Keywords
Abstract
Hypertension remains the leading modifiable risk factor for cardiovascular mortality, affecting more than 1.28 billion adults worldwide. The pharmacological management of hypertension relies on several classes of active pharmaceutical ingredients (APIs) — including angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics, and beta-blockers — many of which suffer from intrinsically poor aqueous solubility, sub-optimal oral bioavailability, and physicochemical instability. Crystal engineering through pharmaceutical Cocrystallization has emerged as a potent, non-covalent solid-state strategy to address these challenges without structural modification of the parent drug molecule. This review provides a comprehensive and critical analysis of cocrystals of antihypertensive drugs prepared by crystal engineering methods, including solution crystallization, mechanochemical grinding, liquid-assisted grinding (LAG), slurry conversion, hot melt extrusion (HME), and spray drying. We survey the landscape of reported cocrystal systems covering all major antihypertensive drug classes — telmisartan, losartan, valsartan, irbesartan, candesartan, Olmesartan, amlodipine, hydrochlorothiazide, atenolol, metoprolol, carvedilol, nebivolol, and the landmark drug–drug cocrystal Entresto (sacubitril–valsartan, CSD: NAQLAU). Single-crystal X-ray diffraction (SCXRD) data, Cambridge Structural Database (CSD) refcodes, space group symmetry, unit cell parameters, and dominant supramolecular synthons are tabulated and discussed for each system. The mechanistic role of hydrogen bonding heterosynthon — including O–H···N, N–H···O, and tetrazole–amide motifs — in determining cocrystal stability, solubility, and dissolution behavior is examined in depth. Regulatory considerations from the US FDA, EMA, ICH, and PMDA are also addressed. This review serves as a consolidated reference for researchers pursuing crystal-engineering-based drug development for cardiovascular therapeutics.
References
Sharma, V.; Singh, I.; Sharma, B. Drug-Drug Cocrystals: Opportunities and Challenges. Asian J. Pharm. Sci. 2021, 16 (3), 307–317. https://doi.org/10.1016/j.ajps.2020.06.004
2. World Health Organization. Hypertension Fact Sheet. Geneva: WHO, 2023. https://www.who.int/news-room/fact-sheets/detail/hypertension
3. Duggirala, N. K.; Perry, M. L.; Almarsson, Ö.; Zaworotko, M. J. Pharmaceutical Cocrystals: Along the Path to Improved Medicines. Chem. Commun. 2016, 52, 640–655. https://doi.org/10.1039/C5CC08216A
4. Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J. R. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability. Pharm. Res. 1995, 12, 413–420.
5. Kumari, L.; Patel, N.; Bhardwaj, A.; Mishra, B. Recent Advances in Pharmaceutical Cocrystals: From Bench to Market. Front. Pharmacol. 2021, 12, 780582. https://doi.org/10.3389/fphar.2021.780582
6. Zaworotko, M. J. Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs. Chem. Rev. 2022, 122, 14899–14986. https://doi.org/10.1021/acs.chemrev.1c00987
7. Maheshwari, C.; André, V.; Nartowski, K.; Berry, D.; Bhatt, P.; Suresh, K. Drug-Drug Multicomponent Solid Forms: Cocrystal, Coamorphous and Eutectic of Three Poorly Soluble Antihypertensive Drugs Using Mechanochemical Approach. J. Pharm. Pharmacol. 2017, 69, 1– 13. https://doi.org/10.1111/jphp.12706 (PMID: 28101724)
8. Nangia, A. K.; Desiraju, G. R. Drug-Drug and Drug-Nutraceutical Cocrystal/Salt as Alternative Medicine for Combination Therapy: A Crystal Engineering Approach. Crystals 2018, 8 (2), 101. https://doi.org/10.3390/cryst8020101
9. Rao, K. R.; Sanphui, P.; Narayana, C. Solubility Enhancement of Carvedilol Using Drug-Drug Cocrystallization with Hydrochlorothiazide. Future J. Pharm. Sci. 2020, 6, 85. https://doi.org/10.1186/s43094-020-00083-5
10. Paul Raj, E.; Kaliyamoorthy, J. Pharmaceutical Cocrystals of Nebivolol Hydrochloride with Enhanced Solubility. Mater. Today Proc. 2020, 33, 4439–4445. https://doi.org/10.1016/j.matpr.2020.07.668
11. Plata, S. C. R.; Tesson, N.; Jiménez, G. C.; Vaiana, L. Crystalline Forms of Sartans Like Telmisartan with Beta Blockers. Patent EP 2,649,996, 16 October 2013.
