Milling Beads Research Articles

A novel approach for Al-doped sintering of garnet solid electrolyte

Garnet based solid-state electrolyte Li6.75La3Zr1.75Ta0.25O12 (LLZTO) is one of the most promising electrolytes for advanced all-solid-state lithium batteries. However, the ceramic electrolyte is difficult to densify under normal sintering conditions, and hence the Li+ transportation via grain boundary is significantly limited by the loose contact between electrolyte granules, resulting in a high Li+ ionic impedance. Herein, we report a novel 2-step approach to obtain a relatively dense LLZTO ceramic pellet by a special Al-doping method, in which the Al was derived from the erosion of the corundum milling beads by LiOH during ball milling. This approach enables the simultaneous distribution of the aluminum (Al) within the LLZTO lattice and uniformly within the grain boundary, serving as a sintering aid, effectively boosts the fusion of grain boundary and reduced the failure rate during the sintering process. The ceramic pellet had a conductivity of 8.13 × 10−4 S cm−1, higher than that without Al-doping or using Al2O3 as dopant. This method provides an easier way to sinter the garnet ceramic electrolyte.

Comparison of Fabrication Technique and Carrier Oil to Curcumin Nanoemulsion Properties

Turmeric (Curcuma longa L.) is included in the rhizome plant containing curcumin which has various therapeutic properties. However, curcumin has poor bioavailability. The manufacture of nanoemulsion is expected to increase curcumin bioavailability. This study aims to compare 3 methods (wet-ball milling, ultrasonication and microfluidic) and 3 carrier oils (soybean, virgin coconut, and olive oil) in the production of curcumin nanoemulsion. Wet-ball milling reduces particle size through grinding process using milling beads in liquid medium. Microfluidic decreases the particle size via collision of emulsion components in microchannel while ultrasound utilizes sound-wave energy to break down the particle size. Parameters compared were particle size, polydispersity index and entrapment efficiency. Particle size and polydispersity index were observed using Particle Size Analyzer with Dynamic Light Scattering technique while entrapment efficiency was measured based on the curcumin absorbance in UV-Visible spectrophotometer at 420 nm. Our study concludes that microfluidic is the most effective and efficient fabrication method which produces the smallest particle size and polydispersity index compared to ultrasonication and microfluidic. The resulting particle sizes using microfluidic are 154, 140 and 132 nm with polydispersity index of 0.224; 0.200 and 0.208 in soybean, virgin coconut, and olive oil respectively. However, entrapment efficiency is best achieved using wet-ball milling method with the average value of 49±10%. Soybean oil appears to be the most curcumin solubilizing oil compared to olive and virgin coconut oil. Thus, it can be concluded that fabrication methods and carrier oils determine curcumin nanoemulsion properties.

Correlation of the Vector Gradient of a Magnetic Field with the Kinetic Energy of Hard Magnetic Milling Beads in Electromechanical Mills

AbstractThis paper describes the experimental investigation and numerical simulation of a novel electromechanical milling principle: the direct transformation of energy into the movement of milling beads with special magnetic properties. The experimental results show that this principle is ideally suited for the finest grinding of organic agents. Anthraquinone particles with a median size of 25.5 µm were electromechanically ground to 1 µm and the magnetic field strength in the process chamber has the greatest influence on milling results. The developed model reveals that the distribution of the time‐ and location‐dependent vector gradient of the magnetic field in the process chamber determines the energy transfer from the exciter systems to the milling beads and hence the grinding results. With a suitable characterization of the vector gradient distribution, it is possible to establish a correlation between the vector gradient and specific milling beads power. This correlation is fundamental for the design of electromechanical milling machines.

Wet nanomilling of naproxen using a novel stabilization mechanism via zirconium complexation

Using a novel electrostatic stabilization mechanism that utilizes complexation of Zr(IV) species by carboxylic acid groups at the particle surface, the true grinding limit of monocrystalline naproxen nanoparticles was identified at 30 nm under an optimized naproxen/Zr(IV)-salt formulation. In a stirred media mill, we studied the influence of stress energy and number of stress events by varying the milling bead diameter. Small milling beads provide a compromise between sufficiently high stress energy and stress number and are beneficial for nanomilling of naproxen in terms of grinding kinetics. It is shown that the product particle size can be controlled by adjusting the colloidal stability via the Zr(IV) concentration. Regardless of formulation properties, particle fracture propagates along the grain boundaries as revealed by crystallite size analysis. Investigations of the solvent phase and the particle geometry reveal that mechanical stress leads to enhanced solubility of the drug, which in return promotes recrystallization and thus particle growth. The solubility can be reduced by lowering the process temperature and stabilizer concentration. In contrast to inorganic nanoparticles, which are almost free of lattice imperfections at the true grinding limit, we find a clear indication of lattice strain in the stressed naproxen nanoparticles. Since the nanoparticle yield is still limited to 40% due to particle ripening, fast removal of the nanoparticles from the mill must be a further next step to be solved in nanoparticle processing.

Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability.

Nanocrystal suspensions proved to be a potent enabling principle for biopharmaceutics classification system class II drugs with dissolution limited bioavailability. In the example of itraconazole (ITZ) as a model drug combined with electrosteric stabilization using hydroxypropyl cellulose (HPC-SL), sodium dodecyl sulfate (SDS) and polysorbate 80 (PS80), the impacts of formulation and process parameters of a dual centrifugal mill on material attributes such as particle size, zeta potential, particle morphology, storage stability and especially solid-state characteristics were evaluated. A minimal concentration of 0.9% (w/w) HPC-SL, 0.14% (w/w) SDS and 0.07% (w/w) PS80 was necessary for sufficient nanoparticle stabilization. Despite the minor effect of PS80, its presence was beneficial for electrosteric stabilization. Choosing lower stabilizer concentrations resulted in a pronounced increase in particle size due to agglomeration, which was confirmed by SEM imaging and a decrease in zeta potential in combination with an amorphization of the particles. Milling temperature had no significant impact on the particle size, whereas milling speed and the size of the milling beads used were found to have a strong impact on the critical material attributes such as particle size and polydispersity index. The smallest particle sizes could be obtained by using the smallest milling bead size. However, the smallest obtainable particle size could only be achieved by using two-fold stabilizer concentrations, as smaller particles exhibit a larger specific surface area.

Preparation of Curcumin Nanoemulsion in Soybean Oil – Tween 80 System by Wet Ball Milling Method

Curcumin nanoemulsion which has a particle size of 20-200 nm, is one of the curcumin drug delivery system that can increase curcumin solubility and bioavailability. The previous method of curcumin nanoemulsion formulation is modified thin-film hydration followed by sonication that has a long process and using organic solvent. This study aims to make curcumin nanoemulsion by wet ball milling method in soybean oil – Tween 80 system. Nanoemulsion is expected to have smallest particle size, high curcumin loading capacity and good stability during storage. Preparation of curcumin nanoemulsion is done by wet milling method which consists of curcumin as drug, soybean oil as curcumin solvent, tween 80 as stabilizer, water as dispersed medium and milling beads as milling media on the vial with various milling time. Particle size and polydispersity index are monitored using dynamic light scattering while nanoemulsion morphology is observed using digital imaging microscope. Results show that optimum milling times is 24 h and the highest curcumin added which produces less than 500 nm particles is 300 mg which is stable during 60 days of storage. Particle size of the nanoemulsion is ranging from 127 – 338 nm. In addition, wet ball milling methods is relatively simple and easy to apply.

Design of swellable ordered-mixed spherical drug particles (Swell-OM-spheres) using a dry powder milling and coating technique to improve dissolution behavior

A novel dry powder milling/ordered-mixing technique using a mechanical powder processor was previously developed to improve the dissolution properties of poorly water-soluble drugs. Mecanofused composite particles with an ordered-mixing principle, named OM particles, were designed using corn starch (CS) as a core particle and drug as a coating layer. In the present study this dry powder processing technique was modified to improve the dissolution behavior further by means of two approaches. First, wettable composite particles were produced by co-formulating the water-soluble waxy additive to enhance the hydrophilicity of the outer drug layer. Second, swellable composite particles were designed by replacing CS with a modified starch having expanding property as the core particle. It was found that the latter (swellable) approach was more effective than the former (wettable) one to improve the dissolution behavior of poorly water-soluble model drug. The swellable OM particles promptly expanded on contact with water and induced the effective detachment of fine drug particles from the core particles, resulting in rapid drug release. The present research suggests that the proposed contamination-free dry milling technique, which does not use hard milling balls or beads, can generate spherical drug particles with improved dissolution characteristics.

