CLSM as quantitative method to determine the size of drug crystals in a solid dispersion

Hans de Waard*, Martin J T Hessels, Maarten Boon, Klaas A Sjollema, Wouter L J Hinrichs, Anko C Eissens, Henderik W Frijlink

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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PURPOSE: To test whether confocal laser scanning microscopy (CLSM) can be used as an analytical tool to determine the drug crystal size in a powder mixture or a crystalline solid dispersion.

METHODS: Crystals of the autofluorescent drug dipyridamole were incorporated in a matrix of crystalline mannitol by physical mixing or freeze-drying. Laser diffraction analysis and dissolution testing were used to validate the particle size that was found by CLSM.

RESULTS: The particle size of the pure drug as determined by laser diffraction and CLSM were similar (D(50) of approximately 22 μm). CLSM showed that the dipyridamole crystals in the crystalline dispersion obtained by freeze-drying of less concentrated solutions were of sub-micron size (0.7 μm), whereas the crystals obtained by freeze-drying of more concentrated solutions were larger (1.3 μm). This trend in drug crystal size was in agreement with the dissolution behavior of the tablets prepared from these products.

CONCLUSION: CLSM is a useful technique to determine the particle size in a powder mixture. Furthermore, CLSM can be used to determine the drug crystal size over a broad size distribution. A limitation of the method is that the drug should be autofluorescent.

Original languageEnglish
Pages (from-to)2567-2574
Number of pages8
JournalPharmaceutical Research
Issue number10
Publication statusPublished - Oct-2011


  • confocal laser scanning miscroscopy
  • controlled crystallization during freeze-drying
  • dipyridamole
  • dissolution
  • freeze-drying
  • mannitol
  • nanoparticle
  • article
  • autofluorescence
  • confocal laser microscopy
  • controlled study
  • crystal
  • dispersion
  • drug crystal size
  • drug mixture
  • drug purity
  • freeze drying
  • image analysis
  • intermethod comparison
  • laser diffraction
  • particle size
  • particle size distribution
  • physical phenomena
  • powder
  • priority journal
  • quantitative analysis
  • scanning electron microscopy
  • solid dispersion
  • solid state
  • tablet formulation
  • validation process
  • X ray powder diffraction

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