Synthesis, Characterization and Morphological Study of Nicotinamide and p-Coumaric Acid Cocrystal

Mohamad Nor Amirul Azhar Kamis(1), Hamizah Mohd Zaki(2*), Nornizar Anuar(3), Mohammad Noor Jalil(4)

(1) Faculty of Applied Science, Universiti Teknologi Mara, 40450 Shah Alam, Selangor, Malaysia
(2) Faculty of Applied Science, Universiti Teknologi Mara, 40450 Shah Alam, Selangor, Malaysia
(3) Faculty of Chemical Engineering, Universiti Teknologi MARA, 40450 Shah Alam, Selangor, Malaysia
(4) Faculty of Applied Science, Universiti Teknologi Mara, 40450 Shah Alam, Selangor, Malaysia
(*) Corresponding Author


Cocrystallization is one of the potent methods used to modify the physicochemical properties of drugs. Cocrystal of nicotinamide (NIC):p-coumaric acid (COU) was synthesized by a slow evaporation method using acetonitrile. The cocrystals with different feed molar ratios (NIC:COU : 1:1, 1:2, and 2:1) were characterized using DSC, PXRD, and FTIR, which revealed the formation of different polymorphs for each feed molar ratio. A single crystal of the NIC:COU (1:1) cocrystal was analyzed using single crystal X-ray diffraction (SCD), and 1H-NMR revealed a greater cocrystal structure stability compared to the previously published cocrystal. The intermolecular hydrogen bonds, N-H···O, and O-H···O interactions played a major role in stabilizing the cocrystal structure. A molecular modeling technique was used for prediction and surface chemistry assessment of the morphology showed an elongated (along y-axis) octagonal crystal shape which was in a reasonable agreement with the experimental crystal morphology. The reduction in values of the cocrystal solubility in ethanol was supported by the DSC data and simulation of crystal facets where most the crystal facets exposed to polar functional groups. At the concentration of 31.3 µM, NIC:COU (1:1) cocrystal showed more effective DPPH scavenging with 77.06% increased activity compared to NIC at the same concentration.


physicochemical properties; cocrystal; molecular interaction; single crystal XRD; computational simulation


[1] Song, J.X., Chen, J.M., and Lu, T.B., 2015, Lenalidomide–gallic acid cocrystals with constant high solubility, Cryst. Growth Des., 15 (10), 4869–4875.

[2] Huang, Y., Zhang, B., Gao, Y., Zhang, J., and Shi, L., 2014, Baicalein-nicotinamide cocrystal with enhanced solubility, dissolution, and oral bioavailability, J. Pharm. Sci., 103 (8), 2330–2337.

[3] Cheney, M.L., Weyna, D.R., Shan, N., Hanna, M., Wojtas, L., and Zaworotko, M.J., 2010, Supramolecular architectures of meloxicam carboxylic acid cocrystals, a crystal engineering case study, Cryst. Growth Des., 10 (10), 4401–4413.

[4] Raghuram, M., Sarwar Alam, M., Prasad, M., and Has Khanduri, C., 2014, Pharmaceutical cocrystal of prulifloxacin with nicotinamide, Int. J. Pharm. Pharm. Sci., 6 (10), 180–184.

[5] Shayanfar, A., Velaga, S., and Jouyban, A., 2014, Solubility of carbamazepine, nicotinamide and carbamazepine–nicotinamide cocrystal in ethanol–water mixtures, Fluid Phase Equilib., 363, 97–105.

[6] Hino, T., Ford, J.L., and Powell, M.W., 2001, Assessment of nicotinamide polymorphs by differential scanning calorimetry, Thermochim. Acta, 374 (1), 85–92.

[7] Bevill, M.J., Vlahova, P.I., and Smit, J.P., 2014, Polymorphic cocrystals of nutraceutical compound p-coumaric acid with nicotinamide: Characterization, relative solid-state stability, and conversion to alternate stoichiometries, Cryst. Growth Des., 14 (3), 1438–1448.

[8] Aakeröy, C.B., Beatty, A.M., and Helfrich, B.A., 2002, A high-yielding supramolecular reaction, J. Am. Chem. Soc., 124 (48), 14425–14432.