Cryo-milling using a spherical sugar: Contamination-free media milling technology

Milling beads experience wear upon repeated use. And milling beads made of material that is safe when ingested have not yet been developed. The present report describes the development and characteristics of spherical d-mannitol (SDM) beads, which would be safe when ingested.The model drug phenytoin was dispersed in liquid nitrogen along with SDM and the materials were agitated at high speed. The effects of the amount of beads, agitation speed, and milling time on phenytoin particle size, yield, and bead fractures were investigated using a central composite experimental design.The diameter of milled phenytoin particles decreased significantly as the amount of SDM beads and agitation speed increased. In contrast, no difference was found in the diameter with milling time. Although the fractured SDM ratio increased slightly at higher agitation speeds, the SDM was not broken and was durable enough for milling. This milling technique was applicable not only to phenytoin but also to other drug substances.Bead durability and applicability indicated that SDM can be used as wet milling beads that are considered safe for use if ingested.

Electromechanical Milling - Conception and Design of the Excitation System

The novel electromechanical milling principle is a solution providing reduced energy consumption with milling beads directly moved with a time- and local-variable magnetic field, which is generated in a working chamber by an external, electrical excitation system. Hence, the main design parameters of such machines for electromechanical milling (so-called EMZ plants) must be derived from the time- and local-variable magnetic flux density, the resulting vector gradient and the electromagnetic force distribution in the process room. For the calculation and optimization of these distributions we developed a numerical model on the basis of the commercial software tool ANSYS Maxwell®. We verified this model with experimental measurements of the electromagnetic field in the process room. Furthermore, we have studied the influence of the excitation system design on the vector gradient distribution and discuss selected results in this paper. The study identifies potentials for the further improvement of electromechanical units built in the past.

Assessing the influence of viscosity and milling bead size on the stressing conditions in a stirred media mill by single particle probes

Milling processes in stirred media mills can be essentially described by the collision bead frequency distribution (stress number) and the transferred stress energy distribution. Although general dependencies on the mills’ operating parameters have been extensively studied, the underlying distributions are widely unknown. Recently, we established an experimental protocol to determine the aforesaid distributions by using well-characterized spherical metal particle probes. To this end, the plastic deformation of the particle probes which is caused by stressing in the apparatus is accessed by electron microscopy and is related to single particle compression testing described via a finite element model. Within this account we focus on the influences of grinding media size and fluid viscosity on the stressing conditions in a small-scale horizontal stirred media mill which is operated in open-circuit mode. We show that larger milling beads lead to higher stress energies, whereas an increase of viscosity leads to lower transferred stressing energies. Surprisingly, however, the overall amount of stressed particle probes decreases with the milling bead size. At the same time the fraction of the probes which has been stressed shows many contacts. We relate this effect to the slurry flow through the agitated packed milling bead bed. The effect of viscosity is attributed to squeezing flows which form as a result of approaching milling beads.

Development of an electromechanical principle for wet and dry milling

The paper presents a novel electromechanical principle for wet and dry milling of different materials, in which the milling beads are moved under a time- and local-variable magnetic field. A possibility to optimize the milling process in such a milling machine by simulation of the vector gradient distribution of the electromagnetic field in the process room is presented. The mathematical model and simulation methods based on standard software packages are worked out. The results of numerical simulations and experimental measurements of the electromagnetic field in the working chamber of a developed and manufactured laboratory plant correlate well with each other. Using the obtained operating parameters, dry milling experiments with crushed cement clinker and wet milling experiments of organic agents in the laboratory plant are performed and the results are discussed here.

Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling

The aim of this study is to develop nanosuspension of carvedilol (CRV) by wet media milling. Concentration of polymeric stabilizer (hydroxypropyl cellulose-HPC-SL), milling speed and size of milling beads were identified as critical formulation and process parameters and their effect on CRV particle size after 60 min of milling was assessed using a Box-Behnken experimental design. Optimized nanosuspension was solidified using spray drying and freeze drying and subjected to solid state characterization. Low stabilizer concentration (10%), low milling speed (300 rpm) with small milling beads (0.1 mm) were found as optimal milling conditions. Crystal lattice simulation identified potential slip plane within CRV crystals, where fractures are the most likely to occur. Calculated mechanical properties of CRV crystal indicates that low energy stress is sufficient to initiate fracture, if applied in the correct direction, explaining the advantage of using smaller milling beads. Only spray dried nanosuspension redispersed to original nanoparticles, while particle agglomeration during freeze drying prevented sample redispersion. Wet milling and spray drying did not induce polymorphic transition of CRV, while there is indication of polymorphic transition during freeze drying, making spray drying as the preferred solidification method.

