Enhancing In Vitro Dissolution of Ferulic Acid Through Co-Crystal Formation Using Malonic Acid and Nicotinamide Co-formers
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Keywords:
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Ferulic Acid, Co-Crystal, Microwave Irradiation, Solubility, Dissolution Rate
Abstract
Ferulic acid is categorized as a Biopharmaceutical Classification System (BCS) class II drug, which exhibits low solubility in water (0.91 mg/mL). The formation of a co-crystal using malonic acid and nicotinamide as co-formers by the microwave irradiation method is an approach to enhance its solubility and dissolution. This study aims to evaluate the effect of co-crystal formation using these two co-formers at a 1:1 molar ratio on the solubility and dissolution of ferulic acid. The result emphasizes the formation of new peaks and peak shifting compared to the pure materials characterized from the Fourier Transform Infrared (FT-IR) spectrum. Moreover, the Differential Scanning Calorimetry (DSC) thermogram exhibits the differences in the co-crystal melting point compared to the pure drug and co-former, indicating the alteration of molecular structure on the crystal lattice of ferulic acid caused by the strong interaction between supramolecular homomer and heteromeric synthon. The formation of a new crystalline phase is also observed from the X-ray Diffraction (XRD) diffractogram, suggesting the formation of a different phase from its co-crystal component. The morphology characterization using Scanning Electron Microscope (SEM) revealed that the ferulic acid crystal habit changes into different forms, which is acclaimed as a co-crystal formation. The results of this study also disclosed that the co-crystal formation of ferulic acid significantly enhances ferulic acid solubility and dissolution characteristics compared to the pure drug and physical mixture (p < 0.05). The enhancement of solubility is 11.85% and 10.39% for ferulic acid–malonic acid and ferulic acid–nicotinamide co-crystal, respectively. Moreover, the dissolution rate of ferulic acid increases 3.50-fold and 3.61-fold from the formation of those co-crystals. Therefore, the formation of ferulic acid–malonic acid as well as ferulic acid–nicotinamide co-crystals in a 1:1 molar ratio by the microwave irradiation method is effective in improving ferulic acid solubility and dissolution.
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European Medicine Agency (2022). ICH Guideline Q2(R2) on Validation of Analytical Procedures. Technical report
Garbacz, P. and M. Wesolowski (2018). DSC, FTIR and Raman Spectroscopy Coupled with Multivariate Analysis in a Study of Co-Crystals of Pharmaceutical Interest. Molecules, 23(9); 2136
Han, X., T. Wei, H. Jiang, W. Li, and G. Zhang (2020). Enhanced Water Solubility, Stability, and In Vitro Antitumor Activity of Ferulic Acid by Chemical Conjugation with Amino-????-Cyclodextrins. Journal of Materials Science, 55(20); 8694–8709
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Khan, F. M., M. Ahmad, and H. A. Idrees (2020). Simvastatin Nicotinamide Co-Crystals: Formation, Pharmaceutical Characterization and In Vivo Profile. Drug Design, Development and Therapy, 14; 4303–4313
Kumar, A., Y. Kuang, Z. Liang, and X. Sun (2020). Microwave Chemistry, Recent Advancements, and Eco-Friendly Microwave-Assisted Synthesis of Nanoarchitectures and Their Applications: A Review. Materials Today Nano, 11; 100076
Lässer, J. and D. E. Braun (2025). Exploring Coformer Substitution in Cocrystallization: Griseofulvin and Phenol Derivatives. Crystal Growth & Design, 25(5); 1688–1707
