Authors : Anil Kumar; Dr. Vikas Gupta

Volume/Issue : Volume 11 - 2026, Issue 10 - October

Google Scholar : https://tinyurl.com/3prexhrh

DOI : https://doi.org/10.38124/ijisrt/26Oct1685

Note : A published paper may take 4-5 working days from the publication date to appear in PlumX Metrics, Semantic Scholar, and ResearchGate.

Abstract : Poor aqueous solubility remains a major limitation in oral drug delivery, particularly for Biopharmaceutics Classification System (BCS) Class II drugs. Carbamazepine (CBZ), a widely prescribed anticonvulsant, exhibits high permeability but low aqueous solubility, resulting in variable dissolution behaviour and inconsistent therapeutic response. The present study aimed to design and evaluate pharmaceutical co-crystals of carbamazepine using rational crystal engineering approaches to enhance solubility and dissolution characteristics. Cocrystals were prepared using nicotinamide, saccharin, and glutaric acid as co-formers through solvent evaporation, slurry crystallization, and liquid-assisted grinding techniques.

Keywords : Carbamazepine, Co-Crystals, Crystal Engineering, Solubility Enhancement, Dissolution Kinetics, Solid-State Characterization.

References :

1. Abramov, Y. A., Iuzzolino, L., Jin, Y., York, G., Chen, C. H., Shultz, C. S., Yang, Z., Chang, C., Shi, B., Zhou, T., Greenwell, C., Sekharan, S., & Lee, A. Y. (2023) Cocrystal Synthesis through Crystal Structure Prediction. Mol Pharm 20:3380-3392. 10.1021/acs.molpharmaceut.2c01098
2. Adhikari, B. R., Gordon, K. C., & Das, S. C. (2022) Solid state of inhalable high dose powders. Adv Drug Deliv Rev 189:114468. 10.1016/j.addr.2022.114468
3. Aikawa, S., Tanaka, H., Ueda, H., Maruyama, M., & Higaki, K. (2022) Formation of a Stable Co-Amorphous System for a Brick Dust Molecule by Utilizing Sodium Taurocholate with High Glass Transition Temperature. Pharmaceutics 15:10.3390/pharmaceutics15010084
4. Al-Nimry, S. S., & Khanfar, M. S. (2022) Enhancement of the Solubility of Asenapine Maleate Through the Preparation of Co-Crystals. Curr Drug Deliv 19:788-800. 10.2174/1567201818666210805154345
5. Alkalla, N., Alhalaweh, A., Bergström, C. A. S., Li, N., & Taylor, L. S. (2026) Coadministration of a crystalline drug compromises supersaturation and membrane transport of an amorphous drug. Int J Pharm 687:126388.10.1016/j.ijpharm.2025.126388
6. Aytekin, E., Kaya, M. Z., İlkar, G. E., Polat, H. K., Öztürk, N., Vural, İ., Çakmak, H. B., Çelebier, M., Palaska, E., Çalış, S., & Bozdağ Pehlivan, S. (2025) Optimizing riboflavin delivery with co-crystal and in situ hydrogel formulations for management of keratoconus: A comprehensive investigation with in vitro, ex vivo and in vivo studies. Int J Pharm 674:125435. 10.1016/j.ijpharm.2025.125435
7. Bairagi, K. M., Ingle, K. S., Bhowal, R., Mohurle, S. A., Hasija, A., Alwassil, O. I., Venugopala, K. N., Chopra, D., & Nayak, S. K. (2021) Interplay of Halogen and Hydrogen Bonding through Co-Crystallization in Pharmacologically Active Dihydropyrimidines: Insights from Crystal Structure and Energy Framework. Chempluschem 86:1167-1176. 10.1002/cplu.202100259
