• NAVEEN BIDHURI Department of Pharmaceutics, Noida Institute of Engineering and Technology, Pharmacy Institute, Greater Noida, Gautam Buddha Nagar-201306, Uttar Pradesh, India
  • SWARUPANJALI PADHI Department of Pharmaceutics, Noida Institute of Engineering and Technology, Pharmacy Institute, Greater Noida, Gautam Buddha Nagar-201306, Uttar Pradesh, India



Slurry Conversion, Cocrystal engineering, Antisolvent technique, neat grinding,, Solid dosage forms, Crystallization


Over the past few decades, co-crystal Drug Delivery System (DDS) has attracted interest due to their potential to increase the solubility, stability, and bioavailability of medications that aren't sufficiently soluble. In this study, we factualized to develop a co-crystal chemical delivery system utilizing an experimental model. We utilized caffeine and succinic acid as model chemicals and prepared co-crystals utilizing different methods, including solvent evaporation, grinding, and spray drying. The co-crystals have been characterized utilizing X-ray powder diffraction, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. The solubility and dissolution rate of the co-crystals has been evaluated in simulated digestive and intestinal juices. The outcomes showed that when compared to co-crystals made utilizing the solvent evaporation and spray drying procedures, those organized utilizing the grinding approach exhibited the maximum solubility and dissolution rate. This study underlines the potential of co-crystals as a workable method for enhancing the administration of pharmaceuticals that are not adequately soluble and provides a helpful experimental paradigm for the development of co-crystal chemical delivery systems.


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Cerreia Vioglio PC, Chierotti MR, Gobetto R. Pharmaceutical aspects of salt and cocrystal forms of APIs and characterization challenges. Adv Drug Deliv Rev. 2017 Aug 1;117:86-110. doi: 10.1016/j.addr.2017.07.001. PMID 28687273.

Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B. 2015 Sep 1;5(5):442-53. doi: 10.1016/j.apsb.2015.07.003. PMID 26579474.

Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des. 2009 Jun 3;9(6):2950-67. doi: 10.1021/cg900129f, PMID 19503732.

Datta S, Grant DJ. Crystal structures of drugs: advances in determination, prediction and engineering. Nat Rev Drug Discov. 2004 Jan;3(1):42-57. doi: 10.1038/nrd1280, PMID 14708020.

Umeda Y, Fukami T, Furuishi T, Suzuki T, Tanjoh K, Tomono K. Characterization of multicomponent crystal formed between indomethacin and lidocaine. Drug Dev Ind Pharm. 2009 Jul 1;35(7):843-51. doi: 10.1080/03639040802660489, PMID 19466900.

Karpinski PH. Polymorphism of active pharmaceutical ingredients. Chem Eng Technol. 2006 Feb;29(2):233-7.

Khankari RK, Grant DJW. Pharmaceutical hydrates. Thermochim Acta. 1995 Jan 2;248:61-79. doi: 10.1016/0040-6031(94)01952-D.

Healy AM, Worku ZA, Kumar D, Madi AM. Pharmaceutical solvates, hydrates and amorphous forms: a special emphasis on cocrystals. Adv Drug Deliv Rev. 2017 Aug 1;117:25-46. doi: 10.1016/j.addr.2017.03.002. PMID 28342786.

Remenar JF, Morissette SL, Peterson ML, Moulton B, MacPhee JM, Guzman HR. Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids. J Am Chem Soc. 2003 Jul 16;125(28):8456-7. doi: 10.1021/ja035776p, PMID 12848550.

Duggirala NK, Perry ML, Almarsson O, Zaworotko MJ. Pharmaceutical cocrystals: along the path to improved medicines. Chem Commun (Camb). 2016;52(4):640-55. doi: 10.1039/c5cc08216a, PMID 26565650.

Yousef MAE, Vangala VR. Pharmaceutical cocrystals: molecules, crystals, formulations, medicines. Cryst Growth Des. 2019 Oct 31;19(12):7420-38. doi: 10.1021/acs.cgd.8b01898.

