Skip to main content
SpringerLink
Log in

Formulation of Ketoconazole Nanocrystal-Based Cryopellets

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

Abstract

Commercial development of nanosuspensions for oral drug delivery generally involves a drying step which aims to generate a stable product that rapidly releases the nanocrystals once rehydrated and can be easily processed into a final dosage form (e.g., filled into hard capsule). Cryopelletisation is a freeze drying technique allowing the production of lyophilised micrometric spheres with good flowability. In the current work, the possibility to formulate redispersible ketoconazole nanocrystal-based cryopellets able to withstand intensive handling was investigated. Cryopellets were generated by first freezing regular droplets of nanosuspension using liquid nitrogen followed by water removal by sublimation in a standard freeze dryer. Low-friable cryopellets (< 1%) were produced by embedding the nanocrystals in a stabilizing hydroxypropyl cellulose SSL grade matrix, thus proving that these structures can withstand intensive handling. A threshold quantity of hydroxypropyl cellulose SSL grade (5/20 hydroxypropyl cellulose SSL grade-to-drug mass ratio) was required in combination with D-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) to successfully recover the nanocrystals over storage. A further addition of micronised crospovidone has shown a positive effect on the dissolution performance of cryopellets. Altogether, this study demonstrated that the design of cryopellets combining the strengths of freeze-dried powders (porous internal structure, low residual humidity) and pellets (free-flowing units, mechanical resistance during handling) can potentially improve the nanocrystal’s redispersibility compared with other drying techniques while facilitating the downstream processing.

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

Similar content being viewed by others

References

  1. Lipinski CA. Poor aqueous solubility - an industry wide problem in drug discovery. Am Pharm Rev. 2002;5:82–5.

    Google Scholar 

  2. Kesisoglou F, Panmai S, Wu Y. Nanosizing — oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev. 2007;59(7):631–44.

    Article  CAS  Google Scholar 

  3. Gao L, Liu G, Ma J, Wang X, Zhou L, Li X. Drug nanocrystals: in vivo performances. J Control Release. 2012;160(3):418–30.

    Article  CAS  Google Scholar 

  4. Peltonen L, Hirvonen J. Drug nanocrystals – versatile option for formulation of poorly soluble materials. Int J Pharm. 2018;537(1):73–83.

    Article  CAS  Google Scholar 

  5. Junghanns J-UAH, Müller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine. 2008;3(3):295–310.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Müller RH, Keck CM. Twenty years of drug nanocrystals: where are we, and where do we go? Eur J Pharm Biopharm. 2012;80(1):1–3.

    Article  Google Scholar 

  7. Liversidge GG, Cundy KC. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int J Pharm. 1995;125(1):91–7.

    Article  CAS  Google Scholar 

  8. Moschwitzer JP. Drug nanocrystals in the commercial pharmaceutical development process. Int J Pharm. 2013;453(1):142–56.

    Article  Google Scholar 

  9. Peltonen L, Hirvonen J. Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods. J Pharm Pharmacol. 2010;62(11):1569–79.

    Article  CAS  Google Scholar 

  10. Tuomela A, Hirvonen J, Peltonen L. Stabilizing agents for drug nanocrystals: effect on bioavailability. Pharmaceutics. 2016;8(2):16.

    Article  Google Scholar 

  11. Wang Y, Zheng Y, Zhang L, Wang Q, Zhang D. Stability of nanosuspensions in drug delivery. J Control Release. 2013;172(3):1126–41.

    Article  CAS  Google Scholar 

  12. Wu L, Zhang J, Watanabe W. Physical and chemical stability of drug nanoparticles. Adv Drug Deliv Rev. 2011;63(6):456–69.

    Article  CAS  Google Scholar 

  13. Chin WW, Parmentier J, Widzinski M, Tan EH, Gokhale R. A brief literature and patent review of nanosuspensions to a final drug product. J Pharm Sci. 2014;103(10):2980–99.

