Crystal Engineering Approach in Physicochemical Properties Modifications of Phytochemical

Dhea Sultana Lutfiyah, Lili Fitriani, Muhammad Taher, Erizal Zaini


Phytochemicals have been used to reduce the risk of diseases and maintain good health and well-being. However, most phytochemicals have a limitation in their physicochemical properties, which can be modified by reforming the shape of the crystals. Therefore, crystal engineering is a promising approach to optimize physicochemical characteristics of the active pharmaceutical ingredients (APIs) in a phytochemical without altering its pharmacological efficacy. Hence, this paper reviews current strategies for the use of crystal engineering to optimize physicochemical properties of phytochemicals, which is followed by the design of the synthesis and characterization of particular phytochemicals, including piperine (PIP), quercetin (QUE), curcumin (CUR), genistein (GEN), and myricetin (MYR). The literature indicates that crystal engineering of multicomponent crystals (MCCs) enhances phytochemical physicochemical properties, including solubility, dissolution rate, stability, and permeability. The MCCs provide a lower lattice energy and noncovalent bonding, which translate into lower melting points and weak intermolecular interactions that generate greater solubility, higher dissolution rate, and better stability of the APIs. Nevertheless, the absence of reported studies of phytochemical crystal engineering leads to a lack of variation in the selection of coformers, methods of preparation, and improvement of physicochemical properties. Therefore, more extensive evaluation of the design and physicochemical characteristics of phytochemicals using MCCs is necessary and manifests the opportunity to enhance the application of phytochemicals in the pharmaceutical industry.


Aditya, N., M. Shim, I. Lee, Y. Lee, M.-H. Im, and S. Ko (2013). Curcumin and Genistein Coloaded Nanostructured Lipid Carriers: in Vitro Digestion and Antiprostate Cancer Activity. Journal of Agricultural and Food Chemistry, 61(8); 1878–1883

Al-Dulaimi, A. F., M. Al-kotaji, and F. T. Abachi (2022). Co-Crystals For Improving Solubility And Bioavailability of Pharmaceutical Products. Egyptian Journal of Chemistry, 65(1); 81–89

Alippilakkotte, S. and L. Sreejith (2018). Pectin Mediated Synthesis of Curcumin Loaded Poly (Lactic Acid) Nanocapsules for Cancer Treatment. Journal of Drug Delivery Science and Technology, 48; 66–74

Andrés, S., M. L. Tejido, R. Bodas, L. Morán, N. Prieto, C. Blanco, and F. J. Giráldez (2013). Quercetin Dietary Supplementation of Fattening Lambs at 0.2% Rate Reduces Discolouration and Microbial Growth in Meat During Refrigerated Storage. Meat Science, 93(2); 207–212

Athiyah, U., P. A. Kusuma, T. Tutik, M. L. Lestari, D. Isadiartuti, D. P. Paramita, and D. Setyawan (2019). Crystal Engineering of Quercetin by Liquid Assisted Grinding Method. Jurnal Teknologi, 81(1); 39–45

Aytac, Z., S. I. Kusku, E. Durgun, and T. Uyar (2016). Quercetin/β-Cyclodextrin Inclusion Complex Embedded Nanofibres: Slow Release and High Solubility. Food Chemistry, 197; 864–871

B. Arnao, M. and J. Hernández-Ruiz (2018). The Potential of Phytomelatonin as a Nutraceutical. Molecules, 23(1); 238

Balan, P., G. Mal, S. Das, and H. Singh (2016). Synergistic and Additive Antimicrobial Activities of Curcumin, Manuka Honey and Whey Proteins. Journal of Food Biochemistry, 40(5); 647–654

Barzegar, A. (2016). Antioxidant Activity of Polyphenolic Myricetin in Vitro Cell-Free and Cell-Based Systems. Molecular Biology Research Communications, 5(2); 87

Batisai, E. (2021). Solubility Enhancement of Antidiabetic Drugs Using a Co-Crystallization Approach. Chemistry Open, 10(12); 1260–1268

Bhalekar, M. R., A. R. Madgulkar, P. S. Desale, and G. Marium (2017). Formulation of Piperine Solid Lipid Nanoparticles (SLN) for Treatment of Rheumatoid Arthritis. Drug Development and Industrial Pharmacy, 43(6); 1003–1010

Boksa, K., A. Otte, and R. Pinal (2014). Matrix Assisted Cocrystallization (MAC) Simultaneous Production and Formulation of Pharmaceutical Cocrystals by Hot Melt Extrusion. Journal of Pharmaceutical Sciences, 103(9); 2904–2910

Božič, M., S. Gorgieva, and V. Kokol (2012). Homogeneous and Heterogeneous Methods for Laccase Mediated Functionalization of Chitosan by Tannic Acid and Quercetin. Carbohydrate Polymers, 89(3); 854–864