Karimi Jafari M, Padrela L, Walker GM, Croker DM. Creating cocrystals: a review of pharmaceutical cocrystal preparation routes and applications. Cryst Growth Des. 2018 Aug 10;18(10):6370-87. doi: 10.1021/acs.cgd.8b00933.

Novartis Pharmaceuticals Corporation. Drug trials snapshot: Entresto. Approval Date. Jul 7, 2015. Available from:

Merck. Sharpe, Dohme corp. Drug trials snapshots: Steglatro. Approval Date. Dec 19, 2017. Available from:

Videla S, Lahjou M, Vaque A, Sust M, Encabo M, Soler L. Single‐dose pharmacokinetics of co‐crystal of tramadol–celecoxib: results of a four-way randomized open‐label phase I clinical trial in healthy subjects. Br J Clin Pharmacol. 2017 Dec;83(12):2718-28. doi: 10.1111/bcp.13395, PMID 28810061.

Kimoto K, Yamamoto M, Karashima M, Hohokabe M, Takeda J, Yamamoto K. Pharmaceutical cocrystal development of TAK-020 with enhanced oral absorption. Crystals. 2020 Mar 18;10(3):211. doi: 10.3390/cryst10030211.

Banerjee M, Nimkar K, Naik S, Patravale V. Unlocking the potential of drug-drug cocrystals–a comprehensive review. J Control Release. 2022 Aug 1;348:456-69. doi: 10.1016/j.jconrel.2022.06.003. PMID 35691502.

Walsh RD, Bradner MW, Fleischman S, Morales LA, Moulton B, Rodriguez Hornedo N. Crystal engineering of the composition of pharmaceutical phases. Chem Commun (Camb). 2003;2003(2):186-7. doi: 10.1039/b208574g, PMID 12585383.

Childs SL, Chyall LJ, Dunlap JT, Smolenskaya VN, Stahly BC, Stahly GP. Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids. J Am Chem Soc. 2004 Oct 20;126(41):13335-42. doi: 10.1021/ja048114o, PMID 15479089.

Fleischman SG, Kuduva SS, McMahon JA, Moulton B, Bailey Walsh RD, Rodriguez Hornedo N. Crystal engineering of the composition of pharmaceutical phases: multiple-component crystalline solids involving carbamazepine. Cryst Growth Des. 2003 Nov 5;3(6):909-19. doi: 10.1021/cg034035x.

Kale DP, Zode SS, Bansal AK. Challenges in translational development of pharmaceutical cocrystals. J Pharm Sci. 2017 Feb 1;106(2):457-70. doi: 10.1016/j.xphs.2016.10.021. PMID 27914793.

Chiarella RA, Davey RJ, Peterson ML. Making co-crystals the utility of ternary phase diagrams. Cryst Growth Des. 2007 Jul 3;7(7):1223-6. doi: 10.1021/cg070218y.

Blagden N, Berry DJ, Parkin A, Javed H, Ibrahim A, Gavan PT. Current directions in co-crystal growth. New J Chem. 2008;32(10):1659-72. doi: 10.1039/b803866j.

Weyna DR, Shattock T, Vishweshwar P, Zaworotko MJ. Synthesis and structural characterization of cocrystals and pharmaceutical cocrystals: mechanochemistry vs slow evaporation from solution. Cryst Growth Des. 2009 Feb 4;9(2):1106-23. doi: 10.1021/cg800936d.

Basavoju S, Boström D, Velaga SP. Pharmaceutical cocrystal and salts of norfloxacin. Cryst Growth Des. 2006 Dec 6;6(12):2699-708. doi: 10.1021/cg060327x.

Chow SF, Chen M, Shi L, Chow AH, Sun CC. Simultaneously improving the mechanical properties, dissolution performance, and hygroscopicity of ibuprofen and flurbiprofen by cocrystallization with nicotinamide. Pharm Res. 2012 Jul;29(7):1854-65. doi: 10.1007/s11095-012-0709-5, PMID 22359146.

