Skip to main content
SpringerLink
Log in

Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to develop an amorphous solid dispersion (SD) of an extremely water-insoluble and very weakly basic drug, itraconazole (ITZ), by interaction with weak organic acids and then drying that would enhance dissolution rate of drug and physical stability of formulation.

Methods

Aqueous solubility of ITZ in concentrated solutions of weak organic acids, such as glutaric, tartaric, malic and citric acid, was determined. Solutions with high drug solubility were dried using vacuum oven and the resulting SDs having 2 to 20% drug load were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The dissolution of SDs was initially studied in 250 mL of 0.1 N HCl (pH 1.1), and any undissolved solids were collected and analyzed by PXRD. The pH of the dissolution medium was then changed from 1.1 to 5.5, particle size of precipitates were measured, and drug concentrations in solution were determined by filtration through membrane filters of varying pore sizes.

Results

The aqueous solubility of ITZ was greatly enhanced in presence of weak acids. While the solubility of ITZ in water was ~4 ng/ mL, it increased to 25–40 mg per g of solution at 25°C and 200 mg per g of solution at 65°C at a high acid concentration leading to extremely high solubilization. PXRD of SDs indicated that ITZ was present in the amorphous form, wherein the acid formed a partially crystalline matrix. ATR-FTIR results showed possible weak interactions, such as hydrogen bonding, between drug and acid but there was no salt formation. SDs formed highly supersaturated solutions at pH 1.1 and had superior dissolution rate as compared to amorphous drug and physical mixtures of drug and acids. Following the change in pH from 1.1 to 5.5, ITZ precipitated as mostly nanoparticles, providing high surface area for relatively rapid redissolution.

Conclusions

A method of highly solubilizing an extremely water-insoluble drug, ITZ, in aqueous media and converting it into an amorphous form in a physically stable SD was successfully investigated. The dissolution rate and the extent of supersaturation of the drug in dissolution media improved greatly, and any precipitate formed at high pH had very small particle size.

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

Similar content being viewed by others

Abbreviations

ATR-FTIR:

Attenuated total reflectance-Fourier transform infrared spectroscopy

DSC:

Differential scanning calorimetry

HPMC:

Hydroxypropylmethyl cellulose

HPMCAS:

Hydroxypropylmethyl cellulose acetate succinate

ITZ:

Itraconazole

PXRD:

Powder X-ray diffractometry

SD:

Solid dispersion

TGA:

Thermogravimetric analysis

References

  1. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44(1):235–49.

    Article  CAS  PubMed  Google Scholar 

  2. Huang LF, Tong WQ. Impact of solid state properties on developability assessment of drug candidates. Adv Drug Deliv Rev. 2004;56(3):321–34.

    Article  CAS  PubMed  Google Scholar 

  3. Selen A, Dickinson PA, Müllertz A, Crison JR, Mistry HB, Cruañes MT, et al. The biopharmaceutics risk assessment roadmap for optimizing clinical drug product performance. J Pharm Sci. 2014;103(11):3377–97.

    Article  CAS  PubMed  Google Scholar 

  4. Janssens S, De Zeure A, Paudel A, Van Humbeeck J, Rombaut P, Van den Mooter G. Influence of preparation methods on solid state supersaturation of amorphous SD: a case study with itraconazole and Eudragit E 100. Pharm Res. 2010;27:775–85.

    Article  CAS  PubMed  Google Scholar 

  5. Gilis P, De Conde V, Vandecruys R. Beads having a core coated with an antifungal and a polymer. Patent no. WO-94/05263 (A1). 1994.

  6. O’Neil M.J. (ed.). The Merck index - an encyclopedia of chemicals, drugs, and biologicals. Whitehouse station, NJ: Merck and Co., Inc., 2006., p. 907

  7. Brewster M, Neekens P, Peeters J. Solubilization of itraconazole as a function of cyclodextrin structural space. J Incl Phenom Macrocycl Chem. 2007;57:561–6.

