Effect of cocrystallization in augmentation of in vitro and in vivo performance of irbesartan

Year 2025, Volume: 29 Issue: 5, 2117 - 2125, 01.09.2025

Monika Nijhawan , Rajeswari Aleti Sailaja Gunnam , Dr Trapti Saxena

https://doi.org/10.12991/jrespharm.1763707

Abstract

Pharmaceutical co-crystals are a promising approach for fine-tuning the physicochemical properties of
active pharmaceutical ingredients (APIs) like solubility and dissolution. The current study describes generation of
irbesartan cocrystal with succinic acid, its characterization and bioavailability assessment. Irbesartan (poorly water-
soluble drug) is used in treatment of diseases like hypertension, heart failure, myocardial infarction and diabetic
nephropathy. It is a fluffy material, with relatively low bulk and tap density. Irbesartan has certain undesirable flow
characteristics, for example, is sticky and can adhere to surfaces such as tablet punch faces and dies, causing problems in
tableting, Hence, cocrystal was prepared to enhance solubility, dissolution, bioavailability and to improve its
micromeritic properties. Solvent drop grinding method was used to formulate irbesartan-succinic acid cocrystal.
Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR), and Powder X-Ray
Diffraction (PXRD) were used to identify the emergence of a new crystalline phase. Saturation solubility studies were
conducted in 0.1NHCl solution. The pharmacokinetic behavior of irbesartan and its cocrystal was investigated in male
Albino rats. The significant improvement in solubility and dissolution rate was observed in the case of cocrystals than
pure irbesartan. The AUC0-24 hr of the cocrystal and Cmax was found to be 1.65-fold and 1.56-fold increase respectively in
terms of bioavailability as compared to the pure drug. Hence Cocrystal approach can be successfully used for solid state
manipulation for the possible improved bioavailability of BCS class II drugs – irbesartan.