Braxas, H., M. Rafraf, S. K. Hasanabad, and M. A. Jafarabadi (2019). Effectiveness of Genistein Supplementation on Metabolic Factors and Antioxidant Status in Postmenopausal Women with Type 2 Diabetes Mellitus. Canadian Journal of Diabetes, 43(7); 490–497

Buddhiranon, S. and T. Kyu (2012). Solubilization of Genistein in Poly (Oxyethylene) Through Eutectic Crystal Melting. The Journal of Physical Chemistry B, 116(27); 7795–7802

Chen, C. Y., W. Li, K. P. Qu, and C. R. Chen (2013a). Piperine Exerts Anti Seizure Effects via the TRPV1 Receptor in Mice. European Journal of Pharmacology, 714(1-3); 288–294

Chen, F., J. Peng, D. Lei, J. Liu, and G. Zhao (2013b). Optimization of Genistein Solubilization by κ-Carrageenan Hydrogel Using Response Surface Methodology. Food Science and Human Wellness, 2(4); 124-131

Chen, J., Y. Wu, J. Zou, and K. Gao (2016). α-Glucosidase Inhibition and Antihyperglycemic Activity of Flavonoids from Ampelopsis Grossedentata and the Flavonoid Derivatives. Bioorganic & Medicinal Chemistry, 24(7); 1488–1494

Chen, X., D. J. McClements, Y. Zhu, Y. Chen, L. Zou, W. Liu, C. Cheng, D. Fu, and C. Liu (2018). Enhancement of The Solubility, Stability and Bioaccessibility of Quercetin Using Protein Based Excipient Emulsions. Food Research International, 114; 30–37

Choi, H., J. S. Park, K. M. Kim, M. Kim, K. W. Ko, C. G. Hyun, J. W. Ahn, J. H. Seo, and S. Y. Kim (2018). Enhancing
The Antimicrobial Effect of Genistein by Biotransformation in Microbial System. Journal of Industrial and Engineering Chemistry, 63; 255–261

Clarke, H. D. (2012). Crystal Engineering of Multi-Component Crystal Forms: The Opportunities and Challenges in Design. University of South Florida

Coballase-Urrutia, E., J. Pedraza-Chaverri, N. Cárdenas-Rodríguez, B. Huerta-Gertrudis, M. E. García-Cruz, H. Montesinos-Correa, D. J. Sánchez-González, R. Camacho-Carranza, and J. J. Espinosa-Aguirre (2013). Acetonic and Methanolic Extracts of Heterotheca Inuloides, and Quercetin, Decrease CCl4 Oxidative Stress in Several Rat Tissues. Evidence-Based Complementary and Alternative Medicine, 2013; 1–13

Da Cruz, G. M. P., C. F. B. Felipe, F. A. Scorza, M. A. C. da Costa, A. F. Tavares, M. L. F. Menezes, G. M. de Andrade, L. K. A. Leal, G. A. C. Brito, and M. da Graça Naffah-Mazzacoratti (2013). Piperine Decreases Pilocarpine Induced Convulsions by GABAergic Mechanisms. Pharmacology Biochemistry and Behavior, 104; 144–153

Dal Magro, C., A. E. dos Santos, M. M. Ribas, G. P. Aguiar, C. R. Volfe, M. L. Lopes, A. M. Siebel, L. G. Müller, A. J. Bortoluzzi, and M. Lanza (2021). Production of Curcumin Resveratrol Cocrystal Using Cocrystallization with Supercritical Solvent. The Journal of Supercritical Fluids, 171; 105190

Danciu, C., C. Soica, M. Oltean, S. Avram, F. Borcan, E. Csanyi, R. Ambrus, I. Zupko, D. Muntean, and C. A. Dehelean (2014). Genistein in 1: 1 inclusion Complexes with Ramified Cyclodextrins: Theoretical, Physicochemical and Biological Evaluation. International Journal of Molecular Sciences, 15(2); 1962–1982

Dang, Y., G. Lin, Y. Xie, J. Duan, P. Ma, G. Li, and G. Ji (2014). Quantitative Determination of Myricetin in Rat Plasma by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry and its Absolute Bioavailability. Drug Research, 64(10); 516–522

Daruházi, Á. E., T. Kiss, M. Vecsernyés, L. Szente, É. Szőke, and É. Lemberkovics (2013). Investigation of Transport of Genistein, Daidzein and Their Inclusion Complexes Prepared with Different Cyclodextrins on Caco-2 Cell Line. Journal of Pharmaceutical and Biomedical Analysis, 84; 112–116

