Novel aspects of wet milling for the production of microsuspensions and nanosuspensions of poorly water-soluble drugs

Abstract

Micronization and nanoparticle production of poorly water-soluble drugs was investigated using single wet milling equipment operating in the attritor and stirred media modes. The drug particles in the median size range of 0.2–2 µm were prepared by changing the milling mode and operating conditions of a Micros mill with a purpose of elucidating the dynamics of the wet milling process. It was determined that particle breakage due to mechanical stresses and aggregation due to insufficient stabilization are two competing mechanisms which together control the wet milling dynamics of the poorly water-soluble drugs. The study in the attritor mode using four different classes of stabilizers with six drugs indicated that steric stabilization worked better than electrostatic stabilization for the drugs studied. In addition, the existence of different minimum polymer concentrations for the stabilization of microsuspensions and nanosuspensions was indicated. The major role of a non-ionic polymer during the production of fine particles is its stabilization action through steric effects, and no experimental evidence was found to support the so-called Rehbinder effect. Periodic addition of the polymer as opposed to the addition of the polymer at the start of milling process was introduced as a novel processing method. This novel method of polymer addition provided effective stabilization and breakage of drug particles leading to a narrower and finer particle size distribution. Alternatively, it may allow shorter processing time and lower overall power consumption of the milling process for a desired particle size.

Keywords::

• Bioavailability enhancement
• nanoparticles
• wet stirred media mill
• breakage dynamics
• Rehbinder effect

Acknowledgements

We thank Afolawemi Afolabi for his help with the experiments and Daniel To and Maxx Capece for providing valuable comments on a previous draft of this manuscript.

Declaration of interest

The authors gratefully acknowledge financial support from the National Science Foundation Engineering Research Center for Structured Organic Particulate Systems (NSF ERC for SOPS) through the Grant EEC-0540855.