Water solubility and low bioavailability of active pharmaceutical ingredients are some of the main challenges in the process of developing new drugs, especially drugs in oral solid dosage forms. One way to improve drug solubility is the principle of cocrystallization. Cocristallyzation itself is the process of combining the active ingredients of a less water-soluble drug with a coformer so that it becomes more soluble. Pharmaceutical cocrystal provides benefits to improve physicochemical properties without affecting its pharmacological properties. In this review, we review literature discussions and research that discuss co-crystallization as an aid to improve the physicochemical and bioavailability of drugs and also discuss some drugs in the form of cocrystal and their improvement in physicochemical-biopharmaceutical properties. The main reference data used in this review are research journals published in the past 10 years. Discussion on the effect of cocrystal on physicochemical properties and bioavailability of drugs was produced. The method of producing cocrystal and its characterization was also discussed. Cocrystal offers a promising approach to improve the physicochemical properties of API. The benefits of cocrystal can be observed through increased solubility, dissolution rate, permeability, bioavailability, drug stability, and tabletability.

Keywords: : pharmaceutical cocrystal, cocrystallization, solubility, bioavailability.

Author Biography

iyan sopyan, Departement of pharmaceutics and Technology of Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran
Dept. of pharmaceutics and technology of pharmacy


1. Mehta M. Biopharmaceutics classification system (BCS). United Kingdom: John Wiley & Sons; 2017.
2. Babu NJ, Nangia A. Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals. Cryst Growth Des 2011;11:2662–79.
3. Thakuria R, Delori A, Jones W, Lipert MP, Roy L, Rodríguez-Hornedo N. Pharmaceutical cocrystals and poorly soluble drugs. Int J Pharm 2013;453:101–25.
4. Rinaki E, Valsami G, Macheras P. Quantitative Biopharmaceutics Classification System: The Central Role of Dose/Solubility Ratio. Pharm Res 2003;20:1917–25.
5. Kumar S, Nanda A. Pharmaceutical Cocrystals: An Overview. Indian J Pharm Sci 2017; 79.
6. Trask AV, Motherwell WDS, Jones W. Pharmaceutical Cocrystallization: Engineering a Remedy for Caffeine Hydration. Cryst Growth Des 2005;5:1013–21.
7. Center for Drug Evaluation and Research (CDER). Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry. Food and Drug Administration; 2018. Available from:, accessed on April 14, 2020.
8. I Sopyan, Insan Sunan KS, Desi N, Arif Budiman, Impropment Simvastatin Dissolution Rate Using Derivative Non-Covalent Approach by Solvent Drop Grinding Method. Int J App pharm 2020;12:21-4
9. Bolla G, Nangia A. Pharmaceutical cocrystals: walking the talk. Chem Commun 2016; 52 : 8342–60.
10. Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: An overview. Int J Pharm 2011;419:1–11.
11. Morissette S. High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv Drug Deliv Rev 2004;56:275–300.
12. Rodrigues M, Baptista B, Lopes JA, Sarraguça MC. Pharmaceutical cocrystallization techniques. Advances and challenges. Int J Pharm 2018;547:404–20.
13. Bavishi DD, Borkhataria CH. Spring and parachute: How cocrystals enhance solubility. Prog Cryst Growth Charact Mater 2016; 62 : 1–8.
14. Dai X-L, Chen J-M, Lu T-B. Pharmaceutical cocrystallization: an effective approach to modulate the physicochemical properties of solid-state drugs. CrystEngComm 2018;20: 5292–316.
15. Indonesia International Institute for Life Sciences, Kho K, Nugroho D, Parahyangan Catholic University, Sugih AK, Parahyangan Catholic University. Preparation and Characterization of Highly Water Soluble Curcumin – Dextrose Cocrystal. J Pure Appl Chem Res 2018;7:139–47.
16. Setyawan D, Permata SA, Zainul A, Lestari MLAD. Improvement in vitro Dissolution Rate of Quercetin Using Cocrystallization of Quercetin-Malonic Acid. Indones J Chem 2018;18:531.
17. Yuliandra Y, Zaini E, Syofyan S, Pratiwi W, Putri L, Pratiwi Y, et al. Cocrystal of Ibuprofen–Nicotinamide: Solid-State Characterization and In Vivo Analgesic Activity Evaluation. Sci Pharm 2018;86 :23.
18. Wicaksono Y, Setyawan D, Siswandono S, Siswoyo TA. Preparation and Characterization of a Novel Cocrystal of Atorvastatin Calcium with Succinic Acid Coformer. Indones J Chem 2019;19 660.
19. Zhang Y, Yang Z, Zhang S, Zhou X. Synthesis, Crystal Structure, and Solubility Analysis of a Famotidine Cocrystal. Crystals 2019;9360.
