Skip to main content

Advertisement

SpringerLink
Log in

Drug-Drug Multicomponent Solid Forms: Cocrystal, Coamorphous and Eutectic of Three Poorly Soluble Antihypertensive Drugs Using Mechanochemical Approach

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The present study deals with the application of mechanochemical approach for the preparation of drug-drug multicomponent solid forms of three poorly soluble antihypertensive drugs (telmisartan, irbesartan and hydrochlorothiazide) using atenolol as a coformer. The resultant solid forms comprise of cocrystal (telmisartan-atenolol), coamorphous (irbesartan-atenolol) and eutectic (hydrochlorothiazide-atenolol). The study emphasizes that solid-state transformation of drug molecules into new forms is a result of the change in structural patterns, diminishing of dimers and creating new facile hydrogen bonding network based on structural resemblance. The propensity for heteromeric or homomeric interaction between two different drugs resulted into diverse solid forms (cocrystal/coamorphous/eutectics) and become one of the interesting aspects of this research work. Evaluation of these solid forms revealed an increase in solubility and dissolution leading to better antihypertensive activity in deoxycorticosterone acetate (DOCA) salt-induced animal model. Thus, development of these drug-drug multicomponent solid forms is a promising and viable approach to addressing the issue of poor solubility and could be of considerable interest in dual drug therapy for the treatment of hypertension.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

REFERENCES

  1. 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;1889-96.

  2. Steed JW. The role of co-crystals in pharmaceutical design. Trends Pharmacol Sci. 2013;34:185–93.

    Article  CAS  PubMed  Google Scholar 

  3. Thakuria R, Delori A, Jones W, Lipert MP, Roy L, Rodriguez-Hornedo N. Pharmaceutical cocrystals and poorly soluble drugs. Int J Pharm. 2013;453:101–25.

    Article  CAS  PubMed  Google Scholar 

  4. Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: an overview. Int J Pharm. 2011;419:1–11.

    Article  CAS  PubMed  Google Scholar 

  5. Brittain HG. Cocrystal Systems of Pharmaceutical Interest: 2010. CrystGrowth Des. 2012;12:1046–54.

    CAS  Google Scholar 

  6. Miroshnyk I, Mirza S, Sandler N. Pharmaceutical co-crystals-an opportunity for drug product enhancement. Expert Opin Drug Deliv. 2009;6:333–41.

    Article  CAS  PubMed  Google Scholar 

  7. Bhatt PM, Azim Y, Thakur TS, Desiraju GR. Co-crystals of the anti-HIV drugs lamivudine and zidovudine. Cryst Growth Des. 2009;9:951–7.

    Article  CAS  Google Scholar 

  8. Evora AOL, Castro RAE, Maria TMR, Rosado MTS, Silva MR, Beja AM, et al. Pyrazinamide-diflunisal: a new dual-drug co-crystal. Cryst Growth Des. 2011;11:4780–8.

    Article  CAS  Google Scholar 

  9. Jiang L, Huang Y, Zhang Q, He H, Xu Y, Mei X. Preparation and solid-state characterization of dapsone drug-drug co-crystals. Cryst Growth Des. 2014;14:4562–73.

    Article  CAS  Google Scholar 

  10. Umeda Y, Fukami T, Furuishi T, Suzuki T, Tanjoh K, Tomono K. Characterization of multicomponent crystal formed between indomethacin and lidocaine. Drug Dev Ind Pharm. 2009;35:843–51.

    Article  CAS  PubMed  Google Scholar 

  11. Vitorino GP, Sperandeo NR, Caira MR, Mazzieri MR. A supramolecular assembly formed by heteroassociation of ciprofloxacin and norfloxacin in the solid state: co-crystal synthesis and characterization. Cryst Growth Des. 2013;13:1050–8.

    Article  Google Scholar 

  12. Srinivasulu A, Chow PS, Tan RBH. Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients: potential relevance to combination drugs. CrystEngComm. 2009;11:1823–7.

    Article  Google Scholar 

  13. Grobelny P, Mukherjee A, Desiraju GR. Drug-drug co-crystals: temperature-dependent proton mobility in the molecular complex of isoniazid with 4-aminosalicylic acid. CrystEngComm. 2011;13:4358–64.

    Article  CAS  Google Scholar 

  14. Cheney ML, Weyna DR, Shan N, Hanna M, Wojtas L, Zaworotko MJ. Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics. J Pharm Sci. 2011;100:2172–81.

