Ferulic Acid-Nicotinamide Cocrystal: Synthesis, Experimental, and Computation Study
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Keywords:
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Cocrystal, Ferulic Acid, Solvent Evaporation, DFT, QTAIM
Abstract
Ferulic acid-nicotinamide cocrystals have been successfully synthesized using the solvent evaporation method. In this case, nicotinamide which acts as a coformer is mixed with ferulic acid with a 1:1 molar ratio via dissolving process in ethanol. The obtained cocrystals were characterized through Differential Scanning Calorimetric (DSC), Powder X-Ray Diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and computational analyses. The DSC characterization revealed distinct endothermic peaks at 99.5°C and 128.5°C with a W-shaped profile. This result is different from the thermal behavior of pure ferulic acid which indicates that the ferulic acid-nicotinamide cocrystal is successfully formed. This result is also supported by the PXRD result which reveals distinct peaks at 5.24°, 16.31°, and 34.69° belong to crystal deformation of ferulic acid cocrystal due to the coexistence of nicotinamide coformer. The FTIR data also further indicate the formation of cocrystals marked by the disappearance of the NH(v) functional group at 3400 cm−1 and the emergence of a fuse-like peak at around 1600 cm−1 corresponding to the C-O(v) and NH() functional groups. SEM analysis also demonstrated morphological differences between the obtained cocrystal with pure ferulic acid crystals. The pure ferulic acid crystals exhibit a rectangular shape, whereas the cocrystals display a sword-like morphology. The phenomenon of cocrystal formation was also studied using computational studies through Density Functional Theory (DFT) and Quantum Theory of Atoms in Molecules (QTAIM) which confirmed that the cocrystals were stabilized through intermolecular hydrogen bonding.
References
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Ali, U. S., W. A. Siddiqui, A. Ashraf, M. A. Raza, K. M. Batoo, M. Imran, S. E. Shirsath, M. Ashfaq, M. N. Tahir, and S. Niaz (2024). Structure Elucidation {Single X-Ray Crystal Diffraction Studies, Hirshfeld Surface Analysis, DFT} and Antibacterial Studies of 1, 2-Benzothiazine Metal Complexes. Journal of Molecular Structure, 1306; 137824.
Aygün, M., D. B. Celepci, Ö. Akgül, and V. Pabuccuoglu (2024). Single-Crystal X-Ray Structure, Theoretical (Hirshfeld, Electronic Properties, NBO, NLO, RDG), and Molecular Docking Studies of Three Phthalimidoethanesulfonamide Derivatives. Journal of Molecular Structure; 139094.
Birolo, R., E. Alladio, F. Bravetti, M. R. Chierotti, and R. Gobetto (2024). Predictive Tools for Cocrystal Formation. In Novel Formulations and Future Trends. Elsevier, pages 483–512.
Cantele, C., K. Martina, G. Potenziani, A. M. Rossi, V. Cardenia, and M. Bertolino (2023). Antioxidant Properties of Ferulic Acid-Based Lipophenols in Oil-In-Water (O/W) Emulsions. LWT, 189; 115505.
Chaudhary, A., V. S. Jaswal, S. Choudhary, A. Sharma, V. Beniwal, H. S. Tuli, and S. Sharma (2019). Ferulic Acid: A Promising Therapeutic Phytochemical and Recent Patents Advances. Recent Patents on Inflammation & Allergy Drug Discovery, 13(2); 115–123.
Chaudhary, P., P. Janmeda, A. O. Docea, B. Yeskaliyeva, A. F. Abdull Razis, B. Modu, D. Calina, and J. Sharifi-Rad (2023). Oxidative Stress, Free Radicals and Antioxidants: Potential Crosstalk in the Pathophysiology of Human Diseases. Frontiers in Chemistry, 11.
Contardi, M., M. Lenzuni, F. Fiorentini, M. Summa, R. Bertorelli, G. Suarato, and A. Athanassiou (2021). Hydroxycinnamic Acids and Derivatives Formulations for Skin Damages and Disorders: A Review. Pharmaceutics, 13(7); 999.
Ding, F., W. Cao, R. Wang, N. Wang, A. Li, Y. Wei, S. Qian, J. Zhang, Y. Gao, and Z. Pang (2023). Mechanistic Study on Transformation of Coamorphous Baicalein-Nicotinamide to Its Cocrystal Form. Journal of Pharmaceutical Sciences, 112(2); 513–524.
dos Santos, J. A. B., J. V. C. Júnior, R. S. de Araújo Batista, D. P. de Sousa, G. L. R. Ferreira, S. A. de Lima Neto, A. de Santana Oliveira, F. S. de Souza, and C. F. S. Aragão (2021). Preparation, Physicochemical Characterization and Solubility Evaluation of Pharmaceutical Cocrystals of Cinnamic Acid. Journal of Thermal Analysis and Calorimetry, 145; 379–390.
Dragan, M., C. D. Stan, A. T. Iacob, O. Dragostin, and L. Profire (2018). Ferulic Acid: Potential Therapeutic Applications. The Medical-Surgical Journal, 122(2); 388–395.
