Skip to main content
SpringerLink
Log in

Novel Co-crystals and Eutectics of Febuxostat: Characterization, Mechanism of Formation, and Improved Dissolution

  • Research Article
  • Theme: Advancements in Amorphous Solid Dispersions to Improve Bioavailability
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Co-crystallization studies were undertaken to improve the solubility of a highly water-insoluble drug febuxostat (FXT), used in the treatment of gout and hyperuricemia. The selection of co-crystal former (CCF) molecules such as 1-hydroxy 2-naphthoic acid (1H-2NPH), 4-hydroxy benzoic acid (4-HBA), salicylic acid (SAC), 5-nitro isophthalic acid (5-NPH), isonicotinamide (ISNCT), and picolinamide (PICO) was based on the presence of complementary functional groups capable of forming hydrogen bond and the ΔpKa difference between FXT and CCF. A liquid-assisted grinding (LAG) method was successfully employed for the rapid screening of various pharmaceutical adducts. These adducts were characterized based on their unique thermal (differential scanning calorimetry) and spectroscopic (Fourier transform infrared and Raman spectroscopy) profiles. Binary phase diagrams (BPD) were plotted to establish a relationship between the thermal events and adduct formed. Powder X-ray diffraction (PXRD) studies were carried out to confirm the formation of eutectic/co-crystal. Thermogravimetric analysis (TGA) was also performed for the novel co-crystals obtained. The propensity for strong homo-synthons over weak hetero-synthons and strong hetero-synthons over weak homo-synthons during supramolecular growth resulted in the formation of eutectics and co-crystals respectively. FXT:1H-2NPH (1), FXT:4-HBA (1), FXT:SAC (1, 2), and FXT:5-NPH (2-1) gave rise to pure eutectic systems, while FXT:ISNCT (2-1) and FXT:PICO (1) gave rise to novel co-crystals with characteristic DSC heating curves and PXRD pattern. Additionally, the impact of microenvironmental pH and microspeciation profile on the improved dissolution profile of the co-crystals was discussed.

Graphical Abstract

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
Fig. 10
Fig. 11
Fig. 12
Flowchart 1

Similar content being viewed by others

References

  1. Savjani KT, Gajjar AK, Savjani JK. Drug solubility: importance and enhancement techniques. ISRN Pharm. 2012;2012:1–10.

    Google Scholar 

  2. Stahl PH. Handbook of pharmaceutical salts properties, selection, and use. In: Stahl PH, Wermuth CG, editors. International Union of Pure and Applied Chemistry. John Wiley & Sons; 2008. p. 374.

  3. Sun CC. Cocrystallization for successful drug delivery. Expert Opin Drug Deliv. 2013;10(2):201–13.

    Article  CAS  PubMed  Google Scholar 

  4. Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. Pharmaceutical co-crystals. J Pharm Sci. 2006;95(3):499–516.

    Article  CAS  PubMed  Google Scholar 

  5. Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des. 2009;9(6):2950–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Good DJ, Rodríguez-Hornedo N. Solubility advantage of pharmaceutical cocrystals. Cryst Growth Des. 2009;9(5):2252–64.

    Article  CAS  Google Scholar 

  7. Duggirala NK, Perry ML, Almarsson Ö, Zaworotko MJ. Pharmaceutical cocrystals: along the path to improved medicines. Chem Commun. 2016;52(4):640–55.

    Article  CAS  Google Scholar 

  8. Remenar JF, Morissette SL, Peterson ML, Moulton B, MacPhee JM, Guzmán HR, et al. Crystal engineering of novel cocrystals of a triazole drug with 1, 4-dicarboxylic acids. J Am Chem Soc. 2003;125(28):8456–7.

    Article  CAS  PubMed  Google Scholar 

  9. Jung MS, Kim JS, Kim MS, Alhalaweh A, Cho W, Hwang SJ, Velaga SP. Bioavailability of indomethacin-saccharin cocrystals. J Pharm Pharmacol. 2010;62(11):1560–8.

    Article  CAS  PubMed  Google Scholar 

  10. Rahman Z, Agarabi C, Zidan AS, Khan SR, Khan MA. Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide. AAPS PharmSciTech. 2011;12(2):693–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Karki S, Friščić T, Fábián L, Laity PR, Day GM, Jones W. Improving mechanical properties of crystalline solids by cocrystal formation: new compressible forms of paracetamol. Adv Mater. 2009;21(38-39):3905–9.

    Article  CAS  Google Scholar 

  12. Trask AV, Motherwell WS, Jones W. Physical stability enhancement of theophylline via cocrystallization. Int J Pharm. 2006;320(1):114–23.