    Article  CAS  Google Scholar 

  14. Bhakay A, Azad M, Bilgili E, Dave R. Redispersible fast dissolving nanocomposite microparticles of poorly water-soluble drugs. Int J Pharm. 2014;461(1–2):367–79.

    Article  CAS  Google Scholar 

  15. Cerdeira AM, Mazzotti M, Gander B. Formulation and drying of miconazole and itraconazole nanosuspensions. Int J Pharm. 2013;443(1–2):209–20.

    Article  CAS  Google Scholar 

  16. Van Eerdenbrugh B, Froyen L, Van Humbeeck J, Martens JA, Augustijns P, Van den Mooter G. Drying of crystalline drug nanosuspensions—the importance of surface hydrophobicity on dissolution behavior upon redispersion. Eur J Pharm Sci. 2008;35(1–2):127–35.

    Article  Google Scholar 

  17. Yue P-F, Li Y, Wan J, Yang M, Zhu W-F, Wang C-H. Study on formability of solid nanosuspensions during nanodispersion and solidification: I. novel role of stabilizer/drug property. Int J Pharm. 2013;454(1):269–77.

    Article  CAS  Google Scholar 

  18. Bose S, Schenck D, Ghosh I, Hollywood A, Maulit E, Ruegger C. Application of spray granulation for conversion of a nanosuspension into a dry powder form. Eur J Pharm Sci. 2012;47(1):35–43.

    Article  CAS  Google Scholar 

  19. Hou Y, Shao J, Fu Q, Li J, Sun J, He Z. Spray-dried nanocrystals for a highly hydrophobic drug: increased drug loading, enhanced redispersity, and improved oral bioavailability. Int J Pharm. 2017;516(1):372–9.

    Article  CAS  Google Scholar 

  20. Azad M, Moreno J, Bilgili E, Dave R. Fast dissolution of poorly water soluble drugs from fluidized bed coated nanocomposites: impact of carrier size. Int J Pharm. 2016;513(1–2):319–31.

    Article  CAS  Google Scholar 

  21. Niwa T, Danjo K. Design of self-dispersible dry nanosuspension through wet milling and spray freeze-drying for poorly water-soluble drugs. Eur J Pharm Sci. 2013;50(3–4):272–81.

    Article  CAS  Google Scholar 

  22. Ali ME, Lamprecht A. Spray freeze drying for dry powder inhalation of nanoparticles. Eur J Pharm Biopharm. 2014;87(3):510–7.

    Article  CAS  Google Scholar 

  23. Wanning S, Suverkrup R, Lamprecht A. Pharmaceutical spray freeze drying. Int J Pharm. 2015;488(1–2):136–53.

    Article  CAS  Google Scholar 

  24. Erber M, Lee G. Cryopellets based on amorphous organic calcium salts: production, characterization and their usage in coagulation diagnostics. Powder Technol. 2015;280:10–7.

    Article  CAS  Google Scholar 

  25. Erber M, Lee G. Development of cryopelletization and formulation measures to improve stability of Echis carinatus venum protein for use in diagnostic rotational thromboelastometry. Int J Pharm. 2015;495(2):692–700.

    Article  CAS  Google Scholar 

  26. Erber M, Lee G. Production and characterization of rapidly dissolving cryopellets. J Pharm Sci. 2015;104(5):1668–76.

    Article  CAS  Google Scholar 

  27. Peeters OM, Blaton NM, De Ranter CJ. Cis-1-Acetyl-4-(4-{[2-(2,4-dichlorophenyl)-2-(1H-1-imidazolylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine: ketoconazole. A crystal structure with disorder. Acta Crystallogr Sect B. 1979;35(10):2461–4.

  28. Viseras C, Salem II, Galan ICR, Galan AC, Galindo AL. The effect of recrystallization on the crystal growth, melting point and solubility of ketoconazole. Thermochim Acta. 1995;268:143–51.

  29. Kasper JC, Friess W. The freezing step in lyophilization: physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals. Eur J Pharm Biopharm. 2011;78(2):248–63.

