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NanoXCT: A Novel Technique to Probe the Internal Architecture of Pharmaceutical Particles

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Abstract

Purpose

To demonstrate the novel application of nano X-ray computed tomography (NanoXCT) for visualizing and quantifying the internal structures of pharmaceutical particles.

Methods

An Xradia NanoXCT-100, which produces ultra high-resolution and non-destructive imaging that can be reconstructed in three-dimensions (3D), was used to characterize several pharmaceutical particles. Depending on the particle size of the sample, NanoXCT was operated in Zernike Phase Contrast (ZPC) mode using either: 1) large field of view (LFOV), which has a two-dimensional (2D) spatial resolution of 172 nm; or 2) high resolution (HRES) that has a resolution of 43.7 nm. Various pharmaceutical particles with different physicochemical properties were investigated, including raw (2-hydroxypropyl)-beta-cyclodextrin (HβCD), poly (lactic-co-glycolic) acid (PLGA) microparticles, and spray-dried particles that included smooth and nanomatrix bovine serum albumin (BSA), lipid-based carriers, and mannitol.

Results

Both raw HβCD and PLGA microparticles had a network of voids, whereas spray-dried smooth BSA and mannitol generally had a single void. Lipid-based carriers and nanomatrix BSA particles resulted in low quality images due to high noise-to-signal ratio. The quantitative capabilities of NanoXCT were also demonstrated where spray-dried mannitol was found to have an average void volume of 0.117 ± 0.247 μm3 and average void-to-material percentage of 3.5%. The single PLGA particle had values of 1993 μm3 and 59.3%, respectively.

Conclusions

This study reports the first series of non-destructive 3D visualizations of inhalable pharmaceutical particles. Overall, NanoXCT presents a powerful tool to dissect and observe the interior of pharmaceutical particles, including those of a respirable size.

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References

  1. Chow AHL, Tong HHY, Chattopadhyay P, Shekunov BY. Particle engineering for pulmonary drug delivery. Pharm Res. 2007;24:411–37.

    Article  PubMed  CAS  Google Scholar 

  2. Vehring R, Lechuga-Ballesteros D, Joshi V, Noga B, Dwivedi SK. Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers. Langmuir. 2012;28:15015–23.

    Article  PubMed  CAS  Google Scholar 

  3. Vanbever R, Mintzes J, Wang J, Nice J, Chen D, Batycky R, et al. Formulation and physical characterization of large porous particles for inhalation. Pharm Res. 1999;16:1735–42.

  4. Dellamary LA, Tarara TE, Smith DJ, Woelk CH, Adractas A, Costello ML, et al. Hollow porous particles in metered dose inhalers. Pharm Res. 2000;17:168–74.

  5. Crowder TM, Rosati JA, Schroeter JD, Hickey AJ, Martonen TB. Fundamental effects of particle morphology on lung delivery: Predictions of Stoke’s law and the particular relevance to dry powder inhaler formulation and development. Pharm Res. 2002;19:239–45.

    Article  PubMed  CAS  Google Scholar 

  6. D’Addio SM, Chan JGY, Kwok PCL, Prud’homme RK, Chan H-K. Constant size, variable density aerosol particles by ultrasonic spray freeze drying. Int J Pharm. 2012;427:185–91.

    Article  PubMed  Google Scholar 

  7. Chew NYK, Tang P, Chan H-K, Raper JA. How much particle surface corrugation is sufficient to improve aerosol performance of powders? Pharm Res. 22:148–152 (2005).

  8. Heng D, Tang P, Cairney J, Chan H-K, Cutler D, Salama R, et al. Focused-ion-beam milling: A novel approach to probing the interior of particles used for inhalation aerosols. Pharm Res. 2007;24:1608–17.

  9. Chew NYK, Chan H-K. Influence of particle size, air flow, and inhaler device on the dispersion of mannitol powders as aerosols. Pharm Res. 1999;16:1098–103.

    Article  PubMed  CAS  Google Scholar 

  10. Chew NYK, Chan H-K. Use of solid corrugated particles to enhance powder aerosol performance. Pharm Res. 2001;18:1570–7.

    Article  PubMed  CAS  Google Scholar 

  11. Chiou H, Chan H-K, Heng D, Prud’homme RK, Raper JA. A novel production method for inhalable cyclosporine A powders by confined liquid impinging jet precipitation. J Aerosol Sci. 2008;39:500–509.