8. Biscaia, I. F. B., Gomes, S. N., Bernardi, L. S., & Oliveira, P. R. (2021) Obtaining Cocrystals by Reaction Crystallization Method: Pharmaceutical Applications. Pharmaceutics 13:10.3390/pharmaceutics13060898
9. C, A., N, J., R, P. R., S, H., P, R., A, S., & S, J. (2026) Solubility enhancement of rosuvastatin using co-crystal approach. Drug Dev Ind Pharm 52:617-625. 10.1080/03639045.2026.2624588
10. Chen, Y., Lubach, J. W., Tang, S., & Narang, A. S. (2021) Effect of Counterions on Dissolution of Amorphous Solid Dispersions Studied by Surface Area Normalized Dissolution. Mol Pharm 18:3429-3438. 10.1021/acs.molpharmaceut.1c00325
11. Du, Y., Frank, D., Chen, Z., Struppe, J., & Su, Y. (2023) Ultrafast magic angle spinning NMR characterization of pharmaceutical solid polymorphism: A posaconazole example. J Magn Reson 346:107352. 10.1016/j.jmr.2022.107352
12. Elshaer, M., Osman, S. K., Mohammed, A. M., & Zayed, G. (2024) Co-crystallization of Hesperidin with different co-formers to enhance solubility, antioxidant and anti-inflammatory activities. Pharm Dev Technol 29:691-702.10.1080/10837450.2024.2378498
13. Fayed, N. D., Arafa, M. F., Essa, E. A., & El Maghraby, G. M. (2022) Lopinavir-menthol cocrystals for enhanced dissolution rate and intestinal absorption. J Drug Deliv Sci Technol 74:103587. 10.1016/j.jddst.2022.103587
14. Furuishi, T., Sato-Hata, N., Fukuzawa, K., & Yonemochi, E. (2023) Characterization of coamorphous carvedilol-maleic acid system prepared by solvent evaporation. Pharm Dev Technol 28:309-317. 10.1080/10837450.2023.2194406
15. Guo, M., Sun, X., Chen, J., & Cai, T. (2021) Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications. Acta Pharm Sin B 11:2537-2564. 10.1016/j.apsb.2021.03.030
16. Ibraheem, B., & Wagner, K. G. (2021) Influence of high pressure compaction on solubility and intrinsic dissolution of ibuprofen binary mixtures employing standard excipients. Int J Pharm X 3:100075. 10.1016/j.ijpx.2021.100075
17. Kumar Bandaru, R., Rout, S. R., Kenguva, G., Gorain, B., Alhakamy, N. A., Kesharwani, P., & Dandela, R. (2021) Recent Advances in Pharmaceutical Cocrystals: From Bench to Market. Front Pharmacol 12:780582. 10.3389/fphar.2021.780582
18. Li, R., Sun, J., Luo, K., Luo, N., Sun, R., Gao, F., Wang, Y., Xia, Y., Li, X., Chen, L., Ma, R., Shao, X., Liang, Y., & Fang, J. (2024) Electroacupuncture and carbamazepine for patients with trigeminal neuralgia: a randomized, controlled, 2 × 2 factorial trial. J Neurol 271:5122-5136. 10.1007/s00415-024-12433-x
19. Liu, J., Klinzing, G. R., & Nie, H. (2023) Effect of Material Properties and Variability of Mannitol on Tablet Formulation Development. Pharm Res 40:2071-2085. 10.1007/s11095-023-03577-y
20. Lösing, H., Eriksen, J. B., Scherließ, R., & Bauer-Brandl, A. (2023) Inexpensive and Easy-ToUse Alternative to the Die Holder for Pharmacopoeial Intrinsic Dissolution Tests. J Pharm Sci 112:2292-2296. 10.1016/j.xphs.2023.02.020
21. Luebbert, C., & Stoyanov, E. (2023) Tailored ASD destabilization - Balancing shelf life stability and dissolution performance with hydroxypropyl cellulose. Int J Pharm X 5:100187. 10.1016/j.ijpx.2023.100187
