Wet Stirred Media Milling Research Articles

A Novel PBM for Nanomilling of Drugs in a Recirculating Wet Stirred Media Mill: Impacts of Batch Size, Flow Rate, and Back-Mixing.

We examined the evolution of fenofibrate (FNB, drug) particle size distribution (PSD) during the production of nanosuspensions via wet stirred media milling (WSMM) with a cell-based population balance model (PBM). Our objective was to elucidate the potential impacts of batch size, suspension volumetric flow rate, and imperfect mixing in a recirculating WSMM. Various specific breakage rate functions were fitted to experimental PSD data at baseline conditions assuming perfect mixing. Then, the best function was used to simulate the PSD evolution at various batch sizes and flow rates to validate the model. A novel function, which is a product of power-law and logistic functions, fitted the evolution the best, signifying the existence of a transition particle size commensurate with a grinding limit. Although larger batches yielded coarser and wider PSDs, the suspensions had identical PSDs when milled for the same effective milling time. The flow rate had an insignificant influence on the PSD. Furthermore, the imperfect mixing in the mill chamber was simulated by considering more than one cell and different back-mixing flow ratios. The effects were weak and restricted to the first few turnovers. These insights contribute to our understanding of recirculating WSMM, providing valuable guidance for process development.

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.

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.

Impact of solvents during wet stirred media milling of cross-linked biopolymer suspensions

The aim of this study was to examine the impact of solvents during the wet stirred media milling of cross-linked biopolymers considering breakage kinetics, physical stability of the suspensions, and microhydrodynamics. To this end, a model cross-linked biopolymer, sodium starch glycolate (SSG), was milled in acetone and water wherein SSG was non-swellable and swellable, respectively. Suspensions containing SSG particles with and without two stabilizers, i.e., hydroxypropyl cellulose and sodium dodecyl sulfate, were prepared. The temporal evolution of the SSG particle size during the milling was tracked by laser diffraction. Swelling of the SSG particles in water was independently characterized using microscopy and laser diffraction, which revealed fast swelling within a few minutes. Results also suggest that SSG particles were broken faster in water than in acetone, and stabilizers could not prevent severe aggregation in acetone. Despite the greater viscous dampening in water, water was more favorable for faster production of stable suspensions than acetone. The superior performance of aqueous milling was primarily attributed to favorable nanoparticle stabilization in water and secondarily to swelling-induced softening and coarsening of SSG particles. Hence, also being environmentally benign and safe, it is preferred over organic solvent-based milling for the preparation of cross-linked biopolymer nanosuspensions.

Kinetic and Microhydrodynamic Modeling of Fenofibrate Nanosuspension Production in a Wet Stirred Media Mill.

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.

Use of Bead Mixtures as a Novel Process Optimization Approach to Nanomilling of Drug Suspensions.

We aimed to evaluate the feasibility of cross-linked polystyrene (CPS)-yttrium-stabilized zirconia (YSZ) bead mixtures as a novel optimization approach for fast, effective production of drug nanosuspensions during wet stirred media milling (WSMM). Aqueous suspensions of 10% fenofibrate (FNB, drug), 7.5% HPC-L, and 0.05% SDS were wet-milled at 3000-4000rpm and 35%-50% volumetric loading of CPS:YSZ bead mixtures (CPS:YSZ 0:1-1:0 v:v). Laser diffraction, SEM, viscometry, DSC, and XRPD were used for characterization. An nth-order model described the breakage kinetics, while a microhydrodynamic model allowed us to gain insights into the impact of bead materials. CPS beads achieved the lowest specific power consumption, whereas YSZ beads led to the fastest breakage. Breakage followed second-order kinetics. Optimum conditions were identified as 3000rpm and 50% loading of 0.5:0.5v/v CPS:YSZ mixture from energy-cycle time-heat dissipation perspectives. The microhydrodynamic model suggests that YSZ beads experienced more energetic/forceful collisions with smaller contact area as compared with CPS beads owing to the higher density-elastic modulus of the former. We demonstrated the feasibility of CPS-YSZ bead mixtures and rationalized its optimal use in WSMM through their modulation of breakage kinetics, energy utilization, and heat dissipation.

