Microwave-Assisted Cocrystallization of p-Methoxycinnamic Acid with Saccharin and Nicotinamide: Comparative Effects on Solubility and Dissolution
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Keywords:
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p-Methoxycinnamic Acid, Nicotinamide, Saccharin, Cocrystal, Microwave Radiation, Dissolution
Abstract
p-methoxycinnamic acid (pMCA) has activity as an anti- inflammatory and analgesic but is difficult to dissolve in water with a solubility of only 0.712 mg/mL at 25 oC. Poor solubility will result a low dissolution rate so that drug absorption becomes limited, affects the bioavailability, and causes therapeutic effect to become less optimal. The formation of co-crystals are able to improve the solubility properties and dissolution rate by physically modifying the active compound. Cocrystals are crystalline materials composed of two or more molecules at specific stoichiometric ratios to form non-covalent bonds. Both saccharin and nicotinamide can be use as coformers because saccharin and nicotinamide were able to increase the solubility and dissolution rate of active compounds due to the formation of non-covalent bonds. The results showed that the formation of cocrystals using the microwave radiation had a higher solubility and dissolution rate of pMCA compared to pure pMCA. The pMCA-nicotinamide cocrystal increased solubility 1.29 times higher than a single pMCA while the pMCA-saccharin cocrystal increased solubility only 1.26 times higher than a single pMCA. In the dissolution rate test, the pMCA-Nicotinamide cocrystal increased the dissolution rate 3.67 times higher while the pMCA-Saccharin only increased 3.55 times higher than a single pMCA. These results show that both cocrystals have better solubility and dissolution rate properties than pure pMCA so it can be said that forming cocrystals can increase the solubility and dissolution rate of pMCA. Based on this study findings, it can also confirm that formation cocrystal pMCA using nicotinamide coformers has a
good solubility and dissolution rate than formation cocrystal using saccharin coformers.
References
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Palanisamy, M. and J. Khanam (2011). Solid Dispersion of Prednisolone: Solid State Characterization and Improvement of Dissolution Profile. Drug Development and Industrial Pharmacy, 37(4); 373–386
Panzade, P. and G. Shendarkar (2019). Superior Solubility and Dissolution of Zaltoprofen via Pharmaceutical Cocrystals. Turkish Journal of Pharmaceutical Sciences, 16(3); 310–316
Prashanth, J., K. V. Drozd, G. L. Perlovich, S. Balasubramanian, and A. Surov (2022). Cocrystal and Coamorphous Solid Forms of Enzalutamide with Saccharin: Structural Characterization and Dissolution Studies. Crystal Growth & Design, 22(11); 6703–6716
Puspita, O. E., M. I. Sulistyowaty, R. Salam, and D. Setyawan (2025). Microwave-Assisted Synthesis: A Green Chemistry Approach for Drug Cocrystals Synthesis. Science and Technology Indonesia, 10; 1130–1147
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
Rahman, Z., R. Samy, V. A. Sayeed, and M. A. Khan (2012). Physicochemical and Mechanical Properties of Carbamazepine Cocrystals with Saccharin. Pharmaceutical Development and Technology, 17(4); 457–465