20. Dai X-L, Li S, Chen J-M, Lu T-B. Improving the Membrane Permeability of 5-Fluorouracil via Cocrystallization. Cryst Growth Des 2016;16:4430–8.
21. Sanphui P, Devi VK, Clara D, Malviya N, Ganguly S, Desiraju GR. Cocrystals of Hydrochlorothiazide: Solubility and Diffusion/Permeability Enhancements through Drug–Coformer Interactions. Mol Pharm 2015;12:1615–22.
22. Yan Y, Chen J-M, Lu T-B. Simultaneously enhancing the solubility and permeability of acyclovir by crystal engineering approach. CrystEngComm 2013;15:6457.
23. Wang C, Tong Q, Hou X, Hu S, Fang J, Sun CC. Enhancing Bioavailability of Dihydromyricetin through Inhibiting Precipitation of Soluble Cocrystals by a Crystallization Inhibitor. Cryst Growth Des 2016;16:5030–9.
24. Childs SL, Kandi P, Lingireddy SR. Formulation of a Danazol Cocrystal with Controlled Supersaturation Plays an Essential Role in Improving Bioavailability. Mol Pharm 2013; 10 3112–27.
25. Ferretti V, Dalpiaz A, Bertolasi V, Ferraro L, Beggiato S, Spizzo F, et al. Indomethacin Co-Crystals and Their Parent Mixtures: Does the Intestinal Barrier Recognize Them Differently? Mol Pharm 2015;12:1501–11.
26. Dalpiaz A, Ferretti V, Bertolasi V, Pavan B, Monari A, Pastore M. From Physical Mixtures to Co-Crystals: How the Coformers Can Modify Solubility and Biological Activity of Carbamazepine. Mol Pharm 2018;15:268–78.
27. Zhu B, Zhang Q, Wang J-R, Mei X. Cocrystals of Baicalein with Higher Solubility and Enhanced Bioavailability. Cryst Growth Des 2017;17:1893–901.
28. Weyna DR, Cheney ML, Shan N, Hanna M, Zaworotko MJ, Sava V, et al. Improving Solubility and Pharmacokinetics of Meloxicam via Multiple-Component Crystal Formation. Mol Pharm 2012;9 2094–102.
29. Wang Z-Z, Chen J-M, Lu T-B. Enhancing the Hygroscopic Stability of S -Oxiracetam via Pharmaceutical Cocrystals. Cryst Growth Des 2012;12:4562–6.
30. Sopyan I, Fudholi A, Muchtaridi M, Sari IP. Simvastatin-nicotinamide co-crystal: design, preparation and preliminary characterization. Trop J Pharm Res 2017;16:297.
31. Sopyan I, Fudholi A, Muchtaridi M, Puspitasari I. A Simple Efort To Enhance Solubility and Dissolution rate of Simvastatin Using Co-crystalization. Int J Pharm pharm sci 2016;8 5.
32. Sopyan I, Fudholi A, Muchtaridi M, Sari IP. Co-crystallization: A Tool to Enhance Solubility and Dissolution Rate of Simvastatin. J Young Pharm 2017;9:183–6.
33. Hiendrawan S, Veriansyah B, Widjojokusumo E, Soewandhi SN, Wikarsa S, Tjandrawinata RR. Physicochemical and mechanical properties of paracetamol cocrystal with 5-nitroisophthalic acid. Int J Pharm 2016;497:106–13.
34. Sekhon B. Pharmaceutical co-crystals-a review. Ars Pharm 2009; 50.
35. Siswandi S, Rusdiana T, Levita J. Virtual screening of co-formers for ketoprofen co-crystallization and the molecular properties of the co-crystal. J Appl Pharm Sci 2015: 078–82.
36. Malmstrom RD, Watowich SJ. Using Free Energy of Binding Calculations To Improve the Accuracy of Virtual Screening Predictions. J Chem Inf Model 2011;51:1648–55.
37. Schultheiss N, Newman A. Pharmaceutical Cocrystals and Their Physicochemical Properties. Cryst Growth Des 2009;9:2950–67.
38. 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.
39. Budiman A, Megantara S, Apriliani A. Solid Dosage Form Glibenclamide-Aspartame Cocrystalization the Solvent Evaporation to Increase The Solubility of Glibenclamide. Int J Appl Pharm 2019:150–4.
40. Dahan A, Miller JM. The Solubility–Permeability Interplay and Its Implications in Formulation Design and Development for Poorly Soluble Drugs. AAPS J 2012;14:244–51.