Mechanistic Modeling of Wet Stirred Media Milling for Production of Drug Nanosuspensions.

Drug nanocrystals have been used for a wide range of drug delivery platforms in the pharmaceutical industry, especially for bioavailability enhancement of poorly water-soluble drugs. Wet stirred media milling (WSMM) is the most widely used process for producing dense, stable suspensions of drug nanoparticles, also referred to as nanosuspensions. Despite a plethora of review papers on the production and applications of drug nanosuspensions, modeling of WSMM has not been thoroughly covered in any review paper before. The aim of this review paper is to briefly expose the pharmaceutical scientists and engineers to various modeling approaches, mostly mechanistic, including computational fluid dynamics (CFD), discrete element method (DEM), population balance modeling (PBM), coupled methods, the stress intensity-number model (SI-SN model), and the microhydrodynamic (MHD) model with a main focus on the MHD model for studying the WSMM process. A total of 71 studies, 30 on drugs and 41 on other materials, were reviewed. Analysis of the pharmaceutics literature reveals that WSMM modeling is largely based on empirical, statistically based modeling approaches, and mechanistic modeling could help pharmaceutical engineers develop a fundamental process understanding. After a review of the salient features and various pros-cons of each modeling approach, recent advances in microhydrodynamic modeling and process insights gained therefrom were highlighted. The SI-SN and MHD models were analyzed and critiqued objectively. Finally, the review points out potential research directions such as more mechanistic and accurate CFD-DEM-PBM simulations and the coupling of the MHD-PBM models with the CFD.

Electro-Hydrodynamic Drop-on-Demand Printing of Aqueous Suspensions of Drug Nanoparticles.

We demonstrate the ability to fabricate dosage forms of a poorly water-soluble drug by using wet stirred media milling of a drug powder to produce an aqueous suspension of nanoparticles and then print it onto a porous biocompatible film. Contrary to conventional printing technologies, a deposited material is pulled out from the nozzle. This feature enables printing highly viscous materials with a precise control over the printed volume. Drug (griseofulvin) nanosuspensions prepared by wet media milling were printed onto porous hydroxypropyl methylcellulose films prepared by freeze-drying. The drug particles retained crystallinity and polymorphic form in the course of milling and printing. The versatility of this technique was demonstrated by printing the same amount of nanoparticles onto a film with droplets of different sizes. The mean drug content (0.19–3.80 mg) in the printed films was predicted by the number of droplets (5–100) and droplet volume (0.2–1.0 µL) (R2 = 0.9994, p-value < 10−4). Our results also suggest that for any targeted drug content, the number-volume of droplets could be modulated to achieve acceptable drug content uniformity. Analysis of the model-independent difference and similarity factors showed consistency of drug release profiles from films with a printed suspension. Zero-order kinetics described the griseofulvin release rate from 1.8% up to 82%. Overall, this study has successfully demonstrated that the electro-hydrodynamic drop-on-demand printing of an aqueous drug nanosuspension enables accurate and controllable drug dosing in porous polymer films, which exhibited acceptable content uniformity and reproducible drug release.

Preparation of coconut shell nanoparticles by wet-stirred media milling

Coconut shell nanoparticles have been prepared via top-down approach from wet-stirred media mill. Milling parameters like milling time, feed concentration, effect of surfactants and surfactant concentration have been investigated for efficient production of nanoparticles. Particle size of nanoparticles was estimated from Particle Size Analyzer and chemical composition of raw and nanosized Coconut Shell Particles (CSPs) was analysed from Fourier Transform Infrared Spectroscopy. Particle size of nanoparticles was confirmed from Transmission Electron Microscopy (TEM), which also revealed the spherical morphology of the nanoparticles. X-Ray Diffraction patterns reflected presence of constituents of CSPs and crystallite size derived from it was comparable with the one obtained from TEM images. The work proposes an improvised and effective process of mechanical preparation over dry ball milling method to prepare nanoparticles.