Dual centrifugation – A new technique for nanomilling of poorly soluble drugs and formulation screening by an DoE-approach

The development of nanosuspensions of poorly soluble APIs takes a lot of time and high amount of active material is needed. In this publication the use of dual centrifugation (DC) for an effective and rapid API-nanomilling is described for the first time. DC differs from normal centrifugation by an additional rotation of the samples during centrifugation, resulting in a very fast and powerful movement of the samples inside the vials, which − in combination with milling beads − result in effective milling. DC-nanomilling was compared to conventional wet ball milling and results in same or even smaller particle sizes. Also drug concentrations up to 40% can be processed. The process is fast (typical 90min) and the temperature can be controlled. DC-nanomilling appears to be very gentle, experiments showed no change of the crystal structure during milling. Since batch sizes are very small (100–1000mg) and since 40 sample vials can be processed in parallel, DC is ideal for the screening of suitable polymer/surfactant combinations. Fenofibrate was used to investigate DC-nanomilling for formulation screening by applying a DoE-approach. The presented data also show that the results of DC-nanomilling experiments are highly comparable to the results obtained by common agitator mills.

One step preparation of spherical drug particles by contamination-free dry milling technique with corn starch beads

The novel dry milling technique has been developed by using a mechanical powder processor for improving the dissolution properties of poorly water-soluble drugs. It was found that the drug crystals were well pulverized by co-processing with fine particles of corn starch (CS). The morphological observation and particle size evaluation revealed that the processed products formed the composite particles with ordered-mixed structure, having double-layered particles with a core of CS and a coating layer of phenytoin (Phe), as a model drug. This result suggested that the drug crystals were selectively micronized and the resultant miniaturized Phe particles were adhered/fixed on the surface of un-milled CS particles. The mechanical characteristics detected by the indentation test assumed that the brittle Phe crystals sandwiched between elastic CS particles would be successfully crushed down by high shearing stress in the processor. The newly-established dispersion-sedimentation test indicated that the fine Phe particles were immediately detached from the composite particles in aqueous phase, constructing the suspension. The dissolution behavior from the processed particles was found to be improved and strongly dependent on the size and amount of detached Phe particles. Such milling and ordered-mixturization have been also successfully done by using recrystallized larger Phe particles than 100μm. These results would propose the contamination-free dry milling technique without using hard milling balls or beads. The mechanism of the current milling and ordered-mixing phenomena is also provided in this report.

Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis

Cystic fibrosis (CF) patients are suffering from multiple often chronic endobronchial infection. The stiff mucus in these patients represents a compartment, which cannot easily be reached by systemic treatment. While bacterial infections are now successfully treated with repeated inhalation of antibiotics such as tobramycine, 57% of CF patients are colonized by Aspergillus species. About 10–20% of colonized patients develop symptoms of allergic bronchopulmonary aspergillosis (ABPA). While current standard of treatment of ABPA in CF patients is to suppress the allergy related symptoms by administration of glucocorticoids, itraconazole (ITRA), administered orally at high doses, can alleviate the symptoms of ABPA. However, no inhalable formulation of ITRA is available to enable local treatment of aspergillosis. The aim of this study was to describe an aqueous nanosuspension of ITRA and to characterize the pharmacokinetics after single dose inhalation. Using wet-milling with organic milling beads, a stable nanosuspension with particle size in the range of 200nm and an ITRA concentration of 20% (v/w) could be obtained, using polysorbate 80 at a concentration of 14% relative to ITRA. The suspension was stable if stored at 8°C for 3months without particle growth and could be nebulized using standard nebulizer technologies including mesh technology and pressured air nebulizers. A 10% suspension was well tolerated upon repeated dose inhalation once daily for 7days at a predicted dose of 45mg/kg in rats. A single dose inhalation at a predicted dose of 22.5mg/kg resulted in maximum lung tissue concentration of 21.4μg/g tissue with a terminal half-life of 25.4h. Serum concentrations were lower, with a maximum concentration of 104ng/ml at 4h after dosing and a terminal half-life of 10.5h.The data indicate that ITRA nanosuspension represents an interesting formulation for inhaled administration in CF patients suffering from ABPA. High and long lasting lung tissue concentrations well above the minimal inhibitory concentration of Aspergillus species enable once daily administration with minimal systemic exposure.

