PHARMACEUTICAL CO-CRYSTALS: A NOVEL STRATEGY FOR ENHANCING DRUG PERFORMANCE
Main Article Content
Keywords
.
Abstract
Pharmaceutical co-crystals have attracted significant attention as a novel approach to enhancing the physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs) without altering their chemical identity. Such co-crystals, synthesized through non-covalent interactions between an API and a suitable co-former, can hopefully improve solubility, dissolution rate, permeability, stability, and mechanical strength and hence overcome major drug development challenges such as poor bioavailability. A broad range of preparation methods—ranging from solid-state methods like grinding as well as hot-melt extrusion to solution methods like solvent evaporation as well as slurry crystallization—has been utilized, supported by advanced methods like ultrasound-assisted crystallization and supercritical fluid atomization. Regulatory guideline-defined specifications, as well as experimental screening protocols and computational modelling, guide the choice of co-formers. Approved by the FDA and EMA as novel solid-state phases but not new chemical entities, co-crystals facilitate drug development with efficacy and safety. Overall, they are a green, scalable, and versatile method for modern drug formulation.
References
[1] Fda, Cder, Stewart, Felicia. Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry. 2018.
[2] Aitipamula S, Banerjee R, Bansal AK, Biradha K, Cheney ML, Choudhury AR, et al. Polymorphs, salts, and cocrystals: What’s in a name? Cryst Growth Des 2012;12:2147–52. https://doi.org/10.1021/cg3002948.
[3] Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: An overview. Int J Pharm 2011;419:1–11. https://doi.org/10.1016/j.ijpharm.2011.07.037.
[4] Ainurofiq A, Putro DS, Ramadhani DA, Putra GM, Do Espirito Santo LDC. A review on solubility enhancement methods for poorly water-soluble drugs. Journal of Reports in Pharmaceutical Sciences 2021;10:137–47. https://doi.org/10.4103/jrptps.JRPTPS_134_19.
[5] Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. Pharmaceutical co-crystals. J Pharm Sci 2006;95:499–516. https://doi.org/10.1002/jps.20578.
[6] Etter MC. Encoding and decoding hydrogen-bond patterns of organic compounds. Accounts of Chemical Research. 1990;4;1;23(4):120-6. https://doi.org/10.1021/ar00172a005
[7] Etter MC. Hydrogen bonds as design elements in organic chemistry. The Journal of Physical Chemistry. 1991;95(12):4601-10. https://doi.org/10.1021/j100165a007
[8] Reddy DS, Ovchinnikov YE, Shishkin OV, Struchkov YT, Desiraju GR. Supramolecular synthons in crystal engineering. 3. Solid state architecture and synthon robustness in some 2, 3-dicyano-5, 6-dichloro-1, 4-dialkoxybenzenes1. Journal of the American Chemical Society. 1996 May 1;118(17):4085-9. https://doi.org/10.1021/ja953372u
[9] Patrick Stahly G. A survey of cocrystals reported prior to 2000. Cryst Growth Des 2009;9:4212–29. https://doi.org/10.1021/cg900873t.
[10] Dunitz JD. Crystal and co-crystal: A second opinion. CrystEngComm 2003;5:506. https://doi.org/10.1039/b315687g.
[11] Childs SL, Stahly GP, Park A. The salt-cocrystal continuum: The influence of crystal structure on ionization state. Mol Pharm 2007;4:323–38. https://doi.org/10.1021/mp0601345.
[12] Huang LF, Tong WQ. Impact of solid state properties on developability assessment of drug candidates. Adv Drug Deliv Rev 2004;56:321–34. https://doi.org/10.1016/j.addr.2003.10.007.
[13] Chadha R, Rani D, Goyal P. Novel cocrystals of gliclazide: characterization and evaluation. CrystEngComm. 2016;18(13):2275-83. https://doi.org/10.1039/C5CE02402A
[14] Zawilska JB, Wojcieszak J, Olejniczak AB. Prodrugs: a challenge for the drug development. Pharmacological reports. 2013;65(1):1-14. https://doi.org/10.1016/S1734-1140(13)70959-9
[15] Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. European Journal of Pharmaceutics and Biopharmaceutics 2000;50:47–60. https://doi.org/10.1016/S0939-6411(00)00076-X.
[16] Varshosaz J, Talari R, Mostafavi SA, Nokhodchi A. Dissolution enhancement of gliclazide using in situ micronization by solvent change method. Powder Technol 2008;187:222–30. https://doi.org/10.1016/j.powtec.2008.02.018.
[17] Loh GOK, Tan YTF, Peh KK. Enhancement of norfloxacin solubility via inclusion complexation with β-cyclodextrin and its derivative hydroxypropyl-β-cyclodextrin. Asian J Pharm Sci 2016;11:536–46. https://doi.org/10.1016/j.ajps.2016.02.009.
[18] Singhal D, Curatolo W. Drug polymorphism and dosage form design: A practical perspective. Adv Drug Deliv Rev 2004;56:335–47. https://doi.org/10.1016/j.addr.2003.10.008.
[19] Kalepu S, Nekkanti V. Improved delivery of poorly soluble compounds using nanoparticle technology: a review. Drug Deliv Transl Res 2016;6:319–32. https://doi.org/10.1007/s13346-016-0283-1.
[20] Perlovich GL, Manin AN. Design of pharmaceutical cocrystals for drug solubility improvement. Russ J Gen Chem 2014;84:407–14. https://doi.org/10.1134/S107036321402042X.
[21] Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: An overview. Int J Pharm 2011;419:1–11. https://doi.org/10.1016/j.ijpharm.2011.07.037.
[22] Aitipamula S, Bolla G. Optimizing Drug Development: Harnessing the Sustainability of Pharmaceutical Cocrystals. Mol Pharm 2024;21:3121–43. https://doi.org/10.1021/acs.molpharmaceut.4c00289.
[23] Aitipamula S, Banerjee R, Bansal AK, Biradha K, Cheney ML, Choudhury AR, et al. Polymorphs, salts, and cocrystals: What’s in a name? Cryst Growth Des 2012;12:2147–52. https://doi.org/10.1021/cg3002948.
[24] Bhogala BR, Basavoju S, Nangia A. Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4,4′-bipyridines and isonicotinamide. From binary to ternary cocrystals. CrystEngComm 2005;7:551–62. https://doi.org/10.1039/b509162d.
[25] Morissette SL, Almarsson Ö, Peterson ML, Remenar JF, Read MJ, Lemmo A V., et al. High-throughput crystallization: Polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv Drug Deliv Rev 2004;56:275–300. https://doi.org/10.1016/j.addr.2003.10.020.
[26] Ross SA, Lamprou DA, Douroumis D. Engineering and manufacturing of pharmaceutical co-crystals: A review of solvent-free manufacturing technologies. Chemical Communications 2016;52:8772–86. https://doi.org/10.1039/c6cc01289b.
[27] Madusanka N, Eddleston MD, Arhangelskis M, Jones W. Polymorphs, hydrates and solvates of a co-crystal of caffeine with anthranilic acid. Acta Crystallogr B Struct Sci Cryst Eng Mater 2014;70:72–80. https://doi.org/10.1107/S2052520613033167.
[28] Bag PP, Kothur RR, Malla Reddy C. Tautomeric preference in polymorphs and pseudopolymorphs of succinylsulfathiazole: Fast evaporation screening and thermal studies. CrystEngComm 2014;16:4706–14. https://doi.org/10.1039/c3ce42159g.
[29] Bag PP, Chen M, Sun CC, Reddy CM. Direct correlation among crystal structure, mechanical behaviour and tabletability in a trimorphic molecular compound. CrystEngComm 2012;14:3865–7. https://doi.org/10.1039/c2ce25100k.
[30] Gadade DD, Pekamwar SS. Pharmaceutical cocrystals: Regulatory and strategic aspects, design and development. Adv Pharm Bull 2016;6:479–94. https://doi.org/10.15171/apb.2016.062.