  12. Zhu B, Traini D, Chan H-K, Young PM. The effect of ethanol on the formation and physico-chemical properties of particles generated from budesonide solution-based pressurized metered-dose inhalers. Drug Dev Ind Pharm. 2013;39:1625–37.

    Article  PubMed  CAS  Google Scholar 

  13. Larson D, Foord D, Petford-Long A, Anthony T, Rozdilsky I, Cerezo A, et al. Focused ion-beam milling for field-ion specimen preparation: Preliminary investigations. Ultramicroscopy. 1998;75:147–59.

  14. Miller MK, Russell KF, Thompson K, Alvis R, Larson DJ. Review of atom probe FIB-based specimen preparation methods. Microsc Microanal. 2007;13:428–36.

    Article  PubMed  CAS  Google Scholar 

  15. Vieu C, Gierak J, Launois H, Aign T, Meyer P, Jamet J, et al. High resolution magnetic patterning using focused ion beam irradiation. Microelectron Eng. 2000;53:191–4.

  16. Fu Y, Bryan NKA, Shing O, Hung N. Influence of the redeposition effect for focused ion beam 3D micromachining in silicon. Int J Adv Manuf Technol. 2000;16:877–80.

    Article  Google Scholar 

  17. Shurand J, Price R. Advanced microscopy techniques to assess solid-state properties of inhalation medicines. Adv Drug Deliv Rev. 2012;64:369–82.

    Article  Google Scholar 

  18. Ketchamand RA, Carlson WD. Acquisition, optimization and interpretation of X-ray computed tomographic imagery: Applications to the geosciences. Comput Geosci. 2001;27:381–400.

    Article  Google Scholar 

  19. Taina I, Heck R, Elliot T. Application of X-ray computed tomography to soil science: A literature review. Can J Soil Sci. 2008;88:1–19.

    Article  Google Scholar 

  20. Momose A, Takeda T, Itai Y, Hirano K. Phase–contrast X–ray computed tomography for observing biological soft tissues. Nat Med. 1996;2:473–5.

    Article  PubMed  CAS  Google Scholar 

  21. Farber L, Tardos G, Michaels JN. Use of X-ray tomography to study the porosity and morphology of granules. Powder Technol. 2003;132:57–63.

    Article  CAS  Google Scholar 

  22. Sinka IC, Burch SF, Tweed JH, Cunningham JC. Measurement of density variations in tablets using X-ray computed tomography. Int J Pharm. 2004;271:215–24.

    Article  PubMed  CAS  Google Scholar 

  23. Fu X, Dutt M, Bentham AC, Hancock BC, Cameron RE, Elliott JA. Investigation of particle packing in model pharmaceutical powders using X-ray microtomography and discrete element method. Powder Technol. 2006;167:134–40.

    Article  CAS  Google Scholar 

  24. Attwood D. Microscopy: Nanotomography comes of age. Nature. 2006;442:642–3.

    Article  PubMed  CAS  Google Scholar 

  25. Sakdinawatand A, Attwood D. Nanoscale X-ray imaging Nature Photonics. 2010;4:840–8.

    Article  Google Scholar 

  26. Kasturi SP, Skountzou I, Albrecht RA, Koutsonanos D, Hua T, Nakaya HI, et al. Programming the magnitude and persistence of antibody responses with innate immunity. Nature. 2011;470:543–7.

  27. Adi S, Adi H, Tang P, Traini D, Chan H-K, Young PM. Micro-particle corrugation, adhesion and inhalation aerosol efficiency. Eur J Pharm Sci. 2008;35:12–8.

  28. Kwok P, Tunsirikongkon A, Glover W, Chan H-K. Formation of protein nano-matrix particles with controlled surface architecture for respiratory drug delivery. Pharm Res. 2011;28:788–96.

    Article  PubMed  CAS  Google Scholar 

  29. Tarara TE, Hartman MS, Gill H, Kennedy AA, Weers JG. Characterization of suspension-based metered dose inhaler formulations composed of spray-dried budesonide microcrystals dispersed in HFA-134a. Pharm Res. 2004;21:1607–14.