Saganowska, P. and M. Wesolowski (2018). DSC as a Screening Tool for Rapid Co-Crystal Detection in Binary Mixtures of Benzodiazepines with Co-Formers. Journal of Thermal Analysis and Calorimetry, 133(1); 785–795
Sathisaran, I. and S. V. Dalvi (2018). Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium. Pharmaceutics, 10(3); 108
Savjani, K. T., A. K. Gajjar, and J. K. Savjani (2012). Drug Solubility: Importance and Enhancement Techniques. International Scholarly Research Notices, 2012; 195727
Setyawan, D., A. Paramanandana, V. E. Erfadrin, R. Sari, and P. Diajeng Putri (2020). Compression Force Effect on Characteristics of Loratadine–Succinic Acid Cocrystal Prepared by Slurry Method. Journal of Research in Pharmacy, 24(3); 410–415
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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(Suppl. 1); 62–65
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Subositi, D., N. Kurnianingrum, R. Mujahid, and Y. Widiyastuti (2020). Kaempferia galanga L.: A Medicinal Plant Used by Indonesian Ethnic Groups. Biodiversitas, 42(1); 45–52
Sulistyowaty, M. I., S. Fitri, N. Yuliati, T. Amrillah, C. A. C. Abdullah, and D. Setyawan (2024). Solubility and Dissolution Improvement of Paramethoxycinnamic Acid (PMCA) Induced by Cocrystal Formation Using Caffeine as a Coformer. Sains Malaysiana, 53(10); 3445–3454
Svärd, M., D. Ahuja, and Å. C. Rasmuson (2020). Calorimetric Determination of Cocrystal Thermodynamic Stability: Sulfamethazine–Salicylic Acid Case Study. Crystal Growth & Design, 20(7); 4243–4251
Tambosi, G., P. F. Coelho, S. Luciano, I. C. S. Lenschow, M. Zétola, H. K. Stulzer, and B. R. Pezzini (2018). Challenges to Improve the Biopharmaceutical Properties of Poorly Water-Soluble Drugs and the Application of the Solid Dispersion Technology. Matéria (Rio de Janeiro), 23(4); e12224
Thakuria, R. and B. Sarma (2018). Drug-Drug and Drug-Nutraceutical Cocrystal/Salt As Alternative Medicine for Combination Therapy: A Crystal Engineering Approach. Crystals, 8(2); 101
Wicaksono, Y., D. Setyawan, and Siswandono (2017). Formation of Ketoprofen–Malonic Acid Cocrystal by Solvent Evaporation Method. Indonesian Journal of Chemistry, 17(2); 161–166
Wicaksono, Y., D. Setyawan, S. Siswandono, and T. A. Siswoyo (2019). Preparation and Characterization of a Novel Cocrystal of Atorvastatin Calcium with Succinic Acid Coformer. Indonesian Journal of Chemistry, 19(3); 660–667
Wichianphong, N. and M. Charoenchaitrakool (2018). Statistical Optimization for Production of Mefenamic Acid–Nicotinamide Cocrystals Using Gas Anti-Solvent (GAS) Process. Journal of Industrial and Engineering Chemistry, 62; 375–382
Xia, M. Y., B. Q. Zhu, J. R. Wang, Z. E. Yang, and X. F. Mei (2022). Superior Dissolution Behavior and Bioavailability of Pharmaceutical Cocrystals and Recent Regulatory Issues. ACS Medicinal Chemistry Letters, 13(1); 29–37
Xiao, Y., T. Jin, X. Geng, and X. Zhu (2022). Azilsartan–Nicotinamide Cocrystal: Preparation, Characterization and In Vitro/In Vivo Evaluation. European Journal of Pharmaceutical Sciences, 176; 106241
Zaini, E., Afriyani, L. Fitriani, F. Ismed, A. Horikawa, and H. Uekusa (2020). Improved Solubility and Dissolution Rates in Novel Multicomponent Crystals of Piperine with Succinic Acid. Scientia Pharmaceutica, 88(2); 21