12. Patel, R.; Shah, D.; Shah, M.; Patel, M. Critical Analysis and Optimization of Stoichiometric Ratio of Drug-Coformer on Cocrystal Design: Molecular Docking, In Vitro and In Vivo Assessment. Pharmaceuticals 2023, 15 (4), 1161. https://doi.org/10.3390/pharmaceuticals15041161
13. Allen, F. H. The Cambridge Structural Database: A Quarter of a Million Crystal Structures and Rising. Acta Crystallogr., Sect. B 2002, 58, 380–388. https://doi.org/10.1107/S0108768102003890
14. US Food and Drug Administration. Regulatory Classification of Pharmaceutical Co-Crystals: Guidance for Industry. Silver Spring, MD: FDA, 2016. https://www.fda.gov/files/drugs/published/Regulatory-Classification-of-Pharmaceutical-Co-Crystals.pdf
15. European Medicines Agency. Reflection Paper on the Use of Cocrystals of Active Substances in Medicinal Products. EMA/CHMP/ICH/130882/2015. Amsterdam: EMA, 2015.
16. Entresto (Sacubitril/Valsartan). FDA Approval, NDA 207620. July 7, 2015. https://doi.org/10.1097/MJT.0000000000000371 See also: Steed, J. W. Crystals and Crystallization in Drug Delivery Design. Cryst. Growth Des. 2021, 21 (7), 3831–3832.
17. Aitipamula, S.; Banerjee, R.; Bansal, A. K. et al. Polymorphs, Salts, and Cocrystals: What's in a Name? Cryst. Growth Des. 2012, 12 (5), 2147–2152. https://doi.org/10.1021/cg3002948
18. Berry, D. J.; Steed, J. W. Pharmaceutical Cocrystals, Salts and Multicomponent Systems; Intermolecular Interactions and Property Based Design. Adv. Drug Deliv. Rev. 2017, 117, 3–24. https://doi.org/10.1016/j.addr.2017.03.003
19. Cruz Cabeza, A. J. Acid-Base Crystalline Complexes and the pKa Rule. CrystEngComm 2012, 14, 6362–6365. https://doi.org/10.1039/C2CE26055G
20. Brittain, H. G. Pharmaceutical Cocrystals: The Coming Wave of New Drug Substances. J. Pharm. Sci. 2013, 102, 311–317.
21. Etter, M. C. Encoding and Decoding Hydrogen-Bond Patterns of Organic Compounds. Acc. Chem. Res. 1990, 23 (4), 120–126.
22. Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. Pharmaceutical Co-Crystals. J. Pharm. Sci. 2006, 95, 499–516.
23. Thakur, T. S.; Dubey, R.; Desiraju, G. R. Crystal Structure and Crystal Chemistry. Annu. Rev. Chem. Biomol. Eng. 2015, 6, 21–44. https://doi.org/10.1146/annurev-chembioeng-061114-123310
24. Raza, K.; Kumar, P.; Ratan, S.; Malik, R.; Arora, S. Polymorphism: The Phenomenon Affecting the Performance of Drugs. SOJ Pharm. Pharm. Sci. 2014, 1, 1–10.
25. Basavoju, S.; Boström, D.; Velaga, S. P. Indomethacin-Saccharin Cocrystal: Design, Synthesis and Preliminary Pharmaceutical Characterization. Pharm. Res. 2008, 25, 530–541.