    Article  PubMed  CAS  Google Scholar 

  30. Weers JG, Tarara TE, Gill H, English BS, Dellamary LA. Homodispersion technology for HFA suspensions: particle engineering to reduce dosing variance. Respiratory Drug Delivery. 2000;2:91–7.

    Google Scholar 

  31. Iveyand JW, Vehring R. The use of modeling in spray drying of emulsions and suspensions accelerates formulation and process development. Comput Chem Eng. 2010;34:1036–40.

    Article  Google Scholar 

  32. D’Sa D, Chan H-K, Chrzanowski W. Attachment of micro- and nano-particles on tipless cantilevers for colloidal probe microscopy. J Colloid Interface Sci (2014).

  33. Russ JC. The Image Processing Handbook. London: Boca Raton; 1995.

    Google Scholar 

  34. Elverssonand J, Millqvist-Fureby A. Particle size and density in spray drying — Effects of carbohydrate properties. J Pharm Sci. 2005;94:2049–60.

    Article  Google Scholar 

  35. Diaz A, Trtik P, Guizar-Sicairos M, Menzel A, Thibault P, Bunk O. Quantitative X-ray phase nanotomography. Phys Rev B. 2012;85:020104.

  36. Brisard S, Chae RS, Bihannic I, Michot L, Guttmann P, Thieme J, et al. Morphological quantification of hierarchical geomaterials by X-ray nano-CT bridges the gap from nano to micro length scales. Am Mineral. 2012;97:480–3.

    Article  CAS  Google Scholar 

  37. Dong P, Pacureanu A, Zuluaga MA, Olivier C, Frouin F, Grimal Q, Peyrin F. A new quantitative approach for estimating bone cell connections from nano-CT images, Engineering in Medicine and Biology Society (EMBC), 2013 35th Annual International Conference of the IEEE, 2013, pp. 3694–3697.

  38. Trtik P, Soos M, Münch B, Lamprou A, Mokso R, Stampanoni M. Quantification of a single aggregate inner porosity and pore accessibility using hard X-ray phase-contrast nanotomography. Langmuir. 2011;27:12788–91.

  39. Kerckhofs G, Sainz J, Wevers M, Van de Putte T, Schrooten J. Contrast-enhanced nanofocus computed tomography images the cartilage subtissue architecture in three dimensions. Eur Cell Mater. 2013;25:179–89.

    PubMed  CAS  Google Scholar 

  40. D’Sa D, Chan H-K, Chrzanowski W. Predicting physical stability in pressurized metered dose inhalers via dwell and instantaneous force colloidal probe microscopy. Eur J Pharm Sci (Submitted).

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ACKNOWLEDGMENTS AND DISCLOSURES

Jennifer Wong and Dexter D'Sa contributed equally to this work.

The authors acknowledge the facilities and technical assistance of Steve Moody (SEM and FIB Specialist) and the Australian Microscopy & Microanalysis Research Facility at the Australian Centre for Microscopy & Microanalysis, University of Sydney. Jennifer Wong, Dexter D’Sa and John Chan were recipients of the Australian Postgraduate Award, and Dexter D’Sa was also the recipient of the Australian IPRS scholarship. This work was supported under the Australian Research Council“s Discovery Projects funding scheme (projects DP120102778 & 110105161).

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Authors and Affiliations

  1. Advanced Drug Delivery Group, Faculty of Pharmacy, University of Sydney, Camperdown, NSW, 2006, Australia

    Jennifer Wong, Dexter D’Sa, John Gar Yan Chan & Hak-Kim Chan

  2. Australian Center for Microscopy & Microanalysis, University of Sydney, Camperdown, NSW, 2006, Australia

    Matthew Foley

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  1. Jennifer Wong
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  2. Dexter D’Sa
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  3. Matthew Foley
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  4. John Gar Yan Chan
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Corresponding author

Correspondence to Hak-Kim Chan.

SUPPLEMENTARY MATERIAL

SUPPLEMENTARY MATERIAL

A video showing the reconstructed 3D particles of all samples rotating 360° around an axis can be found in the supplementary materials.

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Wong, J., D’Sa, D., Foley, M. et al. NanoXCT: A Novel Technique to Probe the Internal Architecture of Pharmaceutical Particles. Pharm Res 31, 3085–3094 (2014). https://doi.org/10.1007/s11095-014-1401-8

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  • DOI: https://doi.org/10.1007/s11095-014-1401-8

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