[9] Aakeröy, C.B., Beatty, A.M., Helfrich, B.A., and Nieuwenhuyzen, M., 2003, Do polymorphic compounds make good cocrystallizing agents? A structural case study that demonstrates the importance of synthon flexibility, Cryst. Growth Des., 3 (2)., 159–165.

[10] Bhogala, B.R., Basavoju, S., and Nangia, A., 2005, Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4,4′-bipyridines and isonicotinamide. From binary to ternary cocrystals, CrystEngComm, 7 (90), 551–562.

[11] Fábián, L., Hamill, N., Eccles, K.S., Moynihan, H.A., Maguire, A.R., McCausland, L., and Lawrence, S.E., 2011, Cocrystals of fenamic acids with nicotinamide, Cryst. Growth Des., 11 (8), 3522–3528.

[12] Lemmerer, A., Báthori, N.B., and Bourne, S.A., 2008, Chiral carboxylic acids and their effects on melting-point behaviour in co-crystals with isonicotinamide, Acta Crystallogr., Sect. B: Struct. Sci., 64 (Pt 6), 780–790.

[13] Vishweshwar, P., Nangia, A., and Lynch, V.M., 2003, Supramolecular synthons in phenol–isonicotinamide adducts, CrystEngComm, 5 (31), 164–168.

[14] Vishweshwar, P., Nangia, A., and Lynch, V.M., 2003, Molecular complexes of homologous alkanedicarboxylic acids with isonicotinamide: X-ray crystal structures, hydrogen bond synthons, and melting point alternation, Cryst. Growth Des., 3 (5), 783–790.

[15] Berry, D.J., Seaton, C.C., Clegg, W., Harrington, R.W., Coles, S.J., Horton, P.N., Hurtshouse, M.B., Storey, R., Jones, W., and Friscic, T., 2008, Applying hot-stage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients, Cryst. Growth Des., 8 (5), 1697–1712.

[16] Zhang, S.W., Harasimowicz, M.T., de Villiers, M.M., and Yu, L., 2013, Cocrystals of nicotinamide and (R)-mandelic acid in many ratios with anomalous formation properties, J. Am. Chem. Soc., 135 (50), 18981–18989.

[17] Setyawan, D., Sari, R., Yusuf, H., and Primaharinastiti, R., 2014, Preparation and characterization of artesunate–nicotinamide co-crystal by solvent evaporation and slurry method, Asian J. Pharm. Clin. Res., 7 (Suppl. 1), 62–65.

[18] Rahman, Z., Agarabi, C., Zidan, A.S., Khan, S.R., and Khan, M.A., 2011, Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide, AAPS PharmSciTech, 12 (2), 693–704.

[19] Remenar, J.F., Peterson, M.L., Stephens, P.W., Zhang, Z., Zimenkov, Y., and Hickey, M.B., 2007, Celecoxib: Nicotinamide dissociation: Using excipients to capture the cocrystal's potential, Mol. Pharmaceutics, 4 (3), 386–400.

[20] Nicoli, S., Bilzi, S., Santi, P., Caira, M. R., Li, J., and Bettini, R., 2008, Ethyl-paraben and nicotinamide mixtures: Apparent solubility, thermal behavior and X-ray structure of the 1:1 co-crystal, J. Pharm. Sci., 97 (11), 4830–4839.

[21] Sopyan, I., Fudholi, A., Muchtaridi, M., and Sari, I.P., 2017, Simvastatin-nicotinamide co-crystal: Design, preparation and preliminary characterization, Trop. J. Pharm. Res., 16 (2), 297–303.

[22] Keramatnia, F., Shayanfar, A., and Jouyban, A., 2015, Thermodynamic solubility profile of carbamazepine-cinnamic acid cocrystal at different pH, J. Pharm. Sci., 104 (8), 2559–2565.

[23] Shayanfar, A., Asadpour-Zeynali, K., and Jouyban, A., 2013, Solubility and dissolution rate of a carbamazepine–cinnamic acid cocrystal, J. Mol. Liq., 187, 171–176.