Fenofibrate Nanocrystal Composite Microparticles for Intestine-Specific Oral Drug Delivery System.

Hydrophobic drug nanocrystals (NCs) manufactured by particle engineering have been extensively investigated for enhanced oral bioavailability and therapeutic effectiveness. However, there are significant drawbacks, including fast dissolution of the nanocrystals in the gastric environment, leading to physicochemical instability. To solves this issue, we developed an innovative technique that involves the encapsulation of nanocrystals in composite spherical microparticles (NCSMs). Fenofibrate (FNB) NCs (FNB-NCs) manufactured by a wet stirred media milling (WSMM) technique and an ionotropic crosslinking method were used for FNB-NC encapsulation within gastroresistant NCSMs. Various solid-state methods were used for characterizing NCSMs. The pH-sensitive NCSMs showed a site-specific release pattern at alkaline pH and nearly 0% release at low pH (gastric environment). This phenomenon was confirmed by a real-time in situ UV-imaging system known as the surface dissolution imager (SDI), which was used to monitor drug release events by measuring the color intensity and concentration gradient formation. All these results proved that our NCSM approach is an innovative idea in oral drug delivery systems, as it resolves significant challenges in the intestine-specific release of hydrophobic drugs while avoiding fast dissolution or burst release.

Tailoring product formulation properties to reduce grinding media wear

The generation of grinding media wear during wet stirred media milling of organic particles was studied in dependence of product formulation parameters. It was shown that targeted product formulation leads to the reduction of ceramic grinding media wear for a certain product quality. Solids concentration and agglomerate size of product particles were identified as key parameters. Both influence the effective stress intensity of grinding media which has a significant impact on the generation of grinding media wear. Moreover, the reduction of grinding media wear can be attributed to the damping properties of comparatively soft organic particles. Their potential to protect ceramic grinding media from abrasion can be increased by tailoring formulation properties. Therefore, especially the increase of solids concentration was identified as most practical formulation variable which affects also grinding efficiency and production capacity.

Model based process optimization of nanosuspension preparation via wet stirred media milling

The present study focuses on model based parameter optimization of nanosuspension preparation via wet stirred media milling. Based on experimental data of nanomilling a crystalline organic material, two different approaches for process optimization were evaluated: The stress model for stirred media mills, introduced by Kwade, was compared to the microhydrodynamic approach modified by Bilgili and Afolabi. The different approaches to describe influences of operating parameters were discussed with respect to their applicability on process optimization of nanosuspension preparation. Both approaches yield characteristic values which are derived from proportionalities to process parameters. Despite of different physical assumptions, the milling process can be optimized by both approaches. A more detailed insight into physical interactions can be only generated by numerical procedures. Limitations of the applied procedures were observed especially with respect to the accessibility of parameters required for calculation.

Plant-Mediated Synthesis of Silver Nanoparticles and Their Stabilization by Wet Stirred Media Milling

Within this study, a stable nanosuspension of silver nanoparticles (Ag NPs) was prepared using a two-step synthesis and stabilization approach. The Ag NPs were synthesized from a silver nitrate solution using the Origanum vulgare L. plant extract as the reducing agent. The formation of nanoparticles was finished upon 15 min, and subsequently, stabilization by polyvinylpyrrolidone (PVP) using wet stirred media milling was applied. UV-Vis spectra have shown a maximum at 445 nm, corresponding to the formation of spherical Ag NPs. Infrared spectroscopy was used to examine the interaction between Ag NPs and the capping agents. TEM study has shown the formation of Ag NPs with two different average sizes (38 ± 10 nm and 7 ± 3 nm) after the plant-mediated synthesis, both randomly distributed within the organic matrix. During milling in PVP, the clusters of Ag NPs were destroyed, the Ag NPs were fractionized and embedded in PVP. The nanosuspensions of PVP-capped Ag NPs were stable for more than 26 weeks, whereas for the non-stabilized nanosuspensions, only short-term stability for about 1 week was documented.

