AAPS PharmSciTech

, 20:217 | Cite as

Isolation of Itraconazole Nanostructured Microparticles via Spray Drying with Rational Selection of Optimum Base for Successful Reconstitution and Compaction

  • Kate P. M. McComiskey
  • Alan McDonagh
  • Lidia TajberEmail author
Research Article


The addition of matrix formers within a formulation provides a means for enhancing the redispersibility of nanoparticles (NPs) enabling them to retain their advantageous properties imparted onto them by their sub-micron size. In this work, NPs were isolated in the solid state via spray drying with a range of sugars. The processed powders were characterized, establishing that itraconazole (ITR) nanostructured microparticles (NMPs) spray dried in the presence of mannitol and trehalose had favorable redispersibility confirmed by dynamic light scattering and nanoparticle tracking analysis. Solid-state analysis confirmed the crystalline nature of NMPs based on mannitol and the amorphous character of trehalose-based NMPs. The NMPs powders were compacted at a range of pressures, producing tablets with high tensile strength without compromising their disintegration time. A greater amount of ITR was solubilized from trehalose NMPs compared to the mannitol-based compacts in 0.1 M HCl, showing a promise for enhanced in vivo activity. Overall, as trehalose exhibited superior carrier properties for ITR NMPs, this type of excipient included in the formulation warrants careful consideration. The structured approach to matrix former selection and tabletting studies can reduce the amount of material and time required for testing in the initial stages of product development.


itraconazole nanoparticle spray drying solid state tablets 



Research leading to these results was supported by the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund (Grant Number 12/RC/2275). The authors would like to thank Mark Lynch for his help in the study.

Supplementary material

12249_2019_1436_MOESM1_ESM.docx (1.3 mb)
ESM 1 (DOCX 1286 kb)