    Article  CAS  Google Scholar 

  8. Sporanox capsule product information. https://www.janssen.com.au/files/Products/SPORANOX_CAPSULES_PI.pdf (last accessed: 20 July 2015)

  9. Beule K. Itraconazole: pharmacology, clinical experience and future development. Int J Antimicrob Agents. 1996;6:175–81.

    Article  PubMed  Google Scholar 

  10. Sporanox oral solution product information. https://www.janssen.com.au/files/Products/SPORANOX_SOLUTION_PI.pdf (last accessed: 20 July 2015)

  11. Tao T, Zhao Y, Wu J, Zhou B. Preparation and evaluation of itraconazole dihydrochloride for the solubility and dissolution rate enhancement. Int J Pharm. 2009;367:109–14.

    Article  CAS  PubMed  Google Scholar 

  12. Namburi R, Kerr J. Oral itraconazole formulations and methods of making the same. Patent no. US 6,663,897 B2. 2003.

  13. Remenar J, Morissette S, Peterson M, 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;125:8456–7.

    Article  CAS  PubMed  Google Scholar 

  14. Wei S, Mao S, Shi Y, Li L, Fang L. Nanoization of itraconazole by high pressure homogenization: stabilizer optimization and effect of particle size on oral absorption. J Pharm Sci. 2011;24:297–303.

    Google Scholar 

  15. Mou D, Chen H, Wan J, Xu H, Yang X. Potent dried drug nanosuspensions for oral bioavailability enhancement of poorly soluble drugs with pH-dependent solubility. Int J Pharm. 2011;413:237–44.

    Article  CAS  PubMed  Google Scholar 

  16. Vasanthavada M, Tong WQ, Serajuddin ATM. Development of solid dispersions for poorly water-soluble drug. In: Liu R, editor. Water-insoluble drug formulations. 2nd ed. New York: Informa healthcare; 2008. p. 149–84.

    Google Scholar 

  17. Janssens S, de Armas HN, D’ Autry W, Van Schepdael A, Van den Mooter G. Characterization of ternary solid dispersions of itraconazole in polyethylene glycol 6000/ polyvidone- vinylacetate 64 blends. Eur J Pharm Biopharm. 2008;69:1114–20.

  18. Baert L, Peeters J, Verreck G. Solid mixtures of cyclodextrins prepared via melt extrusion. Patent no. US 6,365,188 B1, 2002.

  19. Mellaerts R, Mole R, Jammaer J, Aerts CA, Paudel A, Van Humbeeck J, et al. Increasing the oral bioavailability of the poorly water soluble drug itraconazole with ordered mesoporous silica. Eur J Pharm Biopharm. 2008;69:223–30.

    Article  CAS  PubMed  Google Scholar 

  20. Miller D, DiNunzio J, Yang W, McGinity J, Williams R. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic to neutral pH transition. Drug Dev Ind Pharm. 2008;34:890–902.

    Article  CAS  PubMed  Google Scholar 

  21. Bhardwaj S, Arora K, Kwong E, Templeton A, Clas S, Suryanarayanan R. Correlation between molecular mobility and physical stability of amorphous itraconazole. Mol Pharm. 2013;10:694–700.

    Article  CAS  PubMed  Google Scholar 

  22. Sarode A, Sandhu H, Shah N, Malick W, Zia H. Hot melt extrusion for amorphous solid dispersions: temperature and moisture activated drug – polymer interactions for enhanced stability. Mol Pharm. 2013;10:3665–75.

    Article  CAS  PubMed  Google Scholar 

  23. Holvoet C, Vander Heyden Y, Plaizier-Vercammen J. Influence of preparation method on itraconazole oral solutions using cyclodextrins as complexing agents. Die Pharmazie. 2007;62(7):510–4.

    CAS  PubMed  Google Scholar 

  24. Singh S, Parikh T, Sandhu HK, Shah NH, Malick AW, Singhal D, et al. Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids. Pharm Res. 2013;30(6):1561–73.

    Article  CAS  PubMed  Google Scholar 

  25. Li S, Wong S, Sethia S, Almoazen H, Joshi YM, Serajuddin ATM. Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH. Pharm Res. 2005;22(4):628–35.