Modani S, Gunnam A, Yadav B, Nangia AK, Shastri NR. Generation and evaluation of pharmacologically relevant drug–drug cocrystal for gout therapy. Cryst Growth Des. 2020 May 18;20(6):3577-83. doi: 10.1021/acs.cgd.0c00106.

Nikam VJ, Patil SB. Pharmaceutical cocrystals of nebivolol hydrochloride with enhanced solubility. J Cryst Growth. 2020 Mar 15;534:125488. doi: 10.1016/j.jcrysgro.2020.125488.

Rodrigues M, Baptista B, Lopes JA, Sarraguça MC. Pharmaceutical cocrystallization techniques. Advances and challenges. Int J Pharm. 2018 Aug 25;547(1-2):404-20. doi: 10.1016/j.ijpharm.2018.06.024. PMID 29890258.

Wang IC, Lee MJ, Sim SJ, Kim WS, Chun NH, Choi GJ. Anti-solvent co-crystallization of carbamazepine and saccharin. Int J Pharm. 2013 Jun 25;450(1-2):311-22. doi: 10.1016/j.ijpharm.2013.04.012. PMID 23598078.

Nishimaru M, Kudo S, Takiyama H. Cocrystal production method reducing deposition risk of undesired single component crystals in anti-solvent cocrystallization. J Ind Eng Chem. 2016 Apr 25;36:40-3. doi: 10.1016/j.jiec.2016.01.027.

Lee MJ, Wang IC, Kim MJ, Kim P, Song KH, Chun NH. Controlling the polymorphism of carbamazepine-saccharin cocrystals formed during antisolvent cocrystallization using kinetic parameters. Korean J Chem Eng. 2015 Sep;32:1910-7.

Chun NH, Wang IC, Lee MJ, Jung YT, Lee S, Kim WS. Characteristics of indomethacin-saccharin (IMC-SAC) co-crystals prepared by an anti-solvent crystallization process. Eur J Pharm Biopharm. 2013;85(3 Pt B):854-61. doi: 10.1016/j.ejpb.2013.02.007. PMID 23454054.

Mullin JW. Crystallization. 4th ed; 2001. p. 536-75.

Yu ZQ, Chow PS, Tan RBH. Operating regions in cooling cocrystallization of caffeine and glutaric acid in acetonitrile. Cryst Growth Des. 2010 May 5;10(5):2382-7. doi: 10.1021/cg100198u.

Rahman F, Winantari AN, Setyawan D, Siswandono S. Comparison study of grinding and slurry method on physicochemical characteristic of acyclovir–succinic acid cocrystal. Asian J Pharm Clin Res. 2017;10(3):153-8. doi: 10.22159/ajpcr.2017.v10i3.15925.

Hickey MB, Peterson ML, Scoppettuolo LA, Morrisette SL, Vetter A, Guzman H. Performance comparison of a co-crystal of carbamazepine with marketed product. Eur J Pharm Biopharm. 2007 Aug 1;67(1):112-9. doi: 10.1016/j.ejpb.2006.12.016. PMID 17292592.

Sheikh AY, Rahim SA, Hammond RB, Roberts KJ. Scalable solution cocrystallization: case of carbamazepine-nicotinamide I. Cryst Eng Comm. 2009;11(3):501-9. doi: 10.1039/B813058B.

Leung DH, Lohani S, Ball RG, Canfield N, Wang Y, Rhodes T. Two novels pharmaceutical cocrystals of a development compound–screening, scale-up, and characterization. Cryst Growth Des. 2012 Mar 7;12(3):1254-62. doi: 10.1021/cg201270s.

Dai XL, Yao J, Wu C, Deng JH, Mo YH, Lu TB. Solubility and permeability improvement of allopurinol by cocrystallization. Cryst Growth Des. 2020 Jun 10;20(8):5160-8. doi: 10.1021/acs.cgd.0c00326.