Demir, Y., L. Durmaz, P. Taslimi, and İ. Gulçin (2019). Antidiabetic Properties of Dietary Phenolic Compounds: Inhibition Effects on α-Amylase, Aldose Reductase, and α-Glycosidase. Biotechnology and Applied Biochemistry, 66(5); 781–786

Dian, L., E. Yu, X. Chen, X. Wen, Z. Zhang, L. Qin, Q. Wang, G. Li, and C. Wu (2014). Enhancing Oral Bioavailability of Quercetin Using Novel Soluplus Polymeric Micelles. Nanoscale Research Letters, 9(1); 1–11

Egbuna, C., J. C. Ifemeje, S. C. Udedi, S. Kumar, and C. Press (2019). Phytochemistry: Fundamentals, Modern Techniques and Applications. CRC Press Taylor & Francis Group

Ezawa, T., Y. Inoue, S. Tunvichien, R. Suzuki, and I. Kanamoto (2016). Changes in The Physicochemical Properties of Piperine β -Cyclodextrin Due to The Formation of Inclusion Complexes. International Journal of Medicinal Chemistry, 2016; 1–9.

Franklin, S. J. and P. B. Myrdal (2015). Solid State and Solution Characterization of Myricetin. AAPS PharmSciTech, 16(6); 1400–1408

Gadade, D. D. and S. S. Pekamwar (2016). Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development. Advanced Pharmaceutical Bulletin, 6(4); 479 Gajda, M., K. P. Nartowski, J. Pluta, and B. Karolewicz (2019). Continuous, One Step Synthesis of Pharmaceutical Cocrystals via Hot Melt Extrusion from Neat to Matrix Assisted Processing State of the Art. International Journal of Pharmaceutics, 558; 426–440

Ghassemi-Rad, J., M. Maleki, A. F. Knickle, and D. W. Hoskin (2018). Myricetin Induced Oxidative Stress Suppresses Murine T Lymphocyte Activation. Cell Biology International, 42(8); 1069–1075

Gorgani, L., M. Mohammadi, G. D. Najafpour, and M. Nikzad (2017). Piperine The Bioactive Compound of Black Pepper: from Isolation to Medicinal Formulations. Comprehensive Reviews in Food Science and Food Safety, 16(1); 124–140

Guitard, R., J. F. Paul, V. Nardello-Rataj, and J. M. Aubry (2016). Myricetin, Rosmarinic and Carnosic Acids as Superior Natural Antioxidant Alternatives to α-Tocopherol for the Preservation of Omega-3 Oils. Food Chemistry, 213; 284–295

Guo, R. X., X. Fu, J. Chen, L. Zhou, and G. Chen (2016). Preparation and Characterization of Microemulsions of Myricetin for Improving its Antiproliferative and Antioxidative Activities and Oral Bioavailability. Journal of Agricultural and Food Chemistry, 64(32); 6286–6294

Hadi, K. (2015). Spray Drying of Cocrystals for Engineering Particle Properties: Diploma Work

Han, D., Z. Han, L. Liu, Y. Wang, S. Xin, H. Zhang, and Z. Yu (2020). Solubility Enhancement of Myricetin by Inclusion Complexation with Heptakis-O-(2-hydroxypropyl)-β-Cyclodextrin: A Joint Experimental and Theoretical Study. International Journal of Molecular Sciences, 21(3); 766

Hasan, M., N. Belhaj, H. Benachour, M. Barberi-Heyob, C. Kahn, E. Jabbari, M. Linder, and E. Arab-Tehrany (2014). Liposome Encapsulation of Curcumin: Physico Chemical Characterizations and Effects on MCF7 Cancer Cell Proliferation. International Journal of Pharmaceutics, 461(1-2); 519–528

Incir, S., I. M. Bolayirli, O. Inan, M. S. Aydın, I. A. Bilgin, I. Sayan, M. Esrefoglu, and A. Seven (2016). The Effects of Genistein Supplementation on Fructose Induced Insulin Resistance, Oxidative Stress and Inflammation. Life Sciences, 158; 57–62

Jäger, R., R. P. Lowery, A. V. Calvanese, J. M. Joy, M. Purpura, and J. M. Wilson (2014). Comparative Absorption of Curcumin Formulations. Nutrition Journal, 13(1); 1–8

Jaiswal, N., J. Akhtar, S. P. Singh, F. Ahsan, et al. (2019). An Overview on Genistein and its Various Formulations. Drug Research, 69(06); 305–313

Javanbakht, M. H., R. Sadria, M. Djalali, H. Derakhshanian, P. Hosseinzadeh, M. Zarei, G. Azizi, R. Sedaghat, and A. Mirshafiey (2014). Soy Protein and Genistein Improves Renal Antioxidant Status in Experimental Nephrotic Syndrome. Nefrologia, 34(4); 483–490

