Crystal engineering approach was utilized for the development of different multicomponent solid forms of telmisartan (TEL) to improve its oral bioavailability. In this context, two cocrystals, gentisic acid (GA) and maleic acid (MA), while two eutectic mixtures, para-aminobenzoic acid (PABA) and adipic acid (AA), were successfully prepared and characterized by different analytical tools. Both the cocrystals exhibited characteristic heterosynthons, viz. OHacid⋯Narom and OHacid⋯O, to propagate new network. Structural features of coformers has been correlated with the outcomes of cocrystallization approach. Coformers having auxiliary functionality in addition to complementary functional groups have high propensity to generate cocrystals. However, multicomponent where auxiliary functionality is lacking, such combinations, is shown to form eutectic mixtures owing to strong homomeric interaction. Besides, the developed cocrystals and eutectic mixtures showed higher aqueous solubility (3–5.5-fold) and intrinsic dissolution rate (1–2.6-fold) over pure TEL. In vivo studies also revealed significant improvement in relative bioavailability (2–2.6-fold). The study also shed light on the implications of eutectic mixtures in mitigating the solubility issues of drugs which are often considered negative results of cocrystallization strategy.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Shan N, Zaworotko MJ. The role of cocrystals in pharmaceutical science. Drug Discov Today. 2008;13(9):440–6. https://doi.org/10.1016/j.drudis.2008.03.004.
Kuminek G, Cao F, Bahia de Oliveira da Rocha A, Goncalves Cardoso S, Rodriguez-Hornedo N. Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5. Adv Drug Deliv Rev. 2016;101:143–66. https://doi.org/10.1016/j.addr.2016.04.022.
Desiraju GR. Crystal engineering: a holistic view. Angew Chem Int Ed Eng. 2007;46(44):8342–56. https://doi.org/10.1002/anie.200700534.
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. 2004;17:1889–96. https://doi.org/10.1039/B402150A.
Berry DJ, Steed JW. 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.
Bolla G, Nangia A. Pharmaceutical cocrystals: walking the talk. Chem Commun. 2016;52(54):8342–60. https://doi.org/10.1039/c6cc02943d.
Cherukuvada S, Nangia A. Eutectics as improved pharmaceutical materials: design, properties and characterization. Chem Commun. 2014;50(8):906–23. https://doi.org/10.1039/c3cc47521b.
Cherukuvada S, Guru Row TN. Comprehending the formation of eutectics and cocrystals in terms of design and their structural interrelationships. CrystGrowth Des. 2014;14(8):4187–98. https://doi.org/10.1021/cg500790q.
Kaur R, Gautam R, Cherukuvada S, Guru Row TN. Do carboximide-carboxylic acid combinations form co-crystals? The role of hydroxyl substitution on the formation of co-crystals and eutectics. IUCr J. 2015;2(Pt 3):341–51. https://doi.org/10.1107/s2052252515002651.
Haneef J, Chadha R. Drug-drug multicomponent solid forms: cocrystal, coamorphous and eutectic of three poorly soluble antihypertensive drugs using mechanochemical approach. AAPS PharmSciTech. 2017;18(6):2279–90. https://doi.org/10.1208/s12249-016-0701-1.
Zhou L, Dodd S, Capacci-Daniel C, Garad S, Panicucci R, Sethuraman V. Co-crystal formation based on structural matching. Eur J Pharm Sci. 2016;88:191–201. https://doi.org/10.1016/j.ejps.2016.02.017.
FDA. Regulatory classification of pharmaceutical co-crystals. 2016 [14 June 2019]; Available from: https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm516813.pdf.
Sharpe M, Jarvis B, Goa KL. Telmisartan: a review of its use in hypertension. Drugs. 2001;61(10):1501–29. https://doi.org/10.2165/00003495-200161100-00009.
Park J, Cho W, Cha KH, Ahn J, Han K, Hwang SJ. Solubilization of the poorly water soluble drug, telmisartan, using supercritical anti-solvent (SAS) process. Int J Pharm. 2013;441(1-2):50–5. https://doi.org/10.1016/j.ijpharm.2012.12.020.
Ahmad J, Kohli K, Mir SR, Amin S. Formulation of self-nanoemulsifying drug delivery system for telmisartan with improved dissolution and oral bioavailability. J Dispers Sci Technol. 2011;32(7):958–68. https://doi.org/10.1080/01932691.2010.488511.
