• BIJAY KUMAR YADAV Deparment of School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India.
  • ATIF KHURSHEED Department of School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India.
  • RATTAN DEEP SINGH Department of School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India.


The active moiety with poor solubility is posing a challenge in drug development which may reduce the effectiveness in patients when administered orally. Cocrystal formation is one of the latest approaches for improving the various parameters of a drug molecule such as solubility, melting point, pharmacokinetic, pharmacodynamic, and bioavailability. Cocrystals are crystalline single state materials composed of two or more than two different molecular amalgams held together in a fixed stoichiometric ratio. There are various techniques used for the preparation of cocrystals such as solvent evaporation, grinding, and cooling crystallization. The quantitative and qualitative aspects of these cocrystals are evaluated using various validated instruments such as nuclear magnetic resonance, powder X-ray diffraction, and differential scanning calorimetry.

Keywords: Cocrystals,, Coformers,, Bioavailability,, Crystallization,, Grinding,, Solubility.


1. Aakeröy CB, Champness NR, Janiak C. Recent advances in crystal engineering. CrystEngComm 2010;12:22-43.
2. Almarsson O, Zaworotko MJ. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines? Chem Commun (Camb) 2004; ???:1889 96.
3. Diniz SL, Souza MS, Ellena J. Crystal engineering applied to the development of novel pharmaceutical solid forms with improved bioavailability: The co crystals case. Adv Bioequi Bioavail 2018;1:1-3.
4. Bolla G, Nangia A. Pharmaceutical cocrystals: Walking the talk. Chem Commun (Camb) 2016;52:8342-60.
5. Chadha R, Bhalla Y, Vashisht MK, Chadha K. Cocrystallization in nutraceuticals. In: Recrystallization in Materials Processing. S.l.: IntechOpen; 2015.
6. Bysouth SR, Bis JA, Igo D. Cocrystallization via planetary milling: Enhancing throughput of solid-state screening methods. Int J Pharm 2011;411:169-71.
7. Rehder S, Klukkert M, Löbmann KA, Strachan CJ, Sakmann A, Gordon K, et al. Investigation of the formation process of two piracetam cocrystals during grinding. Pharmaceutics 2011;3:706-22.
8. Rehder S, Klukkert M, Löbmann KA, Strachan CJ, Sakmann A, Gordon K, et al. Investigation of the formation process of two piracetam cocrystals during grinding. Pharmaceutics 2011;3:706-22.
9. Jung S, Choi I, Kim I. Liquid-assisted grinding to prepare a cocrystal of adefovir dipivoxil thermodynamically less stable than its neat phase. Crystals 2015;5:583-91.
10. Dhumal RS, Kelly AL, York P, Coates PD, Paradkar A. Cocrystalization and simultaneous agglomeration using hot melt extrusion. Pharm Res 2010;27:2725-33.
11. Boksa K, Otte A, Pinal R. Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion. J Pharm Sci 2014;103:2904-10.
12. Manin AN, Voronin AP, Drozd KV, Manin NG, Bauer-Brandl A, Perlovich GL. Cocrystal screening of hydroxybenzamides with benzoic acid derivatives: A comparative study of thermal and solution-based methods. Eur J Pharm Sci 2014;65:56-64.
13. Kumar S. Pharmaceutical cocrystals: An overview. Indian J Pharm Sci 2018;79:858-71.
14. Maroyi A. A comparative study of medicinal plants used in rural areas of Namibia and Zimbabwe. Indian J Indian Knowl 2015;14:401-6.
15. Mirza S, Miroshnyk I, Heinämäki J, Yliruusi J. Co-crystals: An emerging approach for enhancing properties of pharmaceutical solids. Dosis 2008;24:90-6.
16. Oberoi LM, Alexander KS, Riga AT. Study of interaction between ibuprofen and nicotinamide using differential scanning calorimetry, spectroscopy, and microscopy and formulation of a fast-acting and possibly better ibuprofen suspension for osteoarthritis patients. J Pharm Sci 2005;94:93-101.
17. Remenar JF, Morissette SL, Peterson ML, Moulton B, MacPhee JM, Guzmán HR, et al. Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids. J Am Chem Soc 2003;125:8456-7.
