(740d) A Combined Kinetic–Microhydrodynamic Analysis of the Fenofibrate Nanosuspension Production in a Wet Stirred Media Mill

Majority of drug molecules coming out of high-throughput screening have poor water solubility due to their high lipophilicity and molecular weight [1]. 40% of the marketed drugs are poorly water-soluble, which results in low bioavailability. There are several formulation approaches to overcome this challenge such as amorphous solid dispersions, lipid-based formulations, and nanoparticle-based formulations [2]. Drug nanoparticles have been commonly used as they are shown to improve the dissolution rate and bioavailability of drugs due to increased specific surface area, higher saturation solubility as well as a reduction in the thickness of the diffusion layer [3]. These advantages led to the use of nanosuspensions or nanocomposites in several marketed products that have various delivery routes such as oral, parental, pulmonary, ocular, and dermal [4].

In the preparation of drug nanosuspensions, wet stirred media milling (WSMM) appeared to be the most preferred process due to its several advantages, according to a recent literature survey [5]. WSMM has the capability of producing high drug-loaded, stable nanosuspensions and it is a robust, reproducible, scalable, solvent-free, and environmentally benign process [6]. Despite its significant advantages, WSMM has also serious challenges. Most studies on WSMM focus on formulation challenges such as aggregation and crystal growth via Ostwald ripening (see [5] and references cited therein). In contrast, relatively scant information is available about the processing–operational challenges such as energy-intensive operation, high cost due to high energy consumption, long operating hours, and contamination of drug particles by the beads [6,7]. Overcoming these challenges entails a mechanistic understanding of the impact of process variables such as the stirrer speed, the size–material of the beads, and the bead loading on the breakage kinetics, milling time required for the desired product fineness, specific energy consumption, and media wear [8,9].

This study aims to examine the impact of stirrer speed ω, volumetric bead loading c, and bead material type (CPS: cross-linked polystyrene and YSZ: yttrium-stabilized zirconia) on the fenofibrate (FNB) particle breakage during WSMM via three breakage kinetic models and a microhydrodynamic model. FNB was used as a challenging, model poorly water-soluble drug because it is highly prone to aggregation and Ostwald ripening [10,11], unlike griseofulvin used in the previous microhydrodynamic studies [8,12,13] and its milling is relatively slow. In the experiments, 235 g suspensions with 10% FNB, 7.5% HPC-L, and 0.05% SDS were prepared, wherein HPC-L and SDS served as the stabilizers selected based on our prior work [10,11]. The evolution of FNB median particle size was tracked via laser diffraction during WSMM operating at 3000–4000 rpm with 35–50% (v/v) concentration of polystyrene and zirconia beads. First-order, n^th-order, and warped-time breakage kinetic models were fitted to the kinetic data with the objective of identifying the best kinetic model based on statistical analysis and physical plausibility considerations. The evaluation of breakage kinetic parameters with respect to the low and high values of the operating parameters was made via main effects plots. Main effects plots helped to visualize the influence of the milling variables on the breakage kinetics and microhydrodynamic parameters. Based on a recent modification [14] of the microhydrodynamic theory [15], several microhydrodynamic parameters, i.e., granular temperature θ, average bead oscillation velocity u_b, frequency of a single bead oscillation n, maximum contact pressure σ_b^max, radius of bead contact circle α_b, average frequency of drug particle compressions a, and pseudo energy dissipation rate for the drug particles Πσ_y were calculated using the measured process variables, power consumption, and suspension viscosity–density. A subset selection algorithm was used along with Multiple Linear Regression Model (MLRM) to delineate how the breakage rate constant is affected by the microhydrodynamic parameters.

When the fitting capability of the first-order, n^th-order and warped-time kinetic models is compared (see Fig. 1) and statistically analyzed, n^th-order and warped-time kinetic models were found to better fit the experimental data than the first-order kinetic model. We assessed n^th-order and warped time models via main effects plots with changing process conditions and statistical analysis. The warped-time model was found hard to interpret because both of its paramaters n and k₀ drastically changed in opposite directions with increasing intensity of the process conditions. On the other hand, the n^th-order model with n ≅ 2 turned out to be the best overall model that explained the temporal evolution of the median size well. Whereas the variations in n and limiting particle size d_lim upon process parameter changes were relatively small, k was the sole parameter that directly and significantly changed with the process parameters. Therefore, the n^th-order model was used for correlating the breakage rate constant k to the physical microhydrodynamic parameters.

