(674a) An Intensified Wet Media Milling Process for Faster Production of Dense, Stable Drug Suspensions With Sub-100 Nanometer Particles

About 40% of drug substances identified through combinatorial screening programs in pharmaceutical industry are poorly water-soluble (Lipinski, 2002). Size reduction of drug crystals increases the specific surface area, which can improve the dissolution rate of drugs according to the Noyes–Whitney equation (Noyes et al., 1897). As a robust size reduction process, wet stirred media milling has found common use for the production of stable suspensions with drug nanoparticles, i.e., particles less than 1 μm (Bhakay et al., 2011; Bruno et al., 1996; Merisko-Liversidge et al., 2003). Typically, 100–500 nm particles were prepared by several hours of milling with relatively high energy consumption (Bose et al., 2012; Cerdeira et al., 2010; Knieke et al., 2013). In this study, we use a combined experimental and theoretical approach with the objective of achieving faster production of sub-100 nm BCS class II drug particles with reduced energy consumption. In the experiments, the effects of media (bead) size on the energy consumption and breakage kinetics of two model poorly water-soluble drugs, griseofulvin (GF) and naproxen (NPX) were studied. Then, this baseline process with the optimal bead size was intensified by increasing the stirrer tip speed, bead loading, and suspension flow rate systematically, as guided by a microhydrodynamic model of the process (Eskin et al., 2005). In all milling experiments, the suspensions were physically stabilized using hydroxypropyl methyl cellulose (neutral polymer) and sodium dodecyl sulfate (anionic surfactant), which were shown to have synergistic, electrosteric stabilization of fenofibrate, another poorly water-soluble drug (Knieke et al., 2013). Static light scattering, dynamic light scattering, scanning electron microscopy, and powder X-ray diffraction were used to characterize the milled drug particles.
Experimental investigation of the effects of bead size on GF particle size and mill energy consumption shows that smallest (100 micron) milling media (beads) studied with the baseline process were the most effective in producing sub-100 nm particles with lower energy consumption at the end of 6 h. Microhydrodynamic analysis of the bead–bead collisions using the model developed by Eskin et al. (2005) suggests that higher mill efficiency with the smaller beads is due to a significant increase in bead collision frequency and number of drug particle compression events despite a relatively small decrease in bead compression stress. A milling intensity factor, which is proportional to the energy dissipation rate during deformation of the drug particles (Afolabi et al., 2013), appears to capture the overall positive effects of the smaller beads on the observed faster breakage kinetics. To increase the breakage rate further, a higher milling intensity factor was targeted by increasing the mill tip speed, bead load, and feed flow rate, which is referred to as process intensification. The intensified process led to the production of sub-100 nm particles within 30 min. This resulted in a twelve times reduction in cycle time as compared to the baseline process with 6 h of milling, and a reduction in mill energy consumption up to 48%. Similarly, milling of NPX also led to sub-100 nm particles within 30 min. The use of small beads has enabled us to intensify the process, increase the breakage rate, and reduce the energy consumption without causing gross contamination of the drug product with worn-out beads. The intensified process methodology developed in this work presents an opportunity for formulators/engineers to design an intensified wet-milling process for production of sub-100 nm drug particles with reduced cycle time and acceptable media contamination and/or to optimize existing wet-milling processes.

References

Afolabi, A., Akinlabi, O., Bilgili, E., 2013. Impact of process parameters on the breakage kinetics of poorly water-soluble drugs during wet stirred media milling: a microhydrodynamic view, Eur. J. Pharm. Sci. (under review).
Bhakay, A., Merwade, M., Bilgili, E., Dave, R.N., 2011. Novel aspects of wet milling for the production of microsuspensions and nanosuspensions of poorly water soluble drugs. Drug Dev. Ind. Pharm. 37, 963–976.
Bose,S., Schenck,D., Ghosh, I., Hollywood,A., Maulit, E., Ruegger, C.,2012. Application of spray granulation for conversion of nanosuspensions in to dry powder form. Eur. J. Pharm. Sci. 47, 35-43.
Bruno, J.A., Doty, B.D., Gustow, E., Illig, K.J., Rajagopalan, N., Sarpotdar, P., 1996. Method of grinding pharmaceutical substances. US Pat. 5518187.
Cerdeira, A.M., Mazzotti, M., Gander, B., 2010. Miconazole nanosuspensions: Influence of formulation variables on particle size reduction and physical stability, Int. J. Pharm. 396, 210–218.
Eskin, D., Zhupanska, O., Hamey, R., Moudgil, B., Scarlett, B., 2005. Microhydrodynamic analysis of nanogrinding in stirred media mills. AlChE J. 51, 1346–1358.
Knieke, C., Azad, M.A., Davé, R.N., Bilgili, E., 2013. A study of the physical stability of wet media-milled fenofibrate suspensions using dynamic equilibrium curves. CHERD, doi: 10.1016/j.cherd.2013.02.008
Lipinski, C.A., 2002. Poor aqueous solubility: an industry wide problem in drug discovery. American Pharm. Rev. 5, 82–85.
Merisko-Liversidge, E., Liversidge, G.G., Cooper, E.R., 2003. Nanosizing: a formulation approach for poorly-water soluble compounds. Eur. J. Pharm. Sci. 18, 113–120.
Noyes, A.A., Whitney, W.R., 1897. The rate of solution of solid substances in their own solutions. J. Am. Chem. Soc. 19, 930–934.