[31] Guo C, Zhang Q, Zhu B, Zhang Z, Ma X, Dai W, et al. Drug-Drug Cocrystals Provide Significant Improvements of Drug Properties in Treatment with Progesterone. Cryst Growth Des 2020;20:3053–63. https://doi.org/10.1021/acs.cgd.9b01688.
[32] Duggirala NK, Smith AJ, Wojtas Ł, Shytle RD, Zaworotko MJ. Physical stability enhancement and pharmacokinetics of a lithium ionic cocrystal with glucose. Cryst Growth Des 2014;14:6135–42. https://doi.org/10.1021/cg501310d.
[33] McKellar SC, Kennedy AR, McCloy NC, McBride E, Florence AJ. Formulation of liquid propofol as a cocrystalline solid. Cryst Growth Des 2014;14:2422–30. https://doi.org/10.1021/cg500155p.
[34] Guo M, Sun X, Chen J, Cai T. Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications. Acta Pharm Sin B 2021;11:2537–64. https://doi.org/10.1016/j.apsb.2021.03.030.
[35] Bofill L, De Sande D, Barbas R, Prohens R. New Cocrystal of Ubiquinol with High Stability to Oxidation. Cryst Growth Des 2020;20:5583–8. https://doi.org/10.1021/acs.cgd.0c00749.
[36] Guo C, Zhang Q, Zhu B, Zhang Z, Bao J, Ding Q, et al. Pharmaceutical Cocrystals of Nicorandil with Enhanced Chemical Stability and Sustained Release. Cryst Growth Des 2020;20:6995–7005. https://doi.org/10.1021/acs.cgd.0c01043.
[37] Vangala VR, Chow PS, Tan RB. Characterization, physicochemical and photo-stability of a co-crystal involving an antibiotic drug, nitrofurantoin, and 4-hydroxybenzoic acid. CrystEngComm. 2011;13(3):759-62. https://doi.org/10.1039/C0CE00772B
[38] Mannava MKC, Gunnam A, Lodagekar A, Shastri NR, Nangia AK, Solomon KA. Enhanced solubility, permeability, and tabletability of nicorandil by salt and cocrystal formation. CrystEngComm 2021;23:227–37. https://doi.org/10.1039/d0ce01316a.
[39] Chattoraj S, Shi L, Chen M, Alhalaweh A, Velaga S, Sun CC. Origin of deteriorated crystal plasticity and compaction properties of a 1: 1 cocrystal between piroxicam and saccharin. Crystal growth & design. 2014;6;14(8):3864-74. https://doi.org/10.1021/cg500388s.
[40] Yadav JP, Yadav RN, Uniyal P, Chen H, Wang C, Sun CC, et al. Molecular Interpretation of Mechanical Behavior in Four Basic Crystal Packing of Isoniazid with Homologous Cocrystal Formers. Cryst Growth Des 2020;20:832–44. https://doi.org/10.1021/acs.cgd.9b01224.
[41] Yan D, Evans DG. Molecular crystalline materials with tunable luminescent properties: From polymorphs to multi-component solids. Mater Horiz 2014;1:46–57. https://doi.org/10.1039/c3mh00023k.
[42] Wuest JD. Molecular solids: Co-crystals give light a tune-up. Nat Chem 2012;4:74–5. https://doi.org/10.1038/nchem.1256.
[43] Huang Y, Zhou L, Yang W, Li Y, Yang Y, Zhang Z, et al. Preparation of theophylline-benzoic acid cocrystal and on-line monitoring of cocrystallization process in solution by raman spectroscopy. Crystals (Basel) 2019;9. https://doi.org/10.3390/cryst9070329.
[44] Li M, Li Z, Zhang Q, Peng B, Zhu B, Wang JR, et al. Fine-tuning the colors of natural pigment emodin with superior stability through cocrystal engineering. Cryst Growth Des 2018;18:6123–32. https://doi.org/10.1021/acs.cgd.8b01002.
[45] Chavan DD, Thorat VM, Shete AS, Bhosale RR, Patil SJ, Tiwari DD. Current Perspectives on Development and Applications of Cocrystals in the Pharmaceutical and Medical Domain. Cureus 2024. https://doi.org/10.7759/cureus.70328.
[46] Kumar S, Nanda A. Approaches to Design of Pharmaceutical Cocrystals: A Review. Molecular Crystals and Liquid Crystals 2018;667:54–77. https://doi.org/10.1080/15421406.2019.1577462.
[47] Friščič T, Jones W. Recent advances in understanding the mechanism of cocrystal formation via grinding. Cryst Growth Des 2009;9:1621–37. https://doi.org/10.1021/cg800764n.
[48] Li S, Yu T, Tian Y, Lagan C, Jones DS, Andrews GP. Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Enhancing Cocrystal Yield. Mol Pharm 2018;15:3741–54. https://doi.org/10.1021/acs.molpharmaceut.7b00979.
[49] Chaudhari S, Nikam SA, Khatri N, Wakde S. CO-CRYSTALS: A REVIEW. Journal of Drug Delivery and Therapeutics 2018;8:350–8. https://doi.org/10.22270/jddt.v8i6-s.2194.
[50] Douroumis D, Ross SA, Nokhodchi A. Advanced methodologies for cocrystal synthesis. Adv Drug Deliv Rev 2017;117:178–95. https://doi.org/10.1016/j.addr.2017.07.008.
[51] Desai H, Rao L, Amin P. Carbamazepine cocrystals by solvent evaporation technique: formulation and characterization studies. Am J of Pharm Tech Res. 2014; 2;2:4.
[52] Kaupp G. Mechanochemistry: The varied applications of mechanical bond-breaking. CrystEngComm 2009;11:388–403. https://doi.org/10.1039/b810822f.
[53] Ober CA, Gupta RB. Formation of itraconazole-succinic acid cocrystals by gas antisolvent cocrystallization. AAPS PharmSciTech 2012;13:1396–406. https://doi.org/10.1208/s12249-012-9866-4.
[54] Rodríguez-Hornedo N, Nehm SJ, Seefeldt KF, Pagán-Torres Y, Falkiewicz CJ. Reaction crystallization of pharmaceutical molecular complexes. Mol Pharm 2006;3:362–7. https://doi.org/10.1021/mp050099m.
[55] Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res 2008;25:999–1022. https://doi.org/10.1007/s11095-007-9475-1.
[56] Padrela L, Rodrigues MA, Tiago J, Velaga SP, Matos HA, De Azevedo EG. Insight into the Mechanisms of Cocrystallization of Pharmaceuticals in Supercritical Solvents. Cryst Growth Des 2015;15:3175–81. https://doi.org/10.1021/acs.cgd.5b00200.
[57] Titapiwatanakun V, Basit AW, Gaisford S. A New Method for Producing Pharmaceutical Co-crystals: Laser Irradiation of Powder Blends. Cryst Growth Des 2016;16:3307–12. https://doi.org/10.1021/acs.cgd.6b00289.
[58] Karimi-Jafari M, Padrela L, Walker GM, Croker DM. Creating cocrystals: A review of pharmaceutical cocrystal preparation routes and applications. Cryst Growth Des 2018;18:6370–87. https://doi.org/10.1021/acs.cgd.8b00933.
[59] Pawar N, Saha A, Nandan N, Parambil J V. Solution cocrystallization: A scalable approach for cocrystal production. Crystals (Basel) 2021;11. https://doi.org/10.3390/cryst11030303.
[60] Steed JW. The role of co-crystals in pharmaceutical design. Trends Pharmacol Sci 2013;34:185–93. https://doi.org/10.1016/J.TIPS.2012.12.003.
[61] Thipparaboina R, Kumar D, Chavan RB, Shastri NR. Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug Discov Today 2016;21:481–90. https://doi.org/10.1016/J.DRUDIS.2016.02.001.
[62] Chettri A, Subba A, Singh GP, Pratim P. Pharmaceutical co-crystals: A green way to enhance drug stability and solubility for improved therapeutic efficacy. Journal of Pharmacy and Pharmacology 2024;76:1–12. https://doi.org/10.1093/jpp/rgad097.
