(695h) Nanomilling with CPS Beads for the Production of Drug Nanosuspensions: Heat Generation and Particle Breakage

Wet stirred media milling (WSMM) has emerged as an indispensable unit operation in the pharmaceutical industry to produce drug nanosuspensions, offering numerous advantages such as increased dissolution rates, enhanced bioavailability, and improved physical and chemical stability of poorly water-soluble drugs. However, the WSMM process is associated with a significant challenge: the generation of substantial heat due to dissipation of high mechanical energy input. Excessive heat generation and associated high temperatures during milling can lead to adverse consequences, including thermal degradation of drugs, solid-state changes of drugs, and destabilization of nanosuspensions, ultimately compromising the quality and stability of the final drug product [1]. Only a few studies have aimed to maintain the milling temperature below a set value, often employing intermittent milling strategies to mitigate excessive temperature rise during WSMM [2]. While previous studies have indicated the issue of high heat generation during WSMM, a comprehensive investigation of the impact of process parameters on temperature rise has attracted little attention [1]. Guner et al. conducted the first investigation into the influence of process parameters on heat generation when zirconia beads were used in WSMM [2].

In this study, we undertook a comprehensive investigation of the effects of three critical process parameters – stirrer speed, bead loading, and bead size – on the evolution of mill outlet temperature during the milling of fenofibrate (FNB) suspensions using crosslinked polystyrene (CPS) beads. The choice of CPS beads, with their lower density compared to the traditionally used zirconia (YSZ) beads, was motivated by the hypothesis that the use of lower-density beads could potentially mitigate heat dissipation and facilitate better temperature control during the milling process. Particle sizes, temperature evolution, and net power consumption were measured. The aqueous suspension formulation was fixed: 10% FNB, 8% hydroxypropylcellulose (HPC, L-grade), and 0.05% sodium dodecyl sulfate (SDS) in deionized water. Here, FNB is a poorly soluble, model drug; HPC and SDS serve as stabilizer and wetting agent. A microhydrodynamic model was used to elucidate the impact of the process parameters. The temperature at the mill outlet was aimed to be below 45°C to avoid potential gelation of the stabilizer (HPC-L) [1].

Salient features of temperature evolution during the milling experiments were as follows: a monotonic increase in temperature with a decreasing rate was observed with the attainment of a steady-state outlet temperature. This can be explained by heat generated by various dissipative processes, including bead-to-bead and bead-to-wall collisions, as well as viscous heat generation [3,4]. Higher power consumption, facilitated by higher stirrer speeds, higher bead loadings, and larger beads, resulted in faster temperature rise and higher maximum temperatures. However, a notable finding was that even at the highest power consumption, the maximum temperature rise was limited to 25°C, eliminating the need for intermittent milling, which is a common practice when using zirconia (YSZ) beads under medium-to-high energetic conditions.

Power-law correlations were established, relating the normalized temperature rise and the power consumption to the process parameters. The analysis revealed that the stirrer speed had the most significant impact on power consumption and temperature rise, followed by bead loading and bead size. The established power-law correlations provide a quantitative understanding of the heat generation–temperature rise dynamics during WSMM, enabling the prediction and optimization of process parameters to maintain desired temperature ranges.

To gain deeper insights into the intricate relationships between process parameters, particle size reduction, and heat generation, we employed the microhydrodynamic (MHD) model [3,4]. It is based on the kinetic theory of granular flows and fundamental granular energy balance [5]. Various MHD parameters, such as granular temperature, average bead oscillation velocity, and average frequency of drug particle compression were calculated at different processing conditions. It was found that bead loading had the highest impact on most MHD parameters, followed by the stirrer speed, while the bead size had a relatively weak effect. A correlation was established between the median particle size and the average frequency of drug particle compression, indicating a strong relationship between these two variables. Furthermore, a power-law correlation was developed between the dimensionless temperature rise and the MHD parameters, providing a quantitative understanding of the interplay between heat generation, particle size reduction, and process parameters. The microhydrodynamic analysis further elucidated the intricate relationships between process parameters, particle size reduction, and heat generation, highlighting the pivotal role of the average frequency of drug particle compression in governing particle breakage kinetics [6].

In a notable comparative analysis, we juxtaposed the performance of CPS beads with previously reported results [1] with zirconia (YSZ) beads under similar conditions. Figure 1 illustrates a comparative analysis of the temperature rise of the suspension at the mill outlet when utilizing YSZ beads and CPS beads, considering various bead loadings. The stirrer speed was maintained at 4000 rpm, and the bead size was set at 400 𝜇m. The findings revealed that the use of CPS beads led to lower heat generation rates and lower temperature rise during the milling process, while still producing fine, stable fenofibrate suspensions with comparable particle size distributions. Remarkably, the maximum temperature attained during the process was consistently lower when using CPS beads compared to YSZ beads. This temperature difference became more pronounced at higher stirrer speeds and bead loadings, further highlighting the distinct heat dissipation characteristics of the two bead types. Most remarkably, the use of CPS beads eliminated the need for intermittent milling, even at higher stirrer speeds, which was a necessity when using YSZ beads due to excessive temperature rise in the lab-scale mill [7,8]. For YSZ beads, Figure 1 illustrates a multitude of cycles; each cycle consists of milling–cooling up to 45 ^oC followed by cooling to ~18 ^oC. There was only one cycle for the CPS beads. These findings underscore the advantageous use of CPS beads for low heat generation and easy temperature control during the wet media milling of thermally labile drugs, where strict temperature control is critical for maintaining product quality and stability.

In conclusion, we have demonstrated that the conversion of mechanical power into heat led to temperature rise during the WSMM process, and stirrer speed was the most influential parameter affecting temperature rise, followed by bead loading and bead size. Moreover, this study contributes to the understanding of heat generation dynamics in WSMM and provides valuable insights into process optimization strategies for temperature control. We have demonstrated that CPS beads may be preferred over traditional YSZ beads to produce nanosuspensions of temperature-sensitive drugs, offering potential benefits in terms of product quality, process efficiency, and energy conservation.

References

[1] Guner, G., et al., Analysis of heat generation during the production of drug nanosuspensions in a wet stirred media mill. International Journal of Pharmaceutics, 2022. 624: p. 122020.

[2] Afolabi, A., O. Akinlabi, and E. Bilgili, Impact of process parameters on the breakage kinetics of poorly water-soluble drugs during wet stirred media milling: A microhydrodynamic view. European journal of pharmaceutical sciences, 2014. 51: p. 75-86.

[3] Bilgili, E. and A. Afolabi, A combined microhydrodynamics–polymer adsorption analysis for elucidation of the roles of stabilizers in wet stirred media milling. International journal of pharmaceutics, 2012. 439(1-2): p. 193-206.

[4] Eskin, D., et al., Microhydrodynamics of stirred media milling. Powder Technology, 2005. 156(2-3): p. 95-102

[5] Gidaspow, D., Multiphase flow and fluidization: continuum and kinetic theory descriptions. 1994: Academic press.

[6] Guner, G., et al., Effects of bead packing limit concentration on microhydrodynamics-based prediction of breakage kinetics in wet stirred media milling. Powder Technology, 2022. 403: p. 117433.

[7] Guner, G., et al., Use of bead mixtures as a novel process optimization approach to nanomilling of drug suspensions. Pharmaceutical Research, 2021. 38(7): p. 1279-1296.

[8] Parker, N., M. Rahman, and E. Bilgili, Impact of media material and process parameters on breakage kinetics–energy consumption during wet media milling of drugs. European Journal of Pharmaceutics and Biopharmaceutics, 2020. 153: p. 52-67.