Molecular Interaction and Solubility Enhancement of Ketoconazole through Co-Amorphisation with Oxalic Acid
DOI:
https://doi.org/10.24252/djps.v9i1.60940Keywords:
Amorphous solid dispersion, ball milling, co-amorphous system, dissolution enhancement, ketoconazoleAbstract
Introduction: In the modern pharmaceutical field, enhancing the solubility and bioavailability of poorly water-soluble drugs remains a key challenge in formulation. Ketoconazole, a weakly soluble antifungal agent, serves as a model compound in this study. Aims: This research aims to develop and characterise a co-amorphous system of ketoconazole with oxalic acid to enhance solubility and dissolution behaviour. Result: The co-amorphous system was prepared using solvent evaporation and evaluated using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and construction of a binary phase diagram. Dissolution studies were performed under biorelevant pH conditions, and equilibrium solubility was assessed using standard shake-flask methods. The co-amorphous ketoconazole–oxalic acid system exhibited a single glass transition and absence of sharp PXRD peaks, confirming successful amorphisation. FTIR analysis indicated intermolecular hydrogen bonding, while thermal analysis demonstrated enhanced physical stability. Dissolution studies revealed significantly improved drug release across pH 1.2, 4.5, and 6.8, and equilibrium solubility increased more than threefold compared to the crystalline form. Conclusion: Co-amorphous formulation with oxalic acid markedly enhances ketoconazole solubility and dissolution, offering a promising strategy for improving the performance of poorly soluble drugs through molecular-level interaction and amorphisation.
Downloads
References
Adachi, M., Hinatsu, Y., Kusamori, K., Katsumi, H., Sakane, T., Nakatani, M., Wada, K., & Yamamoto, A. (2016). Effects of Manufacturing Methods on Dissolution and Absorption of Ketoconazole in the Presence of Organic Acid as a pH Modifier. Aaps Pharmscitech, 18(4), 1203–1212. https://doi.org/10.1208/s12249-016-0583-2
Ainurofiq, A., Mauludin, R., Mudhakir, D., & Soewandhi, S. N. (2018). Synthesis, Characterization, and Stability Study of Desloratadine Multicomponent Crystal Formation. Research in Pharmaceutical Sciences, 13(2), 93. https://doi.org/10.4103/1735-5362.223775
Ainurofiq, A., Mauludin, R., Mudhakir, D., Umeda, D., Soewandhi, S. N., Putra, O. D., & Yonemochi, E. (2018). Improving mechanical properties of desloratadine via multicomponent crystal formation. European Journal of Pharmaceutical Sciences, 111(August 2017), 65–72. https://doi.org/10.1016/j.ejps.2017.09.035
Ajaz, S. A., Majaz, Q., Kalam, I., Shaikh, A., Shaikh, M. M., & Ayyaj, P. (2024). Solubility Enhancement of BCS Class 2 Drugs by Solid Dispersion Technique. Research Journal of Pharmaceutical Dosage Forms and Technology, 215–220. https://doi.org/10.52711/0975-4377.2024.00034
Ali, A. M. A., Ali, A. A., & Maghrabi, I. A. (2015). Clozapine-Carboxylic Acid Plasticized Co-Amorphous Dispersions: Preparation, Characterization and Solution Stability Evaluation. Acta Pharmaceutica, 65(2), 133–146. https://doi.org/10.1515/acph-2015-0014
An, J.-H., Lim, C., Kiyonga, A. N., Chung, I. J., Lee, I. K., Mo, K., Park, M., Youn, W., Choi, W. R., Suh, Y., & Jung, K. (2018). Co-Amorphous Screening for the Solubility Enhancement of Poorly Water-Soluble Mirabegron and Investigation of Their Intermolecular Interactions and Dissolution Behaviors. Pharmaceutics, 10(3), 149. https://doi.org/10.3390/pharmaceutics10030149
An, J., Lim, C., Kiyonga, A., Chung, I., Lee, I., Mo, K., Park, M., Youn, W., Choi, W. R., Suh, Y., & Jung, K. (2018). Co-Amorphous Screening for the Solubility Enhancement of Poorly Water-Soluble Mirabegron. Pharmaceutics. https://doi.org/10.3390/pharmaceutics10030149
Aragón-Aburto, S. O., Mondragón-Vásquez, K., Alfaro, G. V, & Domínguez-Chávez, J. G. (2022). Characterization, Stability and Solubility of Co-Amorphous Systems of Glibenclamide and L-Arginine at Different pH. Tropical Journal of Pharmaceutical Research, 21(7), 1355–1364. https://doi.org/10.4314/tjpr.v21i7.1
Aucamp, M., Milne, M., & Liebenberg, W. (2015). Amorphous Sulfadoxine: A Physical Stability and Crystallization Kinetics Study. Aaps Pharmscitech, 17(5), 1100–1109. https://doi.org/10.1208/s12249-015-0436-4
Baghel, S., Cathcart, H., & O’Reilly, N. J. (2016). Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs. Journal of Pharmaceutical Sciences, 105(9), 2527–2544. https://doi.org/10.1016/j.xphs.2015.10.008
Chen, H., Wang, C., Kang, H., Zhi, B., Haynes, C. L., Aburub, A., & Sun, C. C. (2020). Microstructures and pharmaceutical properties of ferulic acid agglomerates prepared by different spherical crystallization methods. International Journal of Pharmaceutics, 574, 118914. https://doi.org/10.1016/j.ijpharm.2019.118914
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Indra Indra, Riris Dianti, Rika Yulianti, Ade Yeni Aprillia, Winda Trisna Wulandari
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Once an article was published in the journal, the author(s) are:
- granted to the journal right licensed under Creative Commons License Attribution that allows others to share the work with an acknowledgement of the work's authorship.
- permitted to publish their work online in third parties as it can lead to wider dissemination of the work.
- continue to be the copyright owner and allow the journal to publish the article with the CC BY-SA license
- receiving a DOI (Digital Object Identifier) of the work.
1.png)