[24] Lemmerer, A., Esterhuysen, C., and Bernstein, J., 2010, Synthesis, characterization, and molecular modeling of a pharmaceutical co-crystal: (2-Chloro-4-nitrobenzoic acid):(nicotinamide), J. Pharm. Sci., 99 (9), 4054–4071.

[25] Etter, M.C., 1990, Encoding and decoding hydrogen-bond patterns of organic compounds, Acc. Chem. Res., 23 (4), 120–126.

[26] Bernstein, J., Davis, R.E., Shimoni, L., and Chang, N.L., 1995, Patterns in hydrogen bonding: Functionality and graph set analysis in crystals, Angew. Chem. Int. Ed., 34 (15), 1555–1573.

[27] Etter, M.C., MacDonald, J.C., and Bernstein, J., 1990, Graph‐set analysis of hydrogen‐bond patterns in organic crystals, Acta Crystallogr., Sect. B: Struct. Sci., 46, 256–262.

[28] Karki, S., Friščić, T., and Jones, W., 2009, Control and interconversion of cocrystal stoichiometry in grinding: stepwise mechanism for the formation of a hydrogen-bonded cocrystal, CrystEngComm, 11 (3), 470–481.

[29] Nićiforović, N., and Abramovič, H., 2014, Sinapic acid and its derivatives: Natural sources and bioactivity, Compr. Rev. Food Sci. Food Saf., 13 (1), 34–51.

[30] Kulik, T.V., Lipkovska, N.O., Barvinchenko, V.M., Palyanytsya, B.B., Kazakova, O.A., Dudik, O.O., Menyhard, A., and Laszlo, K., 2016, Thermal transformation of bioactive caffeic acid on fumed silica seen by UV-Vis spectroscopy, thermogravimetric analysis, temperature programmed desorption mass spectrometry and quantum chemical methods, J. Colloid Interface Sci., 470, 132–141.

[31] Schultheiss, N., Roe, M., and Boerrigter, S.X.M., 2011, Cocrystals of nutraceutical p-coumaric acid with caffeine and theophylline: polymorphism and solid-state stability explored in detail using their crystal graphs, CrystEngComm, 13 (2), 611–619.

[32] Ravikumar, N., Gaddamanugu, G., and Solomon, K.A., 2013, Structural, spectroscopic (FT-IR, FT-Raman) and theoretical studies of the 1:1 cocrystal of isoniazid with p-coumaric acid, J. Mol. Struct., 1033, 272–279.

[33] Du, N., Cao, S., and Yu, Y., 2011, Research on the adsorption property of supported ionic liquids for ferulic acid, caffeic acid and salicylic acid, J. Chromatogr. B, 879 (19), 1697–1703.

[34] Kumar, N., Pruthi, V., and Goel, N., 2015, Structural, thermal and quantum chemical studies of p-coumaric and caffeic acids, J. Mol. Struct., 1085, 242–248.

[35] Jacobs, A., and Noa, F.M.A., 2013, Hybrid salt–cocrystal solvate: p-coumaric acid and quinine system, J. Chem. Crystallogr., 44 (2), 57–62.

[36] Swapna, B., Maddileti, D., and Nangia, A., 2014, Cocrystals of the tuberculosis drug isoniazid: Polymorphism, isostructurality, and stability, Cryst. Growth Des., 14 (11), 5991–6005.

[37] Shi, W., Xia, M., Lei, W., and Wang, F., 2014, Solvent effect on the crystal morphology of 2,6-diamino-3,5-dinitropyridine-1-oxide: A molecular dynamics simulation study, J. Mol. Graphics Modell., 50, 71–77.

[38] Zhang, M., Liang, Z., Wu, F., Chen, J.F., Xue, C., and Zhao, H., 2017, Crystal engineering of ibuprofen compounds: From molecule to crystal structure to morphology prediction by computational simulation and experimental study, J. Cryst. Growth, 467, 47–53.