Lennernäs, H., M. Brisander, C. Liljebris, G. Jesson, and P. Andersson (2024). Enhanced Bioavailability and Reduced Variability of Dasatinib and Sorafenib with a Novel Amorphous Solid Dispersion Technology Platform. Clinical Pharmacology in Drug Development, 13(9); 985–999
Liu, K., G. Zhang, J. Luan, Z. Chen, P. Su, and Y. Shu (2016). Crystal Structure, Spectrum Character and Explosive Property of a New Cocrystal CL-20/DNT. Journal of Molecular Structure, 1110; 91–96
Moreschi, E. C. P., J. R. Matos, and L. B. Almeida-Muradian (2009). Thermal Analysis of Vitamin PP Niacin and Niacinamide. Journal of Thermal Analysis and Calorimetry, 98(1); 161–164
Panzade, P. and G. Shendarkar (2019). Superior Solubility and Dissolution of Zaltoprofen via Pharmaceutical Cocrystals. Turkish Journal of Pharmaceutical Sciences, 16(3); 310–316
Pujiono, F. E., J. Ekowati, T. Amrillah, and D. Setyawan (2025). Ferulic Acid-Nicotinamide Cocrystal: Synthesis, Experimental, and Computation Study. Science and Technology Indonesia, 10(2); 402–410
Qiao, N., M. Li, W. Schlindwein, N. Malek, A. Davies, and G. Trappitt (2011). Pharmaceutical Cocrystals: An Overview. International Journal of Pharmaceutics, 419(1-2); 1–11
Sakhiya, D. C. and C. H. Borkhataria (2024). A Review on Advancement of Cocrystallization Approach and a Brief on Screening, Formulation and Characterization of the Same. Heliyon, 10(7); e29057
Sathisaran, I. and S. Dalvi (2018). Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium. Pharmaceutics, 10(3); 108
Sathisaran, I. and S. V. Dalvi (2021). Cocrystallization of an Antiretroviral Drug Nevirapine: An Eutectic, a Cocrystal Solvate, and a Cocrystal Hydrate. Crystal Growth & Design, 21(4); 2076–2092
Setyawan, D., R. O. Jovita, M. Iqbal, A. Paramanandana, H. Yusuf, and M. L. Lestari (2018a). Co-Crystallization of Quercetin and Malonic Acid Using Solvent-Drop Grinding Method. Tropical Journal of Pharmaceutical Research, 17(6); 997–1002
Setyawan, D., S. A. Permata, A. Zainul, and M. L. A. D. Lestari (2018b). Improvement In Vitro Dissolution Rate of Quercetin Using Cocrystallization of Quercetin-Malonic Acid. Indonesian Journal of Chemistry, 18(3); 531–538
Setyawan, D., R. Sari, H. Yusuf, and R. Primaharinastiti (2014). Preparation and Characterization of Artesunate Nicotinamide Cocrystal by Solvent Evaporation and Slurry Method. Asian Journal of Pharmaceutical and Clinical Research, 7(1); 62–65
Sharif, N., M.-T. Golmakani, M. Niakousari, S. M. H. Hosseini, B. Ghorani, and A. Lopez-Rubio (2018). Active Food Packaging Coatings Based on Hybrid Electrospun Gliadin Nanofibers Containing Ferulic Acid/Hydroxypropyl-Beta Cyclodextrin Inclusion Complexes. Nanomaterials, 8(11); 919
Shimpi, M. R., A. Alhayali, K. L. Cavanagh, N. Rodríguez Hornedo, and S. P. Velaga (2018). Tadalafil–Malonic Acid Cocrystal: Physicochemical Characterization, pH-Solubility, and Supersaturation Studies. Crystal Growth & Design, 18(8); 4378–4387
Shukla, D., N. K. Nandi, B. Singh, A. Singh, B. Kumar, R. K. Narang, and C. Singh (2022). Ferulic Acid-Loaded Drug Delivery Systems for Biomedical Applications. Journal of Drug Delivery Science and Technology, 75; 103621
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Sopyan, I., T. Q. Alfauziah, and D. Gozali (2019). Better in Solubility Enhancement: Salt or Cocrystal? International Journal of Research in Pharmaceutical Sciences, 10(4); 3013–3025
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Authors
Setyawan, D. ., Soraya, Y., Ekowati, J., Winantari, A. N., Rani, K. C., Kanzaffa, F. A. T. ., & Pujiono, F. E. (2025). Enhancing In Vitro Dissolution of Ferulic Acid Through Co-Crystal Formation Using Malonic Acid and Nicotinamide Co-formers . Science and Technology Indonesia, 10(4), 1255–1269. https://doi.org/10.26554/sti.2025.10.4.1255-1269
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