The microhydrodynamic parameters provided valuable insights and a physical basis for the observed breakage behaviors under different operating conditions An increase in the stirrer speed led to increase in all microhydrodynamic parameters, thus favouring faster breakage. While an increase in bead loading led to two counteracting effects, i.e., more frequent, albeit less energetic bead–bead collisions, faster breakage was observed at the higher bead loading. YSZ beads led to faster breakage than CPS beads, which can be attributed to the higher values of all microhydrodynamic parameters, except the radius of contact circle α_b. Finally, a correlation between the breakage rate constant k and 4 microhydrodynamic parameters, i.e., maximum contact pressure σ_b^max, radius of contact circle α_b, average frequency of drug particle compressions a, and pseudo energy dissipation rate for the drug particles Πσ_y was established. A statistically significant (p-value ≤ 0.01) MLRM of three microhydrodynamic parameters explained the variation in the breakage rate constant k best (R² ≥ 0.99). This optimal model demonstrated that the average frequency of drug particle compressions interacting with the pseudo energy dissipation rate and the radius of the bead–bead contact circle govern the breakage kinetics in WSMM.

Overall, this study has offered the first comprehensive treatment of breakage kinetics during WSMM in view of the fundamental physics (microhydrodynamics) and revealed the microhydrodynamic parameters that govern the breakage kinetics. In a future study, we will combine the microhydrodynamic model with a population balance model to predict the evolution of the whole particle size distribution.

REFERENCES

1. Ding Z, Wang L, Xing Y, Zhao Y, Wang Z, Han J. Enhanced Oral Bioavailability of Celecoxib Nanocrystalline Solid Dispersion based on Wet Media Milling Technique: Formulation, Optimization and In Vitro/In Vivo Evaluation. Pharmaceutics. 2019;11(7):328.

2. Junyaprasert VB, Morakul B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian Journal of Pharmaceutical Sciences. 2015;10(1):13-23. doi: https://doi.org/10.1016/j.ajps.2014.08.005.

3. Nakach M, Authelin J-R, Perrin M-A, Lakkireddy HR. Comparison of high pressure homogenization and stirred bead milling for the production of nano-crystalline suspensions. Int J Pharm. 2018;547(1):61-71. doi: https://doi.org/10.1016/j.ijpharm.2018.05.042.

4. Malamatari M, Taylor KMG, Malamataris S, Douroumis D, Kachrimanis K. Pharmaceutical nanocrystals: production by wet milling and applications. Drug Discovery Today. 2018;23(3):534-47. doi: https://doi.org/10.1016/j.drudis.2018.01.016.

5. Bhakay A, Rahman M, Dave RN, Bilgili E. Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation⁻Processing Aspects and Challenges. Pharmaceutics. 2018;10(3):86. doi: 10.3390/pharmaceutics10030086.

6. Li M, Azad M, Davé R, Bilgili E. Nanomilling of Drugs for Bioavailability Enhancement: A Holistic Formulation-Process Perspective. Pharmaceutics. 2016 doi: 10.3390/pharmaceutics8020017.

7. Bilgili E, Guner G. Mechanistic Modeling of Wet Stirred Media Milling for Production of Drug Nanosuspensions. AAPS PharmSciTech. 2020;22(1):2. doi: 10.1208/s12249-020-01876-w.

8. Afolabi A, Akinlabi O, Bilgili E. 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. 2014;51:75-86. doi: https://doi.org/10.1016/j.ejps.2013.09.002.

9. Bilgili E, Capece M, Afolabi A. Modeling of milling processes via DEM, PBM, and microhydrodynamics. In: Pandey P, Bharadwaj R, editors. Predictive Modeling of Pharmaceutical Unit Operations. Woodhead Publishing; 2017. p. 159-203.

10. Azad M, Afolabi A, Bhakay A, Leonardi J, Davé R, Bilgili E. Enhanced physical stabilization of fenofibrate nanosuspensions via wet co-milling with a superdisintegrant and an adsorbing polymer. Eur J Pharm Biopharm. 2015;94:372-85. doi: https://doi.org/10.1016/j.ejpb.2015.05.028.

11. Knieke C, Azad MA, Davé RN, Bilgili E. A study of the physical stability of wet media-milled fenofibrate suspensions using dynamic equilibrium curves. Chem Eng Res Des. 2013;91(7):1245-58. doi: https://doi.org/10.1016/j.cherd.2013.02.008.

12. Parker N, Rahman M, Bilgili E. Impact of media material and process parameters on breakage kinetics–energy consumption during wet media milling of drugs. Eur J Pharm Biopharm. 2020;153:52-67. doi: https://doi.org/10.1016/j.ejpb.2020.05.024.

13. Li M, Alvarez P, Bilgili E. A microhydrodynamic rationale for selection of bead size in preparation of drug nanosuspensions via wet stirred media milling. Int J Pharm. 2017;524(1):178-92. doi: https://doi.org/10.1016/j.ijpharm.2017.04.001.

14. Guner G, Yilmaz D, Bilgili E. Breakage kinetic models and microhydrodynamic correlations for wet stirred media milling of fenofibrate. Drug Dev Ind Pharm. 2021, under review.

15. Eskin D, Zhupanska O, Hamey R, et al. Microhydrodynamic analysis of nanogrinding in stirred media mills. AIChE J. 2005;51(5):1346-1358, doi: https://doi.org/10.1002/aic.10392.