Abstract
This study examined the impact of stirrer speed and bead material loading on fenofibrate particle breakage during wet stirred media milling (WSMM) via three kinetic models and a microhydrodynamic model. Evolution of median particle size was tracked via laser diffraction during WSMM operating at 3000–4000 rpm with 35–50% (v/v) concentration of polystyrene or zirconia beads. Additional experiments were performed at the center points of the above conditions, as well as outside the range of these conditions, in order to test the predictive capability of the models. First-order, nth-order, and warped-time kinetic models were fitted to the data. Main effects plots helped to visualize the influence of the milling variables on the breakage kinetics and microhydrodynamic parameters. A subset selection algorithm was used along with a multiple linear regression model (MLRM) to delineate how the breakage rate constant k was affected by the microhydrodynamic parameters. As a comparison, a purely empirical correlation for k was also developed in terms of the process/bead parameters. The nth-order model was found to be the best model to describe the temporal evolution; nearly second-order kinetics (n ≅ 2) was observed. When the process was operated at a higher stirrer speed and/or higher loading with zirconia beads as opposed to polystyrene beads, the breakage occurred faster. A statistically significant (p-value ≤ 0.01) MLRM of three microhydrodynamic parameters explained the variation in the breakage rate constant best (R2 ≥ 0.99). Not only do the models and the nth-order kinetic–microhydrodynamic correlation enable deeper process understanding toward developing a WSMM process with reduced cycle time, but they also provide good predictive capability, while outperforming the purely empirical correlation.
Highlights
The majority of drug molecules coming out of high-throughput screening have poor water solubility due to their high lipophilicity and molecular weight [1]
The main assumptions and limitations of the microhydrodynamic model have been mentioned in Section 2.2.4; here, we focus on those related to the kinetic models
This study has examined the FNB breakage rate in wet stirred media milling (WSMM) operating at various stirrer speeds and volumetric loadings of CPS–YSZ beads via three kinetic models
Summary
The majority of drug molecules coming out of high-throughput screening have poor water solubility due to their high lipophilicity and molecular weight [1]. Forty percent of marketed drugs are poorly water-soluble, which results in low bioavailability. 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, and a reduction in the thickness of the diffusion layer [3,4,5]. Nanoparticles with sizes greater than 100 nm prepared via mechanical methods could exhibit higher saturation solubility than bulk crystals [8], due to mechanically induced disorder and crystal defects [8,9,10,11], amorphization, and solubilization by the stabilizers [12,13]. Kesisoglou and Wu [14] estimated the solubility
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