Abstract
We report novel pharmaceutical salts of an anti-hypertensive drug carvedilol (CVD) with pharmaceutically acceptable salt formers, including oxalic acid (OXA), fumaric acid (FUMA), benzoic acid (BZA), and mandelic acid (MDA) via conventional solvent evaporation technique. The pKa difference between CVD and selected acids was greater than 3, thus suggesting salt formation. Two polymorphic forms of CVD/MDA salts and one p-Dioxane solvate of CVD/FUMA salt were also reported in this paper. The salts were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). Stability of the salts was assessed by storage at 40°C/75% RH for 1 month. All CVD salts exhibited higher solubility in phosphate buffer solution pH 6.8 compared to the parent drug CVD and showed good stability in accelerated ICH conditions at 40°C/75% RH for 1 month. CVD/FUMA salt showed the highest solubility (1.78 times). Based on thermal analysis and slurry experiment, it was found that CVD/MDA polymorphs were related monotropically with Form 1 as the stable form. The results suggested that salt formation could be an alternative method to improve CVD solubility.
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Abbreviations
- API:
-
Active pharmaceutical ingredient
- BCS:
-
Biopharmaceutics Classification System
- BZA:
-
Benzoic acid
- CVD:
-
Carvedilol
- DI:
-
De-ionized
- DSC:
-
Differential scanning calorimetry
- FTIR:
-
Fourier transform infrared spectroscopy
- FUMA:
-
Fumaric acid
- GRAS:
-
Generally recognized as safe
- HPLC:
-
High performance liquid chromatography
- MDA:
-
Mandelic acid
- OPA:
-
Orthophosphoric acid
- OXA:
-
Oxalic acid
- PTFE:
-
Polytetrafluoroethylene
- PXRD:
-
Powder X-ray diffraction
- RH:
-
Relative humidity
- SEDDS:
-
Self-emulsifying drug delivery systems
- SEM:
-
Scanning electron microscopy
- SMEDDS:
-
Self-microemulsifying drug delivery systems
- TGA:
-
Thermogravimetric analysis
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Acknowledgments
The authors acknowledge Dexa Laboratories of Biomolecular Sciences (DLBS)-PT Dexa Medica for financial support. The authors would like to thank Isabela Anjani for critical review on this manuscript.
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Hiendrawan, S., Widjojokusumo, E., Veriansyah, B. et al. Pharmaceutical Salts of Carvedilol: Polymorphism and Physicochemical Properties. AAPS PharmSciTech 18, 1417–1425 (2017). https://doi.org/10.1208/s12249-016-0616-x
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DOI: https://doi.org/10.1208/s12249-016-0616-x