    Article  CAS  PubMed  Google Scholar 

  13. Blagden N, Coles S, Berry D. Pharmaceutical co-crystals–are we there yet? CrystEngComm. 2014;16(26):5753–61.

    Article  CAS  Google Scholar 

  14. Kumar A, Kumar S, Nanda A. A review about regulatory status and recent patents of pharmaceutical co-crystals. Adv Pharm Bull. 2018;8(3):355–63.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Cherukuvada S, Nangia A. Eutectics as improved pharmaceutical materials: design, properties and characterization. Chem Commun. 2014;50(8):906–23.

    Article  CAS  Google Scholar 

  16. Kang Y, Gu J, Hu X. Syntheses, structure characterization and dissolution of two novel cocrystals of febuxostat. J Mol Struct. 2017;1130:480–6.

    Article  CAS  Google Scholar 

  17. Maddileti D, Jayabun S, Nangia A. Soluble cocrystals of the xanthine oxidase inhibitor febuxostat. Cryst Growth Des. 2013;13(7):3188–96.

    Article  CAS  Google Scholar 

  18. Thakuria R, Delori A, Jones W, Lipert MP, Roy L, Rodríguez-Hornedo N. Pharmaceutical cocrystals and poorly soluble drugs. Int J Pharm. 2013;453(1):101–25.

    Article  CAS  PubMed  Google Scholar 

  19. Etter MC. Hydrogen bonds as design elements in organic chemistry. J Phys Chem. 1991;95(12):4601–10.

    Article  CAS  Google Scholar 

  20. Childs SL, Stahly GP, Park A. The salt-cocrystal continuum: the influence of crystal structure on ionization state. Mol Pharm. 2007;4(3):323–38.

    Article  CAS  PubMed  Google Scholar 

  21. Childs SL, Rodríguez-Hornedo N, Reddy LS, Jayasankar A, Maheshwari C, McCausland L, Shipplett R, Stahly BC. Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine. CrystEngComm. 2008;10(7):856–64.

    Article  CAS  Google Scholar 

  22. Friščić T, Childs SL, Rizvi SA, Jones W. The role of solvent in mechanochemical and sonochemical cocrystal formation: a solubility-based approach for predicting cocrystallisation outcome. CrystEngComm. 2009;11(3):418–26.

    Article  Google Scholar 

  23. Toda F, Braga D, editors. Organic solid state reactions. In: Volume 254 of topics in current chemistry. Springer Science & Business Media; 2005. pp. 313 

  24. Stoler E, Warner JC. Non-covalent derivatives: cocrystals and eutectics. Molecules. 2015;20(8):14833–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Leung DH, Lohani S, Ball RG, Canfield N, Wang Y, Rhodes T, Bak A. Two novel pharmaceutical cocrystals of a development compound–screening, scale-up, and characterization. Cryst Growth Des. 2012;12(3):1254–62.

    Article  CAS  Google Scholar 

  26. Sekhon B. Pharmaceutical co-crystals-a review. Ars Pharm. 2009;50(3):99–117.

    Google Scholar 

  27. Cruz-Cabeza AJ. Acid–base crystalline complexes and the p K a rule. CrystEngComm. 2012;14(20):6362–5.

    Article  CAS  Google Scholar 

  28. Patel J, Jagia M, Bansal AK, Patel S. Characterization and thermodynamic relationship of three polymorphs of a xanthine oxidase inhibitor, febuxostat. J Pharm Sci. 2015;104(11):3722–30.

    Article  CAS  PubMed  Google Scholar 

  29. Badawy SIF, Hussain MA. Microenvironmental pH modulation in solid dosage forms. J Pharm Sci. 2007;96(5):948–59.

    Article  CAS  PubMed  Google Scholar 

  30. Lawrence XY, Carlin AS, Amidon GL, Hussain AS. Feasibility studies of utilizing disk intrinsic dissolution rate to classify drugs. Int J Pharm. 2004;270(1):221–7.

    Google Scholar 

  31. Issa MG, Ferraz HG. Intrinsic dissolution as a tool for evaluating drug solubility in accordance with the biopharmaceutics classification system. Dissolut Technol. 2011;18(3):6–11.

    Article  CAS  Google Scholar 

  32. Lu E, Rodríguez-Hornedo N, Suryanarayanan R. A rapid thermal method for cocrystal screening. CrystEngComm. 2008;10(6):665–8.

    Article  CAS  Google Scholar 

  33. Cherukuvada S, Guru Row TN. Comprehending the formation of eutectics and cocrystals in terms of design and their structural interrelationships. Cryst Growth Des. 2014;14(8):4187–98.

    Article  CAS  Google Scholar 

  34. Yamashita H, Hirakura Y, Yuda M, Terada K. Coformer screening using thermal analysis based on binary phase diagrams. Pharm Res. 2014;31(8):1946–57.

    Article  CAS  PubMed  Google Scholar 

  35. Yamashita H, Hirakura Y, Yuda M, Teramura T, Terada K. Detection of cocrystal formation based on binary phase diagrams using thermal analysis. Pharm Res. 2013;30(1):70–80.