Jessica, A., R. Naura, U. Hasanah, E. Zaini, and L. Fitriani (2021). Pembentukan Multikomponen Kristal Piperin dan Kuersetin. JOPS (Journal Of Pharmacy and Science), 4(2); 1–11

Jiao, D., J. Wang, W. Lu, X. Tang, J. Chen, H. Mou, and Q. Y. Chen (2016). Curcumin Inhibited HGF Induced EMT and Angiogenesis Through Regulating c-Met Dependent PI3K/Akt/mTOR Signaling Pathways in Lung Cancer. Molecular Therapy-Oncolytics, 3; 16018

Kantatasiri, P. (2012). Future of Functional Foods and Nutraceutical Products: The Challenge and Potential of Thailand to ASEAN. GMSARN International Journal, 6(3); 87–96

Karagianni, A., M. Malamatari, and K. Kachrimanis (2018). Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs. Pharmaceutics, 10(1); 18

Katherine, D. Nugroho, and A. K. Sugih (2018). Preparation and Characterization of Highly Water Soluble Curcumin Dextrose Cocrystal. The Journal of Pure and Applied Chemistry Research, 7(2); 140–148

Kharbanda, C., M. S. Alam, H. Hamid, K. Javed, S. Bano, Y. Ali, A. Dhulap, P. Alam, and M. Q. Pasha (2016). Novel Piperine Derivatives with Antidiabetic Effect as PPAR-γ Agonists. Chemical Biology & Drug Design, 88(3); 354-362

Kim, M. E., T. K. Ha, J. H. Yoon, and J. S. Lee (2014). Myricetin Induces Cell Death of Human Colon Cancer Cells via BAX/BCL2 Dependent Pathway. Anticancer Research, 34(2); 701–706

Kumar, S. (2018). Pharmaceutical Cocrystals: an Overview. Indian Journal of Pharmaceutical Sciences, 79(6); 858–871

Larson, A. J., J. D. Symons, and T. Jalili (2012). Therapeutic Potential of Quercetin to Decrease Blood Pressure: Review of Efficacy and Mechanisms. Advances in Nutrition, 3(1); 39–46

Lee, G. H., S. J. Lee, S. W. Jeong, H. C. Kim, G. Y. Park, S. G. Lee, and J. H. Choi (2016). Antioxidative and Antiinflammatory Activities of Quercetin Loaded Silica Nanoparticles. Colloids and Surfaces B: Biointerfaces, 143; 511–517

Lee, S. Y., K. H. Kim, I. K. Lee, K. H. Lee, S. U. Choi, and K. R. Lee (2012). A New Flavonol Glycoside from Hylomecon Vernalis. Archives of Pharmacal Research, 35(3); 415–421

Li, B., S. Konecke, K. Harich, L. Wegiel, L. S. Taylor, and K. J. Edgar (2013). Solid Dispersion of Quercetin in Cellulose Derivative Matrices Influences Both Solubility and Stability. Carbohydrate Polymers, 92(2); 2033–2040

Liu, M., C. Hong, G. Li, P. Ma, and Y. Xie (2016a). The Generation of Myricetin Nicotinamide Nanococrystals by Top Down and Bottom Up Technologies. Nanotechnology, 27(39); 395601

Liu, M., C. Hong, Y. Yao, H. Shen, G. Ji, G. Li, and Y. Xie (2016b). Development of a Pharmaceutical Cocrystal with Solution Crystallization Technology: Preparation, Characterization, and Evaluation of Myricetin Proline Cocrystals. European Journal of Pharmaceutics and Biopharmaceutics, 107; 151–159

Lombard, J., D. A. Haynes, and T. le Roex (2020). Assessment of Co Sublimation for The Formation of Multicomponent Crystals. Crystal Growth & Design, 20(12); 7840–7849

Ma, Z., G. Wang, L. Cui, and Q. Wang (2015). Myricetin Attenuates Depressant Like Behavior in Mice Subjected to Repeated Restraint Stress. International Journal of Molecular Sciences, 16(12); 28377–28385

Maciel, R., M. Costa, D. Martins, R. Franca, R. Schmatz, D. Graça, M. Duarte, C. Danesi, C. Mazzanti, and M. Schetinger (2013). Antioxidant and Anti Inflammatory Effects of Quercetin in Functional and Morphological Aterations in Streptozotocin Induced Diabetic Rats. Research in Veterinary Science, 95(2); 389–397

Maeno, Y., T. Fukami, M. Kawahata, K. Yamaguchi, T. Tagami, T. Ozeki, T. Suzuki, and K. Tomono (2014). Novel Pharmaceutical Cocrystal Consisting of Paracetamol and Trimethylglycine, a New Promising Cocrystal Former. International Journal of Pharmaceutics, 473(1-2); 179–186