Graphene Production With Stirred Media Mills

AbstractSince the discovery of stable graphene sheets by Novoselov und Geim in 2004 the one atom thick carbon material has been attracted great interest because of its outstanding physical, mechanical and chemical properties. Although there had been intensive research to find new ways in the preparation of single-layer graphene sheets in the last few years, especially the large-scale production of graphene still remains challenging. In this paper we present a new approach, which allows the high-yield production of graphene sheets in a simple stirred media milling process. Under mild milling conditions single- and multilayer graphene sheets have been successfully produced from commercial graphite powder in a liquid medium. During the delamination procedure, the graphite particles were stressed between the milling beads. Shear and compressive normal forces can lead under mild milling conditions, i.e. low stress energies, to a continuous mechanical peeling of graphene sheets from the graphite surface. By means of Atomic Force Microscopy a high yield of single- and multilayer graphene sheets was detected. A concentration of exfoliated sheets of 2 wt% starting from a 5 wt% suspension of coarse graphite particles could be determined after a milling time of only 3 h. This concentration is much higher than those, which were reached by most of the known chemical methods. Since stirred media milling can be realized as large-scale process, a high-yield and low-cost production of graphene flakes becomes possible at ambient temperature.

Effects of Calcination and Milling Process Conditions for Ceria Slurry on Shallow-Trench-Isolation Chemical–Mechanical Polishing Performance

To improve the performance of shallow trench isolation chemical–mechanical polishing (STI-CMP) in terms of the removal selectivity of oxide and nitride films and the formation of surface defects, we investigated the effects of the calcination and milling process conditions during ceria slurry synthesis. We have focused on the effects of particle size distribution, the large-particle size, and the dispersion stability in a ceria slurry. We determined the optimum bead size for milling and appropriate calcination temperatures in order to obtain a reasonable particle distribution, with lower numbers of fine primary particles and large, agglomerated particles, in ceria slurry. This was achieved by reducing the quantity of aggregated particles during milling and two-step calcination process generating higher-density particles. These results can be qualitatively explained by abrasive collisions occurring between the milling beads and the decarbonation of cerium carbonate through diffusion during the manufacturing process used for the ceria slurry.

Influence of ball milling parameters on blue phosphor for cathode ray tube

A series of experiments have been conducted to examine ball milling parameters, such as the size of beads, ball milling time, the ratio of beads/phosphor/water, and the material composition of the ball milling beads to optimize the milling conditions for phosphor powders. It is concluded that longer time, smaller size of Φ2 Al 2O 3 beads, and higher ratio of beads/phosphor/water = 2:1:0.5 can produce phosphor powder with higher dispersibility which in turn creates a densely packed coating of phosphor particles on the screen, a necessity for high resolution and high cathodoluminescence. When harder material with higher density are applied in the disagglomeration process or lower density beads which have undergone a longer ball milling time, the dispersion result is more effective. Nevertheless, the brightness of phosphor powder may deteriorate, a side effect which is undesirable for high quality phosphor powders. The concept of dispersibility is also proposed by evaluating the sediment volume, hardness, and ratio of water absorption.

Microhydrodynamics of stirred media milling

The milling media dynamics on micro-scale is considered. It is assumed that the turbulence energy dissipates due to media–liquid viscous friction, lubrication and partially inelastic collisions of the milling beads with each other. Both the mean velocity of the milling media oscillations and their frequency are estimated. The numerical study of the milling bead dynamics in the mixing tank is performed. The media radial stratification due to the centrifugal force is estimated by a simple model based on equilibrium of the mass fluxes caused by the centrifugal force and the turbulent dispersion.

Microhydrodynamic analysis of nanogrinding in stirred media mills

AbstractThe dynamics of the milling media in a turbulent flow is considered. The mean velocity of the milling beads is calculated on the assumption that the power spent on stirring is transferred into the energy of turbulent eddies. The energy spent on stirring dissipates as a result of media–liquid viscous friction, lubrication, and by inelastic collisions of the beads with each other. The maximum force at which the milling beads can compress particles between them is calculated by the Hertzian theory of elastic impact. The frequency of compressions for a single particle is evaluated by probabilistic analysis. A criterion of milling efficiency, based on calculating the energy spent on the plastic particle deformation, is proposed. A numerical study of the milling bead dynamics and their interactions with the particles in the mixing tank is performed. The numerical results are in qualitative agreement with the experimental data. Both the numerical and experimental analyses show that, from the perspective of hydrodynamics, an optimization of stirred media mills can be achieved by choosing the optimum size and concentration of the milling media. © 2005 American Institute of Chemical Engineers AIChE J, 2005