Adisakwattana, S., S. Roengsamran, W. H. Hsu, and S. Yibchok-Anun (2005). Mechanisms of Antihyperglycemic Effect of p-Methoxycinnamic Acid in Normal and Streptozotocin-Induced Diabetic Rats. Life Sciences, 78(4); 406–412
Ahammad, T., M. Begum, A. F. M. Towheedur Rahman, M. Hasan, S. R. Paul, S. Eamen, M. I. Hussain, M. H. Ali, M. A. Islam, M. M. Rahman, and M. Rashid (2015). Formulation and In Vitro Release Pattern Study of Gliclazide Matrix Tablet. Pharmacology & Pharmacy, 6(3); 125–131
Ahmad, S., R. Jaiswal, R. Yadav, and S. Verma (2024). Recent Advances in Green Chemistry Approaches for Pharmaceutical Synthesis. Sustainable Chemistry One World, 4; 100029
Basavoju, S., D. Boström, and S. P. Velaga (2008). Indomethacin-Saccharin Cocrystal: Design, Synthesis and Preliminary Pharmaceutical Characterization. Pharmaceutical Research, 25(3); 530–541
Bavishi, D. D. and C. H. Borkhataria (2016). Spring and Parachute: How Cocrystals Enhance Solubility. Progress in Crystal Growth and Characterization of Materials, 62; 1–8
Chadha, R., D. Rani, and P. Goyal (2017). Supramolecular Cocrystals of Gliclazide: Synthesis, Characterization and Evaluation. Pharmaceutical Research, 34(3); 552–563
Chaves Júnior, J. V., J. A. B. dos Santos, T. B. Lins, R. S. de Araújo Batista, S. A. de Lima Neto, A. de Santana Oliveira, F. H. A. Nogueira, A. P. B. Gomes, D. P. de Sousa, F. S. de Souza, and C. F. S. Aragão (2020). A New Ferulic Acid-Nicotinamide Cocrystal with Improved Solubility and Dissolution Performance. Journal of Pharmaceutical Sciences, 109(3); 1330–1337
Dias, J. L., E. A. Rebelatto, D. Hotza, A. J. Bortoluzzi, M. Lanza, and S. R. S. Ferreira (2022). Production of Quercetin-Nicotinamide Cocrystals by Gas Antisolvent (GAS) Process. Journal of Supercritical Fluids, 188; 105670
Diaz, D. A., S. T. Colgan, C. S. Langer, N. T. Bandi, M. D. Likar, and L. Van Alstine (2016). Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations? AAPS Journal, 18(1); 15–22
Ekowati, J. and N. W. Diyah (2013). Antinociceptive In Silico Cyclooxygenase of p-Methoxycinnamic Acid. Berkala Ilmiah Kimia Farmasi, 2(1); 33–40
Gillespie, P. M. (2005). Microwave Chemistry: An Approach to the Assessment of Chemical Reaction Hazards. Institution of Chemical Engineers Symposium Series, 150; 533–543
Huang, Y., G. Kuminek, L. Roy, K. L. Cavanagh, Q. Yin, and N. Rodríguez-Hornedo (2019). Cocrystal Solubility Advantage Diagrams as a Means to Control Dissolution, Supersaturation, and Precipitation. Molecular Pharmaceutics, 16(9); 3887–3895
Johnson, P., V. Krishnan, C. Loganathan, K. Govindhan, V. Raji, P. Sakayanathan, S. Vijayan, P. Sathishkumar, and T. Palvannan (2018). Rapid Biosynthesis of Bauhinia variegata Flower Extract-Mediated Silver Nanoparticles: An Effective Antioxidant Scavenger and α-Amylase Inhibitor. Artificial Cells, Nanomedicine and Biotechnology, 46(7); 1488–1494
Jung, M. S., J. S. Kim, M. S. Kim, A. Alhalaweh, W. Cho, S. J. Hwang, and S. P. Velaga (2010). Bioavailability of Indomethacin–Saccharin Cocrystals. Journal of Pharmacy and Pharmacology, 62(11); 1560–1568
Kakran, M., N. G. Sahoo, and L. Li (2011). Dissolution Enhancement of Quercetin Through Nanofabrication, Complexation, and Solid Dispersion. Colloids and Surfaces B: Biointerfaces, 88(1); 121–130