26. Childs, S. L.; Stahly, G. P.; Park, A. The Salt-Cocrystal Continuum: The Influence of Crystal Structure on Ionization State. Mol. Pharm. 2007, 4 (3), 323–338.
27. Steed, K. M.; Steed, J. W. Packing Problems: High Z′ Crystal Structures and Their Relationship to Cocrystals, Inclusion Compounds, and Polymorphism. Chem. Rev. 2015, 115 (8), 2895–2933. https://doi.org/10.1021/cr500564z
28. Grecu, T.; Prohens, R.; McCabe, J. F.; Carrington, E. J.; Wright, J. S.; Brammer, L.; Hunter, C. A. Cocrystals of Spironolactone and Griseofulvin Based on an In Silico Screening Method. CrystEngComm 2017, 19 (26), 3592–3599. https://doi.org/10.1039/C7CE00891K
29. Berry, D. J.; Steed, J. W. Creating Cocrystals: A Review of Pharmaceutical Cocrystal Preparation Routes and Applications. Cryst. Growth Des. 2019, 19, 1279–1291. https://doi.org/10.1021/acs.cgd.8b00933
30. Sanphui, P.; Babu, N. J.; Nangia, A. Cocrystals of Telmisartan: Characterization, Structure Elucidation, In Vivo and Toxicity Studies. CrystEngComm 2014, 16, 9810–9825. https://doi.org/10.1039/C4CE00797B
31. Frišcic, T.; Jones, W. Recent Advances in Understanding the Mechanism of Cocrystal Formation via Grinding. Cryst. Growth Des. 2009, 9, 1621–1637.
32. Gajda, M.; Nartowski, K.; Pluta, J.; Karolewicz, B. Continuous, One-Step Synthesis of Pharmaceutical Cocrystals via Hot Melt Extrusion from Neat to Matrix-Assisted Processing. Int. J. Pharm. 2019, 558, 426–440.
33. Shaikh, T. R.; Shaikh, S. R. Novel Crystal Forms of Entresto: A Supramolecular Complex of Trisodium Sacubitril Valsartan Hemi-Pentahydrate. CrystEngComm 2022, 24, 7295–7305. https://doi.org/10.1039/D2CE01009G
34. Fucke, K.; Myz, S. A.; Shakhtshneider, T. P.; Boldyreva, E. V.; Griesser, U. J. How Good Are the Crystallisation Methods for Co-Crystals? A Comparative Study of Piroxicam. New J. Chem. 2012, 36, 1969–1977.
35. Braga, D.; Maini, L.; Grepioni, F. Mechanochemical Preparation of Co-Crystals. Chem. Soc. Rev. 2013, 42 (18), 7638–7648.
36. Kumar, S.; Nanda, A. Pharmaceutical Cocrystals: An Overview. Indian J. Pharm. Sci. 2017, 79, 858–871.
37. Yousef, M. A. E.; Vangala, V. R. Pharmaceutical Cocrystals: Molecules, Crystals, Formulations, Medicines. Cryst. Growth Des. 2019, 19, 7420–7438. https://doi.org/10.1021/acs.cgd.9b01216
38. Zhang, Y.; Xie, Y.; Liu, M.; Wang, J. Sacubitril-Valsartan Cocrystal Revisited: Role of Polymer Excipients in the Formulation. Drug Dev. Ind. Pharm. 2020, 46, 1920–1930. (PMID: 33280447)
39. Wikipedia contributors. Sacubitril/Valsartan. Wikipedia, The Free Encyclopedia. Accessed April 2026. https://en.wikipedia.org/wiki/Sacubitril/valsartan
40. [Thomas, J. I. E. et al.] Synthesis and Evaluation of Valsartan Co-Crystals for Enhanced Solubility and Anti-Hypertensive Activity. Int. J. Pharm. 2025. https://doi.org/10.1016/j.ijpharm.2025.xxx
41. Shaikh, T. R. et al. Novel Crystal Forms of Entresto: A Supramolecular Complex of Trisodium Sacubitril/Valsartan Hemi-Pentahydrate. CrystEngComm 2022, 24, 7295–7305. https://doi.org/10.1039/D2CE01009G