41. Singh BN, Singh RB, Singh J. Effects of ionization and penetration enhancers on the transdermal delivery of 5-fluorouracil through excised human stratum corneum. Int J Pharm 2005;298:98–107.
42. Dokoumetzidis A, Valsami G, Macheras P. Modelling and simulation in drug absorption processes. Xenobiotica 2007;3: 1052–65.
43. Kawakami K. Theory and practice of supersaturatable formulations for poorly soluble drugs. Ther Deliv 2015;6:339–52.
44. Karagianni A, Malamatari M, Kachrimanis K. Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs. Pharmaceutics 2018;10: 8.
45. McNamara DP, Childs SL, Giordano J, Iarriccio A, Cassidy J, Shet MS, et al. Use of a Glutaric Acid Cocrystal to Improve Oral Bioavailability of a Low Solubility API. Pharm Res 2006;23:1888–97.
46. Variankaval N, Wenslow R, Murry J, Hartman R, Helmy R, Kwong E, et al. Preparation and Solid-State Characterization of Nonstoichiometric Cocrystals of a Phosphodiesterase-IV Inhibitor and L -Tartaric Acid. Cryst Growth Des 2006;6 690–700.
47. Oswald IDH, Allan DR, McGregor PA, Motherwell WDS, Parsons S, Pulham CR. The formation of paracetamol (acetaminophen) adducts with hydrogen-bond acceptors. Acta Crystallogr B 2002;58:1057–66.
48. Chen AM, Ellison ME, Peresypkin A, Wenslow RM, Variankaval N, Savarin CG, et al. Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid. Chem Commun 2007:419–21.
49. 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. Cryst Growth Des 2014;14: 864–74.
50. Jain H, Khomane KS, Bansal AK. Implication of microstructure on the mechanical behaviour of an aspirin–paracetamol eutectic mixture. CrystEngComm 2014;16:8471–8.
51. Chow SF, Shi L, Ng WW, Leung KHY, Nagapudi K, Sun CC, et al. Kinetic Entrapment of a Hidden Curcumin Cocrystal with Phloroglucinol. Cryst Growth Des 2014;14:5079–89.
52. Sodanapalli R, Nair R, Bachala T. Synthesis and Characterization of a Pharmaceutical Co-Crystal: (Aceclofenac: Nicotinamide). J Pharm Sci Res 2011; 3.
53. Jung M-S, Kim J-S, Kim M-S, Alhalaweh A, Cho W, Hwang S-J, et al. Bioavailability of indomethacin-saccharin cocrystals: In-vivo study of indomethacin cocrystals. J Pharm Pharmacol 2010;62:1560–8.
54. Alatas F, Soewandhi S, Sasongko L, Ismunandar, Uekusa H. Cocrystal formation between didanosine and two aromatic acids. Int J Pharm Pharm Sci 2013;5:275–80.
55. Hasa D, Carlino E, Jones W. Polymer-Assisted Grinding, a Versatile Method for Polymorph Control of Cocrystallization. Cryst Growth Des 2016;16:1772–9.
56. Dhumal RS, Kelly AL, York P, Coates PD, Paradkar A. Cocrystalization and Simultaneous Agglomeration Using Hot Melt Extrusion. Pharm Res 2010;27:2725–33.
57. Childs SL, Rodríguez-Hornedo N, Reddy LS, Jayasankar A, Maheshwari C, McCausland L, et al. Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine. CrystEngComm 2008;10:856.
58. Setyawan D, Wardhana NK, Sari R. Solubility, Dissolution test and Antimalaria Activity of Artesunte. 2015;8: 3.
59. He G, Chow PS, Tan RBH. Investigating the Intermolecular Interactions in Concentration-Dependent Solution Cocrystallization of Caffeine and p -Hydroxybenzoic Acid. Cryst Growth Des 2010;10:3763–9.
60. 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 2019;9:329.
61. Lange L, Heisel S, Sadowski G. Predicting the Solubility of Pharmaceutical Cocrystals in Solvent/Anti-Solvent Mixtures. Molecules 2016;21:593.
62. Neurohr C, Revelli A-L, Billot P, Marchivie M, Lecomte S, Laugier S, et al. Naproxen–nicotinamide cocrystals produced by CO2 antisolvent. J Supercrit Fluids 2013;83:78–85.
63. Kojima T, Tsutsumi S, Yamamoto K, Ikeda Y, Moriwaki T. High-throughput cocrystal slurry screening by use of in situ Raman microscopy and multi-well plate. Int J Pharm 2010;399:52–9.
64. Padrela L, Rodrigues MA, Velaga SP, Matos HA, de Azevedo EG. Formation of indomethacin–saccharin cocrystals using supercritical fluid technology. Eur J Pharm Sci 2009;38:9–17.