Critical Material Attributes of Strip Films Loaded With Poorly Water-Soluble Drug Nanoparticles: II. Impact of Polymer Molecular Weight

Recent work established polymer strip films as a robust platform for delivery of poorly water-soluble drug particles. However, a simple means of manipulating rate of drug release from films with minimal impact on film mechanical properties has yet to be demonstrated. This study explores the impact of film-forming polymer molecular weight (MW) and concentration on properties of polymer films loaded with poorly water-soluble drug nanoparticles. Nanoparticles of griseofulvin, a model Biopharmaceutics Classification System class II drug, were prepared in aqueous suspension via wet stirred media milling. Aqueous solutions of 3 viscosity grades of hydroxypropyl methylcellulose (14, 21, and 88 kDa) at 3 viscosity levels (∼9500, ∼12,000, and ∼22,000 cP) were mixed with drug suspension, cast, and dried to produce films containing griseofulvin nanoparticles. Few differences in film tensile strength or elongation at break were observed between films within each viscosity level regardless of polymer MW despite requiring up to double the time to achieve 100% drug release. This suggests film-forming polymer MW can be used to manipulate drug release with little impact on film mechanical properties by matching polymer solution viscosity. In addition, changing polymer MW and concentration had no negative impact on drug content uniformity or nanoparticle redispersibility.

Application of the product related stress model for product dispersity control in dry stirred media milling

Ground ultrafine and nano- materials are mainly produced by wet stirred media milling. The product related stress model can be used for the optimization of such grinding processes; the operational parameters can be related to the particle size or specific surface of the product. At the same time, for many materials dry grinding is required. During dry stirred media milling different problems arise, such as aggregation, agglomeration and particles sticking on the mill liners and on the grinding media. Consequently, the processes taking place in the mill and the effects of the operational parameters on the product properties are not as thoroughly known as in the case of wet stirred milling. In the present paper the application of the product related stress model for product dispersity control in dry batch stirred media milling is presented. Modifications of the models' main parameters such as stress intensity and stress number are introduced. The applications of the modified main parameters are presented for the optimization of the material and grinding media filling ratio, as well as functions for the characterization of the effect of the stress number and stress intensity on the product. With the introduced modifications, the product related stress model proved to be suitable for the characterization of dry batch stirred media milling.

Scale-up from batch to flow-through wet milling process for injectable depot formulation

Injectable depot formulations are aimed at providing long-term sustained release of a drug into systemic circulation, thus reducing plasma level fluctuations and improving patient compliance. The particle size distribution of the formulation in the form of suspension is a key parameter that controls the release rate. In this work, the process of wet stirred media milling (ball milling) of a poorly water-soluble substance has been investigated with two main aims: (i) to determine the parametric sensitivity of milling kinetics; and (ii) to develop scale-up methodology for process transfer from batch to flow-through arrangement. Ball milling experiments were performed in two types of ball mills, a batch mill with a 30ml maximum working volume, and a flow-through mill with a 250ml maximum working volume. Milling parameters were investigated in detail by methodologies of QbD to map the parametric space. Specifically, the effects of ball size, ball fill level, and rpm on the particle breakage kinetics were systematically investigated at both mills, with an additional parameter (flow-rate) in the case of the flow-through mill. The breakage rate was found to follow power-law kinetics with respect to dimensionless time, with an asymptotic d50 particle size in the range of 200–300nm. In the case of the flow-through mill, the number of theoretical passes through the mill was found to be an important scale-up parameter.

Wet gringing of zeolite in stirred media mill

In the present study the results of systematic experimental series are presented with the specific goal of optimizing the zeolite nanoparticles' production using a wet stirred media mill. The diameter of the grinding media as well as the rotor velocity were varied in the experiments. Particle size distribution and "outer" specific surface area of the ground samples were measured by a laser particle size analyser. Additionally, BET, XRD and FT-IR analyses were performed for the characterization of the "total" specific surface area as well as the crystalline and material structure, respectively. Based on the results of the laboratory experiments it was found that wet stirred media milling provided significant reductions in the particle size of zeolite. Furthermore, the crystallinity of the samples also decreased, so not only the physical but the mineralogical characteristics of zeolite can be controlled by stirred media milling.

