Formation of Itraconazole–Succinic Acid Cocrystals by Gas Antisolvent Cocrystallization

Abstract

Cocrystals of itraconazole, an antifungal drug with poor bioavailability, and succinic acid, a water-soluble dicarboxylic acid, were formed by gas antisolvent (GAS) cocrystallization using pressurized CO2 to improve itraconazole dissolution. In this study, itraconazole and succinic acid were simultaneously dissolved in a liquid solvent, tetrahydrofuran, at ambient conditions. The solution was then pressurized with CO2, which decreased the solvating power of tetrahydrofuran and caused crystallization of itraconazole–succinic acid cocrystals. The cocrystals prepared by GAS cocrystallization were compared to those produced using a traditional liquid antisolvent, n-heptane, for crystallinity, chemical structure, thermal behavior, size and surface morphology, potential clinical relevance, and stability. Powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, and scanning electron microscopy analyses showed that itraconazole–succinic acid cocrystals with physical and chemical properties similar to cocrystals produced using a traditional liquid antisolvent technique can be prepared by CO2 antisolvent cocrystallization. The dissolution profile of itraconazole was significantly enhanced through GAS cocrystallization with succinic acid, achieving over 90% dissolution in less than 2 h. The cocrystals appeared stable against thermal stress for up to 4 weeks under accelerated stability conditions, showing only moderate decreases in their degree of crystallinity but no change in their crystalline structure. This study shows the utility of an itraconazole–succinic acid cocrystal for improving itraconazole bioavailability while also demonstrating the potential for CO2 to replace traditional liquid antisolvents in cocrystal preparation, thus making cocrystal production more environmentally benign and scale-up more feasible.

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REFERENCES

  1. 1.

    Aakeröy CB, Forbes S, Desper J. Using cocrystals to systematically modulate aqueous solubility and melting behavior of an anticancer drug. J Am Chem Soc. 2009;131(47):17048–9.

    PubMed  Article  Google Scholar 

  2. 2.

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

    Article  CAS  Google Scholar 

  3. 3.

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

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Sun CC, Hou H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Cryst Growth Des. 2008;8(5):1575–9.

    Article  CAS  Google Scholar 

  5. 5.

    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 

  6. 6.

    Morissette SL, Almarsson Ö, Peterson ML, Remenar JF, Read MJ, Lemmo AV, et al. High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv Drug Deliv Rev. 2004;56(3):275–300.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Trask AV, Jones W. Crystal engineering of organic cocrystals by the solid-state grinding approach. Org Solid State React. 2005;41–70.

  8. 8.

    Horst JH, Cains PW. Co-crystal polymorphs from a solvent-mediated transformation. Cryst Growth Des. 2008;8(7):2537–42.

    Article  Google Scholar 

  9. 9.

    Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: an overview. Int J Pharm. 2011;419(1–2):1–11.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Padrela L, Rodrigues MA, Velaga SP, Matos HA, De Azevedo EG. Formation of indomethacin-saccharin cocrystals using supercritical fluid technology. Eur J Pharm Sci. 2009;38(1):9–17.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Padrela L, Rodrigues MA, Velaga SP, Fernandes AC, Matos HA, de Azevedo EG. Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process. J Supercrit Fluids. 2010;53(1–3):156–64.

    Article  CAS  Google Scholar 

  12. 12.

    Subramaniam B, Rajewski RA, Snavely K. Pharmaceutical processing with supercritical carbon dioxide. J Pharm Sci. 1997;86(8):885–90.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Berends EM, Bruinsma OSL, De Graauw J, van Rosmalen GM. Crystallization of phenanthrene from toluene with carbon dioxide by the GAS process. AIChE J. 1996;42(2):431–9.

    Article  CAS  Google Scholar 

  14. 14.

    Kitamura M, Yamamoto M, Yoshinaga Y, Masuoka H. Crystal size control of sulfathiazole using high pressure carbon dioxide. J Cryst Growth. 1997;178(3):378–86.

    Article  CAS  Google Scholar 

  15. 15.