Malik, P., R. Ameta, and M. Singh (2014). Preparation and Characterization of Bionanoemulsions for Improving and Modulating the Antioxidant Efficacy of Natural Phenolic Antioxidant Curcumin. Chemico Biological Interactions, 222; 77–86

Mao, Q. Q., Z. Huang, X. M. Zhong, Y. F. Xian, and S. P. Ip (2014). Brain Derived Neurotrophic Factor Signalling Mediates the Antidepressant Like Effect of Piperine in Chronically Stressed Mice. Behavioural Brain Research, 261; 140–145

Martinez-Perez, C., C. Ward, G. Cook, P. Mullen, D. McPhail, D. J. Harrison, and S. P. Langdon (2014). Novel Flavonoids as Anti Cancer Agents: Mechanisms of Action and Promise for Their Potential Application in Breast Cancer. Biochemical Society Transactions, 42(4); 1017–1023

McClements, D. (2012). Requirements for Food Ingredient and Nutraceutical Delivery Systems. In Encapsulation Technologies and Delivery Systems for Food Ingredients and Nutraceuticals. Elsevier; 3–18

Moretti, E., L. Mazzi, G. Terzuoli, C. Bonechi, F. Iacoponi, S. Martini, C. Rossi, and G. Collodel (2012). Effect of Quercetin, Rutin, Naringenin and Epicatechin on Lipid Peroxidation Induced in Human Sperm. Reproductive Toxicology, 34(4); 651–657

Naldi, M., J. Fiori, M. Pistolozzi, A. F. Drake, C. Bertucci, R. Wu, K. Mlynarczyk, S. Filipek, A. De Simone, and V. Andrisano (2012). Amyloid β Peptide 25–35 Self Assembly and its Inhibition: a Model Undecapeptide System to Gain Atomistic and Secondary Structure Details of The Alzheimer’s Disease Process and Treatment. ACS Chemical Neuroscience, 3(11); 952–962

Nascimento, A. L., R. P. Fernandes, M. D. Charpentier, J. H. ter Horst, F. J. Caires, and M. Chorilli (2021). Co Crystals of Non Steroidal Anti Inflammatory Drugs (NSAIDs): Insight Toward Formation, Methods, and Drug Enhancement. Particuology, 58; 227–241

Nguyen, T. T. H., H. J. Woo, H. K. Kang, V. D. Nguyen, Y. M. Kim, D. W. Kim, S. A. Ahn, Y. Xia, and D. Kim (2012). Flavonoid Mediated Inhibition of SARS Coronavirus 3C Like Protease Expressed in Pichia Pastoris. Biotechnology Letters, 34(5); 831–838

Nguyen, T. T. H., S. H. Yu, J. Kim, E. An, K. Hwang, J. S. Park, and D. Kim (2015). Enhancement of Quercetin Water Solubility with Steviol Glucosides and The Studies of Biological Properties. Functional Foods in Health and Disease, 5(12); 437–449

Nwosu, O. K. and K. I. Ubaoji (2020). Nutraceuticals: History, Classification and Market Demand. In Functional Foods and Nutraceuticals. Springer; 13–22

Ouyang, D. y., L. H. Zeng, H. Pan, L. H. Xu, Y. Wang, K. P. Liu, and X. H. He (2013). Piperine Inhibits the Proliferation of Human Prostate Cancer Cells via Induction of Cell Cycle Arrest and Autophagy. Food and Chemical Toxicology, 60; 424–430

Pachauri, M., E. D. Gupta, and P. C. Ghosh (2015). Piperine Loaded PEG-PLGA Nanoparticles: Preparation, Characterization and Targeted Delivery for Adjuvant Breast Cancer Chemotherapy. Journal of Drug Delivery Science and Technology, 29; 269–282

Pal, R., S. Panigrahi, D. Bhattacharyya, and A. S. Chakraborti (2013). Characterization of Citrate Capped Gold Nanoparticl Equercetin Complex: Experimental and Quantum Chemical Approach. Journal of Molecular Structure, 1046; 153–163

Pan, K., Q. Zhong, and S. J. Baek (2013). Enhanced Dispersibility and Bioactivity of Curcumin by Encapsulation in Casein Nanocapsules. Journal of Agricultural and Food Chemistry, 61(25); 6036–6043

Pandit, R. S., S. C. Gaikwad, G. A. Agarkar, A. K. Gade, and M. Rai (2015). Curcumin Nanoparticles: Physico-Chemical Fabrication and its in Vitro Efficacy Against Human Pathogens. 3 Biotech, 5(6); 991–997

Pang, W., Y. Wu, N. Xue, Y. Li, S. Du, B. He, C. Yang, J. Wang, and Y. Zeng (2019). Retracted: Cocrystals of Curcumin-Isonicotinamide and Curcumin-Gallic Acid: Does The Weak Forces in Cocrystals Effect on Binding Profiles with BSA and Cell Cytotoxicity?