[63] Kumar S, Nanda A. Approaches to Design of Pharmaceutical Cocrystals: A Review. Molecular Crystals and Liquid Crystals 2018;667:54–77. https://doi.org/10.1080/15421406.2019.1577462.
[64] Roshni J, Karthick T. A Comprehensive Review on Theoretical Screening Methods for Pharmaceutical Cocrystals. J Mol Struct 2025;1321:139868. https://doi.org/10.1016/J.MOLSTRUC.2024.139868.
[65] Singh M, Barua H, Jyothi VG, Dhondale MR, Nambiar AG, Agrawal AK, Kumar P, Shastri NR, Kumar D. Cocrystals by design: a rational coformer selection approach for tackling the API problems. Pharmaceutics. 2023; 6;15(4):1161. https://doi.org/10.3390/pharmaceutics15041161.
[66] Kumar R, Sheela MA, Sachdeva M. Formulation and Evaluation of Orodispersible Tablets Containing Co-Crystals of Modafinil. Journal of Drug Delivery and Therapeutics 2022;12:82–9. https://doi.org/10.22270/jddt.v12i5-s.5634.
[67] Yu YM, Liu L, Bu FZ, Li YT, Yan CW, Wu ZY. A novice cocrystal nanomicelle formulation of 5-fluorouracil with proline: The design, self-assembly and in vitro/vivo biopharmaceutical characteristics. Int J Pharm 2022;617:121635. https://doi.org/10.1016/J.IJPHARM.2022.121635.
[68] Muthusamy AR, Singh A, Sundaram MSS, Wagh Y, Jegorov A, Jain AK. In-Silico Aided Screening and Characterization Results in Stability Enhanced Novel Roxadustat Co-Crystal. J Pharm Sci 2024;113:1190–201. https://doi.org/10.1016/j.xphs.2023.10.024.
[69] Devi S, Kumar A, Kapoor A, Verma V, Yadav S, Bhatia M. Ketoprofen–FA Co-crystal: In Vitro and In Vivo Investigation for the Solubility Enhancement of Drug by Design of Expert. AAPS PharmSciTech 2022;23. https://doi.org/10.1208/s12249-022-02253-5.
[70] Rathi R, Singh I, Sangnim T, Huanbutta K. Development and Evaluation of Fluconazole Co-Crystal for Improved Solubility and Mechanical Properties. Pharmaceutics 2025;17. https://doi.org/10.3390/pharmaceutics17030371.
[71] Pagire SK, Seaton CC, Paradkar A. Improving Stability of Effervescent Products by Co-Crystal Formation: A Novel Application of Crystal Engineered Citric Acid. Cryst Growth Des 2020;20:4839–44. https://doi.org/10.1021/acs.cgd.0c00616.
[72] Patidar VK, Sharma A. Design, Formulation and evaluation of Amiodarone HCl co-crystal tablet. European Journal of Molecular & Clinical Medicine. 2021;7(8):2020.
[73] Ammanage A, Rodriques P, Kempwade A, Hiremath R. Formulation and evaluation of buccal films of piroxicam co-crystals. Futur J Pharm Sci 2020;6. https://doi.org/10.1186/s43094-020-00033-1.
[74] Pantwalawalkar J, More H, Bhange D, Patil U, Jadhav N. Novel curcumin ascorbic acid cocrystal for improved solubility. J Drug Deliv Sci Technol 2021;61. https://doi.org/10.1016/j.jddst.2020.102233.
[75] Vyas G, Shah J, Jacob S. DoE implementation for Telmisartan and hydrochlorothiazide drug-drug cocrystal synthesis to enhance physicochemical and pharmacokinetic properties. J Appl Pharm Sci 2023;13:67–76. https://doi.org/10.7324/JAPS.2023.90012.
[76] Popat Jadhav S, Machhindra Patil D, Devidas Sonawane D, Dilip Patil P, Gorakshanath Ghugarkar P, Saad M, et al. Formulation Of Tablet Of Ivermectin Co-Crystal For Enhancement Of Solubility And Other Physical Properties. Journal of Pharmaceutical Negative Results ¦ n.d.;14. https://doi.org/10.47750/pnr.2023.14.S01.60.
[77] Kaviani R, Jouyban A, Shayanfar A. Chiral resolution of RS-ofloxacin through a novel diastereomeric cocrystal formation with L-glutamic acid by evaporative crystallization and quantification with capillary electrophoresis. Sep Purif Technol 2025;354. https://doi.org/10.1016/j.seppur.2024.129040.
[78] Zerrouki K, Bouchene R, Tüzün B, Retailleau P. Novel supramolecular co-crystal of 8-hydroxyquinoline with acetone-(2,4-dinitrophenyl)hydrazone: One pot synthesis, structural characterization, Hirshfeld surface and energy framework analysis, computational investigation and molecular docking study. J Mol Struct 2024;1300. https://doi.org/10.1016/j.molstruc.2023.137290.
[79] Bhatia M, Kumar A, Kumar V, Devi S. Development of Ketoprofen-p-Aminobenzoic Acid Co-Crystal: Formulation, Characterization, Optimization and Evaluation 2021. https://doi.org/10.21203/rs.3.rs-596789/v1.
[80] Jubeen F, Liaqat A, Amjad F, Sultan M, Iqbal SZ, Sajid I, Khan Niazi MB, Sher F. Synthesis of 5-fluorouracil cocrystals with novel organic acids as coformers and anticancer evaluation against HCT-116 colorectal cell lines. Crystal Growth & Design. 2020;10;20(4):2406-14. https://doi.org/10.1021/acs.cgd.9b01570.
[81] Dai XL, Yao J, Wu C, Deng JH, Mo YH, Lu TB, et al. Solubility and Permeability Improvement of Allopurinol by Cocrystallization. Cryst Growth Des 2020;20:5160–8. https://doi.org/10.1021/ACS.CGD.0C00326.
[82] Wang LY, Bu FZ, Li YT, Wu ZY, Yan CW. A Sulfathiazole-Amantadine Hydrochloride Cocrystal: The First Codrug Simultaneously Comprising Antiviral and Antibacterial Components. Cryst Growth Des 2020;20:3236–46. https://doi.org/10.1021/ACS.CGD.0C00075/SUPPL_FILE/CG0C00075_SI_001.PDF.
[83] Haneef J, Chadha R. Sustainable synthesis of ambrisentan – syringic acid cocrystal: employing mechanochemistry in the development of novel pharmaceutical solid form. CrystEngComm 2020;22:2507–16. https://doi.org/10.1039/C9CE01818B.
[84] Li P, Ramaiah T, Zhang M, Zhang Y, Huang Y, Lou B. Two cocrystals of berberine chloride with myricetin and dihydromyricetin: crystal structures, characterization, and antitumor activities. ACS PublicationsP Li, T Ramaiah, M Zhang, Y Zhang, Y Huang, B LouCrystal Growth & Design, 2019•ACS Publications 2020;20:157–66. https://doi.org/10.1021/ACS.CGD.9B00939.
[85] Allu S, Bolla G, Tothadi S, Nangia AK. Novel pharmaceutical cocrystals and salts of bumetanide. ACS PublicationsS Allu, G Bolla, S Tothadi, AK NangiaCrystal Growth & Design, 2019•ACS Publications 2020;20:793–803. https://doi.org/10.1021/ACS.CGD.9B01195.
[86] Nemec V, Vitasović T, Cinčić D. Halogen-bonded cocrystals of donepezil with perfluorinated diiodobenzenes. CrystEngComm. 2020;22(34):5573-7. https://doi.org/10.1039/D0CE01065K
[87] Kozak A, Marek PH, Pindelska E. Structural characterization and pharmaceutical properties of three novel cocrystals of ethenzamide with aliphatic dicarboxylic acids. Journal of pharmaceutical sciences. 2019;1;108(4):1476-85. https://doi.org/10.1016/j.xphs.2018.10.060
[88] Bernasconi D, Bordignon S, Rossi F, Priola E, Nervi C, Gobetto R, et al. Selective synthesis of a salt and a cocrystal of the ethionamide–salicylic acid system. ACS PublicationsD Bernasconi, S Bordignon, F Rossi, E Priola, C Nervi, R Gobetto, D Voinovich, D HasaCrystal Growth & Design, 2019•ACS Publications 2020;20:906–15. https://doi.org/10.1021/ACS.CGD.9B01299.