    Article  CAS  PubMed  Google Scholar 

  15. Newman A. Specialized solid form screening techniques. Org Process Res Dev. 2013;17:457–71.

    Article  CAS  Google Scholar 

  16. Rodriguez-Hornedo N, Nehm SJ, Seefeldt KF, Pagan-Torres Y, Falkiewicz CJ. Reaction crystallization of pharmaceutical molecular complexes. Mol Pharmaceutics. 2006;3:362–7.

    Article  CAS  Google Scholar 

  17. James SL, Adams CJ, Bolm C, Braga D, Collier P, Friscic T, et al. Mechanochemistry: opportunities for new and cleaner synthesis. Chem Soc Rev. 2012;41:413–47.

    Article  CAS  PubMed  Google Scholar 

  18. Weyna DR, Shattock T, Vishweshwar P, Zaworotko MJ. Synthesis and structural characterization of cocrystals and pharmaceutical cocrystals: mechanochemistry vs slow evaporation from solution. Cryst Growth Des. 2009;9:1106–23.

    Article  CAS  Google Scholar 

  19. Kaupp G. Mechanochemistry: the varied applications of mechanical bond-breaking. CrystEngComm. 2009;11:388–403.

    Article  CAS  Google Scholar 

  20. Karki S, Friscic T, Jones W. Control and interconversion of cocrystal stoichiometry in grinding: stepwise mechanism for the formation of a hydrogen-bonded cocrystal. CrystEngComm. 2009;11:470–81.

    Article  CAS  Google Scholar 

  21. Friscic T, Jones W. Recent advances in understanding the mechanism of cocrystal formation via grinding. Cryst Growth Des. 2009;9:1621–37.

    Article  CAS  Google Scholar 

  22. Cherukuvada S, Guru Row TN. Comprehending the formation of eutectics and cocrystals in terms of design and their structural interrelationships. CrystGrowth Des. 2014;14:4187–98.

    CAS  Google Scholar 

  23. Cherukuvada S, Nangia A. Eutectics as improved pharmaceutical materials: design, properties and characterization. Chem Commun. 2014;50:906–23.

    Article  CAS  Google Scholar 

  24. Willart JF, Descamps M. Solid state amorphization of pharmaceuticals. Mol Pharmaceutics. 2008;5:905–20.

    Article  CAS  Google Scholar 

  25. Shayanfar A, Jouyban A. Drug-drug coamorphous systems: characterization and physicochemical properties of coamorphous atorvastatin with carvedilol and glibenclamide. J Pharm Innov. 2013;8:218–28.

    Article  Google Scholar 

  26. Gao Y, Liao J, Qi X, Zhang J. Coamorphous repaglinide-saccharin with enhanced dissolution. Int J Pharm. 2013;450:290–5.

    Article  CAS  PubMed  Google Scholar 

  27. Dengale SJ, Ranjan OP, Hussen SS, Krishna BSM, Musmade PB, Gautham Shenoy G, et al. Preparation and characterization of co-amorphous Ritonavir-Indomethacin systems by solvent evaporation technique: improved dissolution behavior and physical stability without evidence of intermolecular interactions. EurJPharm Sci. 2014;62:57–64.

    CAS  Google Scholar 

  28. Dengale SJ, Hussen SS, Krishna BSM, Musmade PB, Gautham SG, Bhat K. Fabrication, solid state characterization and bioavailability assessment of stable binary amorphous phases of Ritonavir with Quercetin. Eur J Pharm Biopharm. 2015;89:329–38.

    Article  CAS  PubMed  Google Scholar 

  29. Wairkar S, Gaud R. Co-amorphous combination of nateglinide-metformin hydrochloride for dissolution enhancement. AAPS PharmSciTech. 2016;17:673–81.

    Article  CAS  PubMed  Google Scholar 

  30. Lou H, Liu M, Wang L, Mishra SR, Qu W, Johnson J, et al. Development of a mini-tablet of co-grinded prednisone-neusilin complex for pediatric use. AAPS PharmSciTech. 2013;14:950–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jensen KT, Larsen FH, Cornett C, Lobmann K, Grohganz H, Rades T. Formation mechanism of coamorphous drug-amino acid mixtures. Mol Pharmaceutics. 2015;12:2484–92.

    Article  CAS  Google Scholar 

  32. Alatas F, Ratih H, Soewandhi SN. Enhancement of solubility and dissolution rate of telmisartan by telmisartan-oxalic acid cocrystal formation. Int J Pharm Pharm Sci. 2015;7:423–6.

