Impact of process parameters on the breakage kinetics of poorly water-soluble drugs during wet stirred media milling: A microhydrodynamic view

Afolawemi Afolabi, Olakemi Akinlabi, Ecevit Bilgili

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Wet stirred media milling has proven to be a robust process for producing nanoparticle suspensions of poorly water-soluble drugs. As the process is expensive and energy-intensive, it is important to study the breakage kinetics, which determines the cycle time and production rate for a desired fineness. Although the impact of process parameters on the properties of final product suspensions has been investigated, scant information is available regarding their impact on the breakage kinetics. Here, we elucidate the impact of stirrer speed, bead concentration, and drug loading on the breakage kinetics via a microhydrodynamic model for the bead-bead collisions. Suspensions of griseofulvin, a model poorly water-soluble drug, were prepared in the presence of two stabilizers: hydroxypropyl cellulose and sodium dodecyl sulfate. Laser diffraction, scanning electron microscopy, and rheometry were used to characterize them. Various microhydrodynamic parameters including a newly defined milling intensity factor was calculated. An increase in either the stirrer speed or the bead concentration led to an increase in the specific energy and the milling intensity factor, consequently faster breakage. On the other hand, an increase in the drug loading led to a decrease in these parameters and consequently slower breakage. While all microhydrodynamic parameters provided significant physical insight, only the milling intensity factor was capable of explaining the influence of all parameters directly through its strong correlation with the process time constant. Besides guiding process optimization, the analysis rationalizes the preparation of a single high drug-loaded batch (20% or higher) instead of multiple dilute batches.

Original languageEnglish (US)
Pages (from-to)75-86
Number of pages12
JournalEuropean Journal of Pharmaceutical Sciences
Volume51
Issue number1
DOIs
StatePublished - 2014

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Keywords

  • Breakage kinetics
  • Microhydrodynamics
  • Milling intensity factor
  • Nanoparticles-
  • Poorly water-soluble drugs
  • Wet media milling

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