Espinosa, E., E. Molins, and C. Lecomte (1998). Hydrogen Bond Strengths Revealed by Topological Analyses of Experimentally Observed Electron Densities. Chemical Physics Letters, 285(3–4); 170–173.
Fazeli, F. (2021). Antioxidant Properties of Ferulic Acid on Cardiovascular Diseases. International Journal of Advanced Biological and Biomedical Research, 9(3); 228–240.
Hammami, F. and N. Issaoui (2022). A DFT Study of the Hydrogen Bonded Structures of Pyruvic Acid–Water Complexes. Frontiers in Physics, 10; 901736.
Hibbard, T., K. Shankland, and H. Al-Obaidi (2024). Preparation and Formulation of Progesterone Para-Aminobenzoic Acid Co-Crystals with Improved Dissolution and Stability. European Journal of Pharmaceutics and Biopharmaceutics, 196; 114202.
Huang, S., V. K. R. Cheemarla, D. Tiana, and S. E. Lawrence (2023). Experimental and Theoretical Investigation of Hydrogen-Bonding Interactions in Cocrystals of Sulfaguanidine. Crystal Growth & Design, 23(4); 2306–2320.
Jin, C., H. Zhang, F. Ren, J. Wang, and S. Yin (2023). Preparation and Characterization of Ferulic Acid Wheat Gluten Nanofiber Films with Excellent Antimicrobial Properties. Foods, 12(14); 2778.
Kanchana, S., T. Kaviya, P. Rajkumar, M. D. Kumar, N. Elangovan, and S. Sowrirajan (2023). Computational Investigation of Solvent Interaction (TD-DFT, MEP, HOMO-LUMO), Wavefunction Studies and Molecular Docking Studies of 3-(1-(3-(5-((1-Methylpiperidin-4-Yl)Methoxy)Pyrimidin-2-Yl)Benzyl)-6-Oxo-1,6-Dihydropyridazin-3-Yl)Benzonitrile. Chemical Physics Impact, 7; 100263.
Karagianni, A., M. Malamatari, and K. Kachrimanis (2018). Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs. Pharmaceutics, 10(1); 18.
Khan, A., N. Agrawal, R. Chaudhary, A. Yadav, J. Pandey, A. Narayan, S. Ali, P. Tandon, and V. R. Vangala (2025). Study of Chemical Reactivity and Molecular Interactions of the Hydrochlorothiazide-4-Aminobenzoic Acid Cocrystal Using Spectroscopic and Quantum Chemical Approaches. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 324; 124960.
Khan, I. M., A. Khan, S. Shakya, and M. Islam (2023). Exploring the Photocatalytic Activity of Synthesized Hydrogen Bonded Charge Transfer Co-Crystal of Chloranilic Acid with 2-Ethylimidazole: DFT, Molecular Docking and Spectrophotometric Studies in Different Solvents. Journal of Molecular Structure, 1277; 134862.
Khatun, M. M., M. S. Bhuia, R. Chowdhury, S. Sheikh, A. Ajmee, F. Mollah, M. S. Al Hasan, H. D. M. Coutinho, and M. T. Islam (2024). Potential Utilization of Ferulic Acid and Its Derivatives in the Management of Metabolic Diseases and Disorders: An Insight into Mechanisms. Cellular Signalling, 121; 111291.
Li, D., Y. Rui, S. Guo, F. Luan, R. Liu, and N. Zeng (2021). Ferulic Acid: A Review of Its Pharmacology, Pharmacokinetics and Derivatives. Life Sciences, 284; 119921.
Liu, H., H. C. S. Chan, X. Yu, J. Li, J. Li, and Z. Zhou (2023). Two Polymorphic Cocrystals of Theophylline with Ferulic Acid. Crystal Growth & Design, 23(6); 4448–4459.
Liu, L., J.-R. Wang, and X. Mei (2022). Enhancing the Stability of Active Pharmaceutical Ingredients by the Cocrystal Strategy. CrystEngComm, 24(11); 2002–2022.
Lu, T. (2024). A Comprehensive Electron Wavefunction Analysis Toolbox for Chemists, Multiwfn. The Journal of Chemical Physics, 161(8).
Martín Pendás, A., E. Francisco, D. Suárez, A. Costales, N. Díaz, J. Munárriz, T. Rocha-Rinza, and J. M. Guevara-Vela (2023). Atoms in Molecules in Real Space: A Fertile Field for Chemical Bonding. Physical Chemistry Chemical Physics, 25(15); 10231–10262.
Miar, M., A. Shiroudi, K. Pourshamsian, A. R. Oliaey, and F. Hatamjafari (2020). Theoretical Investigations on the HOMO–LUMO Gap and Global Reactivity Descriptor Studies, Natural Bond Orbital, and Nucleus-Independent Chemical Shifts Analyses of 3-Phenylbenzo[d]thiazole-2(3H)-imine and Its Para-Substituted Derivatives: Solvent and Substituent Effects. Journal of Chemical Research, 45(1–2); 147–158.