[89] Saikia B, Sultana N, Kaushik T, Sarma B. Engineering a remedy to improve phase stability of famotidine under physiological ph environments. ACS PublicationsB Saikia, N Sultana, T Kaushik, B SarmaCrystal Growth & Design, 2019•ACS Publications 2019;19:6472–81. https://doi.org/10.1021/ACS.CGD.9B00931.
[90] Modani S, Gunnam A, Yadav B, Nangia AK, Nangia AK, Shastri NR. Generation and evaluation of pharmacologically relevant drug–drug cocrystal for gout therapy. ACS PublicationsS Modani, A Gunnam, B Yadav, AK Nangia, NR ShastriCrystal Growth & Design, 2020•ACS Publications 2020;20:3577–83. https://doi.org/10.1021/ACS.CGD.0C00106.
[91] Rosa J, Machado TC, Da Silva AK, Kuminek G, Bortolluzzi AJ, Caon T, et al. Isoniazid-resveratrol cocrystal: a novel alternative for topical treatment of cutaneous tuberculosis. ACS PublicationsJ Rosa, TC Machado, AK Da Silva, G Kuminek, AJ Bortolluzzi, T Caon, SG CardosoCrystal Growth & Design, 2019•ACS Publications 2019;19:5029–36. https://doi.org/10.1021/ACS.CGD.9B00313.
[92] Weng J, Wong SN, Xu X, Xuan B, Wang C, Chen R, et al. Cocrystal engineering of itraconazole with suberic acid via rotary evaporation and spray drying. ACS PublicationsJ Weng, SN Wong, X Xu, B Xuan, C Wang, R Chen, CC Sun, R Lakerveld, PCL KwokCrystal Growth & Design, 2019•ACS Publications 2019;19:2736–45. https://doi.org/10.1021/ACS.CGD.8B01873.
[93] Eisa M, Brondi M, Williams C, Hejl R, Baltrusaitis J. From urea to urea cocrystals: A critical view of conventional and emerging nitrogenous fertilizer materials for improved environmental sustainability. Sustainable Chemistry for the Environment 2025;9. https://doi.org/10.1016/j.scenv.2025.100209.
[94] Solomon C, Sârbu I, Anuța V, Ozon EA, Musuc AM, Fița AC, et al. PREFORMULATION STUDIES OF TABLETS CONTAINING RIVAROXABAN – NIACINAMIDE COCRYSTALLIZATION COMPOUNDS. Farmacia 2025;73:706–12. https://doi.org/10.31925/farmacia.2025.3.17.
[95] Wang Z, Li S, Li Q, Wang W, Liu M, Yang S, et al. A Novel Cocrystal of Daidzein with Piperazine to Optimize the Solubility, Permeability and Bioavailability of Daidzein. Molecules 2024;29. https://doi.org/10.3390/molecules29081710.
[96] Kim J, Lim S, Kim M, Ban E, Kim Y, Kim A. Using the Cocrystal Approach as a Promising Drug Delivery System to Enhance the Dissolution and Bioavailability of Formononetin Using an Imidazole Coformer. Pharmaceuticals 2024;17. https://doi.org/10.3390/ph17111444.
[97] Ishihara S, Hattori Y, Otsuka M, Sasaki T. Cocrystal formation through solid-state reaction between ibuprofen and nicotinamide revealed using THz and IR spectroscopy with multivariate analysis. Crystals (Basel) 2020;10:1–12. https://doi.org/10.3390/cryst10090760.
[98] Sakhiya DC, Borkhataria CH. A review on advancement of cocrystallization approach and a brief on screening, formulation and characterization of the same. Heliyon 2024;10. https://doi.org/10.1016/j.heliyon.2024.e29057.
[99] Aitipamula S, Vangala VR. X-Ray Crystallography and its Role in Understanding the Physicochemical Properties of Pharmaceutical Cocrystals. J Indian Inst Sci, vol. 97, Springer International Publishing; 2017, p. 227–43. https://doi.org/10.1007/s41745-017-0026-4.
[100] Bruni G, Maggi L, Mustarelli P, Sakaj M, Friuli V, Ferrara C, et al. Enhancing the Pharmaceutical Behavior of Nateglinide by Cocrystallization: Physicochemical Assessment of Cocrystal Formation and Informed Use of Differential Scanning Calorimetry for Its Quantitative Characterization. J Pharm Sci 2019;108:1529–39. https://doi.org/10.1016/j.xphs.2018.11.033.
[101] Saganowska P, Wesolowski M. DSC as a screening tool for rapid co-crystal detection in binary mixtures of benzodiazepines with co-formers. J Therm Anal Calorim 2018;133:785–95. https://doi.org/10.1007/s10973-017-6858-3.
[102] Kumar A, Singh P, Nanda A. Hot stage microscopy and its applications in pharmaceutical characterization. Appl Microsc 2020;50. https://doi.org/10.1186/s42649-020-00032-9.
[103] Ali HRH, Alhalaweh A, Mendes NFC, Ribeiro-Claro P, Velaga SP. Solid-state vibrational spectroscopic investigation of cocrystals and salt of indomethacin. CrystEngComm 2012;14:6665–74. https://doi.org/10.1039/c2ce25801c.
[104] Du S, Wang Y, Wu S, Yu B, Shi P, Bian L, et al. Two novel cocrystals of lamotrigine with isomeric bipyridines and in situ monitoring of the cocrystallization. European Journal of Pharmaceutical Sciences 2017;110:19–25. https://doi.org/10.1016/j.ejps.2017.06.001.
[105] Du Y, Xue J, Cai Q, Zhang Q. Spectroscopic investigation on structure and pH dependent Cocrystal formation between gamma-aminobutyric acid and benzoic acid. Spectrochim Acta A Mol Biomol Spectrosc 2018;191:377–81. https://doi.org/10.1016/j.saa.2017.10.036.
[106] Peach AA, Hirsh DA, Holmes ST, Schurko RW. Mechanochemical syntheses and 35Cl solid-state NMR characterization of fluoxetine HCl cocrystals. CrystEngComm 2018;20:2780–92. https://doi.org/10.1039/c8ce00378e.
[107] Karimi-Jafari M, Padrela L, Walker GM, Croker DM. Creating cocrystals: A review of pharmaceutical cocrystal preparation routes and applications. Cryst Growth Des 2018;18:6370–87. https://doi.org/10.1021/acs.cgd.8b00933.
[108] BIJAY KUMAR YADAV, ATIF KHURSHEED, RATTAN DEEP SINGH. COCRYSTALS: A COMPLETE REVIEW ON CONVENTIONAL AND NOVEL METHODS OF ITS FORMATION AND ITS EVALUATION. Asian Journal of Pharmaceutical and Clinical Research 2019:68–74. https://doi.org/10.22159/ajpcr.2019.v12i7.33648.
[109] Chaudhari S, Nikam SA, Khatri N, Wakde S. CO-CRYSTALS: A REVIEW. Journal of Drug Delivery and Therapeutics 2018;8:350–8. https://doi.org/10.22270/jddt.v8i6-s.2194.
[110] Banerjee M, Nimkar K, Naik S, Patravale V. Unlocking the potential of drug-drug cocrystals–A comprehensive review. Journal of Controlled Release. 2022;1;348:456-69. https://doi.org/10.1016/j.jconrel.2022.06.003
[111] Sarangi S, Remya PN, Damodharan N. Advances in solvent based cocrystallization: Bridging the gap between theory and practice. Journal of Drug Delivery Science and Technology. 2024; 1;95:105619. https://doi.org/10.1016/j.jddst.2024.105619
[2] Aitipamula S, Banerjee R, Bansal AK, Biradha K, Cheney ML, Choudhury AR, et al. Polymorphs, salts, and cocrystals: What’s in a name? Cryst Growth Des 2012;12:2147–52. https://doi.org/10.1021/cg3002948.