    Corrigan OI, Crean AM. Comparative physicochemical properties of hydrocortisone-PVP composites prepared using supercritical carbon dioxide by the GAS anti-solvent recrystallization process, by coprecipitation and by spray drying. Int J Pharm. 2002;245(1–2):75–82.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    De Gioannis B, Jestin P, Subra P. Morphology and growth control of griseofulvin recrystallized by compressed carbon dioxide as antisolvent. J Cryst Growth. 2004;262(1–4):519–26.

    Article  Google Scholar 

  17. 17.

    Roy C, Vrel D, Vega-González A, Jestin P, Laugier S, Subra-Paternault P. Effect of CO2-antisolvent techniques on size distribution and crystal lattice of theophylline. J Supercrit Fluids. 2011;57:267–77.

    Article  CAS  Google Scholar 

  18. 18.

    Bertucco A, Lora M, Kikic I. Fractional crystallization by gas antisolvent technique: theory and experiments. AIChE J. 1998;44(10):2149–58.

    Article  CAS  Google Scholar 

  19. 19.

    Elvassore N, Bertucco A, Caliceti P. Production of insulin-loaded poly (ethylene glycol)/poly (l-lactide)(PEG/PLA) nanoparticles by gas antisolvent techniques. J Pharm Sci. 2001;90(10):1628–36.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Park SJ, Yeo SD. Recrystallization of caffeine using gas antisolvent process. J Supercrit Fluids. 2008;47(1):85–92.

    Article  CAS  Google Scholar 

  21. 21.

    Shikhar A, Bommana MM, Gupta SS, Squillante E. Formulation development of Carbamazepine-Nicotinamide co-crystals complexed with γ-cyclodextrin using supercritical fluid process. J Supercrit Fluids. 2011;55(3):1070–8.

    Article  CAS  Google Scholar 

  22. 22.

    Ober CA, Montgomery SE, Gupta RB. Formation of itraconazole/L-malic acid cocrystals by gas antisolvent cocrystallization. Powder Technol. 2012(In press).

  23. 23.

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

    CAS  Google Scholar 

  24. 24.

    Park SJ, Yeo SD. Recrystallization of phenylbutazone using supercritical fluid antisolvent process. Korean J Chem Eng. 2008;25(3):575–80.

    Article  CAS  Google Scholar 

  25. 25.

    Rodrigues MA, Padrela L, Geraldes V, Santos J, Matos HA, Azevedo EG. Theophylline polymorphs by atomization of supercritical antisolvent induced suspensions. J Supercrit Fluids. 2011;58:303–12.

    Article  CAS  Google Scholar 

  26. 26.

    Yeo SD, Kim MS, Lee JC. Recrystallization of sulfathiazole and chlorpropamide using the supercritical fluid antisolvent process. J Supercrit Fluids. 2003;25(2):143–54.

    Article  CAS  Google Scholar 

  27. 27.

    Subra-Paternault P, Roy C, Vrel D, Vega-Gonzalez A, Domingo C. Solvent effect on tolbutamide crystallization induced by compressed CO2 as antisolvent. J Cryst Growth. 2007;309(1):76–85.

    Article  CAS  Google Scholar 

  28. 28.

    Bakhbakhi Y, Charpentier PA, Rohani S. Experimental study of the GAS process for producing microparticles of beclomethasone-17, 21-dipropionate suitable for pulmonary delivery. Int J Pharm. 2006;309(1):71–80.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Remenar JF, Morissette SL, Peterson ML, Moulton B, MacPhee JM, Guzman 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.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Al-Badr AA, El-Subbagh HI. Itraconazole: comprehensive profile. Profiles Drug Subst Excip Relat Methodol. 2009;34:193–264.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Krishnan S, Raj CJ, Robert R, Ramanand A, Das SJ. Growth and characterization of succinic acid single crystals. Cryst Res Technol. 2007;42(11):1087–90.

    Article  CAS  Google Scholar 

  32. 32.

    Demiana IN. Formulation and evaluation of itraconazole via liquid crystal for topical delivery system. J Pharm Biomed Anal. 2001;26(3):387–99.

    Article  Google Scholar 

  33. 33.

