Impact of Processing and Formulation Parameters On Drug Nanoparticle Suspensions Produced Via Wet Stirred Media Milling

One way to improve the bioavailability of poorly water-soluble drugs is to reduce particle size of drug crystals down to nanoscale via wet stirred media milling. An increase in total surface area per mass loading of the drug and in specific surface area as well as reduced external mass transfer resistance allow a faster dissolution of the poorly-water soluble drug from nanocrystals. To prevent aggregation of nanoparticles, polymers and surfactants are dissolved in water acting as stabilizers via adsorption onto the drug crystals.

In the last two decades, ample experimental data were generated in the area of nanoparticle suspension production via media milling (see e.g. Bhakay et al., 2011; Bilgili et al., 2004, 2006; and references cited therein). Recirculation mode of milling operation, where the particle suspension in a holding tank continuously circulates through the stirred media mill, has been commonly used in lab, pilot, and commercial scales. To explain the impact of some of the processing parameters, stress intensity and stress number concepts have been widely used (Kwade, 1999), which do not account for the effect of suspension viscosity. We conducted a comprehensive study on the production of Griseofulvin nanosuspensions in a wet stirred media mill operating in the recirculation mode. Griseofulvin has been selected as a model poorly water-soluble BCS Class II drug. Impact of various processing parameters such as rotor speed, media loading, and media type (yttria stabilized Zirconia vs. crosslinked polystyrene) as well as of formulation parameters such as stabilizer type–loading and stabilizer addition method (initial vs. step-wise) was studied. A major novelty of the present contribution is that we have analyzed and interpreted the impact of processing and formulation parameters using a Microhydrodynamics analysis (Eskin et al., 2005). The key results suggest a minimum stabilizer-to-drug ratio, synergistic stabilizing effect of a hydrophilic polymer and surfactant, and a dampening effect of the polymer on the breakage kinetics above an optimum loading level. The paper also discusses applications of nanosuspensions and practical issues encountered during media milling.

 References

A. Bhakay, M. Merwade, E. Bilgili, R. N. Dave, “Novel Aspects of Wet Milling for the Production of Microsuspensions and Nanosuspensions of Poorly Water-Soluble Drugs,” Drug Dev. Ind. Pharm., doi:10.3109/03639045.2010.551775, (2011).

E. Bilgili, R. Hamey, B. Scarlett, "Nano-Milling of Pigment Agglomerates Using a Wet Stirred Media Mill: Elucidation of the Kinetics and Breakage Mechanisms," Chem. Eng. Sci., 61, 149–157 (2006).

E. Bilgili, R. Hamey, B. Scarlett, "Production of Pigment Nanoparticles Using a Wet Stirred Mill with Polymeric Media" China Particuology, 2, 93–100 (2004).

D. Eskin, O. Zhupanska, R. HameY, B. Scarlett, "Microhydrodynamics of Stirred Media Mills", Powder Technol., 156, 95–102 (2005).

A. Kwade, " Wet Comminution in Stirred Media Mills – Research and its Practical Application", Powder Technol., 105, 14–20 (1999).