[3] Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: An overview. Int J Pharm 2011;419:1–11. https://doi.org/10.1016/j.ijpharm.2011.07.037.
[4] Ainurofiq A, Putro DS, Ramadhani DA, Putra GM, Do Espirito Santo LDC. A review on solubility enhancement methods for poorly water-soluble drugs. Journal of Reports in Pharmaceutical Sciences 2021;10:137–47. https://doi.org/10.4103/jrptps.JRPTPS_134_19.
[5] Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. Pharmaceutical co-crystals. J Pharm Sci 2006;95:499–516. https://doi.org/10.1002/jps.20578.
[6] Etter MC. Encoding and decoding hydrogen-bond patterns of organic compounds. Accounts of Chemical Research. 1990;4;1;23(4):120-6. https://doi.org/10.1021/ar00172a005
[7] Etter MC. Hydrogen bonds as design elements in organic chemistry. The Journal of Physical Chemistry. 1991;95(12):4601-10. https://doi.org/10.1021/j100165a007
[8] Reddy DS, Ovchinnikov YE, Shishkin OV, Struchkov YT, Desiraju GR. Supramolecular synthons in crystal engineering. 3. Solid state architecture and synthon robustness in some 2, 3-dicyano-5, 6-dichloro-1, 4-dialkoxybenzenes1. Journal of the American Chemical Society. 1996 May 1;118(17):4085-9. https://doi.org/10.1021/ja953372u
[9] Patrick Stahly G. A survey of cocrystals reported prior to 2000. Cryst Growth Des 2009;9:4212–29. https://doi.org/10.1021/cg900873t.
[10] Dunitz JD. Crystal and co-crystal: A second opinion. CrystEngComm 2003;5:506. https://doi.org/10.1039/b315687g.
[11] Childs SL, Stahly GP, Park A. The salt-cocrystal continuum: The influence of crystal structure on ionization state. Mol Pharm 2007;4:323–38. https://doi.org/10.1021/mp0601345.
[12] Huang LF, Tong WQ. Impact of solid state properties on developability assessment of drug candidates. Adv Drug Deliv Rev 2004;56:321–34. https://doi.org/10.1016/j.addr.2003.10.007.
[13] Chadha R, Rani D, Goyal P. Novel cocrystals of gliclazide: characterization and evaluation. CrystEngComm. 2016;18(13):2275-83. https://doi.org/10.1039/C5CE02402A
[14] Zawilska JB, Wojcieszak J, Olejniczak AB. Prodrugs: a challenge for the drug development. Pharmacological reports. 2013;65(1):1-14. https://doi.org/10.1016/S1734-1140(13)70959-9
[15] Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. European Journal of Pharmaceutics and Biopharmaceutics 2000;50:47–60. https://doi.org/10.1016/S0939-6411(00)00076-X.
[16] Varshosaz J, Talari R, Mostafavi SA, Nokhodchi A. Dissolution enhancement of gliclazide using in situ micronization by solvent change method. Powder Technol 2008;187:222–30. https://doi.org/10.1016/j.powtec.2008.02.018.
[17] Loh GOK, Tan YTF, Peh KK. Enhancement of norfloxacin solubility via inclusion complexation with β-cyclodextrin and its derivative hydroxypropyl-β-cyclodextrin. Asian J Pharm Sci 2016;11:536–46. https://doi.org/10.1016/j.ajps.2016.02.009.
[18] Singhal D, Curatolo W. Drug polymorphism and dosage form design: A practical perspective. Adv Drug Deliv Rev 2004;56:335–47. https://doi.org/10.1016/j.addr.2003.10.008.
[19] Kalepu S, Nekkanti V. Improved delivery of poorly soluble compounds using nanoparticle technology: a review. Drug Deliv Transl Res 2016;6:319–32. https://doi.org/10.1007/s13346-016-0283-1.
[20] Perlovich GL, Manin AN. Design of pharmaceutical cocrystals for drug solubility improvement. Russ J Gen Chem 2014;84:407–14. https://doi.org/10.1134/S107036321402042X.
[21] Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: An overview. Int J Pharm 2011;419:1–11. https://doi.org/10.1016/j.ijpharm.2011.07.037.
[22] Aitipamula S, Bolla G. Optimizing Drug Development: Harnessing the Sustainability of Pharmaceutical Cocrystals. Mol Pharm 2024;21:3121–43. https://doi.org/10.1021/acs.molpharmaceut.4c00289.
[23] Aitipamula S, Banerjee R, Bansal AK, Biradha K, Cheney ML, Choudhury AR, et al. Polymorphs, salts, and cocrystals: What’s in a name? Cryst Growth Des 2012;12:2147–52. https://doi.org/10.1021/cg3002948.
[24] Bhogala BR, Basavoju S, Nangia A. Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4,4′-bipyridines and isonicotinamide. From binary to ternary cocrystals. CrystEngComm 2005;7:551–62. https://doi.org/10.1039/b509162d.
[25] Morissette SL, Almarsson Ö, Peterson ML, Remenar JF, Read MJ, Lemmo A V., et al. High-throughput crystallization: Polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv Drug Deliv Rev 2004;56:275–300. https://doi.org/10.1016/j.addr.2003.10.020.
[26] Ross SA, Lamprou DA, Douroumis D. Engineering and manufacturing of pharmaceutical co-crystals: A review of solvent-free manufacturing technologies. Chemical Communications 2016;52:8772–86. https://doi.org/10.1039/c6cc01289b.
[27] Madusanka N, Eddleston MD, Arhangelskis M, Jones W. Polymorphs, hydrates and solvates of a co-crystal of caffeine with anthranilic acid. Acta Crystallogr B Struct Sci Cryst Eng Mater 2014;70:72–80. https://doi.org/10.1107/S2052520613033167.
[28] Bag PP, Kothur RR, Malla Reddy C. Tautomeric preference in polymorphs and pseudopolymorphs of succinylsulfathiazole: Fast evaporation screening and thermal studies. CrystEngComm 2014;16:4706–14. https://doi.org/10.1039/c3ce42159g.
[29] Bag PP, Chen M, Sun CC, Reddy CM. Direct correlation among crystal structure, mechanical behaviour and tabletability in a trimorphic molecular compound. CrystEngComm 2012;14:3865–7. https://doi.org/10.1039/c2ce25100k.
[30] Gadade DD, Pekamwar SS. Pharmaceutical cocrystals: Regulatory and strategic aspects, design and development. Adv Pharm Bull 2016;6:479–94. https://doi.org/10.15171/apb.2016.062.
[31] Guo C, Zhang Q, Zhu B, Zhang Z, Ma X, Dai W, et al. Drug-Drug Cocrystals Provide Significant Improvements of Drug Properties in Treatment with Progesterone. Cryst Growth Des 2020;20:3053–63. https://doi.org/10.1021/acs.cgd.9b01688.
[32] Duggirala NK, Smith AJ, Wojtas Ł, Shytle RD, Zaworotko MJ. Physical stability enhancement and pharmacokinetics of a lithium ionic cocrystal with glucose. Cryst Growth Des 2014;14:6135–42. https://doi.org/10.1021/cg501310d.
[33] McKellar SC, Kennedy AR, McCloy NC, McBride E, Florence AJ. Formulation of liquid propofol as a cocrystalline solid. Cryst Growth Des 2014;14:2422–30. https://doi.org/10.1021/cg500155p.
[34] Guo M, Sun X, Chen J, Cai T. Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications. Acta Pharm Sin B 2021;11:2537–64. https://doi.org/10.1016/j.apsb.2021.03.030.
[35] Bofill L, De Sande D, Barbas R, Prohens R. New Cocrystal of Ubiquinol with High Stability to Oxidation. Cryst Growth Des 2020;20:5583–8. https://doi.org/10.1021/acs.cgd.0c00749.