22. Nagamatsu, D., Ando, S., Fujimura, Y., Miyano, T., Sugita, K., & Ueda, H. (2023) Formation of Hemihydrate Crystal form Overcomes Milling Issue Induced by Exposed Functional Groups on Cleavage Plane for a Y5 Receptor Antagonist of Neuropeptide Y. J Pharm Sci 112:2516-2523. 10.1016/j.xphs.2023.04.012
23. Ohashi, R., Otake, S., Murata, T., Watari, R., Yoshida, S., Kitade, M., Kondo, D., & Kimura, G. (2025) Selection of Solubility Enhancement Technologies for S-892216, a Novel COVID-19 Drug Candidate. Pharmaceutics 17:10.3390/pharmaceutics17121627
24. Paul, S., Guo, Y., Wang, C., Dun, J., & Calvin Sun, C. (2023) Enabling direct compression tablet formulation of celecoxib by simultaneously eliminating punch sticking, improving manufacturability, and enhancing dissolution through co-processing with a mesoporous carrier. Int J Pharm 641:123041. 10.1016/j.ijpharm.2023.123041
25. Pérez Palacios, A. F., Medina Parra, J. A., Córdoba Velasco, D. S., Zona Rubio, D. C., Alves, I. A., & Aragón Novoa, D. M. (2025) New Strategies to Improve Drug Solubility and Its Impact on Bioavailability: A Patent Review (2015-2024). AAPS PharmSciTech 27:57. 10.1208/s12249-025-03287-1
26. Porat, D., Margolin, N., Lavon, O., & Dahan, A. (2022) Carbamazepine Therapy After Bariatric Surgery: Eight Sleeve Gastrectomy Cases and Review of the Literature. Obes Surg 32:3481-3486. 10.1007/s11695-022-06247-x
27. Shelke, S. J., Bhangare, D. H., & Patil, M. D. (2025) Pharmaceutical Cocrystals: A Review on Design, Preparation, Application and Challenges. Zhongguo Ying Yong Sheng Li Xue Za Zhi 41:e20250022. 10.62958/j.cjap.2025.022
28. Tomar, D., Mainuddin, Anshika, & Jindal, A. (2025) Nano-cocrystals as Nanotechnologybased Approach to Modulate Solubility and Bioavailability of Poorly Soluble Drugs. Curr Top Med Chem 10.2174/0115680266379743250717181526
29. Verma, P., Srivastava, A., Srivastava, K., Tandon, P., & Shimpi, M. R. (2021) Molecular Structure, Spectral Investigations, Hydrogen Bonding Interactions and ReactivityProperty Relationship of Caffeine-Citric Acid Cocrystal by Experimental and DFT Approach. Front Chem 9:708538. 10.3389/fchem.2021.708538
30. Wang, L., Wang, Y., Zhang, R. Y., Wang, Y., Liang, W., & Li, T. G. (2023) Management of acute carbamazepine poisoning: A narrative review. World J Psychiatry 13:816-830. 10.5498/wjp.v13.i11.816
31. Wu, H., Wang, Z., Zhao, Y., Gao, Y., Wang, L., Zhang, H., Bu, R., Ding, Z., & Han, J. (2023) Effect of different seed crystals on the supersaturation state of ritonavir tablets prepared by hot-melt extrusion. Eur J Pharm Sci 185:106440. 10.1016/j.ejps.2023.106440
32. Yarlagadda, D. L., Sai Krishna Anand, V., Nair, A. R., Navya Sree, K. S., Dengale, S. J., & Bhat, K. (2021) Considerations for the selection of co-formers in the preparation of coamorphous formulations. Int J Pharm 602:120649. 10.1016/j.ijpharm.2021.120649
33. Yokoo, H., Koide, T., Miyazaki, T., Aoyama, Y., Ogaeri, Y., Yamamoto, E., Demizu, Y., & Uchiyama, N. (2025) Combination of Microcrystal Electron Diffraction and Solid-State NMR for the Structural Determination of Indomethacin-Nicotinamide Co-crystals. Chem Pharm Bull (Tokyo) 73:813-818. 10.1248/cpb.c25-00377