    Article  CAS  Google Scholar 

  30. Beirowski J, Inghelbrecht S, Arien A, Gieseler H. Freeze drying of nanosuspensions, 2: the role of the critical formulation temperature on stability of drug nanosuspensions and its practical implication on process design. J Pharm Sci. 2011;100(10):4471–81.

    Article  CAS  Google Scholar 

  31. Donoso MD, Haskell RJ, Schartman RR. Surfactant choice and the physical stability of nanosuspensions as a function of pH. Int J Pharm. 2012;439(1–2):1–7.

    Article  CAS  Google Scholar 

  32. Saxena A, Shah D, Padmanabhan S, Gautam SS, Chowan GS, Mandlekar S, et al. Prediction of pH dependent absorption using in vitro, in silico, and in vivo rat models: early liability assessment during lead optimization. Eur J Pharm Sci. 2015;76:173–80.

    Article  CAS  Google Scholar 

  33. Beirowski J, Inghelbrecht S, Arien A, Gieseler H. Freeze-drying of nanosuspensions, part 3: investigation of factors compromising storage stability of highly concentrated drug nanosuspensions. J Pharm Sci. 2012;101(1):354–62.

    Article  CAS  Google Scholar 

  34. Allison SD, Molina MC, Anchordoquy TJ. Stabilization of lipid/DNA complexes during the freezing step of the lyophilization process: the particle isolation hypothesis. Biochim Biophys Acta BBA - Biomembr. 2000;1468(1):127–38.

    Article  CAS  Google Scholar 

  35. Trasi NS, Byrn SR. Mechanically induced amorphization of drugs: a study of the thermal behavior of cryomilled compounds. AAPS PharmSciTech. 2012;13(3):772–84.

    Article  CAS  Google Scholar 

  36. Van den Mooter G, Wuyts M, Blaton N, Busson R, Grobet P, Augustijns P, et al. Physical stabilisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur J Pharm Sci. 2001;12(3):261–9.

    Article  Google Scholar 

  37. Touzet A, Pfefferlé F, van der Wel P, Lamprecht A, Pellequer Y. Active freeze drying for production of nanocrystal-based powder: a pilot study. Int J Pharm. 2018;536(1):222–30.

    Article  CAS  Google Scholar 

  38. Ali ME, Lamprecht A. Spray freeze drying as an alternative technique for lyophilization of polymeric and lipid-based nanoparticles. Int J Pharm. 2017;516(1):170–7.

    Article  CAS  Google Scholar 

  39. Khoshkava V, Kamal MR. Effect of drying conditions on cellulose nanocrystal (CNC) agglomerate porosity and dispersibility in polymer nanocomposites. Powder Technol. 2014;261:288–98.

    Article  CAS  Google Scholar 

  40. Lee J, Cheng Y. Critical freezing rate in freeze drying nanocrystal dispersions. J Control Release. 2006;111(1–2):185–92.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Debiopharm Research and Manufacturing S.A., Rue du Levant 146, 1920, Martigny, Switzerland

    Antoine Touzet & François Pfefferlé

  2. PEPITE EA4267, Univ. Bourgogne Franche-comté, 19 Rue Ambroise Paré, Batiment Socrate, 25030, Besançon, France

    Antoine Touzet, Alf Lamprecht & Yann Pellequer

  3. Department of Pharmaceutics, University of Bonn, Gerhard Domagk straβe 3, 53121, Bonn, Germany

    Alf Lamprecht

Authors
  1. Antoine Touzet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. François Pfefferlé
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alf Lamprecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yann Pellequer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yann Pellequer.

Additional information

Publisher’s Note

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

Appendix

Appendix

Table V Drug Content of the Cryopellets Produced from the Three Starting Nanosuspensions
Full size table

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Touzet, A., Pfefferlé, F., Lamprecht, A. et al. Formulation of Ketoconazole Nanocrystal-Based Cryopellets. AAPS PharmSciTech 21, 50 (2020). https://doi.org/10.1208/s12249-019-1570-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-019-1570-1

Key Words

Search

Navigation