18. Basavoju S, Boström D, Velaga SP. Pharmaceutical cocrystal and salts of norfloxacin. Cryst Growth Des 2006;6:2699-708.
19. Childs SL, Hardcastle KI. Cocrystals of piroxicam with carboxylic acids. Cryst Growth Des 2007;7:1291-304.
20. Nawatila R, Nuneik WA, Siswodhiardjo S, Setyawann D. Prepartion of acyclovir nicotinamide co-crystal with solvent evaporation techniquewith variation of the solvent. Asian J Pharm Clin Res 2017;10:283-7.
21. Chun NH, Lee MJ, Song GH, Chang KY, Kim CS, Choi GJ. Combined anti-solvent and cooling method of manufacturing indomethacin-saccharin (IMC–SAC) co-crystal powders. J Cryst Growth 2014;408:112-8.
22. Bagde SA, Upadhye KP, Dixit GR, Bakhle SS. Formulation and evaluation of co-crystals of poorly water soluble drug. Int J Pharm Res 2016;7:4988-97.
23. Sugandha K, Kaity S, Mukherjee S, Isaac J, Ghosh A. Solubility enhancement of ezetimibe by a cocrystal engineering technique. Cryst Growth Des 2014;14:4475-86.
24. Aher S, Dhumal R, Mahadik K, Paradkar A, York P. Ultrasound assisted cocrystallization from solution (USSC) containing a non-congruently soluble cocrystal component pair: Caffeine/maleic acid. Eur J Pharm Sci 2010;41:597-602.
25. Grossjohann C, Serrano DR, Paluch KJ, O’Connell P, Vella-Zarb L, Manesiotis P, et al. Polymorphism in sulfadimidine/4-aminosalicylic acid cocrystals: Solid-state characterization and physicochemical properties. J Pharm Sci 2015;104:1385-98.
26. Salaman CR, Ces SV, Tesson N, Castano MT. Co-Crystals of Venlafaxine and Celecoxib. Europe: Google Patents; 2013.
27. Rahman F, Winantari AN, Setyawan D, Siswandono S. Comparison study of grinding and slurry method on physicochemical characteristic of aclycovir-succinic acid cocrystal. Asian J Pharm Clin Res 2017;10:153-8.
28. Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: An overview. Int J Pharm 2011;419:1-11.
29. Rantakylä M, Jäntti M, Aaltonen O, Hurme M. The effect of initial drop size on particle size in the supercritical antisolvent precipitation (SAS) technique. J Supercrit Fluids 2002;24:251-63.
30. Adeli E. The use of supercritical anti-solvent (SAS) technique for preparation of Irbesartan-Pluronic® F-127 nanoparticles to improve the drug dissolution. Powder Technol 2016;298:65-72.
31. Kalani M, Yunus R. Application of supercritical antisolvent method in drug encapsulation: A review. Int J Nanomedicine 2011;6:1429-42.
32. 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;21:3148-51.
33. Yamashita H, Hirakura Y, Yuda M, Terada K. Coformer screening using thermal analysis based on binary phase diagrams. Pharm Res 2014;31:1946-57.
34. 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;14:4562-73.
35. 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;478:773-8.
36. Parrott EP, Zeitler JA, Fris?c?ic? T, Pepper M, Jones W, Day GM, et al. Testing the sensitivity of terahertz spectroscopy to changes in molecular and supramolecular structure: a study of structurally similar cocrystals. Cryst Growth Des 2009;9:1452-60.
37. Stevens JS, Byard SJ, Schroeder SL. Salt or co-crystal? Determination of protonation state by X-ray photoelectron spectroscopy (XPS). J Pharm Sci 2010;99:4453-7.
38. van der Wel PC. New applications of solid-state NMR in structural biology. Emerg Top Life Sci 2018;2:57-67.
39. Kijac AZ, Li Y, Sligar SG, Rienstra CM. Magic-angle spinning solid-state NMR spectroscopy of nanodisc-embedded human CYP3A4. Biochemistry 2007;46:13696-703.
40. Bolla G, Chernyshev V, Nangia A. Acemetacin cocrystal structures by powder X-ray diffraction. IUCrJ 2017;4:206-14.
41. Padrela L, de Azevedo EG, Velaga SP. Powder X-ray diffraction method for the quantification of cocrystals in the crystallization mixture. Drug Dev Ind Pharm 2012;38:923-9.