Kamis, M. N. A. A., H. M. Zaki, N. Anuar, and M. N. Jalil (2020). Synthesis, Characterization and Morphological Study of Nicotinamide and p-Coumaric Acid Cocrystal. Indonesian Journal of Chemistry, 20(3); 661–679
Karagianni, A., M. Malamatari, and K. Kachrimanis (2018). Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs. Pharmaceutics, 10(1); 18
Li, Z. and A. J. Matzger (2017). Influence of Coformer Stoichiometric Ratio on Pharmaceutical Cocrystal Dissolution: Three Cocrystals of Carbamazepine/p-Aminobenzoic Acid. Molecular Pharmaceutics, 14(1); 139–148
Miroshnyk, I., S. Mirza, and N. Sandler (2009). Pharmaceutical Co-Crystals: An Opportunity for Drug Product Enhancement. Expert Opinion on Drug Delivery, 6(4); 333–341
Nawatila, R., W. Agnes Nuniek, S. Siswodihardjo, and D. Setyawan (2017). Preparation of Acyclovir-Nicotinamide Cocrystal by Solvent Evaporation Technique with Variation of Solvent. Asian Journal of Pharmaceutical and Clinical Research, 10(3); 283–287
Nyamba, I., C. B. Sombie, M. Yabre, H. Zime-Diawara, J. Yameogo, S. Ouedraogo, A. Lechanteur, R. Semde, and B. Evrard (2024). Pharmaceutical Approaches for Enhancing Solubility and Oral Bioavailability of Poorly Soluble Drugs. European Journal of Pharmaceutics and Biopharmaceutics, 204; 114513
Pagire, S., S. Korde, R. Ambardekar, S. Deshmukh, R. C. Dash, R. Dhumal, and A. Paradkar (2013). Microwave Assisted Synthesis of Caffeine/Maleic Acid Co-Crystals: The Role of the Dielectric and Physicochemical Properties of the Solvent. CrystEngComm, 15(18); 3705–3710
Palanisamy, M. and J. Khanam (2011). Solid Dispersion of Prednisolone: Solid State Characterization and Improvement of Dissolution Profile. Drug Development and Industrial Pharmacy, 37(4); 373–386
Panzade, P. and G. Shendarkar (2019). Superior Solubility and Dissolution of Zaltoprofen via Pharmaceutical Cocrystals. Turkish Journal of Pharmaceutical Sciences, 16(3); 310–316
Prashanth, J., K. V. Drozd, G. L. Perlovich, S. Balasubramanian, and A. Surov (2022). Cocrystal and Coamorphous Solid Forms of Enzalutamide with Saccharin: Structural Characterization and Dissolution Studies. Crystal Growth & Design, 22(11); 6703–6716
Puspita, O. E., M. I. Sulistyowaty, R. Salam, and D. Setyawan (2025). Microwave-Assisted Synthesis: A Green Chemistry Approach for Drug Cocrystals Synthesis. Science and Technology Indonesia, 10; 1130–1147
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
Rahman, Z., R. Samy, V. A. Sayeed, and M. A. Khan (2012). Physicochemical and Mechanical Properties of Carbamazepine Cocrystals with Saccharin. Pharmaceutical Development and Technology, 17(4); 457–465
Saganowska, P. and M. Wesolowski (2018). DSC as a Screening Tool for Rapid Co-Crystal Detection in Binary Mixtures of Benzodiazepines with Co-Formers. Journal of Thermal Analysis and Calorimetry, 133(1); 785–795
Sathisaran, I. and S. V. Dalvi (2018). Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium. Pharmaceutics, 10(3); 108
Savjani, K. T., A. K. Gajjar, and J. K. Savjani (2012). Drug Solubility: Importance and Enhancement Techniques. International Scholarly Research Notices, 2012; 195727
Setyawan, D., A. Paramanandana, V. E. Erfadrin, R. Sari, and P. Diajeng Putri (2020). Compression Force Effect on Characteristics of Loratadine–Succinic Acid Cocrystal Prepared by Slurry Method. Journal of Research in Pharmacy, 24(3); 410–415