Keywords

Irbesartan , cocrystals , succinic acid , dissolution rate , bioavailability

References

• Tupe SA, Khandagale SP, Jadhav AB. Pharmaceutical cocrystals: An emerging approach to modulate physicochemical properties of active pharmaceutical ingredients. J Drug Deliv Ther. 2023; 13(4): 101-112. https://doi.org/10.22270/jddt.v13i4.6016
• Guo M, Sun X, Chen J, Cai T. Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications. Acta Pharm Sin B. 2021; 11(8): 2537-2564. https://doi.org/10.1016/j.apsb.2021.03.030
• Bhardwaj S, Lipert M, Bak A. Mitigating cocrystal physical stability liabilities in preclinical formulations. J Pharm Sci. 2017; 106(1): 31-38. https://doi.org/10.1016/j.xphs.2016.07.018
• Kumar A, Kumar M. Co-Crystallization: A novel technique to ımprovise the pharmaceutical characteristics of API's. Curr Drug Targets. 2023; 24(11): 870-888. https://doi.org/10.2174/1389450124666230726152037
• Pavlović G, Lekšić E, Meštrović E. Supramolecular synthons in hydrates and solvates of lamotrigine: a tool for cocrystal design. Acta Crystallogr B Struct Sci Cryst Eng Mater. 2024; 80(3): 193-200. https://doi.org/10.1107/S2052520624002567
• Meng Y, Tan F, Yao J. Preparation, characterization and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs. Int J Pharm. 2022; 4: 100119. https://doi.org/10.1016/j.ijpx.2022.100119
• Childs SL, Kandi P, Lingireddy SR. Formulation of a danazol cocrystal with controlled supersaturation plays an essential role in improving bioavailability. Mol Pharmaceutics. 2013; 10(8): 3112-3127. https://doi.org/10.1021/mp400176y
• Ullah M, Hussain I, Sun CC. The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance. Drug Dev Ind Pharm. 2016; 42(6): 969-976. https://doi.org/10.3109/03639045.2015.1096281
• Hickey MB, Peterson ML, Scoppettuolo LA, Morrisette SL, Vetter A, Guzmán H, Remenar JF, Zhang Z, Tawa MD, Haley S, Zaworotko MJ, Almarsson O. Performance comparison of a co-crystal of carbamazepine with marketed product. Eur J Pharm Biopharm. 2007; 67(1): 112-119. https://doi.org/10.1016/j.ejpb.2006.12.016.
• Khullar P, Kolhe V, Kulkarni A, Patel S, Phadke Y, Saravanan D, Shingte M. Solid pharmaceutical fixed dose combinations comprising irbesartan and amlodipine, their pharmaceutical applications. 2009; AU20090349125.
• Nijhawan M, Dhyagala S, Gunnam S, Aleti R, Saxena T. Dipyridamole cocrystal tablets with enhanced solubility and dissolution at intestinal pH. Fabad J Pharm Sci. 2024; 49(1): 37-50. https://doi.org/10.55262/fabadeczacilik.1318448
• Nijhawan M, Godugu M, Saxena T, Farheen T, Dwivedi K. Pharmaceutical co-crystals of posaconazole for improvement of physicochemical properties. Braz J Pharm Sci. 2022; 58: e191024. https://doi.org/10.1590/s2175- 97902022e191024
• Thenge RA, Patel R, Kayande NA, Mahajan NI. Co-crystals of carvedilol: preparation, characterization and evaluation. Int J Appl Pharm. 2020; 12(1): 42-49. http://dx.doi.org/10.22159/ijap.2020v12i1.35640.
• Dutt B, Choudhary M, Budhwar V. Preparation, characterization and evaluation of aspirin:benzoic acid cocrystals with enhanced pharmaceutical properties. Futur J Pharm Sci. 2020; 6: 32. https://doi.org/10.1186/s43094-020- 00052-y
• Sawatdee S, Atipairin A, Rakkummerd S, Suriyaphol O, Harding DJ, Muenraya P, Harding P. Preparation and physicochemical characterization of sildenafil cocrystals. J Adv Pharm Technol Res. 2021; 12(4): 408-419. https://doi.org/10.4103/japtr.japtr_72_21.
• Sinko PJ. Martin's physical pharmacy and pharmaceutical sciences. Sixth ed., Lippincott Williams & Wilkins, Philadelphia 2011.
• Shanthala H.K, Jayaprakash H, Radhakrishna M, Gowda B, Paul K, Shankar S, Ahmed M.G, Sanjana A. Enhancement of solubility and dissolution rate of acetylsalicylic acid via co-crystallization technique: A novel ASA- valine cocrystal. Int J App Pharm. 2021; 13(1): 199-205. https://doi.org/10.53555/jrtdd.v6i6s.2763.
• Nijhawan M, Santhosh A, PR Sathesh Babu, Subrahmanyam CVS. Solid state manipulation of lornoxicam for cocrystals- physicochemical characterization. Drug Dev Ind Pharm. 2014; 40(9): 1163-1172. https://doi.org/10.3109/03639045.2013.804834
• Costa P, Sousa lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001; 13: 123-133. https://doi.org/10.1016/S0928-0987(01)00095-1
• Rajeswari A, Ramana Murthy KV. Development and characterization of chronotherapeutic tablets of sacubitril- valsartan supramolecular complex using hupu gum and lannea gum by compression coating. J Appl Pharm Sci. 2023; 13(07): 193–203. https://dx.doi.org/10.7324/JAPS.2023.120714.
• Medhi B, Prakash A. Practical manual of experimental and clinical pharmacology. Jaypee brothers Medical Publishers Ltd: India 2010.
• Cheney ML, Weyna DR, Shan N, Hanna M, Wojtas L, Zaworotko MJ. Coformer selection in pharmaceutical co- crystal development: A case study of a meloxicam aspirin co-crystal that exhibits enhanced solubility and pharmacokinetics. J Pharm Sci. 2011; 100(6): 2172-2181. https://doi.org/10.1002/jps.22434.
• Patel J, Patel A, Raval M, Sheth N. Formulation and development of self nanoemulsifying drug delivery system of irbesartan.J Adv Pharm Techol Res. 2011; 2(1): 9-16. https://doi.org/10.4103/2231-4040.79799.
• Boghra RJ, Kothawade PC, Belgamwar VS, Nerkar PP, Tekade AR, Surana SJ. Solubility, dissolution rate and bioavailability enhancement of irbesartan by solid dispersion technique. Chem Pharm Bull. 2011; 59(4): 438-441. https://doi.org/10.1248/cpb.59.438.
• Raju RR, Babu NB. Development and validation of HPLC method for estimation of irbesartan in pharmaceutical dosage form. Pharmacophore. 2011; 2(2): 145-149.
• Wang Z, Li Q, An Q, Gong L, Yang S, Zhang B, Su B, Yang D, Zhang L, Lu Y, Du G. Optimized solubility and bioavailability of genistein based on cocrystal engineering. Nat Prod Bioprospecting. 2023; 13(1): 30–43. https://doi.org/10.1007/s13659-023-00397-w.
• Zhang Q, Xia M, Zheng C, Yang Y, Bao J, Dai W, Mei X. The cocrystal of ubiquinol: improved stability and bioavailability. Pharmaceutics. 2023; 15(10): 2499. https://doi.org/10.3390/pharmaceutics15102499
• Dahiya S, Kaushik A, Pathak K. Improved pharmacokinetics of aceclofenac immediate release tablets incorporating its inclusion complex with hydroxypropyl-β-cyclodextrin. Sci Pharm. 2015; 83(3): 501-510. https://doi.org/10.3797/scipharm.1509-07.