Preparation of drug nanocrystals by controlled crystallization: Application of a 3-way nozzle to prevent premature crystallization for large scale production

Hans de Waard*, Niels Grasmeijer, Wouter L.J. Hinrichs, Anko C. Eissens, Peter P.F. Pfaffenbach, Henderik W. Frijlink

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

39 Citations (Scopus)


In a previous study we have developed a novel process to produce drug nanocrystals. This process, "controlled crystallization during freeze-drying" has shown to be a successful method to increase the dissolution rate of poorly water-soluble drugs [de Waard, H., Hinrichs, W.L.J., Frijlink, H.W., 2008. A novel bottom-up process to produce drug nanocrystals: controlled crystallization during freeze drying. J. Control. Release 128, 179-183]. This process consisted of two steps: a solution of a matrix material (mannitol) in water was mixed with a solution of a drug (fenofibrate) in tertiary butyl alcohol (TBA). This mixture was frozen and subsequently freeze-dried at relatively high temperature (-25 °C). Since the solution of matrix and drug in the water-TBA mixture is thermodynamically unstable, it had to be frozen immediately and fast after preparation to prevent premature crystallization of the drug resulting in the formation too large drug crystals. Therefore, small quantities were manually mixed in a vial and this vial was immersed in liquid nitrogen. To make this process ready for large scale production, the modification of this batch process to a semi-continuous process by the application of a 3-way nozzle was studied. With this nozzle, the aqueous and TBA-solutions were pumped into the nozzle via two separate channels and mixed just at the moment they left the nozzle. Thorough mixing was facilitated by the atomizing air, supplied via the third channel. Since the mixture was sprayed immediately into liquid nitrogen, premature crystallization was prevented. A further advantage was that the atomizing air generated small droplets which were directly immersed into liquid nitrogen. Consequently, the mixture was frozen even faster than in the batch process. This resulted in a reduced size of the drug crystals and hence a higher dissolution rate. Therefore, using the semi-continuous process does not only result in successfully making this process suitable for large scale production of the controlled crystallized dispersions, but it also results in a better product. © 2009 Elsevier B.V. All rights reserved.
Original languageEnglish
Pages (from-to)224-229
Number of pages6
JournalEuropean Journal of Pharmaceutical Sciences
Issue number3
Publication statusPublished - 8-Oct-2009


  • 3-Way nozzle
  • Crystallization
  • Fenofibrate
  • Lipophilic drug
  • Scale-up
  • fenofibrate
  • liquid nitrogen
  • mannitol
  • nanocrystal
  • tert butyl alcohol
  • article
  • batch process
  • continuous process
  • controlled study
  • crystallization
  • dispersion
  • drug manufacture
  • drug solubility
  • freeze drying
  • particle size
  • priority journal

Cite this