Setyawan, D., S. A. Permata, A. Zainul, and M. L. A. Dwi Lestari (2018). Improvement In Vitro Dissolution Rate of Quercetin Using Cocrystallization of Quercetin–Malonic Acid. Indonesian Journal of Chemistry, 18(3); 531–536
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(Suppl. 1); 62–65
Setyawan, D., Y. Soraya, J. Ekowati, A. N. Winantari, K. C. Rani, F. A. T. Kanzaffa, and F. E. Pujiono (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
Sinko, P. J. and Y. Singh (2011). Martin’s Physical Pharmacy and Pharmaceutical Sciences. Lippincott Williams & Wilkins, 6th edition
Subositi, D., N. Kurnianingrum, R. Mujahid, and Y. Widiyastuti (2020). Kaempferia galanga L.: A Medicinal Plant Used by Indonesian Ethnic Groups. Biodiversitas, 42(1); 45–52
Sulistyowaty, M. I., S. Fitri, N. Yuliati, T. Amrillah, C. A. C. Abdullah, and D. Setyawan (2024). Solubility and Dissolution Improvement of Paramethoxycinnamic Acid (PMCA) Induced by Cocrystal Formation Using Caffeine as a Coformer. Sains Malaysiana, 53(10); 3445–3454
Svärd, M., D. Ahuja, and Å. C. Rasmuson (2020). Calorimetric Determination of Cocrystal Thermodynamic Stability: Sulfamethazine–Salicylic Acid Case Study. Crystal Growth & Design, 20(7); 4243–4251
Tambosi, G., P. F. Coelho, S. Luciano, I. C. S. Lenschow, M. Zétola, H. K. Stulzer, and B. R. Pezzini (2018). Challenges to Improve the Biopharmaceutical Properties of Poorly Water-Soluble Drugs and the Application of the Solid Dispersion Technology. Matéria (Rio de Janeiro), 23(4); e12224
Thakuria, R. and B. Sarma (2018). Drug-Drug and Drug-Nutraceutical Cocrystal/Salt As Alternative Medicine for Combination Therapy: A Crystal Engineering Approach. Crystals, 8(2); 101
Wicaksono, Y., D. Setyawan, and Siswandono (2017). Formation of Ketoprofen–Malonic Acid Cocrystal by Solvent Evaporation Method. Indonesian Journal of Chemistry, 17(2); 161–166
Wicaksono, Y., D. Setyawan, S. Siswandono, and T. A. Siswoyo (2019). Preparation and Characterization of a Novel Cocrystal of Atorvastatin Calcium with Succinic Acid Coformer. Indonesian Journal of Chemistry, 19(3); 660–667
Wichianphong, N. and M. Charoenchaitrakool (2018). Statistical Optimization for Production of Mefenamic Acid–Nicotinamide Cocrystals Using Gas Anti-Solvent (GAS) Process. Journal of Industrial and Engineering Chemistry, 62; 375–382
Xia, M. Y., B. Q. Zhu, J. R. Wang, Z. E. Yang, and X. F. Mei (2022). Superior Dissolution Behavior and Bioavailability of Pharmaceutical Cocrystals and Recent Regulatory Issues. ACS Medicinal Chemistry Letters, 13(1); 29–37
Xiao, Y., T. Jin, X. Geng, and X. Zhu (2022). Azilsartan–Nicotinamide Cocrystal: Preparation, Characterization and In Vitro/In Vivo Evaluation. European Journal of Pharmaceutical Sciences, 176; 106241
Zaini, E., Afriyani, L. Fitriani, F. Ismed, A. Horikawa, and H. Uekusa (2020). Improved Solubility and Dissolution Rates in Novel Multicomponent Crystals of Piperine with Succinic Acid. Scientia Pharmaceutica, 88(2); 21
Authors
Paramanandana, A., Kawaguchi , K. ., Sulistyowaty, M. I., Setyawan, D., & Almaghrabi, M. . (2026). Microwave-Assisted Cocrystallization of p-Methoxycinnamic Acid with Saccharin and Nicotinamide: Comparative Effects on Solubility and Dissolution. Science and Technology Indonesia, 11(2), 436–446. https://doi.org/10.26554/sti.2026.11.2.436-446
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