Ouiyangkul P, Tantishaiyakul V, Hirun N. Exploring potential coformers for oxyresveratrol using principal component analysis. Int J Pharm. 2020 Sep 25;587:119630. doi: 10.1016/j.ijpharm.2020.119630. PMID 32652183.

Yuan ZJ, Dai XL, Huang YL, Lu TB, Chen JM. Cocrystals of penciclovir with hydroxybenzoic acids: synthesis, crystal structures, and physicochemical evaluation. Cryst Growth Des. 2020 Apr 21;20(6):4108-19. doi: 10.1021/acs.cgd.0c00374.

Harfouche LC, Couvrat N, Sanselme M, Brandel C, Cartigny Y, Petit S. Discovery of new proxyphylline-based chiral cocrystals: solid state landscape and dehydration mechanism. Cryst Growth Des. 2020 May 1;20(6):3842-50. doi: 10.1021/acs.cgd.0c00149.

Nagapudi K, Umanzor EY, Masui C. High-throughput screening and scale-up of cocrystals using resonant acoustic mixing. Int J Pharm. 2017 Apr 15;521(1-2):337-45. doi: 10.1016/j.ijpharm.2017.02.027. PMID 28229947.

Michalchuk AAL, Hope KS, Kennedy SR, Blanco MV, Boldyreva EV, Pulham CR. Ball-free mechanochemistry: in situ real-time monitoring of pharmaceutical co-crystal formation by resonant acoustic mixing. Chem Commun (Camb). 2018;54(32):4033-6. doi: 10.1039/c8cc02187b, PMID 29619475.

Am Ende DJ, Anderson SR, Salan JS. Development and scale-up of cocrystals using resonant acoustic mixing. Org Process Res Dev. 2014 Feb 21;18(2):331-41. doi: 10.1021/op4003399.

Kaupp G. Solid-state molecular syntheses: complete reactions without auxiliaries based on the new solid-state mechanism. CrystEngCommission. 2003;5(23):117-33.

Maheshwari C, Jayasankar A, Khan NA, Amidon GE, Rodriguez Hornedo N. Factors that influence the spontaneous formation of pharmaceutical cocrystals by simply mixing solid reactants. CrystEngComm. 2009;11(3):493-500. doi: 10.1039/B812264D.

Chadwick K, Davey R, Cross W. How does grinding produce co-crystals? Insights from the case of benzophenone and diphenylamine. CrystEngComm. 2007;9(9). doi: 10.1039/b709411f.

Nguyen KL, Friscic T, Day GM, Gladden LF, Jones W. Terahertz time-domain spectroscopy and the quantitative monitoring of mechanochemical cocrystal formation. Nat Mater. 2007 Mar;6(3):206-9. doi: 10.1038/nmat1848, PMID 17322867.

Friscic T, Jones W. Recent advances in understanding the mechanism of cocrystal formation via grinding. Cryst Growth Des. 2009 Mar 4;9(3):1621-37. doi: 10.1021/cg800764n.

Fischer F, Scholz G, Benemann S, Rademann K, Emmerling F. Evaluation of the formation pathways of cocrystal polymorphs in liquid-assisted syntheses. CrystEngComm. 2014;16(35):8272-8. doi: 10.1039/C4CE00472H.

Germann LS, Arhangelskis M, Etter M, Dinnebier RE, Friscic T. Challenging the Ostwald rule of stages in mechanochemical cocrystallisation. Chem Sci. 2020;11(37):10092-100. doi: 10.1039/d0sc03629c, PMID 34094270.

Wicaksono Y, Setyawan D, Siswandono S. Formation of ketoprofen-malonic acid cocrystal by solvent evaporation method. Indones J Chem. 2017 Jul 1;17(2):161-6. doi: 10.22146/ijc.24884.