[39] Chen, G., Xia, M., Lei, W., Wang, F., and Gong, X., 2014, Prediction of crystal morphology of cyclotrimethylene trinitramine in the solvent medium by computer simulation: A case of cyclohexanone solvent, J. Phys. Chem. A, 118 (49), 11471–11478.

[40] Han, G., Li, Q.F., Gou, R.J., Zhang, S.H., Ren, F.D., Wang, L., and Guan, R., 2017, Growth morphology of CL-20/HMX cocrystal explosive: Insights from solvent behavior under different temperatures, J. Mol. Model., 23 (12), 360.

[41] Hassan, S., Adam, F., Abu Bakar, M.R., and Abdul Mudalip, S.K., 2018, Evaluation of solvents’ effect on solubility, intermolecular interaction energies and habit of ascorbic acid crystals, J. Saudi Chem. Soc., 23 (2), 239–248.

[42] Hod, I., Mastai, Y., and Medina, D.D., 2011, Effect of solvents on the growth morphology of dl-alanine crystals, CrystEngComm., 13 (2), 502–509.

[43] Wang, C., Zhang, X., Du, W., Huang, Y.H., Guo, M.X., Li, Y., Zhang, Z.X., Hou, B.H., and Yin, Q.X., 2016, Effects of solvent and supersaturation on crystal morphology of cefaclor dihydrate: A combined experimental and computer simulation study, CrystEngComm., 18 (47), 9085–9094.

[44] Rohl, A.L., 2003, Computer prediction of crystal morphology, Curr. Opin. Solid State Mater. Sci., 7 (1), 21–26.

[45] Liu, J., Sun, J., Zhang, H., and Wen, Y., 2016, Prediction of crystal morphology of 1,3,5-triamino-2,4,6-trinitrobenzene in dimethyl sulfoxide via modified attachment energy modeling and its experimental validation, Mol. Cryst. Liq. Cryst., 634 (1), 97–103.

[46] Liu, N., Li, Y.N., Zeman, S., Shu, Y.J., Wang, B.Z., Zhou, Y.S., Zhao, Q.L., and Wang, W.L., 2016, Crystal morphology of 3,4-bis(3-nitrofurazan-4-yl)furoxan (DNTF) in a solvent system: Molecular dynamics simulation and sensitivity study, CrystEngComm., 18 (16), 2843–2851.

[47] Rosbottom, I., Roberts, K.J., and Docherty, R., 2015, The solid state, surface and morphological properties of p-aminobenzoic acid in terms of the strength and directionality of its intermolecular synthons, CrystEngComm, 17 (30), 5768–5788.

[48] Coombes, D.S., Catlow, C.R.A., Gale, J.D., Hardy, M.J., and Saunders, M.R., 2002, Theoretical and experimental investigations on the morphology of pharmaceutical crystals, J. Pharm. Sci., 91 (7), 1652–1658.

[49] ter Horst, J.H., Kramer, H.J.M., van Rosmalen, G.M., and Jansens, P.J., 2002, Molecular modelling of the crystallization of polymorphs. Part I: The morphology of HMX polymorphs, J. Cryst. Growth, 237-239, 2215–2220.

[50] Erk, P., 2001, Crystal design of organic pigments–A prototype discipline of materials science, Curr. Opin. Solid State Mater. Sci., 5 (2-3), 155–160.

[51] Millan, A., 2001, Crystal growth shape of whewellite polymorphs: Influence of structure distortions on crystal shape, Cryst. Growth Des., 1 (3), 245–254.

[52] Grimsey, I.M., Osborn, J.C., Doughty, S.W., York, P., and Rowe, R.C., 2002, The application of molecular modelling to the interpretation of inverse gas chromatography data, J. Chromatogr. A, 969 (1-2), 49–57.

[53] Anuar, N., Wan Daud, W.R., Roberts, K.J., Kamarudin, S.K., and Tasirin, S.M., 2012, Morphology and associated surface chemistry of L-isoleucine crystals modeled under the influence of L-leucine additive molecules, Cryst. Growth Des., 12 (5), 2195–2203.

[54] Shen, F., Lv, P., Sun, C., Zhang, R., and Pang, S., 2014, The crystal structure and morphology of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) p-xylene solvate: A joint experimental and simulation study, Molecules, 19 (11), 18574–18589.