  1. 1.
    Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B. 2015;5:442–53. Scholar
  2. 2.
    Prajapati HN, Dalrymple DM, Serajuddin ATM. A comparative evaluation of mono-, di- and triglyceride of medium chain fatty acids by lipid/surfactant/water phase diagram, solubility determination and dispersion testing for application in pharmaceutical dosage form development. Pharm Res. 2012;29:285–305. Scholar
  3. 3.
    Medina C, Santos-Martinez MJ, Radomski A, Corrigan OI, Radomski MW. Nanoparticles: pharmacological and toxicological significance. Br J Pharmacol. 2009;150:552–8. Scholar
  4. 4.
    Lesniak A, Salvati A, Santos-Martinez MJ, Radomski MW, Dawson KA, Åberg C. Nanoparticle adhesion to the cell membrane and its effect on nanoparticle uptake efficiency. J Am Chem Soc. 2013;135:1438–44. Scholar
  5. 5.
    Molpeceres J, Berges L, Guzman M, Aberturas MR, Chacon M. Stability and freeze-drying of cyclosporine loaded poly ( D , L lactide–glycolide ) carriers. Eur J Pharm Sci. 1999;8(2):99–107. Scholar
  6. 6.
    Malamatari M, Somavarapu S, Taylor KMG, Buckton G. Solidification of nanosuspensions for the production of solid oral dosage forms and inhalable dry powders. Expert Opin Drug Deliv. 2016;13(3):435–50. Scholar
  7. 7.
    Masters K. Spray drying. London: Wiley; 1976.Google Scholar
  8. 8.
    Tsapis N, Bennett D, Jackson B, Weitz DA, Edwards DA. Trojan particles: large porous carriers of nanoparticles for drug delivery. Proc Natl Acad Sci. 2002;99(19):12001–5. Scholar
  9. 9.
    Nekkanti V, Pillai R, Venkateshwarlu V, Harisudhan T. Development and characterization of solid oral dosage form incorporating candesartan nanoparticles. Pharm Dev Technol. 2009;14(3):290–8. Scholar
  10. 10.
    Chaubal MV, Popescu C. Conversion of nanosuspensions into dry powders by spray drying: a case study. Pharm Res. 2008;25(10):2302–8. Scholar
  11. 11.
    Teeranachaideekul V, Junyaprasert VB, Souto EB, Müller RH. Development of ascorbyl palmitate nanocrystals applying the nanosuspension technology. Int J Pharm. 2008;354(1–2):227–34. Scholar
  12. 12.
    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(1–2):237–44. Scholar
  13. 13.
    Adolfsson Å, Nyström C. Tablet strength, porosity, elasticity and solid state structure of tablets compressed at high loads. Int J Pharm. 1996;132(1–2):95–106. Scholar
  14. 14.
    Kesisoglou F, Panmai S, Wu Y. Nanosizing—oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev. 2007;59:631–44. Scholar
  15. 15.
    Amaro MI, Tewes F, Gobbo O, Tajber L, Corrigan OI, Ehrhardt C, et al. Formulation, stability and pharmacokinetics of sugar-based salmon calcitonin-loaded nanoporous/nanoparticulate microparticles (NPMPs) for inhalation. Int J Pharm. 2015;483(1–2):6–18. Scholar
  16. 16.
    Tan EH, Parmentier J, Low A, Möschwitzer JP. Downstream drug product processing of itraconazole nanosuspension: factors influencing tablet material properties and dissolution of compacted nanosuspension-layered sugar beads. Int J Pharm. 2017;532(1):131–8. Scholar
  17. 17.
    Mugheirbi NA, Paluch KJ, Tajber L. Heat induced evaporative antisolvent nanoprecipitation (HIEAN) of itraconazole. Int J Pharm. 2014;471(1–2):400–11. Scholar
  18. 18.
    Mugheirbi NA, Tajber L. Mesophase and size manipulation of itraconazole liquid crystalline nanoparticles produced via quasi nanoemulsion precipitation. Eur J Pharm Biopharm. 2015;96:226–36. Scholar
  19. 19.
    McComiskey KPM, Mugheirbi NA, Stapleton J, Tajber L. In situ monitoring of nanoparticle formation: antisolvent precipitation of azole anti-fungal drugs. Int J Pharm. 2018;543(1–2):201–13. Scholar
  20. 20.
    McComiskey KPM, Tajber L. Comparison of particle size methodology and assessment of nanoparticle tracking analysis (NTA) as a tool for live monitoring of crystallisation pathways. Eur J Pharm Biopharm. 2018;130:314–26. Scholar
  21. 21.
    Van Eerdenbrugh B, Van den Mooter G, Augustijns P. Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm. 2008;364:64–75. Scholar
  22. 22.
    Wlodarski K, Sawicki W, Kozyra A, Tajber L. Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA. Eur J Pharm Biopharm. 2015;96:237–46. Scholar
  23. 23.
    Littringer EM, Mescher A, Schroettner H, Achelis L, Walzel P, Urbanetz NA. Spray dried mannitol carrier particles with tailored surface properties—the influence of carrier surface roughness and shape. Eur J Pharm Biopharm. 2012;82:194–204. Scholar
  24. 24.