[36] Guo C, Zhang Q, Zhu B, Zhang Z, Bao J, Ding Q, et al. Pharmaceutical Cocrystals of Nicorandil with Enhanced Chemical Stability and Sustained Release. Cryst Growth Des 2020;20:6995–7005. https://doi.org/10.1021/acs.cgd.0c01043.
[37] Vangala VR, Chow PS, Tan RB. Characterization, physicochemical and photo-stability of a co-crystal involving an antibiotic drug, nitrofurantoin, and 4-hydroxybenzoic acid. CrystEngComm. 2011;13(3):759-62. https://doi.org/10.1039/C0CE00772B
[38] Mannava MKC, Gunnam A, Lodagekar A, Shastri NR, Nangia AK, Solomon KA. Enhanced solubility, permeability, and tabletability of nicorandil by salt and cocrystal formation. CrystEngComm 2021;23:227–37. https://doi.org/10.1039/d0ce01316a.
[39] Chattoraj S, Shi L, Chen M, Alhalaweh A, Velaga S, Sun CC. Origin of deteriorated crystal plasticity and compaction properties of a 1: 1 cocrystal between piroxicam and saccharin. Crystal growth & design. 2014;6;14(8):3864-74. https://doi.org/10.1021/cg500388s.
[40] Yadav JP, Yadav RN, Uniyal P, Chen H, Wang C, Sun CC, et al. Molecular Interpretation of Mechanical Behavior in Four Basic Crystal Packing of Isoniazid with Homologous Cocrystal Formers. Cryst Growth Des 2020;20:832–44. https://doi.org/10.1021/acs.cgd.9b01224.
[41] Yan D, Evans DG. Molecular crystalline materials with tunable luminescent properties: From polymorphs to multi-component solids. Mater Horiz 2014;1:46–57. https://doi.org/10.1039/c3mh00023k.
[42] Wuest JD. Molecular solids: Co-crystals give light a tune-up. Nat Chem 2012;4:74–5. https://doi.org/10.1038/nchem.1256.
[43] Huang Y, Zhou L, Yang W, Li Y, Yang Y, Zhang Z, et al. Preparation of theophylline-benzoic acid cocrystal and on-line monitoring of cocrystallization process in solution by raman spectroscopy. Crystals (Basel) 2019;9. https://doi.org/10.3390/cryst9070329.
[44] Li M, Li Z, Zhang Q, Peng B, Zhu B, Wang JR, et al. Fine-tuning the colors of natural pigment emodin with superior stability through cocrystal engineering. Cryst Growth Des 2018;18:6123–32. https://doi.org/10.1021/acs.cgd.8b01002.
[45] Chavan DD, Thorat VM, Shete AS, Bhosale RR, Patil SJ, Tiwari DD. Current Perspectives on Development and Applications of Cocrystals in the Pharmaceutical and Medical Domain. Cureus 2024. https://doi.org/10.7759/cureus.70328.
[46] Kumar S, Nanda A. Approaches to Design of Pharmaceutical Cocrystals: A Review. Molecular Crystals and Liquid Crystals 2018;667:54–77. https://doi.org/10.1080/15421406.2019.1577462.
[47] Friščič T, Jones W. Recent advances in understanding the mechanism of cocrystal formation via grinding. Cryst Growth Des 2009;9:1621–37. https://doi.org/10.1021/cg800764n.
[48] Li S, Yu T, Tian Y, Lagan C, Jones DS, Andrews GP. Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Enhancing Cocrystal Yield. Mol Pharm 2018;15:3741–54. https://doi.org/10.1021/acs.molpharmaceut.7b00979.
[49] Chaudhari S, Nikam SA, Khatri N, Wakde S. CO-CRYSTALS: A REVIEW. Journal of Drug Delivery and Therapeutics 2018;8:350–8. https://doi.org/10.22270/jddt.v8i6-s.2194.
[50] Douroumis D, Ross SA, Nokhodchi A. Advanced methodologies for cocrystal synthesis. Adv Drug Deliv Rev 2017;117:178–95. https://doi.org/10.1016/j.addr.2017.07.008.
[51] Desai H, Rao L, Amin P. Carbamazepine cocrystals by solvent evaporation technique: formulation and characterization studies. Am J of Pharm Tech Res. 2014; 2;2:4.
[52] Kaupp G. Mechanochemistry: The varied applications of mechanical bond-breaking. CrystEngComm 2009;11:388–403. https://doi.org/10.1039/b810822f.
[53] Ober CA, Gupta RB. Formation of itraconazole-succinic acid cocrystals by gas antisolvent cocrystallization. AAPS PharmSciTech 2012;13:1396–406. https://doi.org/10.1208/s12249-012-9866-4.
[54] Rodríguez-Hornedo N, Nehm SJ, Seefeldt KF, Pagán-Torres Y, Falkiewicz CJ. Reaction crystallization of pharmaceutical molecular complexes. Mol Pharm 2006;3:362–7. https://doi.org/10.1021/mp050099m.
[55] Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res 2008;25:999–1022. https://doi.org/10.1007/s11095-007-9475-1.
[56] Padrela L, Rodrigues MA, Tiago J, Velaga SP, Matos HA, De Azevedo EG. Insight into the Mechanisms of Cocrystallization of Pharmaceuticals in Supercritical Solvents. Cryst Growth Des 2015;15:3175–81. https://doi.org/10.1021/acs.cgd.5b00200.
[57] Titapiwatanakun V, Basit AW, Gaisford S. A New Method for Producing Pharmaceutical Co-crystals: Laser Irradiation of Powder Blends. Cryst Growth Des 2016;16:3307–12. https://doi.org/10.1021/acs.cgd.6b00289.
[58] Karimi-Jafari M, Padrela L, Walker GM, Croker DM. Creating cocrystals: A review of pharmaceutical cocrystal preparation routes and applications. Cryst Growth Des 2018;18:6370–87. https://doi.org/10.1021/acs.cgd.8b00933.
[59] Pawar N, Saha A, Nandan N, Parambil J V. Solution cocrystallization: A scalable approach for cocrystal production. Crystals (Basel) 2021;11. https://doi.org/10.3390/cryst11030303.
[60] Steed JW. The role of co-crystals in pharmaceutical design. Trends Pharmacol Sci 2013;34:185–93. https://doi.org/10.1016/J.TIPS.2012.12.003.
[61] Thipparaboina R, Kumar D, Chavan RB, Shastri NR. Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug Discov Today 2016;21:481–90. https://doi.org/10.1016/J.DRUDIS.2016.02.001.
[62] Chettri A, Subba A, Singh GP, Pratim P. Pharmaceutical co-crystals: A green way to enhance drug stability and solubility for improved therapeutic efficacy. Journal of Pharmacy and Pharmacology 2024;76:1–12. https://doi.org/10.1093/jpp/rgad097.
[63] Kumar S, Nanda A. Approaches to Design of Pharmaceutical Cocrystals: A Review. Molecular Crystals and Liquid Crystals 2018;667:54–77. https://doi.org/10.1080/15421406.2019.1577462.
[64] Roshni J, Karthick T. A Comprehensive Review on Theoretical Screening Methods for Pharmaceutical Cocrystals. J Mol Struct 2025;1321:139868. https://doi.org/10.1016/J.MOLSTRUC.2024.139868.
[65] Singh M, Barua H, Jyothi VG, Dhondale MR, Nambiar AG, Agrawal AK, Kumar P, Shastri NR, Kumar D. Cocrystals by design: a rational coformer selection approach for tackling the API problems. Pharmaceutics. 2023; 6;15(4):1161. https://doi.org/10.3390/pharmaceutics15041161.
[66] Kumar R, Sheela MA, Sachdeva M. Formulation and Evaluation of Orodispersible Tablets Containing Co-Crystals of Modafinil. Journal of Drug Delivery and Therapeutics 2022;12:82–9. https://doi.org/10.22270/jddt.v12i5-s.5634.