    CAS  Google Scholar 

  33. Chawla G, Bansal A. Improved dissolution of a poorly water soluble drug in solid dispersions with polymeric and non-polymeric hydrophilic additives. Acta Pharm. 2008;58:257–74.

    Article  CAS  PubMed  Google Scholar 

  34. Chawla G, Bansal AK. A comparative assessment of solubility advantage from glassy and crystalline forms of a water-insoluble drug. Eur J Pharm Sci. 2007;32:45–57.

    Article  CAS  PubMed  Google Scholar 

  35. Sanphui P, Rajput L. Tuning solubility and stability of hydrochlorothiazide co-crystals. Acta Cryst. 2014;B70:81–90.

    Google Scholar 

  36. 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 Pharmaceutics. 2015;12:1615–22.

    Article  CAS  Google Scholar 

  37. Taulelle P, Astier JP, Hoff C, Pèpe G, Veesler S. Pharmaceutical compound crystallization: growth mechanism of needle-like crystals. Chem Eng Technol. 2006;29:239–46.

    Article  CAS  Google Scholar 

  38. Chadha R, Bhandari S, Haneef J, Khullar S, Mandal S. Cocrystals of telmisartan: characterization, structure elucidation, in vivo and toxicity studies. CrystEngComm. 2014;16:8375–89.

    Article  CAS  Google Scholar 

  39. Van den Mooter G, Augustijns P, Kinget R. Stability prediction of amorphous benzodiazepines by calculation of the mean relaxation time constant using the Williams- Watts decay function. Eur J Pharm Biopharm. 1999;48:43–8.

    Article  PubMed  Google Scholar 

  40. Monassier L, Combe R, Fertak LE. Mouse models of hypertension. Drug Discov Today Dis Model. 2006;3:273–81.

    Article  Google Scholar 

  41. 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;9:921–37.

    Article  CAS  Google Scholar 

  42. 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;89:1465–79.

    Article  CAS  PubMed  Google Scholar 

  43. de Esteves Castro RA, Canotilho J, Barbosa RM, Silva MR, Beja AM, Paixao JA, et al. Conformational isomorphism of organic crystals: racemic and homochiral atenolol. Cryst Growth Des. 2007;7:496–500.

    Article  Google Scholar 

  44. Miura H, Kanebako M, Shirai H, Nakao H, Inagi T, Terada K. Stability of amorphous drug, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one, in silica mesopores and measurement of its molecular mobility by solid-state (13)C NMR spectroscopy. Int J Pharm. 2011;410:61–7.

    Article  CAS  PubMed  Google Scholar 

  45. Goud NR, Suresh K, Sanphui P, Nangia A. Fast dissolving eutectic compositions of curcumin. Int J Pharm. 2012;439:63–72.

    Article  CAS  PubMed  Google Scholar 

  46. Singh NB, Das SS, Singh NP, Agrawal T. Computer simulation, thermodynamic and microstructural studies of benzamide-benzoic acid eutectic system. J Crystal Growth. 2008;310:2878–84.

    Article  CAS  Google Scholar 

  47. Babu NJ, Nangia A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. CrystGrowth Des. 2011;11:2662–79.

    CAS  Google Scholar 

  48. Baird JA, Taylor LS. Evaluation of amorphous solid dispersion properties using thermal analysis techniques. Adv Drug Delivery Rev. 2012;64:396–421.

    Article  CAS  Google Scholar 

  49. Stanton T, Reid J. Fixed dose combination therapy in the treatment of hypertension. J Hum Hypertens. 2002;16:75–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author Mr Jamshed Haneef gratefully acknowledges Department of Science and Technology (DST), New Delhi, India, for providing Inspire Fellowship vide letter no. 2012/687 to carry out this research work. The authors highly acknowledge the services provided by the Sophisticated Analytical Instrumentation Facility (SAIF), Panjab University, India, to carry out the samples analysis.

Author information

Authors and Affiliations

  1. University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Studies (CAS), Sector 14, Panjab University, Chandigarh, 160 014, India

    Jamshed Haneef & Renu Chadha

Authors
  1. Jamshed Haneef
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Renu Chadha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Renu Chadha.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 437 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haneef, J., Chadha, R. Drug-Drug Multicomponent Solid Forms: Cocrystal, Coamorphous and Eutectic of Three Poorly Soluble Antihypertensive Drugs Using Mechanochemical Approach. AAPS PharmSciTech 18, 2279–2290 (2017). https://doi.org/10.1208/s12249-016-0701-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-016-0701-1

KEY WORDS

Search

Navigation