Zhang Y, Jiang T, Zhang Q, Wang S. Inclusion of telmisartan in mesocellular foam nanoparticles: drug loading and release property. Eur J Pharm Biopharm. 2010;76(1):17–23. https://doi.org/10.1016/j.ejpb.2010.05.010.
Zhong L, Zhu X, Luo X, Su W. Dissolution properties and physical characterization of telmisartan-chitosan solid dispersions prepared by mechanochemical activation. AAPS PharmSciTech. 2013;14(2):541–50. https://doi.org/10.1208/s12249-013-9937-1.
Isaac J, Ganguly S, Ghosh A. Co-milling of telmisartan with poly(vinyl alcohol)-an alkalinizer free green approach to ensure its bioavailability. Eur J Pharm Biopharm. 2016;101:43–52. https://doi.org/10.1016/j.ejpb.2016.01.016.
Jamadar S, Pore Y, Sayyad F. Formation of amorphous telmisartan polymeric microparticles for improvement of physicochemical characteristics. Part Sci Technol. 2014;32(5):512–9. https://doi.org/10.1080/02726351.2014.920444.
Chadha R, Bhandari S, Haneef J, Khullar S, Mandal S. Cocrystals of telmisartan: characterization, structure elucidation, in vivo and toxicity studies. CrystEngComm. 2014;16(36):8375–89. https://doi.org/10.1039/c4ce00797b.
Arora P, Kaur A, Haneef J, Chadha R. Solubility improvement of telmisartan by cocrystallization with citric acid. Int J Pharm Sci Res. 2017;8(9):3768–75. https://doi.org/10.13040/IJPSR.0975-8232.8(9).3768-75.
Kundu S, Kumari N, Soni SR, Ranjan S, Kumar R, Sharon A, et al. Enhanced solubility of telmisartan phthalic acid cocrystals within the pH range of a systemic absorption site. ACS Omega. 2018;3(11):15380–8. https://doi.org/10.1021/acsomega.8b02144.
Vogt FG, Clawson JS, Strohmeier M, Edwards AJ, Pham TN, Watson SA. Solid-state NMR analysis of organic cocrystals and complexes. Cryst Growth Des. 2009;9(2):921–37. https://doi.org/10.1021/cg8007014.
Dinnebier RE, Sieger P, Nar H, Shankland K, David WI. Structural characterization of three crystalline modifications of telmisartan by single crystal and high-resolution X-ray powder diffraction. J Pharm Sci. 2000;89(11):1465–79. https://doi.org/10.1002/1520-6017(200011)89:11<1465::AID-JPS9>3.0.CO;2-C.
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(5):2736–45. https://doi.org/10.1021/acs.cgd.8b01873.
Bavishi DD, Borkhataria CH. Spring and parachute: how cocrystals enhance solubility. Prog Cryst Growth Charact. 2016;62(3):1–8. https://doi.org/10.1016/j.pcrysgrow.2016.07.001.
Mr. Jamshed Haneef is highly thankful to the Department of Science and Technology (DST), New Delhi, India, for providing the Inspire fellowships. Authors are also thankful for the services provided by the Sophisticated Analytical Instrumentation Facility (SAIF), Panjab University, India, to carry out the analysis of the sample.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic Supplementary Material
Supporting information contains Figure 1: Overlay of FTIR spectra of TEL, GA and TEL-GA; Figure 2: Overlay of FTIR spectra of TEL, MA and TEL-MA; Figure 3: Overlay of 13C SSNMR spectra of TEL, GA and TEL-GA; Figure 4: Overlay of 13C SSNMR spectra of TEL, MA and TEL-MA; Figure 5: Overlay of experimental and simulated PXRD patterns of TEL-GA cocrystal; Figure 6: Overlay of experimental and simulated PXRD patterns of TEL-MA cocrystal; Figure 7: Overlay of PXRD patterns of cocrystals (TEL-MA & TEL-GA) before and after stability study; Figure 8: Overlay of PXRD patterns of eutectic mixtures (TEL-PABA & TEL-AA) before and after stability study. Table 1: Multicomponent solid form screening of telmisartan using various coformers. Crystallographic information can be obtained from www.ccdc.cam.ac.uk/data (CCDC nos. 1868619 &1868609) (DOCX 1302 kb)
About this article
Cite this article
Haneef, J., Arora, P. & Chadha, R. Implication of Coformer Structural Diversity on Cocrystallization Outcomes of Telmisartan with Improved Biopharmaceutical Performance. AAPS PharmSciTech 21, 10 (2020). https://doi.org/10.1208/s12249-019-1559-9
- crystal engineering
- eutectic mixtures
- multicomponent solid forms