    Yang M, Lee Y, Wu J, Young PM, Van Den BF, Rantanen J. Polymorphism of spray-dried mannitol as a function of particle size : effect of lysozyme. Eur J Pharm Sci. 2011;44(1–2):489–92. Scholar
  25. 25.
    USP 39-NF 34. General Chapter 701.Google Scholar
  26. 26.
    Matteucci ME, Paguio JC, Miller MA, Williams RO, Johnston KP. Highly supersaturated solutions from dissolution of amorphous ltraconazole microparticles at pH 6.8. Mol Pharm. 2009;6(2):375–85. Scholar
  27. 27.
    Wang Y, Zheng Y, Zhang L, Wang Q, Zhang D. Stability of nanosuspensions in drug delivery. J Control Release. 2013;172:1126–41. Scholar
  28. 28.
    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. Scholar
  29. 29.
    Simperler A, Kornherr A, Chopra R, Bonnet PA, Jones W, Motherwell WDS, et al. Glass transition temperature of glucose, sucrose, and trehalose: an experimental and in silico study. J Phys Chem B. 2006;110(39):19678–84. Scholar
  30. 30.
    Roos Y, Karel M. Plasticizing effect of water on thermal behavior and crystallization of amorphous food models. J Food Sci. 1991;56(1):38–43. Scholar
  31. 31.
    Foster KD, Bronlund JE, Paterson AHJ. Glass transition related cohesion of amorphous sugar powders. J Food Eng. 2006;77(4):997–1006. Scholar
  32. 32.
    Moura Ramos JJ, Pinto SS, Diogo HP. Molecular mobility in raffinose in the crystalline pentahydrate form and in the amorphous anhydrous form. Pharm Res. 2005;22(7):1142–8. Scholar
  33. 33.
    Hulse WL, Forbes RT, Bonner MC, Getrost M. The characterization and comparison of spray-dried mannitol samples characterization of spray-dried mannitol. Drug Dev Ind Pharm. 2009;35(6):712–8. Scholar
  34. 34.
    Yalkowsky SH, Dannenfelser RM. The aquasol database of aqueous solubility. Fifth Ed. Tucson: Univ Az, College of Pharmacy; 1992.Google Scholar
  35. 35.
    Jain NK, Roy I. Effect of trehalose on protein structure. Protein Sci. 2009;18(1):24–36. Scholar
  36. 36.
    Storey BT, Noiles EE, Thompson KA. Comparison of glycerol, other polyols, trehalose, and raffinose to provide a defined cryoprotectant medium for mouse sperm cryopreservation. Cryobiology. 1998;37(1):46–58. Scholar
  37. 37.
    Badawy SIF, Shah KR, Surapaneni MS, Szemraj MM, Hussain M. Effect of spray-dried mannitol on the performance of microcrystalline cellulose-based wet granulated tablet formulation. Pharm Dev Technol. 2010;15(4):339–45. Scholar
  38. 38.
    Cue BW, Zhang J. Green process chemistry in the pharmaceutical industry. Green Chem Lett Rev. 2009;2:193–211. Scholar
  39. 39.
    Saleki-Gerhardt A, Ahlneck C, Zografi G. Assessment of disorder in crystalline solids. Int J Pharm. 1994;101(3):237–47. Scholar
  40. 40.
    Buckton G, Darcy P. The use of gravimetric studies to assess the degree of crystallinity of predominantly crystalline powders. Int J Pharm. 1995;123(2):265–71. Scholar
  41. 41.
    Garr JSM, Rubinstein M. The effect of rate of force application on the properties of microcrystalline cellulose and dibasic calcium phosphate mixtures. Int J Pharm. 1991;73(1):75–80. Scholar
  42. 42.
    Pitt KG, Newton JM, Richardson R, Stanley P. The material tensile strength of convex-faced aspirin tablets. J Pharm Pharmacol. 1989;41(5):289–92. Scholar
  43. 43.
    Maggi L, Conte U, Bettinetti GP. Technological properties of crystalline and amorphous α-cyclodextrin hydrates. Int J Pharm. 1998;172(1–2):211–7. Scholar
  44. 44.
    Paluch KJ, Tajber L, Corrigan OI, Healy AM. Impact of alternative solid state forms and specific surface area of high-dose, hydrophilic active pharmaceutical ingredients on tabletability. Mol Pharm. 2013;10(10):3628–39. Scholar
  45. 45.
    Kumar S, Jog R, Shen J, Zolnik B, Sadrieh N, Burgess DJ. In vitro and in vivo performance of different sized spray-dried crystalline itraconazole. J Pharm Sci. 2015;104:3018–28. Scholar
  46. 46.
    Sun W, Mao S, Shi Y, Li LC, Fang L. Nanonization of itraconazole by high pressure homogenization: stabilizer optimization and effect of particle size on oral absorption. J Pharm Sci. 2011;100:3365–73. Scholar
  47. 47.
    Saleh A, McGarry K, Chaw CS, Elkordy AA. Feasibility of using gluconolactone, trehalose and hydroxy-propyl gamma cyclodextrin to enhance bendroflumethiazide dissolution using lyophilisation and physical mixing techniques. Pharmaceutics. 2018;10.

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Kate P. M. McComiskey
    • 1
  • Alan McDonagh
    • 1
  • Lidia Tajber
    • 1
    Email author
  1. 1.Synthesis and Solid State Pharmaceutical Centre, School of Pharmacy and Pharmaceutical SciencesTrinity College DublinDublin 2Ireland

Personalised recommendations