[55] McMahon, J.A., Bis, J.A., Vishweshwar, P., Shattock, T.R., McLaughlin, O.L., and Zaworotko, M.J., 2005, Crystal engineering of the composition of pharmaceutical phases. 3. Primary amide supramolecular heterosynthons and their role in the design of pharmaceutical co-crystals, Z. Kristallogr. Cryst. Mater., 220 (4), 340–350.

[56] Aitipamula, S., Chow, P.S., and Tan, R.B.H., 2009, Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients: potential relevance to combination drugs, CrystEngComm, 11 (9), 1823–1827.

[57] Spek, A.L., 2003, Single-crystal structure validation with the program PLATON, J. Appl. Crystallogr., 36 (1), 7–13.

[58] Shahidi, F., and Zhong, Y., 2015, Measurement of antioxidant activity, J. Funct. Foods, 18, 757–781.

[59] Chen, Z., Bertin, R., and Froldi, G., 2013, EC50 estimation of antioxidant activity in DPPH assay using several statistical programs, Food Chem., 138 (1), 414–420.

[60] Kiliç, I., and Yeşiloğlu, Y., 2013, Spectroscopic studies on the antioxidant activity of p-coumaric acid, Spectrochim. Acta, Part A, 115, 719–724.

[61] Gholizadeh, R., Wang, Y., and Yu, Y.X., 2017, Molecular dynamics simulations of stability at the early stages of silica materials preparation, J. Mol. Struct., 1138, 198–207.

[62] Manin, A.N., Voronin, A.P., Drozd, K.V., Manin, N.G., Bauer-Brandl, A., and Perlovich, G.L., 2014, Cocrystal screening of hydroxybenzamides with benzoic acid derivatives: A comparative study of thermal and solution-based methods, Eur. J. Pharm. Sci., 65, 56–64.

[63] Ezawa, T., Kawashima, Y., Noguchi, T., Jung, S., and Imai, N., 2017, Amidation of carboxylic acids via the mixed carbonic carboxylic anhydrides and its application to synthesis of antidepressant (1 S,2 R)-tranylcypromine, Tetrahedron: Asymmetry, 28 (12), 1690–1699.

[64] Teranishi, K., 2016, trans-p-Hydroxycinnamic acid as a bioluminescence-activating component in the pileus of the luminous fungus Mycena chlorophos, Tetrahedron., 72 (5), 726–733.

[65] Ren, C., Li, X., and Guo, L., 2019, Chemical insight on decreased sensitivity of CL-20/TNT cocrystal revealed by ReaxFF MD simulations, J. Chem. Inf. Model., 59 (5), 2079–2092.

[66] Singh, M., 2006, First principle study of crystal growth morphology: An application to crystalline urea, arXiv:cond-mat.mtrl-sci, 0602385.

[67] Wu, H., Dang, L., and Wei, H., 2014, Solid–liquid phase equilibrium of nicotinamide in different pure solvents: Measurements and thermodynamic modeling, Ind. Eng. Chem. Res., 53 (4), 1707–1711.

[68] Ji, W., Meng, Q., Ding, L., Wang, F., Dong, J., Zhou, G., and Wang, B., 2016, Measurement and correlation of the solubility of caffeic acid in eight mono and water + ethanol mixed solvents at temperatures from (293.15 to 333.15) K, J. Mol. Liq., 224, 1275–1281.

[69] Aakeröy, C.B., Forbes, S., and Desper, J., 2009, Using cocrystals to systematically modulate aqueous solubility and melting behavior of an anticancer drug, J. Am. Chem. Soc., 131 (47), 17048–17049.

[70] Gülçin, I., 2006, Antioxidant activity of caffeic acid (3,4-dihydroxycinnamic acid), Toxicology, 217 (2-3), 213–220.


Article Metrics

Abstract views : 2107 | views : 1626 | views : 529

Copyright (c) 2019 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.


Indonesian Journal of Chemistry (ISSN 1411-9420 / 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Analytics View The Statistics of Indones. J. Chem.