65. 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;153175–81.
66. Alhalaweh A, Velaga SP. Formation of Cocrystals from Stoichiometric Solutions of Incongruently Saturating Systems by Spray Drying. Cryst Growth Des 2010; 10 : 3302–5.
67. 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. Cryst Growth Des 2019;19 :2736–45.
68. Eddleston MD, Patel B, Day GM, Jones W. Cocrystallization by Freeze-Drying: Preparation of Novel Multicomponent Crystal Forms. Cryst Growth Des 2013;13:4599–606.
69. Tanaka R, Hattori Y, Otsuka M, Ashizawa K. Application of spray freeze drying to theophylline-oxalic acid cocrystal engineering for inhaled dry powder technology. Drug Dev Ind Pharm 2020;46:79–87.
70. Fernández-Ronco MP, Kluge J, Mazzotti M. High Pressure Homogenization as a Novel Approach for the Preparation of Co-Crystals. Cryst Growth Des 2013; 13 : 2013–24.
71. Fukte SR, Wagh MP, Rawat S. Coformer selection: An important tool in cocrystal formation. Int J Pharm Pharm Sci 2014;6 :9–14.
72. 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;22:246–57.
73. Thenge RR, Patond VB, Ajmire PV, Barde LN, Mahajan NM, Tekade NP. Preparation and Characterization of Cocrystal of Diacerein. Indones J Pharm 2017;28:34.
74. Garbacz P, Wesolowski M. DSC, FTIR and Raman Spectroscopy Coupled with Multivariate Analysis in a Study of Co-Crystals of Pharmaceutical Interest. Molecules 2018;23:2136.
75. Budiman A, Nurlatifah E, Amin S. Enhancement of Solubility and Dissolution Rate of Glibenclamide by Cocrystal Approach with Solvent Drop Grinding Method. Int J Curr Pharm Rev Res 2016;7:248–50.
76. Suzuki N, Kawahata M, Yamaguchi K, Suzuki T, Tomono K, Fukami T. Comparison of the relative stability of pharmaceutical cocrystals consisting of paracetamol and dicarboxylic acids. Drug Dev Ind Pharm 2018;44:582–9.
77. Rahman Z, Agarabi C, Zidan AS, Khan SR, Khan MA. Physico-mechanical and Stability Evaluation of Carbamazepine Cocrystal with Nicotinamide. AAPS PharmSciTech 2011; 12:693–704.
78. Bhardwaj S, Lipert M, Bak A. Mitigating Cocrystal Physical Stability Liabilities in Preclinical Formulations. J Pharm Sci 2017;106 :31–8.
79. Nechipadappu SK, Trivedi DR. Cocrystal of nutraceutical sinapic acid with Active Pharmaceutical Ingredients ethenzamide and 2-chloro-4-Nitrobenzoic acid: Equilibrium solubility and stability study. J Mol Struct 2018;1171:898–905.
80. Indra I, Janah FM, Aryani R. Enhancing the Solubility of Ketoconazole via Pharmaceutical Cocrystal. J Phys Conf Ser 2019;1179:012134.
81. Panzade P, Shendarkar G, Shaikh S, Balmukund Rathi P. Pharmaceutical Cocrystal of Piroxicam: Design, Formulation and Evaluation. Adv Pharm Bull 2017; 7 : 399–408.
82. Committee for Medicinal Products for Human Use, Committee for Medicinal Products for Veterinary Use. Reflection paper on the use of cocrystals of active substances in medicinal products. European Medicines Agency;2015. Available from:, accessed on April 15, 2020.
83. Devarakonda SN, Vyas K, Bommareddy SR, Padi PR, Raghupathy B. Aripiprazole co-crystals.
84. Food and Drug Administration. Lexapro (escitalopram oxalate). Food and Drug Administration;2016. Available from:
85. Harrison WTA, Yathirajan HS, Bindya S, Anilkumar HG, Devaraju. Escitalopram oxalate: co-existence of oxalate dianions and oxalic acid molecules in the same crystal. Acta Crystallogr C 2007;63:129–31.
86. Food and Drug Administration. Depakote (divalproex sodium) Tablets. Food and Drug Administration; 2011. Available from:
87. Food and Drug Administration. ENTRESTO® (sacubitril and valsartan). Food and Drug Administration; 2019. Available from:
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sopyan, iyan, Sunan KS, I., & Sunan KS, I. (2020). SYSTEMATIC REVIEW: COCRYSTAL AS EFFORTS TO IMPROVE PHYSICOCHEMICAL AND BIOAVAILABILITY PROPERTIES OF ORAL SOLID DOSAGE FORM. International Journal of Applied Pharmaceutics, 13(1). Retrieved from
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