Kshirsagar SM, Chatale BC, Amin PD. Comparative evaluation of ibuprofen co-crystals prepared by solvent evaporation and hot melt extrusion technology. J Drug Deliv Sci Technol. 2022 Jan 1;67:103003. doi: 10.1016/j.jddst.2021.103003.

Neurohr C, Erriguible A, Laugier S, Subra Paternault P. Challenge of the supercritical antisolvent technique Sas to prepare cocrystal-pure powders of naproxen-nicotinamide. Chem Eng J. 2016 Nov 1;303:238-51. doi: 10.1016/j.cej.2016.05.129.

Mohite R, Mehta P, Arulmozhi S, Kamble R, Pawar A, Bothiraja C. Synthesis of fisetin co-crystals with caffeine and nicotinamide using the cooling crystallization technique: biopharmaceutical studies. New J Chem. 2019;43(34):13471-9.

Soares FLF, Carneiro RL. Green synthesis of ibuprofen–nicotinamide cocrystals and in-line evaluation by Raman spectroscopy. Cryst Growth Des. 2013 Apr 3;13(4):1510-7. doi: 10.1021/cg3017112.

Zhang S, Chen H, Rasmuson ÅC. Thermodynamics and crystallization of a theophylline–salicylic acid cocrystal. Cryst Eng Commission 2015;17(22):4125-35. doi: 10.1039/C5CE00240K.

Gc Z, Lin Hl, Lin Sy. Thermal analysis and FTIR spectral curve-fitting investigation of formation mechanism and stability of indomethacin-saccharin cocrystals via solid-state grinding process. J Pharm Biomed Anal. 2012 Jul 1;66:162-9.

Chaudhari KR, Savjani JK, Savjani KT, Shah H. Improved pharmaceutical properties of ritonavir through co-crystallization approach with liquid-assisted grinding method. Drug Dev Ind Pharm. 2021 Oct 3;47(10):1633-42. doi: 10.1080/03639045.2022.2042553, PMID 35156497.

Yan Y, Chen JM, Lu TB. Thermodynamics and preliminary pharmaceutical characterization of a melatonin–pimelic acid cocrystal prepared by a melt crystallization method. CrystEngComm. 2015;17(3):612-20. doi: 10.1039/C4CE01921K.

Guo M, Sun X, Chen J, Cai T. Pharmaceutical cocrystals: a review of preparations, physicochemical properties and applications. Acta Pharm Sin B. 2021 Aug 1;11(8):2537-64. doi: 10.1016/j.apsb.2021.03.030. PMID 34522597.

Nawatila R, W AN, Siswodihardjo S, Setyawan D. Preparation of acyclovir-nicotinamide cocrystal by solvent evaporation technique with variation of solvent. Asian J Pharm Clin Res. 2017 Mar;10(3):283-7. doi: 10.22159/ajpcr.2017.v10i3.16149.

Mukherjee A, Rogers RD, Myerson AS. Cocrystal formation by ionic liquid-assisted grinding: case study with cocrystals of caffeine. CrystEngComm. 2018;20(27):3817-21. doi: 10.1039/C8CE00859K.

Yan Y, Chen JM, Lu TB. Thermodynamics and preliminary pharmaceutical characterization of a melatonin–pimelic acid cocrystal prepared by a melt crystallization method. CrystEngComm. 2015;17(3):612-20. doi: 10.1039/C4CE01921K.

Liu X, Lu M, Guo Z, Huang L, Feng X, Wu C. Improving the chemical stability of amorphous solid dispersion with cocrystal technique by hot melt extrusion. Pharm Res. 2012 Mar;29(3):806-17. doi: 10.1007/s11095-011-0605-4, PMID 22009589.

Aakeroy CB, Salmon DJ, Smith MM, Desper J. Cyanophenyloximes: reliable and versatile tools for hydrogen-bond directed supramolecular synthesis of cocrystals. Cryst Growth Des. 2006 Apr 5;6(4):1033-42. doi: 10.1021/cg0600492.

