Mechanistic models facilitate efficient development of leucine containing microparticles for pulmonary drug delivery

Int J Pharm. 2011 May 16;409(1-2):156-63. doi: 10.1016/j.ijpharm.2011.02.049. Epub 2011 Feb 26.


Mechanistic models of the spray drying and particle formation processes were used to conduct a formulation study with minimal use of material and time. A model microparticle vehicle suitable for respiratory delivery of biological pharmaceutical actives was designed. L-leucine was chosen as one of the excipients, because of its ability to enhance aerosol dispersibility. Trehalose was the second excipient. The spray drying process parameters used to manufacture the particles were calculated a priori. The kinetics of the particle formation process were assessed using a constant evaporation rate model. The experimental work was focused on the effect of increasing L-leucine mass fraction in the formulation, specifically its effect on leucine crystallinity in the microparticles, on powder density, and on powder dispersibility. Particle, powder and aerosol properties were assessed using analytical methods with minimal sample requirement, namely linear Raman spectroscopy, scanning electron microscopy, time-of-flight aerodynamic diameter measurements, and a new technique to determine compressed bulk density of the powder. The crystallinity of leucine in the microparticles was found to be correlated with a change in particle morphology, reduction in powder density, and improvement in dispersibility. It was demonstrated that the use of mechanistic models in combination with selected analytical techniques allows rapid formulation of microparticles for respiratory drug delivery using batch sizes of less than 80 mg.

MeSH terms

  • Aerosols
  • Crystallization
  • Drug Delivery Systems*
  • Excipients / chemistry*
  • Leucine / chemistry*
  • Lung / metabolism
  • Microscopy, Electron, Scanning
  • Microspheres
  • Models, Theoretical*
  • Spectrum Analysis, Raman
  • Time Factors
  • Trehalose / chemistry


  • Aerosols
  • Excipients
  • Trehalose
  • Leucine