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

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.

An Enthalpy-Balance Model for Timewise Evolution of Temperature during Wet Stirred Media Milling of Drug Suspensions.

PURPOSE: Nanosuspensions have been used for enhancing the bioavailability of poorly soluble drugs. This study explores the temperature evolution during their preparation in a wet stirred media mill using a coupled experimental-enthalpy balance approach. METHODS: Milling was performed at three levels of stirrer speed, bead loading, and bead sizes. Temperatures were recorded over time, then simulated using an enthalpy balance model by fitting the fraction of power converted to heat ξ. Moreover, initial and final power, ξ, and temperature profiles at 5 different test runs were predicted by power-law (PL) and machine learning (ML) approaches. RESULTS: Heat generation was higher at the higher stirrer speed and bead loading/size, which was explained by the higher power consumption. Despite its simplicity with a single fitting parameter ξ, the enthalpy balance model fitted the temperature evolution well with root mean squared error (RMSE) of 0.40-2.34°C. PL and ML approaches provided decent predictions of the temperature profiles in the test runs, with RMSE of 0.93-4.17 and 1.00-2.17°C, respectively. CONCLUSIONS: We established the impact of milling parameters on heat generation-power and demonstrated the simulation-prediction capability of an enthalpy balance model when coupled to the PL-ML approaches.

Analysis of heat generation during the production of drug nanosuspensions in a wet stirred media mill.

Although heat is generated during the wet stirred media milling of drug suspensions, leading to notable temperature rise, a comprehensive analysis of heat generation does not exist. Hence, we investigated the impact of stirrer speed, bead loading, and bead size at three levels on the evolution of suspension temperature at the mill outlet during the milling of fenofibrate. The particle sizes and viscosities of the milled suspensions and power were measured. Our results suggest that stirrer speed had the most significant impact on the temperature increase, followed by bead loading and bead size. Both the time when the temperature reached 22 °C and the temperature at 5 min of milling were strongly correlated with the power. Assessing the impacts of the process parameters on the temperature rise, cycle time, power, and median particle size holistically, an optimal milling process was identified: 3000 rpm with 50% loading of 200 or 400 µm beads. A power number correlation was established to calculate power at any milling condition which determines the heat generation rate. Overall, this study indicated the importance of developing a good understanding of heat generation during nanomilling for development of a robust milling process especially for thermally labile drugs.