    Article  CAS  PubMed  Google Scholar 

  26. Li S, Doyle P, Metz S, Royce AE, Serajuddin ATM. Effect of chloride ion on dissolution of different salt forms of haloperidol, a model basic drug. J Pharm Sci. 2005;94(10):2224–31.

    Article  CAS  PubMed  Google Scholar 

  27. Shah A, Serajuddin ATM. Supersolubilization by using nonsalt-forming acid–base interaction. In: Shah N, Sandhu H, Choi D, Chokshi H, Malick AW, editors. Amorphous solid dispersions theory and practice. New York: Springer-Verlag; 2014. p. 595–611.

    Google Scholar 

  28. Shah A, Serajuddin ATM. Conversion of solid dispersion prepared by acid–base interaction into free-flowing and tabletable powder by using Neusilin® US2. Int J Pharm. 2015;484(1–2):172–80.

    Article  CAS  PubMed  Google Scholar 

  29. Serajuddin ATM, Pudipeddi M. Salt selection strategies. Handbook of pharmaceutical salts - properties, selection and use. Switzerland: Verlag Helvetica Chemica Acta/Wiley–VCH; 2002. p. 158–9.

    Google Scholar 

  30. Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Del Rev. 2007;59(7):603–16.

    Article  CAS  Google Scholar 

  31. Desiraju GR. Crystal and co-crystal. Cryst Eng Comm. 2003;5:466–7.

    Article  CAS  Google Scholar 

  32. Li ZJ, Abramov Y, Bordner J, Leonard J, Medek A, Trask AV. Solid-state acid–base interactions in complexes of heterocyclic bases with dicarboxylic acids: crystallography, hydrogen bond analysis, and 15 N NMR spectroscopy. J Am Chem Soc. 2006;128(25):8199–210.

    Article  CAS  PubMed  Google Scholar 

  33. Vishweshwar P, Nangia A, Lynch VM. Molecular complexes of homologous alkanedicarboxylic acids with isonicotinamide: X-ray crystal structures, hydrogen bond synthons, and melting point alternation. Cryst Growth Des. 2003;3:783–90.

    Article  CAS  Google Scholar 

  34. Walsh RDB, Bradner MW, Fleischman S, Morales LA, Moulton B, Rodriguez-Hornedo N, et al. Crystal engineering of the composition of pharmaceutical phases. Chem Commun. 2003;2:186–7.

    Article  Google Scholar 

  35. Bis JA, McLaughlin OL, Vishweshwar P, Zaworotko MJ. Supramolecular heterocatemers and their role in cocrystal design. Cryst Growth Des. 2006;6:2648–50.

    Article  CAS  Google Scholar 

  36. Etter MC. Encoding and decoding hydrogen bonds patterns of organic compounds. Acc Chem Res. 1990;23:120–6.

    Article  CAS  Google Scholar 

  37. Bis JA, Vishweshwar P, Weyna D, Zaworotko MJ. Hierarchy of supramolecular synthons: persistent hydroxyl…pyridine hydrogen bonds in cocrystals that contain a cyano acceptor. Mol Pharm. 2007;4(3):401–16.

    Article  CAS  PubMed  Google Scholar 

  38. Shattock T, Arora K, Vishweshwar P, Zaworotko M. Hierarchy of supramolecular synthons: persistent carboxylic acid-pyridine hydrogen bonds in cocrystals that also contain hydroxyl moiety. Cryst Growth Des. 2008;8(12):4533–45.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Izutsu KI, Kadoya S, Yomota C, Kawanishi T, Yonemochi E, Terada K. Freeze-drying of proteins in glass solids formed by basic amino acids and dicarboxylic acids. Chem Pharm Bull. 2009;57(1):43–8.

    Article  CAS  PubMed  Google Scholar 

  41. Jensen KT, Löbmann K, Rades T, Grohganz H. Improving co-amorphous drug formulations by the addition of the highly water soluble amino acid proline. Pharmaceutics. 2014;6(3):416–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lobmann K, Laitinen R, Grohganz H, Strachan C, Rades T, Gordon K. Coamorphous drug systems: enhanced physical stability and dissolution rate of indomethacin and naproxen. Mol Pharm. 2011;8(5):1919–28.