[67] Yu YM, Liu L, Bu FZ, Li YT, Yan CW, Wu ZY. A novice cocrystal nanomicelle formulation of 5-fluorouracil with proline: The design, self-assembly and in vitro/vivo biopharmaceutical characteristics. Int J Pharm 2022;617:121635. https://doi.org/10.1016/J.IJPHARM.2022.121635.
[68] Muthusamy AR, Singh A, Sundaram MSS, Wagh Y, Jegorov A, Jain AK. In-Silico Aided Screening and Characterization Results in Stability Enhanced Novel Roxadustat Co-Crystal. J Pharm Sci 2024;113:1190–201. https://doi.org/10.1016/j.xphs.2023.10.024.
[69] Devi S, Kumar A, Kapoor A, Verma V, Yadav S, Bhatia M. Ketoprofen–FA Co-crystal: In Vitro and In Vivo Investigation for the Solubility Enhancement of Drug by Design of Expert. AAPS PharmSciTech 2022;23. https://doi.org/10.1208/s12249-022-02253-5.
[70] Rathi R, Singh I, Sangnim T, Huanbutta K. Development and Evaluation of Fluconazole Co-Crystal for Improved Solubility and Mechanical Properties. Pharmaceutics 2025;17. https://doi.org/10.3390/pharmaceutics17030371.
[71] Pagire SK, Seaton CC, Paradkar A. Improving Stability of Effervescent Products by Co-Crystal Formation: A Novel Application of Crystal Engineered Citric Acid. Cryst Growth Des 2020;20:4839–44. https://doi.org/10.1021/acs.cgd.0c00616.
[72] Patidar VK, Sharma A. Design, Formulation and evaluation of Amiodarone HCl co-crystal tablet. European Journal of Molecular & Clinical Medicine. 2021;7(8):2020.
[73] Ammanage A, Rodriques P, Kempwade A, Hiremath R. Formulation and evaluation of buccal films of piroxicam co-crystals. Futur J Pharm Sci 2020;6. https://doi.org/10.1186/s43094-020-00033-1.
[74] Pantwalawalkar J, More H, Bhange D, Patil U, Jadhav N. Novel curcumin ascorbic acid cocrystal for improved solubility. J Drug Deliv Sci Technol 2021;61. https://doi.org/10.1016/j.jddst.2020.102233.
[75] Vyas G, Shah J, Jacob S. DoE implementation for Telmisartan and hydrochlorothiazide drug-drug cocrystal synthesis to enhance physicochemical and pharmacokinetic properties. J Appl Pharm Sci 2023;13:67–76. https://doi.org/10.7324/JAPS.2023.90012.
[76] Popat Jadhav S, Machhindra Patil D, Devidas Sonawane D, Dilip Patil P, Gorakshanath Ghugarkar P, Saad M, et al. Formulation Of Tablet Of Ivermectin Co-Crystal For Enhancement Of Solubility And Other Physical Properties. Journal of Pharmaceutical Negative Results ¦ n.d.;14. https://doi.org/10.47750/pnr.2023.14.S01.60.
[77] Kaviani R, Jouyban A, Shayanfar A. Chiral resolution of RS-ofloxacin through a novel diastereomeric cocrystal formation with L-glutamic acid by evaporative crystallization and quantification with capillary electrophoresis. Sep Purif Technol 2025;354. https://doi.org/10.1016/j.seppur.2024.129040.
[78] Zerrouki K, Bouchene R, Tüzün B, Retailleau P. Novel supramolecular co-crystal of 8-hydroxyquinoline with acetone-(2,4-dinitrophenyl)hydrazone: One pot synthesis, structural characterization, Hirshfeld surface and energy framework analysis, computational investigation and molecular docking study. J Mol Struct 2024;1300. https://doi.org/10.1016/j.molstruc.2023.137290.
[79] Bhatia M, Kumar A, Kumar V, Devi S. Development of Ketoprofen-p-Aminobenzoic Acid Co-Crystal: Formulation, Characterization, Optimization and Evaluation 2021. https://doi.org/10.21203/rs.3.rs-596789/v1.
[80] Jubeen F, Liaqat A, Amjad F, Sultan M, Iqbal SZ, Sajid I, Khan Niazi MB, Sher F. Synthesis of 5-fluorouracil cocrystals with novel organic acids as coformers and anticancer evaluation against HCT-116 colorectal cell lines. Crystal Growth & Design. 2020;10;20(4):2406-14. https://doi.org/10.1021/acs.cgd.9b01570.
[81] Dai XL, Yao J, Wu C, Deng JH, Mo YH, Lu TB, et al. Solubility and Permeability Improvement of Allopurinol by Cocrystallization. Cryst Growth Des 2020;20:5160–8. https://doi.org/10.1021/ACS.CGD.0C00326.
[82] Wang LY, Bu FZ, Li YT, Wu ZY, Yan CW. A Sulfathiazole-Amantadine Hydrochloride Cocrystal: The First Codrug Simultaneously Comprising Antiviral and Antibacterial Components. Cryst Growth Des 2020;20:3236–46. https://doi.org/10.1021/ACS.CGD.0C00075/SUPPL_FILE/CG0C00075_SI_001.PDF.
[83] Haneef J, Chadha R. Sustainable synthesis of ambrisentan – syringic acid cocrystal: employing mechanochemistry in the development of novel pharmaceutical solid form. CrystEngComm 2020;22:2507–16. https://doi.org/10.1039/C9CE01818B.
[84] Li P, Ramaiah T, Zhang M, Zhang Y, Huang Y, Lou B. Two cocrystals of berberine chloride with myricetin and dihydromyricetin: crystal structures, characterization, and antitumor activities. ACS PublicationsP Li, T Ramaiah, M Zhang, Y Zhang, Y Huang, B LouCrystal Growth & Design, 2019•ACS Publications 2020;20:157–66. https://doi.org/10.1021/ACS.CGD.9B00939.
[85] Allu S, Bolla G, Tothadi S, Nangia AK. Novel pharmaceutical cocrystals and salts of bumetanide. ACS PublicationsS Allu, G Bolla, S Tothadi, AK NangiaCrystal Growth & Design, 2019•ACS Publications 2020;20:793–803. https://doi.org/10.1021/ACS.CGD.9B01195.
[86] Nemec V, Vitasović T, Cinčić D. Halogen-bonded cocrystals of donepezil with perfluorinated diiodobenzenes. CrystEngComm. 2020;22(34):5573-7. https://doi.org/10.1039/D0CE01065K
[87] Kozak A, Marek PH, Pindelska E. Structural characterization and pharmaceutical properties of three novel cocrystals of ethenzamide with aliphatic dicarboxylic acids. Journal of pharmaceutical sciences. 2019;1;108(4):1476-85. https://doi.org/10.1016/j.xphs.2018.10.060
[88] Bernasconi D, Bordignon S, Rossi F, Priola E, Nervi C, Gobetto R, et al. Selective synthesis of a salt and a cocrystal of the ethionamide–salicylic acid system. ACS PublicationsD Bernasconi, S Bordignon, F Rossi, E Priola, C Nervi, R Gobetto, D Voinovich, D HasaCrystal Growth & Design, 2019•ACS Publications 2020;20:906–15. https://doi.org/10.1021/ACS.CGD.9B01299.
[89] Saikia B, Sultana N, Kaushik T, Sarma B. Engineering a remedy to improve phase stability of famotidine under physiological ph environments. ACS PublicationsB Saikia, N Sultana, T Kaushik, B SarmaCrystal Growth & Design, 2019•ACS Publications 2019;19:6472–81. https://doi.org/10.1021/ACS.CGD.9B00931.
[90] Modani S, Gunnam A, Yadav B, Nangia AK, Nangia AK, Shastri NR. Generation and evaluation of pharmacologically relevant drug–drug cocrystal for gout therapy. ACS PublicationsS Modani, A Gunnam, B Yadav, AK Nangia, NR ShastriCrystal Growth & Design, 2020•ACS Publications 2020;20:3577–83. https://doi.org/10.1021/ACS.CGD.0C00106.
