
γ/° | 90 | 90 | 90 | 90 | 90 | 94.624(2) |
V/Å3 | 1973.4(4) | 1959.2(3) | 1930.6(8) | 2187.9(3) | 3614.0(4) | 969.37(10) |
Z | 4 | 4 | 4 | 4 | 8 | 2 |
Dc/g cm−3 | 1.247 | 1.325 | 1.415 | 1.358 | 1.394 | 1.279 |
F(000) | 792 | 824 | 856 | 936 | 1584 | 398 |
Reflections collected | 20,802 | 19,113 | 19,888 | 17,437 | 18,152 | 14,188 |
Unique reflections | 3509 | 3452 | 3396 | 3853 | 3155 | 3366 |
Data/ restraints/parameters | 3509/0/251 | 3452/0/248 | 3396/0/264 | 3853/0/288 | 3155/5/258 | 3366/0/248 |
Goodness-of-fit on F2 | 1.053 | 1.048 | 1.036 | 1.026 | 1.037 | 1.068 |
R1 (I > 2σ(I)) | 0.0398 | 0.0477 | 0.0640 | 0.0633 | 0.0380 | 0.0551 |
wR2 (I > 2σ(I)) | 0.1153 | 0.1315 | 0.1758 | 0.1673 | 0.1044 | 0.1622 |
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Acebedo-Martínez, F.J.; Domínguez-Martín, A.; Alarcón-Payer, C.; Garcés-Bastida, C.; Verdugo-Escamilla, C.; Gómez-Morales, J.; Choquesillo-Lazarte, D. Metformin-NSAIDs Molecular Salts: A Path towards Enhanced Oral Bioavailability and Stability. Pharmaceutics 2023, 15, 449. https://doi.org/10.3390/pharmaceutics15020449
Acebedo-Martínez FJ, Domínguez-Martín A, Alarcón-Payer C, Garcés-Bastida C, Verdugo-Escamilla C, Gómez-Morales J, Choquesillo-Lazarte D. Metformin-NSAIDs Molecular Salts: A Path towards Enhanced Oral Bioavailability and Stability. Pharmaceutics. 2023; 15(2):449. https://doi.org/10.3390/pharmaceutics15020449
Chicago/Turabian StyleAcebedo-Martínez, Francisco Javier, Alicia Domínguez-Martín, Carolina Alarcón-Payer, Carolina Garcés-Bastida, Cristóbal Verdugo-Escamilla, Jaime Gómez-Morales, and Duane Choquesillo-Lazarte. 2023. "Metformin-NSAIDs Molecular Salts: A Path towards Enhanced Oral Bioavailability and Stability" Pharmaceutics 15, no. 2: 449. https://doi.org/10.3390/pharmaceutics15020449
APA StyleAcebedo-Martínez, F. J., Domínguez-Martín, A., Alarcón-Payer, C., Garcés-Bastida, C., Verdugo-Escamilla, C., Gómez-Morales, J., & Choquesillo-Lazarte, D. (2023). Metformin-NSAIDs Molecular Salts: A Path towards Enhanced Oral Bioavailability and Stability. Pharmaceutics, 15(2), 449. https://doi.org/10.3390/pharmaceutics15020449