    Article  CAS  PubMed  Google Scholar 

  43. Morrision RT, Boyd RN. Organic chemistry. 6th ed. Michigan: Prentice Hall International; 1992.

    Google Scholar 

  44. Ober C, Gupta R. Formation of itraconazole-succinic acid cocrystals by gas antisolvent cocrystallization. AAPS PharmSciTech. 2012;13(4):1396–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kashchiev D, Van Rosmalen G. Nucleation in solutions revisited. Cryst Res Technol. 2003;38:555–74.

    Article  CAS  Google Scholar 

  46. Gebauer D, Coelfen H. Prenucleation clusters and non-classical nucleation. Nano Today. 2011;6:564–84.

    Article  CAS  Google Scholar 

  47. Vekilov PG. Nucleation. Cryst Growth Des. 2010;10:5007–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Good D, Rodriguez-Hornedo N. Solubility advantage of pharmaceutical cocrystals. Cryst Growth Des. 2009;9:2252–64.

    Article  CAS  Google Scholar 

  49. Thakuria R, Delori A, Jones W, Lipert M, Roy L, Rodriguez N. Pharmaceutical cocrystals and poorly soluble drugs. Int J Pharm. 2013;453(1):101–25.

    Article  CAS  PubMed  Google Scholar 

  50. Shevchenko A, Bimbo LM, Miroshnyk I, Haarala J, Jelínková K, Syrjänen K, et al. A new cocrystal and salts of itraconazole: comparison of solid-state properties, stability and dissolution behavior. Int J Pharm. 2012;436(1):403–9.

    Article  CAS  PubMed  Google Scholar 

  51. Hancock BC, Zografi G. The relationship between the glass transition temperature and the water content of amorphous pharmaceutical solids. Pharm Res. 1994;11:471–7.

    Article  CAS  PubMed  Google Scholar 

  52. Andronis V, Zografi G. Crystal nucleation and growth of indomethacin polymorphs from the amorphous state. J Non-cryst Sol. 2000;271:236–48.

    Article  CAS  Google Scholar 

  53. Six K, Verreck G, Peeters J, Binnemans K, Berghmans H, Augustijns P, et al. Investigation of thermal properties of glassy itraconazole: identification of a monotropic mesophase. Thermochim Acta. 2001;376(2):175–81.

    Article  CAS  Google Scholar 

  54. Parikh T, Gupta SS, Meena AK, Vitez I, Mahajan N, Serajuddin ATM. Application of film casting technique to investigate drug–polymer miscibility in solid dispersion and hot melt extrudate. J Pharm Sci. 2015;104:2142–52.

    Article  CAS  PubMed  Google Scholar 

  55. Stevenson CL, Bennett DB, Lechuga‐Ballesteros D. Pharmaceutical liquid crystals: the relevance of partially ordered systems. J Pharm Sci. 2005;94(9):1861–80.

    Article  CAS  PubMed  Google Scholar 

  56. Murdande S, Pikal M, Shanker R, Bogner R. Solubility advantage of amorphous pharmaceuticals, part 3: is maximum solubility advantage experimentally attainable and sustainable? J Pharm Sci. 2011;100(10):4349–56.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to acknowledge the support of chemistry department at St. John’s University for providing the equipment to conduct FTIR studies.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not reflect the official policy or position of Food and Drug Administration or any other agency of the U.S. government.

Author information

Author notes

  1. Tapan Parikh

    Present address: Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 20903, USA

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, New York, 11439, USA

    Tapan Parikh, Tanaji T. Talele & Abu T. M. Serajuddin

  2. Kashiv Pharma, 440 US Highway 22, Bridgewater, New Jersey, 08807, USA

    Harpreet K. Sandhu

Authors
  1. Tapan Parikh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harpreet K. Sandhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tanaji T. Talele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abu T. M. Serajuddin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abu T. M. Serajuddin.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parikh, T., Sandhu, H.K., Talele, T.T. et al. Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying. Pharm Res 33, 1456–1471 (2016). https://doi.org/10.1007/s11095-016-1890-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-016-1890-8

Key Words

Search

Navigation