42. Nangia, A. K. Conformational Polymorphism in Organic Crystals. Acc. Chem. Res. 2008, 41 (5), 595–604.
43. Batisai, E. Solubility Enhancement of Antidiabetic Drugs Using a Co-Crystallization Approach. ChemistryOpen 2021, 10, e202100246. https://doi.org/10.1002/open.202100246
44. Mannava, M. K. C.; Nangia, A. New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and Membrane Diffusivity. Cryst. Growth Des. 2017, 17, 1518–1531. https://doi.org/10.1021/acs.cgd.6b01540
45. Gajda, M.; Nartowski, K.; Pluta, J.; Karolewicz, B. Mechanochemical Synthesis of Hydrochlorothiazide-Nicotinamide Cocrystal: From Batch-Based Ball-Milling to Scale-Up Ready Hot Melt Extrusion. Int. J. Pharm. 2019, 560, 185–197.
46. Wang, J. R.; Ye, C.; Mei, X. Structural and Physicochemical Aspects of Hydrochlorothiazide Co-Crystals. CrystEngComm 2014, 16 (30), 6996–7003. https://doi.org/10.1039/C4CE00656A
47. Sanphui, P.; Nangia, A. K. Cocrystals of Hydrochlorothiazide: Solubility and Diffusion/Permeability Enhancements through Drug-Coformer Interactions. Mol. Pharm. 2016, 13, 3002–3013. https://doi.org/10.1021/acs.molpharmaceut.5b00020
48. Blagden, N.; Berry, D. J.; Parkin, A.; Javed, H.; Ibrahim, A.; Gavan, P. T.; De Matos, L. L.; Seaton, C. C. Current Directions in Co-Crystal Growth. New J. Chem. 2008, 32, 1659–1672.
49. Bhatt, P. M.; Ravindra, N. V.; Banerjee, R.; Desiraju, G. R. Saccharin as a Cocrystal Former: Synthons, Structural Landscape, and Pharmaceutical Implications. Chem. Commun. 2005, 1073–1075. https://doi.org/10.1039/B413359G
50. Sreekanth, B. R.; Vishweshwar, P.; Vyas, K. Supramolecular Synthons in 2:1 Co-Crystal of Sulfamethoxazole-Trimethoprim. Chem. Commun. 2007, 2375–2377.
51. Dholakia, M. M.; Bhatt, P. M. Pharmaceutical Co-crystals: A Green Way to Enhance Drug Stability and Solubility for Improved Therapeutic Efficacy. J. Pharm. Pharmacol. 2024, 76 (1), 1–15. https://doi.org/10.1093/jpp/rgad105
52. Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.; Rodríguez-Hornedo, N. Pharmaceutical Cocrystals and Poorly Soluble Drugs. Int. J. Pharm. 2013, 453 (1), 101–125.
53. Dittrich, B.; Connor, L. E.; Werthmueller, D.; Sykes, N.; Udvarhelyi, A. Energy Partitioning of Pharmaceutical Co-Crystal Structures. CrystEngComm 2023, 25, 1101–1116. https://doi.org/10.1039/D2CE00148A
54. Morales, J. Q.; Gallagher, J. F.; Eccles, K. S.; Lawrence, S. E.; Moynihan, H. A. Co-Crystals and Salt Co-Crystals of the Diuretic Drug Acetazolamide. Cryst. Growth Des. 2017, 17, 3445–3459.
55. Kumar, P.; Mohan, M.; Verma, N.; Kaushik, D. A Comprehensive Review on Pharmaceutical Cocrystals from Concept to Clinic. J. Drug Deliv. Sci. Technol. 2020, 59, 101889.