Pantwalawalkar, J., H. More, D. Bhange, U. Patil, and N. Jadhav (2021). Novel Curcumin Ascorbic Acid Cocrystal for Improved Solubility. Journal of Drug Delivery Science and Technology, 61; 102233

Qian, J., H. Meng, L. Xin, M. Xia, H. Shen, G. Li, and Y. Xie (2017). Self Nanoemulsifying Drug Delivery Systems of Myricetin: Formulation Development, Characterization, and in Vitro and in Vivo Evaluation. Colloids and Surfaces B: Biointerfaces, 160; 101–109

Quilaqueo, M., S. Millao, I. Luzardo-Ocampo, R. Campos-Vega, F. Acevedo, C. Shene, and M. Rubilar (2019). Inclusion of Piperine in β Cyclodextrin Complexes Improves Their Bioaccessibility and in Vitro Antioxidant Capacity. Food Hydrocolloids, 91; 143–152

Quiñones, J. P., H. Peniche, and C. Peniche (2018). Chitosan Based Self Assembled Nanoparticles in Drug Delivery. Polymers, 10(3); 235

Ramezani, M., N. Darbandi, F. Khodagholi, and A. Hashemi (2016). Myricetin Protects Hippocampal CA3 Pyramidal Neurons and Improves Learning and Memory Impairments in Rats with Alzheimer’s Disease. Neural Regeneration Research, 11(12); 1976

Rao, R. V., O. Descamps, V. John, and D. E. Bredesen (2012). Ayurvedic Medicinal Plants for Alzheimer’s Disease: a Review. Alzheimer’s Research & Therapy, 4(3); 1–9

Rathi, N., A. Paradkar, and V. G. Gaikar (2019). Polymorphs of Curcumin and its Cocrystals with Cinnamic Acid. Journal of Pharmaceutical Sciences, 108(8); 2505–2516

Raza, S. A., U. Schacht, V. Svoboda, D. P. Edwards, A. J. Florence, C. R. Pulham, J. Sefcik, and I. D. Oswald (2018). Rapid Continuous Antisolvent Crystallization of Multicomponent Systems. Crystal Growth & Design, 18(1); 210–218

Ren, T., M. Hu, Y. Cheng, T. L. Shek, M. Xiao, N. J. Ho, C. Zhang, S. S. Y. Leung, and Z. Zuo (2019). Piperine Loaded Nanoparticles with Enhanced Dissolution and Oral Bioavailability for Epilepsy Control. European Journal of Pharmaceutical Sciences, 137; 104988

Ren, Z., P. Yan, L. Zhu, H. Yang, Y. Zhao, B. P. Kirby, J. L. Waddington, and X. Zhen (2018). Dihydromyricetin Exerts a Rapid Antidepressant Like Eect in Association with Enhancement of BDNF Expression and Inhibition of Neuroinflammation. Psychopharmacology, 235(1); 233–244

Ribas, M. M., G. P. S. Aguiar, L. G. Muller, A. M. Siebel, M. Lanza, and J. V. Oliveira (2019). Curcumin Nicotinamide Cocrystallization with Supercritical Solvent (CSS): Synthesis, Characterization and in Vivo Antinociceptive and Anti Inflammatory Activities. Industrial Crops and Products, 139; 111537

Roy, L., M. Lipert, and N. Rodriguez-Hornedo (2012). Cocrystal Solubility and Thermodynamic Stability. Pharmaceutical Salts and Co-crystals; 247–279

Salama, S. M., M. A. Abdulla, A. S. AlRashdi, S. Ismail, S. S. Alkiyumi, and S. Golbabapour (2013). Hepatoprotective Effect of Ethanolic Extract of Curcuma Longa on Thioacetamide Induced Liver Cirrhosis in Rats. BMC Complementary and Alternative Medicine, 13(1); 1–17

Salsabila, H., L. Fitriani, and E. Zaini (2021). Recent Strategies for Improving Solubility and Oral Bioavailability of Piperine. Int. J. Appl. Pharm, 13(4); 31–39

Sathisaran, I. and S. V. Dalvi (2017). Crystal Engineering of Curcumin with Salicylic Acid and Hydroxyquinol as Coformers. Crystal Growth & Design, 17(7); 3974–3988

Savjani, J. K. (2015). Co†Crystallization: An Approach to Improve the Performance Characteristics of Active Pharmaceutical Ingredients. Asian Journal of Pharmaceutics (AJP), 9(3); 147–151

Seo, J. A., B. Kim, D. N. Dhanasekaran, B. K. Tsang, and Y. S. Song (2016). Curcumin Induces Apoptosis by Inhibiting Sarco/Endoplasmic Reticulum Ca2+ ATPase activity in Ovarian Cancer Cells. Cancer Letters, 371(1); 30–37