42. Vaghela P, Tank H, Jalpa P. Cocrystals: A novel approach to improve the physicochemical and mechanical properties. Indo Am J Pharm Res 2014;4:5055-65.
43. Fukte S, Wagh MP, Rawat S. Coformer selection: An important tool in cocrystal formation. Int J Pharm Pharm Sci 2014;6:9-14.
44. Cheney ML, Weyna DR, Shan N, Hanna M, Wojtas L, Zaworotko MJ. Coformer selection in pharmaceutical cocrystal development: A case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics. J Pharm Sci 2011;100:2172-81.
45. Najar AA, Azim Y. Pharmaceutical co-crystals: A new paradigm of crystal engineering. J Indian Inst Sci 2014;94:45-68.
46. Akhalwaya S, van Vuuren S, Patel M. An in vitro investigation of indigenous South African medicinal plants used to treat oral infections. J Ethnopharmacol 2018;210:359-71.
47. Babu NJ, Sanphui P, Nangia A. Crystal engineering of stable temozolomide cocrystals. Chem Asian J 2012;7:2274-85.
48. Aakeröy CB, Forbes S, Desper J. Using cocrystals to systematically modulate aqueous solubility and melting behavior of an anticancer drug. J Am Chem Soc 2009;131:17048-9.
49. Rajurkar V, Sunil N, Ghawate V. Tablet formulation and enhancement of aqueous solubility of efavirenz by solvent evaporation Co-crystal technique. Med Chem 2015;2:2161-444.
50. Shete AS, Khandagale VV, Murthy M, Yadav AV, Sakhre S, Doijad RC. Solid state characterization and tableting studies of ethanol based cocrystals of fenofibrate with nicotinamide. Indian J Pharm Educ Res 2018;51:71-7.
51. Oertling H, Besnard CL, Alzieu T, Wissenmeyer M, Vinay C, Mahieux J, et al. Ionic cocrystals of sodium chloride with carbohydrates. Cryst Growth Des 2016;17:262-70.
52. Duggirala NK, Perry ML, Almarsson Ö, Zaworotko MJ. Pharmaceutical cocrystals: Along the path to improved medicines. Chem Commun 2016;52:640-55.
53. Batisai E, Ayamine A, Kilinkissa OE, Bathori N. Melting point-solubility-structure correlations in multicomponent crystal containing fumaric or adipic acid. Cryst Eng Comm 2014;16:9992-8.
54. Stanton MK, Bak A. Physicochemical properties of pharmaceutical cocrystals: A case study of ten AMG 517 cocrystals. Cryst Growth Des 2008;8:3856-62.
55. Aakeröy CB, Forbes S, Desper J. Using cocrystals to systematically modulate aqueous solubility and melting behavior of an anticancer drug. J Am Chem Soc 2009;131:17048-9.
56. Fleischman SG, Kuduva SS, McMahon JA, Moulton B, Walsh B, Rodriguez-Hornedo RD, et al. Crystal engineering of the composition of pharmaceutical phases: Multiple-component crystalline solids involving carbamazepine. Cryst Growth Des 2003;3:909-19.
57. Maeno Y, Fukami T, Kawahata M, Yamaguchi K, Tagami T, Ozeki T, et al. Novel pharmaceutical cocrystal consisting of paracetamol and trimethylglycine, a new promising cocrystal former. Int J Pharm 2014;473:179-86.
58. Zhou Z, Li W, Sun WJ, Lu T, Tong HH, Sun CC, et al. Resveratrol cocrystals with enhanced solubility and stability. Int J Pharmacol 2016;509:391-9.
59. Krishna GR, Shi L, Bag PP, Sun CC, Reddy CM. Correlation among crystal structure, mechanical behaviour and stability in cocrystals of vanillin isomers. Cryst Growth Des 2015;15:1827-32.
60. Pawan Preet S, Chadha R. Crystal structure prediction in the context of pharmaceutical polymorph screening and putative polymorphs of ciprofloxacin. Int J Pharm Pharm Sci 2017;9:1-9.
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