Neopane, D., V. A. Ansari, and A. Singh (2023). Ferulic Acid: Signaling Pathways in Aging. Drug Research, 73(06); 318–324.
Nyamba, I., C. B. Sombié, M. Yabré, H. Zimé-Diawara, J. Yaméogo, S. Ouédraogo, A. Lechanteur, R. Semdé, and B. Evrard (2024). Pharmaceutical Approaches for Enhancing Solubility and Oral Bioavailability of Poorly Soluble Drugs. European Journal of Pharmaceutics and Biopharmaceutics, 204; 114513.
Paneru, T. R., M. K. Chaudhary, B. D. Joshi, and P. Tandon (2024). Cocrystal Screening of Benznidazole Based on Electronic Transition, Molecular Reactivity, Hydrogen Bonding, and Stability. Journal of Molecular Modeling, 30(11); 378.
Panzade, P., A. Wagh, P. Harale, and S. Bhilwade (2024). Pharmaceutical Cocrystals: A Rising Star in Drug Delivery Applications. Journal of Drug Targeting, 32(2); 115–127.
Pujiono, F. E., D. Setyawan, and J. Ekowati (2024). Hydrogen Bond Analysis of the p-Coumaric Acid-Nicotinamide Cocrystal Using the DFT and AIM Method. Pharmacy Education, 24(3); 57–62.
Pyrzynska, K. (2024). Ferulic Acid—A Brief Review of Its Extraction, Bioavailability and Biological Activity. Separations, 11(7); 204.
Singh, J. S., M. S. Khan, and S. Uddin (2023). A DFT Study of Vibrational Spectra of 5-Chlorouracil with Molecular Structure, HOMO–LUMO, MEPs/ESPs and Thermodynamic Properties. Polymer Bulletin, 80(3); 3055–3083.
Song, X., C. Liu, Y. Zhang, X. Xiao, G. Han, K. Sun, S. Liu, Z. Zhang, C. Dong, Y. Zheng, X. Chen, T. Xu, Y. Liu, and Y. Li (2023). Sustainable Extraction of Ligustilide and Ferulic Acid from Angelicae Sinensis Radix, for Antioxidant and Anti-inflammatory Activities. Ultrasonics Sonochemistry, 94; 106344.
Sulistyowaty, M. I., D. Setyawan, P. P. M. Prameswari, R. J. K. Susilo, T. Amrillah, E. Zaini, and S. A. H. Zidan (2024). A Comparison Study between Green Synthesis of Microwave Irradiation and Solvent Evaporation Methods in the Formation of p-Methoxycinnamic Acid-Succinic Acid Cocrystals. Science and Technology Indonesia, 9(3); 629–636.
Szewczuk, N. A., P. R. Duchowicz, A. B. Pomilio, and R. M. Lobayan (2023). Resonance Structure Contributions, Flexibility, and Frontier Molecular Orbitals (HOMO–LUMO) of Pelargonidin, Cyanidin, and Delphinidin Throughout the Conformational Space: Application to Antioxidant and Antimutagenic Activities. Journal of Molecular Modeling, 29(1); 2.
Tatsumi, Y., Y. Shimoyama, and S. G. Kazarian (2024). Analysis of the Dissolution Behavior of Theophylline and Its Cocrystal Using ATR-FTIR Spectroscopic Imaging. Molecular Pharmaceutics, 21; 3233–3239.
Thayyil, A. R., T. Juturu, S. Nayak, and S. Kamath (2020). Pharmaceutical Co-Crystallization: Regulatory Aspects, Design, Characterization, and Applications. Advanced Pharmaceutical Bulletin, 10(2); 203.
Tupe, S. A., S. P. Khandagale, and A. B. Jadhav (2023). Pharmaceutical Cocrystals: An Emerging Approach to Modulate Physicochemical Properties of Active Pharmaceutical Ingredients. Journal of Drug Delivery and Therapeutics, 13(4); 101–112.
Velmurugan, V., R. Nandini Asha, B. Ravindran Durai Nayagam, S. Kumaresan, and N. Bhuvanesh (2021). Synthesis, Characterization and Biological Activity of (Phenylthio) Acetic Acid: Theophylline Cocrystal. Journal of Chemical Crystallography, 51(2); 225–234.
Vilas-Boas, S. M., R. S. Alves, P. Brandao, L. M. A. Campos, J. A. P. Coutinho, S. P. Pinho, and O. Ferreira (2020). Solid-Liquid Phase Equilibrium of Trans-Cinnamic Acid, p-Coumaric Acid and Ferulic Acid in Water and Organic Solvents: Experimental and Modelling Studies. Fluid Phase Equilibria, 521; 112747.
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Authors
Pujiono, F. E., Ekowati, J. ., Amrillah, T., & Setyawan, D. . (2025). Ferulic Acid-Nicotinamide Cocrystal: Synthesis, Experimental, and Computation Study. Science and Technology Indonesia, 10(2), 402–410. https://doi.org/10.26554/sti.2025.10.2.402-410
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