Setyawan, D., A. A. Fadhil, D. Juwita, H. Yusuf, and R. Sari (2017). Enhancement of Solubility and Dissolution Rate of Quercetin with Solid Dispersion System Formation Using Hydroxypropyl Methyl Cellulose Matrix. Thai Journal of Pharmaceutical Sciences, 41(3); 112–116

Setyawan, D., S. A. Permata, A. Zainul, and M. L. A. D. Lestari (2018). Improvement in Vitro Dissolution Rate of Quercetin Using Cocrystallization of Quercetin Malonic Acid. Indonesian Journal of Chemistry, 18(3); 531–536

Silva, L. F. C., G. Kasten, C. E. M. de Campos, A. L. Chinelatto, and E. Lemos-Senna (2013). Preparation and Characterization of Quercetin Loaded Solid Lipid Microparticles for Pulmonary Delivery. Powder Technology, 239; 183–192

Sowa, M., K. Ślepokura, and E. Matczak-Jon (2013a). A 1: 2 Cocrystal of Genistein with Isonicotinamide: Crystal Structure and Hirshfeld Surface Analysis. Acta Crystallographica Section C: Crystal Structure Communications, 69(11); 1267–1272

Sowa, M., K. Ślepokura, and E. Matczak-Jon (2013b). Cocrystals of Fisetin, Luteolin and Genistein with Pyridinecarboxamide Coformers: Crystal Structures, Analysis of Intermolecular Interactions, Spectral and Thermal Characterization. CrystEngComm, 15(38); 7696–7708

Sowa, M., K. Ślepokura, and E. Matczak-Jon (2014a). A 1: 1 Pharmaceutical Cocrystal of Myricetin in Combination with Uncommon Piracetam Conformer: X-Ray Single Crystal Analysis and Mechanochemical Synthesis. Journal of Molecular Structure, 1058; 114–121

Sowa, M., K. Ślepokura, and E. Matczak-Jon (2014b). Solid State Characterization and Solubility of a Genistein Caffeine Cocrystal. Journal of Molecular Structure, 1076; 80–88

Stasiłowicz, A., N. Rosiak, E. Tykarska, M. Kozak, J. Jenczyk, P. Szulc, J. Kobus-Cisowska, K. Lewandowska, A. Płazińska, and W. Płaziński (2021). Combinations of Piperine with Hydroxypropyl-β -Cyclodextrin as a Multifunctional System. International Journal of Molecular Sciences, 22(8); 4195

Sun, F., Z. Zheng, J. Lan, X. Li, M. Li, K. Song, and X. Wu (2019). New Micelle Myricetin Formulation for Ocular Delivery: Improved Stability, Solubility, and Ocular Anti Inflammatory Treatment. Drug Delivery, 26(1); 575-585

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

Thenmozhi, K. and Y. J. Yoo (2017). Enhanced Solubility of Piperine Using Hydrophilic Carrier-Based Potent Solid Dispersion Systems. Drug Development and Industrial Pharmacy, 43(9); 1501–1509

Thong-Ngam, D., S. Choochuai, S. Patumraj, M. Chayanupatkul, and N. Klaikeaw (2012). Curcumin Prevents Indomethacin Induced Gastropathy in Rats. World Journal of Gastroenterology: WJG, 18(13); 1479

Toyoda, T., L. Shi, S. Takasu, Y. M. Cho, Y. Kiriyama, A. Nishikawa, K. Ogawa, M. Tatematsu, and T. Tsukamoto (2016). Anti-inammatory Eects of Capsaicin and Piperine on Helicobacter Pylori-Induced Chronic Gastritis in Mongolian gerbils. Helicobacter, 21(2); 131–142

Wu, N., Y. Zhang, J. Ren, A. Zeng, and J. Liu (2020). Preparation of Quercetin Nicotinamide Cocrystals and Their Evaluation Under in Vivo and in Vitro Conditions. RSC Advances, 10(37); 21852–21859

Wu, T., X. Zang, M. He, S. Pan, and X. Xu (2013). Structure Activity Relationship of Flavonoids on Their Anti-Escherichia Coli Activity and Inhibition of DNA Gyrase. Journal of Agricultural and Food Chemistry, 61(34); 8185–8190

Yaffe, P. B., M. R. Power Coombs, C. D. Doucette, M. Walsh, and D. W. Hoskin (2015). Piperine, an Alkaloid from Black Pepper, Inhibits Growth of Human Colon Cancer Cells via G1 Arrest and Apoptosis Triggered by Endoplasmic Reticulum Stress. Molecular Carcinogenesis, 54(10); 1070–1085