    Article  CAS  PubMed  Google Scholar 

  36. Pal S, Roopa B, Abu K, Manjunath SG, Nambiar S. Thermal studies of furosemide–caffeine binary system that forms a cocrystal. J Therm Anal Calorim. 2014;115(3):2261–8.

    Article  CAS  Google Scholar 

  37. Félix-Sonda BC. Rivera-Islas Js, Herrera-Ruiz D, Morales-Rojas H, Höpfl H. Nitazoxanide cocrystals in combination with succinic, glutaric, and 2, 5-dihydroxybenzoic acid. Cryst Growth Des. 2014;14(3):1086–102.

    Article  Google Scholar 

  38. Stuart BH. Infrared spectroscopy: fundamentals and applications. In: Analytical Techniques in the Sciences (AnTs). John Wiley & Sons; 2004. pp. 248.

  39. Bakiler M, Bolukbasi O, Yilmaz A. An experimental and theoretical study of vibrational spectra of picolinamide, nicotinamide, and isonicotinamide. J Mol Struct. 2007;826(1):6–16.

    Article  CAS  Google Scholar 

  40. Castro RAE, Ribeiro JD, Maria TM, Ramos Silva M, Yuste-Vivas C, Canotilho J, et al. Naproxen cocrystals with pyridinecarboxamide isomers. Cryst Growth Des. 2011;11(12):5396–404.

    Article  CAS  Google Scholar 

  41. Wang L, Tan B, Zhang H, Deng Z. Pharmaceutical cocrystals of diflunisal with nicotinamide or isonicotinamide. Org Process Res Dev. 2013;17(11):1413–8.

    Article  CAS  Google Scholar 

  42. Chow SF, Chen M, Shi L, Chow AH, Sun CC. Simultaneously improving the mechanical properties, dissolution performance, and hygroscopicity of ibuprofen and flurbiprofen by cocrystallization with nicotinamide. Pharm Res. 2012;29(7):1854–65.

    Article  CAS  PubMed  Google Scholar 

  43. Ando S, Kikuchi J, Fujimura Y, Ida Y, Higashi K, Moribe K, Yamamoto K. Physicochemical characterization and structural evaluation of a specific 2: 1 cocrystal of naproxen–nicotinamide. J Pharm Sci. 2012;101(9):3214–21.

    Article  CAS  PubMed  Google Scholar 

  44. Parker FS. Applications of infrared, Raman, and resonance Raman spectroscopy in biochemistry. Springer Science & Business Media; 1983. pp. 568.

  45. Lambert JB. Introduction to organic spectroscopy. Macmillan; 1987. pp. 454.

  46. Glombitza BW, Oelkrug D, Schmidt PC. Surface acidity of solid pharmaceutical excipients. I: Determination of the surface acidity. Eur J Pharm Biopharm. 1994;40(5):289–93.

    CAS  Google Scholar 

  47. Jagia M, Daptardar R, Patel K, Bansal AK, Patel S. Role of Structure, Microenvironmental pH, and Speciation To Understand the Formation and Properties of Febuxostat Eutectics. Mol Pharm. 2019;16(11):4610–20.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 Dekalb Avenue, HS Bldg. 612, Brooklyn, New York, 11201, USA

    Moksh Jagia & Sarsvatkumar Patel

  2. Thermo Fisher Scientific, 5900 M.L.K. Jr Hwy, Greenville, North Carolina, 27834, USA

    Moksh Jagia

  3. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Sahibzada Ajit Singh Nagar, Punjab, 160062, India

    Dnyaneshwar P. Kale & Arvind Kumar Bansal

  4. Intas Pharmaceuticals, Ahmedabad, Gujarat, 382440, India

    Dnyaneshwar P. Kale

  5. Repare Therapeutics, 1 Broadway, 15th Floor, Cambridge, Massachusetts, 02142, USA

    Sarsvatkumar Patel

Authors
  1. Moksh Jagia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dnyaneshwar P. Kale
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arvind Kumar Bansal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarsvatkumar Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

• Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: Moksh Jagia and Sarsvatkumar Patel

• Drafting the work or revising it critically for important intellectual content: Moksh Jagia and Dnyaneshwar P. Kale

• Final approval of the version to be published: Sarsvatkumar Patel and Arvind Kumar Bansal

• Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: Moksh Jagia, Dnyaneshwar P. Kale, Sarsvatkumar Patel, and Arvind Kumar Bansal

Corresponding author

Correspondence to Sarsvatkumar Patel.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 2595 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jagia, M., Kale, D.P., Bansal, A.K. et al. Novel Co-crystals and Eutectics of Febuxostat: Characterization, Mechanism of Formation, and Improved Dissolution. AAPS PharmSciTech 23, 43 (2022). https://doi.org/10.1208/s12249-021-02182-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-021-02182-9

KEY WORDS

Search

Navigation