Wu TK, Lin SY, Lin HL, Huang YT. Simultaneous DSC-FTIR microspectroscopy used to screen and detect the co-crystal formation in real time. Bioorg Med Chem Lett. 2011 May 15;21(10):3148-51. doi: 10.1016/j.bmcl.2011.03.001. PMID 21450466.

Jiang L, Huang Y, Zhang Q, He H, Xu Y, Mei X. Preparation and solid-state characterization of dapsone drug–drug co-crystals. Cryst Growth Des. 2014 Sep 3;14(9):4562-73. doi: 10.1021/cg500668a.

Parrott EPJ, Zeitler JA, Friscic T, Pepper M, Jones W, Day GM. Testing the sensitivity of terahertz spectroscopy to changes in molecular and supramolecular structure: a study of structurally similar cocrystals. Cryst Growth Des. 2009 Mar 4;9(3):1452-60. doi: 10.1021/cg8008893.

Stevens JS, Byard SJ, Schroeder SL. Salt or co-crystal? Determination of protonation state by X-ray photoelectron spectroscopy (XPS). J Pharm Sci. 2010 Nov 1;99(11):4453-7. doi: 10.1002/jps.22164, PMID 20845443.

Vogt FG, Clawson JS, Strohmeier M, Edwards AJ, Pham TN, Watson SA. Solid-state NMR analysis of organic cocrystals and complexes. Cryst Growth Des. 2009 Feb 4;9(2):921-37. doi: 10.1021/cg8007014.

El-Gizawy SA, Osman MA, Arafa MF, El Maghraby GM. Aerosil as a novel co-crystal co-former for improving the dissolution rate of hydrochlorothiazide. Int J Pharm. 2015 Jan 30;478(2):773-8. doi: 10.1016/j.ijpharm.2014.12.037. PMID 25529436.

Li J, Liu P, Liu JP, Zhang WL, Yang JK, Fan YQ. Novel tanshinone II a ternary solid dispersion pellets prepared by a single-step technique: in vitro and in vivo evaluation. Eur J Pharm Biopharm. 2012 Feb 1;80(2):426-32. doi: 10.1016/j.ejpb.2011.11.003. PMID 22119664.

Gurunath S, Nanjwade BK, Patila PA. Enhanced solubility and intestinal absorption of candesartan cilexetil solid dispersions using everted rat intestinal sacs. Saudi Pharm J. 2014 Jul 1;22(3):246-57. doi: 10.1016/j.jsps.2013.03.006. PMID 25067902.

Sathali AA, Selvaraj V. Enhancement of solubility and dissolution rate of racecadotril by solid dispersion methods. J Curr Chem Pharm Sci. 2012;2(3):209-25.

Fukte SR, Wagh MP, Rawat S. Conformer selection: an important tool in cocrystal formation. Int J Pharm Pharm Sci. 2014;6(7):9-14.

Seefeldt K, Miller J, Alvarez Nunez F, Rodriguez Hornedo N. Crystallization pathways and kinetics of carbamazepine-nicotinamide cocrystals from the amorphous state by in situ thermomicroscopy, spectroscopy, and calorimetry studies. J Pharm Sci. 2007 May 1;96(5):1147-58. doi: 10.1002/jps.20945, PMID 17455346.

Guo C, Zhang Q, Zhu B, Zhang Z, Ma X, Dai W. Drug-drug cocrystals provide significant improvements of drug properties in treatment with progesterone. Cryst Growth Des. 2020 Apr 7;20(5):3053-63. doi: 10.1021/acs.cgd.9b01688.

Duggirala NK, Smith AJ, Wojtas L, Shytle RD, Zaworotko MJ. Physical stability enhancement and pharmacokinetics of a lithium ionic cocrystal with glucose. Cryst Growth Des. 2014 Nov 5;14(11):6135-42. doi: 10.1021/cg501310d.



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