Yan, Y., J. M. Chen, and T. B. Lu (2013). Simultaneously Enhancing the Solubility and Permeability of Acyclovir by Crystal Engineering Approach. CrystEngComm, 15(33); 6457–6460

Yang, D., J. Cao, L. Jiao, S. Yang, L. Zhang, Y. Lu, and G. Du (2020). Solubility and Stability Advantages of a New Cocrystal of Berberine Chloride with Fumaric Acid. ACS Omega, 5(14); 8283–8292

Yang, Z. J., H. R. Wang, Y. L. Wang, Z. H. Zhai, L. W. Wang, L. Li, C. Zhang, and L. Tang (2019). Myricetin Attenuated Diabetes Associated Kidney Injuries and Dysfunction via Regulating Nuclear Factor (Erythroid Derived 2) Like 2 and Nuclear Factor-κB Signaling. Frontiers in Pharmacology, 10; 647

Ying, H. Z., Y. H. Liu, B. Yu, Z. Y. Wang, J. N. Zang, and C. H. Yu (2013). Dietary Quercetin Ameliorates Nonalcoholic Steatohepatitis Induced by a High Fat Diet in Gerbils. Food and Chemical Toxicology, 52; 53–60

Yu, M. S., J. Lee, J. M. Lee, Y. Kim, Y. W. Chin, J. G. Jee, Y. S. Keum, and Y. J. Jeong (2012). Identication of Myricetin and Scutellarein as Novel Chemical Inhibitors of The SARS Coronavirus Helicase, nsP13. Bioorganic & Medicinal Chemistry Letters, 22(12); 4049–4054

Yusof, Y., C. Etti, and N. Chin (2015). Development of Nutraceutical Product. International Journal on Advanced Science, Engineering and Information Technology, 5(3); 50–5

Zaini, E., L. Fitriani, F. Ismed, A. Horikawa, and H. Uekusa (2020a). Improved Solubility and Dissolution Rates in Novel Multicomponent Crystals of Piperine with Succinic Acid. Scientia Pharmaceutica, 88(2); 21

Zaini, E., L. Fitriani, R. Y. Sari, H. Rosaini, A. Horikawa, and H. Uekusa (2019). Multicomponent Crystal of Mefenamic Acid and N-Methyl-D-Glucamine: Crystal Structures and Dissolution Study. Journal of Pharmaceutical Sciences, 108(7); 2341–2348

Zaini, E., D. Riska, M. D. Oktavia, F. Ismed, and L. Fitriani (2020b). Improving Dissolution Rate of Piperine by Multicomponent Crystal Formation with Saccharin. Research Journal of Pharmacy and Technology, 13(4); 1926–1930

Zarai, Z., E. Boujelbene, N. B. Salem, Y. Gargouri, and A. Sayari (2013). Antioxidant and Antimicrobial Activities of Various Solvent Extracts, Piperine and Piperic Acid from Piper Nigrum. Lwt Food Science and Technology, 50(2); 634–641

Zhai, W. J., Z. B. Zhang, N. N. Xu, Y. F. Guo, C. Qiu, C. Y. Li, G. Z. Deng, and M. Y. Guo (2016). Piperine Plays an Antiinflammatory Role in Staphylococcus Aureus Endometritis by Inhibiting Activation of NF-κB and MAPK Pathways in Mice. Evidence-Based Complementary and Alternative Medicine, 2016; 1–10

Zhang, W., X. Li, T. Ye, F. Chen, X. Sun, J. Kong, X. Yang, W. Pan, and S. Li (2013). Design, Characterization, and in Vitro Cellular Inhibition and Uptake of Optimized Genistein-Loaded NLC for The Prevention of Posterior Capsular Opacification Using Response Surface Methodology. International Journal of Pharmaceutics, 454(1); 354–366

Zhang, Y. N., H. M. Yin, Y. Zhang, D. J. Zhang, X. Su, and H. X. Kuang (2017a). Cocrystals of Kaempferol, Quercetin and Myricetin with 4, 4’-Bipyridine: Crystal Structures, Analyses of Intermolecular Interactions and Antibacterial Properties. Journal of Molecular Structure, 1130; 199–207

Zhang, Y. N., H. M. Yin, Y. Zhang, D. J. Zhang, X. Su, and H. X. Kuang (2017b). Preparation of a 1: 1 Cocrystal of Genistein with 4, 4’-Bipyridine. Journal of Crystal Growth, 458; 103–109


Dhea Sultana Lutfiyah
Lili Fitriani
Muhammad Taher
Erizal Zaini (Primary Contact)
Lutfiyah, D. S., Fitriani, L., Taher, M., & Zaini, E. (2022). Crystal Engineering Approach in Physicochemical Properties Modifications of Phytochemical. Science and Technology Indonesia, 7(3), 353–371.

Article Details