    Krishnan S, Raj CJ, Priya SM, Robert R, Dinakaran S, Das SJ. Optical and dielectric studies on succinic acid single crystals. Cryst Res Technol. 2008;43(8):845–50.

    Article  CAS  Google Scholar 

  34. 34.

    Parkin A, Seaton CC, Blagden N, Wilson CC. Designing hydrogen bonds with temperature-dependent proton disorder: the effect of crystal environment. Cryst Growth Des. 2007;7(3):531–4.

    Article  CAS  Google Scholar 

  35. 35.

    Al Marzouqi AH, Shehatta I, Jobe B, Dowaidar A. Phase solubility and inclusion complex of itraconazole with cyclodextrin using supercritical carbon dioxide. J Pharm Sci. 2006;95(2):292–304.

    Article  Google Scholar 

  36. 36.

    Payne SM, Kerton FM. Solubility of bio-sourced feedstocks in ‘green’ solvents. Green Chem. 2010;12(9):1648–53.

    Article  CAS  Google Scholar 

  37. 37.

    Datta S, Grant DJW. Crystal structures of drugs: advances in determination, prediction and engineering. Nat Rev Drug Discov. 2004;3(1):42–57.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Schutz S, Wengatz I, Goodrow MH, Gee SJ, Hummel HE, Hammock BD. Development of an enzyme-linked immunosorbent assay for azadirachtins. J Agric Food Chem. 1997;45(6):2363–8.

    Article  Google Scholar 

  39. 39.

    Remenar J, MacPhee M, Peterson ML, Morissette SL, Almarsson O. CIS-itraconazole crystalline forms and related processes, pharmaceutical compositions and methods. Google Patents. 2006.

  40. 40.

    Almarsson Ã, Hickey MB, Peterson ML, Zaworotko MJ, Moulton B, Rodriguez-Hornedo N. Pharmaceutical co-crystal compositions. Google Patents. 2011.

  41. 41.

    Morissette SL, Ãlmarsson AR, Peterson ML, Remenar JF, Read MJ, Lemmo AV, et al. High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv Drug Deliv Rev. 2004;56(3):275–300.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Almarsson O, Hickey MB, Peterson ML, Zaworotko MJ, Moulton B, Rodriguez-Hornedo N. Pharmaceutical co-crystal compositions. US Patent 7,927,613; 2011.

  43. 43.

    Padrela L, de Azevedo EG, Velaga SP. Powder X-ray diffraction method for the quantification of cocrystals in the crystallization mixture. Drug Dev Ind Pharm. 2011;00:1–7.

    Google Scholar 

  44. 44.

    Basavoju S, Bostrom D, Velaga SP. Indomethacin-saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization. Pharm Res. 2008;25(3):530–41.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Rohrs BR, Amidon GE, Meury RH, Secreast PJ, King HM, Skoug CJ. Particle size limits to meet USP content uniformity criteria for tablets and capsules. J Pharm Sci. 2006;95(5):1049–59.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Sathigari SK, Ober CA, Sanganwar GP, Gupta RB, Babu RJ. Single step preparation and deagglomeration of itraconazole microflakes by supercritical antisolvent method for dissolution enhancement. J Pharm Sci. 2011;100(7):2952–65.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Subra P, Laudani CG, Vega-Gonzalez A, Reverchon E. Precipitation and phase behavior of theophylline in solvent-supercritical CO2 mixtures. J Supercrit Fluids. 2005;35(2):95–105.

    Article  CAS  Google Scholar 

  48. 48.

    Booij J, Lefferts AG (inventors). Agglomerates by crystallization. 2005.

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ACKNOWLEDGMENT

The authors wish to acknowledge financial support from the National Science Foundation through NIRT grant DMI-0506722.

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Correspondence to Courtney A. Ober.

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Ober, C.A., Gupta, R.B. Formation of Itraconazole–Succinic Acid Cocrystals by Gas Antisolvent Cocrystallization. AAPS PharmSciTech 13, 1396–1406 (2012). https://doi.org/10.1208/s12249-012-9866-4

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KEY WORDS

  • cocrystals
  • dissolution rate
  • gas antisolvent
  • itraconazole