Do Mixtures of Beads with Different Sizes Improve Wet Stirred Media Milling of Drug Suspensions?

Abstract

The impacts of bead sizes and bead mixtures on breakage kinetics, the number of milling cycles applied to prevent overheating, and power consumption during the nanomilling of drug (griseofulvin) suspensions were investigated from both an experimental and theoretical perspective. Narrowly sized zirconia beads with nominal sizes of 100, 200, and 400 µm and their half-and-half binary mixtures were used at 3000 and 4000 rpm with two bead loadings of 0.35 and 0.50. Particle size evolution was measured during the 3 h milling experiments using laser diffraction. An nth-order breakage model was fitted to the experimental median particle size evolution, and various microhydrodynamic parameters were calculated. In general, the beads and their mixtures with smaller median sizes achieved faster breakage. While the microhydrodynamic model explained the impacts of process parameters, it was limited in describing bead mixtures. For additional test runs performed, the kinetics model augmented with a decision tree model using process parameters outperformed that augmented with an elastic-net regression model using the microhydrodynamic parameters. The evaluation of the process merit scores suggests that the use of bead mixtures did not lead to notable process improvement; 100 µm beads generally outperformed bead mixtures and coarser beads in terms of fast breakage, low power consumption and heat generation, and low intermittent milling cycles.

Development of a Semi-Mechanistic Modeling Framework for Wet Bead Milling of Pharmaceutical Nanosuspensions

“…Bead size can be an important process parameter as it may provide combined advantages of faster breakage [ 21 , 50 , 64 ], lower heat generation rate [ 65 , 66 , 67 ], and lower media wear [ 21 , 64 ]. However, its impact on the breakage rate may be more subtle because it has counteracting microhydrodynamic trends where smaller beads capture drug particles more frequently but apply less stress upon contact [ 20 , 60 ].…”

“…The drug product formulations at GSK are proprietary APIs that will not be listed explicitly but simply referred to as a drug product (DP) number, i.e., DP1, DP2, … DP8. Both NJIT studies used Hydroxypropyl cellulose (HPC, L grade, Nisso America Inc., New York, NY, USA) as a nonionic polymeric stabilizer, and sodium dodecyl sulfate (SDS, ACS grade, GFS chemicals, Columbus, OH, USA) as an anionic surfactant where the formulation was 10% drug, 7.5% HPC-L and 0.05% SDS with respect to 200 g DI water [ 49 , 50 ]. In addition, 400 μm nominal sized Zirmil Y grade zirconia beads and HCC grade polystyrene beads were purchased from Saint Gobain ZirPro (Mountainside, NJ, USA) and Norstone Inc. (Bridgeport, PA, USA), respectively.…”

“…PSD was provided by the equipment software, which used the Mie scattering theory. The refractive indices of GF, FNB and water were taken as 1.65, 1.55, and 1.33, respectively [ 49 , 50 ]. Measurements were repeated four times, and the average and standard deviation of these measurements were determined.…”

“…However, this approach may not be practical as it requires accurate measurements of power P and power density P v = P/V m in mills at various scales, as well as density and apparent shear viscosity of the suspensions. Previous studies showed that the granular temperature θ varies with the rotational speed ω of the rotor [ 20 , 29 , 48 , 49 , 50 , 60 ], the volume fraction of the beads in the suspension c [ 20 , 29 , 48 , 49 , 50 ], the density of the beads ρ b [ 29 , 48 , 49 ], the diameter of the beads D b [ 20 , 50 , 60 ], and the apparent shear viscosity of the suspension μ s at the reference temperature [ 16 ]. The density of the suspensions ρ s is another factor that has an impact on θ ( Appendix B ).…”