Preparation and characterization of fast dissolving pullulan films containing BCS class II drug nanoparticles for bioavailability enhancement

The aim of this study is to assess pullulan as a novel steric stabilizer during the wet-stirred media milling (WSMM) of griseofulvin, a model poorly water-soluble drug, and as a film-former in the preparation of strip films via casting–drying the wet-milled drug suspensions for dissolution and bioavailability enhancement. To this end, pullulan films, with xanthan gum (XG) as thickening agent and glycerin as plasticizer, were loaded with griseofulvin nanoparticles prepared by WSMM using pullulan in combination with sodium dodecyl sulfate (SDS) as an ionic stabilizer. The effects of drug loading and milling time on the particle size and suspension stability were investigated, as well as XG concentration and casting thickness on film properties and dissolution rate. The nanosuspensions prepared with pullulan–SDS combination were relatively stable over 7 days; hence, this combination was used for the film preparation. All pullulan-based strip films exhibited excellent content uniformity (most <3% RSD) despite containing only 0.3–1.3 mg drug, which was ensured by the use of precursor suspensions with >5000 cP viscosity. USP IV dissolution tests revealed fast/immediate drug release (t80 < 30 min) from films <120 μm thick. Thinner films, films with lower XG loading, or smaller drug particles led to faster drug dissolution, while drug loading had no discernible effect. Overall, these results suggest that pullulan may serve as an acceptable stabilizer for media milling in combination with surfactant as well as a fast-dissolving film former for the fast release of poorly water-soluble drug nanoparticles.

An Intensified Vibratory Milling Process for Enhancing the Breakage Kinetics during the Preparation of Drug Nanosuspensions.

As a drug-sparing approach in early development, vibratory milling has been used for the preparation of nanosuspensions of poorly water-soluble drugs. The aim of this study was to intensify this process through a systematic increase in vibration intensity and bead loading with the optimal bead size for faster production. Griseofulvin, a poorly water-soluble drug, was wet-milled using yttrium-stabilized zirconia beads with sizes ranging from 50 to 1500 μm at low power density (0.87 W/g). Then, this process was intensified with the optimal bead size by sequentially increasing vibration intensity and bead loading. Additional experiments with several bead sizes were performed at high power density (16 W/g), and the results were compared to those from wet stirred media milling. Laser diffraction, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and dissolution tests were used for characterization. Results for the low power density indicated 800 μm as the optimal bead size which led to a median size of 545 nm with more than 10% of the drug particles greater than 1.8 μm albeit the fastest breakage. An increase in either vibration intensity or bead loading resulted in faster breakage. The most intensified process led to 90% of the particles being smaller than 300 nm. At the high power intensity, 400 μm beads were optimal, which enhanced griseofulvin dissolution significantly and signified the importance of bead size in view of the power density. Only the optimally intensified vibratory milling led to a comparable nanosuspension to that prepared by the stirred media milling.

Use of an Enhanced Stress Model for the Optimization of Wet Stirred Media Milling Processes

AbstractWet grinding processes, especially in terms of nanoparticle production, are extremely energy intensive, and for hard and abrasive product materials, high grinding media wear is produced. In order to minimize energy consumption, the choice of the process parameters is crucial. The decision on the process parameters often depends on experience or a certain number of laboratory‐ or pilot‐scale experiments. Here, an enhanced stress energy model is used, which enables the prediction of optimum process parameters for inorganic materials in wet stirred media milling based on results for a different grinding material. The use of this model to select the process parameters is also valid with regard to grinding media wear: The grinding media wear reaches minimum values if the optimum parameters pertaining to the minimum specific energy are chosen based on this enhanced stress energy model, especially if soft products are ground.