[91] Rosa J, Machado TC, Da Silva AK, Kuminek G, Bortolluzzi AJ, Caon T, et al. Isoniazid-resveratrol cocrystal: a novel alternative for topical treatment of cutaneous tuberculosis. ACS PublicationsJ Rosa, TC Machado, AK Da Silva, G Kuminek, AJ Bortolluzzi, T Caon, SG CardosoCrystal Growth & Design, 2019•ACS Publications 2019;19:5029–36. https://doi.org/10.1021/ACS.CGD.9B00313.
[92] Weng J, Wong SN, Xu X, Xuan B, Wang C, Chen R, et al. Cocrystal engineering of itraconazole with suberic acid via rotary evaporation and spray drying. ACS PublicationsJ Weng, SN Wong, X Xu, B Xuan, C Wang, R Chen, CC Sun, R Lakerveld, PCL KwokCrystal Growth & Design, 2019•ACS Publications 2019;19:2736–45. https://doi.org/10.1021/ACS.CGD.8B01873.
[93] Eisa M, Brondi M, Williams C, Hejl R, Baltrusaitis J. From urea to urea cocrystals: A critical view of conventional and emerging nitrogenous fertilizer materials for improved environmental sustainability. Sustainable Chemistry for the Environment 2025;9. https://doi.org/10.1016/j.scenv.2025.100209.
[94] Solomon C, Sârbu I, Anuța V, Ozon EA, Musuc AM, Fița AC, et al. PREFORMULATION STUDIES OF TABLETS CONTAINING RIVAROXABAN – NIACINAMIDE COCRYSTALLIZATION COMPOUNDS. Farmacia 2025;73:706–12. https://doi.org/10.31925/farmacia.2025.3.17.
[95] Wang Z, Li S, Li Q, Wang W, Liu M, Yang S, et al. A Novel Cocrystal of Daidzein with Piperazine to Optimize the Solubility, Permeability and Bioavailability of Daidzein. Molecules 2024;29. https://doi.org/10.3390/molecules29081710.
[96] Kim J, Lim S, Kim M, Ban E, Kim Y, Kim A. Using the Cocrystal Approach as a Promising Drug Delivery System to Enhance the Dissolution and Bioavailability of Formononetin Using an Imidazole Coformer. Pharmaceuticals 2024;17. https://doi.org/10.3390/ph17111444.
[97] Ishihara S, Hattori Y, Otsuka M, Sasaki T. Cocrystal formation through solid-state reaction between ibuprofen and nicotinamide revealed using THz and IR spectroscopy with multivariate analysis. Crystals (Basel) 2020;10:1–12. https://doi.org/10.3390/cryst10090760.
[98] Sakhiya DC, Borkhataria CH. A review on advancement of cocrystallization approach and a brief on screening, formulation and characterization of the same. Heliyon 2024;10. https://doi.org/10.1016/j.heliyon.2024.e29057.
[99] Aitipamula S, Vangala VR. X-Ray Crystallography and its Role in Understanding the Physicochemical Properties of Pharmaceutical Cocrystals. J Indian Inst Sci, vol. 97, Springer International Publishing; 2017, p. 227–43. https://doi.org/10.1007/s41745-017-0026-4.
[100] Bruni G, Maggi L, Mustarelli P, Sakaj M, Friuli V, Ferrara C, et al. Enhancing the Pharmaceutical Behavior of Nateglinide by Cocrystallization: Physicochemical Assessment of Cocrystal Formation and Informed Use of Differential Scanning Calorimetry for Its Quantitative Characterization. J Pharm Sci 2019;108:1529–39. https://doi.org/10.1016/j.xphs.2018.11.033.
[101] Saganowska P, Wesolowski M. DSC as a screening tool for rapid co-crystal detection in binary mixtures of benzodiazepines with co-formers. J Therm Anal Calorim 2018;133:785–95. https://doi.org/10.1007/s10973-017-6858-3.
[102] Kumar A, Singh P, Nanda A. Hot stage microscopy and its applications in pharmaceutical characterization. Appl Microsc 2020;50. https://doi.org/10.1186/s42649-020-00032-9.
[103] Ali HRH, Alhalaweh A, Mendes NFC, Ribeiro-Claro P, Velaga SP. Solid-state vibrational spectroscopic investigation of cocrystals and salt of indomethacin. CrystEngComm 2012;14:6665–74. https://doi.org/10.1039/c2ce25801c.
[104] Du S, Wang Y, Wu S, Yu B, Shi P, Bian L, et al. Two novel cocrystals of lamotrigine with isomeric bipyridines and in situ monitoring of the cocrystallization. European Journal of Pharmaceutical Sciences 2017;110:19–25. https://doi.org/10.1016/j.ejps.2017.06.001.
[105] Du Y, Xue J, Cai Q, Zhang Q. Spectroscopic investigation on structure and pH dependent Cocrystal formation between gamma-aminobutyric acid and benzoic acid. Spectrochim Acta A Mol Biomol Spectrosc 2018;191:377–81. https://doi.org/10.1016/j.saa.2017.10.036.
[106] Peach AA, Hirsh DA, Holmes ST, Schurko RW. Mechanochemical syntheses and 35Cl solid-state NMR characterization of fluoxetine HCl cocrystals. CrystEngComm 2018;20:2780–92. https://doi.org/10.1039/c8ce00378e.
[107] Karimi-Jafari M, Padrela L, Walker GM, Croker DM. Creating cocrystals: A review of pharmaceutical cocrystal preparation routes and applications. Cryst Growth Des 2018;18:6370–87. https://doi.org/10.1021/acs.cgd.8b00933.
[108] BIJAY KUMAR YADAV, ATIF KHURSHEED, RATTAN DEEP SINGH. COCRYSTALS: A COMPLETE REVIEW ON CONVENTIONAL AND NOVEL METHODS OF ITS FORMATION AND ITS EVALUATION. Asian Journal of Pharmaceutical and Clinical Research 2019:68–74. https://doi.org/10.22159/ajpcr.2019.v12i7.33648.
[109] Chaudhari S, Nikam SA, Khatri N, Wakde S. CO-CRYSTALS: A REVIEW. Journal of Drug Delivery and Therapeutics 2018;8:350–8. https://doi.org/10.22270/jddt.v8i6-s.2194.
[110] Banerjee M, Nimkar K, Naik S, Patravale V. Unlocking the potential of drug-drug cocrystals–A comprehensive review. Journal of Controlled Release. 2022;1;348:456-69. https://doi.org/10.1016/j.jconrel.2022.06.003
[111] Sarangi S, Remya PN, Damodharan N. Advances in solvent based cocrystallization: Bridging the gap between theory and practice. Journal of Drug Delivery Science and Technology. 2024; 1;95:105619. https://doi.org/10.1016/j.jddst.2024.105619
Article Sidebar
Published
Sep 30, 2025
Article Details
How to Cite
Nishit Patel, Dr. Pragnesh Patani, & Dr. Shweta Paroha. (2025). PHARMACEUTICAL CO-CRYSTALS: A NOVEL STRATEGY FOR ENHANCING DRUG PERFORMANCE. Journal of Population Therapeutics and Clinical Pharmacology, 32(7), 1922-1939. https://doi.org/10.53555/savwm114
Section
Articles
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
Author Biographies
Nishit Patel
Khyati College of Pharmacy, Palodia, Ahmedabad, Gujarat, India.
Dr. Pragnesh Patani
Khyati College of Pharmacy, Palodia, Ahmedabad, Gujarat, India.
Dr. Shweta Paroha
Khyati College of Pharmacy, Palodia, Ahmedabad, Gujarat, India.
How to Cite
Nishit Patel, Dr. Pragnesh Patani, & Dr. Shweta Paroha. (2025). PHARMACEUTICAL CO-CRYSTALS: A NOVEL STRATEGY FOR ENHANCING DRUG PERFORMANCE. Journal of Population Therapeutics and Clinical Pharmacology, 32(7), 1922-1939. https://doi.org/10.53555/savwm114