Novel aspects of wet milling for the production of microsuspensions and nanosuspensions of poorly water-soluble drugs

Micronization and nanoparticle production of poorly water-soluble drugs was investigated using single wet milling equipment operating in the attritor and stirred media modes. The drug particles in the median size range of 0.2–2?µm were prepared by changing the milling mode and operating conditions of a Micros mill with a purpose of elucidating the dynamics of the wet milling process. It was determined that particle breakage due to mechanical stresses and aggregation due to insufficient stabilization are two competing mechanisms which together control the wet milling dynamics of the poorly water-soluble drugs. The study in the attritor mode using four different classes of stabilizers with six drugs indicated that steric stabilization worked better than electrostatic stabilization for the drugs studied. In addition, the existence of different minimum polymer concentrations for the stabilization of microsuspensions and nanosuspensions was indicated. The major role of a non-ionic polymer during the production of fine particles is its stabilization action through steric effects, and no experimental evidence was found to support the so-called Rehbinder effect. Periodic addition of the polymer as opposed to the addition of the polymer at the start of milling process was introduced as a novel processing method. This novel method of polymer addition provided effective stabilization and breakage of drug particles leading to a narrower and finer particle size distribution. Alternatively, it may allow shorter processing time and lower overall power consumption of the milling process for a desired particle size.     

Continuous production of drug nanoparticle suspensions via wet stirred media milling: a fresh look at the Rehbinder effect

Nanoparticles of BCS Class II drugs are produced in wet stirred media mills operating in batch or recirculation mode with the goal of resolving the poor water-solubility issue. Scant information is available regarding the continuous production of drug nanoparticles via wet media milling. Griseofulvin and Naproxen were milled in both recirculation mode and multi-pass continuous mode to study the breakage dynamics and to determine the effects of suspension flow rate. The evolution of the median particle size was measured and described by an empirical breakage model. We found that these two operation modes could produce drug nanosuspensions with similar particle size distributions (PSDs). A reduced suspension flow rate slowed the breakage rate and led to a wider PSD and more differentiation between the two operation modes. The latter part of this study focused on the roles of stabilizers (hydroxypropyl cellulose and sodium lauryl sulfate) and elucidation of the so-called Rehbinder effect (reduction in particle strength due to adsorbed stabilizers such as polymers and surfactants). Milling the drugs in the absence of the stabilizers produced primary nanoparticles and their aggregates, while milling with the stabilizers produced smaller primary nanoparticles with minimal aggregation. Using laser diffraction, BET nitrogen adsorption, scanning electron microscopy imaging, and a microhydrodynamic analysis of milling, this study, for the first time, provides sufficient evidence for the existence of the Rehbinder effect during the milling of drugs. Not only do the polymers and surfactants allow proper stabilization of the nanoparticles in the suspensions, but they also do facilitate drug particle breakage.     

Enhanced recovery and dissolution of griseofulvin nanoparticles from surfactant-free nanocomposite microparticles incorporating wet-milled swellable dispersants

Nanocomposite microparticles (NCMPs) incorporating drug nanoparticles and wet-milled swellable dispersant particles were investigated as a surfactant-free drug delivery vehicle with the goal of enhancing the nanoparticle recovery and dissolution rate of poorly water-soluble drugs. Superdisintegrants were used as inexpensive, model, swellable dispersant particles by incorporating them into NCMP structure with or without wet-stirred media milling along with the drug. Suspensions of griseofulvin (GF, model drug) along with various dispersants produced by wet-milling were coated onto Pharmatose® to prepare NCMPs in a fluidized bed process. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as base-line stabilizer/dispersant during milling. Croscarmellose sodium (CCS, superdisintegrant) and Mannitol were used as additional dispersants to prepare surfactant-free NCMPs. Nanoparticle recovery during redispersion and dissolution of the various GF-laden NCMPs were examined. Suspensions prepared by co-milling GF/HPC/CCS or milling GF/HPC/SDS were stable after 30 h of storage. After drying, due to its extensive swelling capacity, incorporation of wet-milled CCS in the NCMPs caused effective breakage of the NCMP structure and bursting of nanoparticle clusters, ultimately leading to fast recovery of the GF nanoparticles. Optimized wet co-milling and incorporation of CCS in NCMP structure led to superior dispersant performance over incorporation of unmilled CCS or physically mixed unmilled CCS with NCMPs. The enhanced redispersion correlated well with the fast GF dissolution from the NCMPs containing either CCS particles or SDS. Overall, swellable dispersant (CCS) particles, preferably in multimodal size distribution, enable a surfactant-free formulation for fast recovery/dissolution of the GF nanoparticles.     

搅拌球磨制备亚微米晶粒Ti(C,N)基金属陶瓷

用搅拌球磨方法制备了亚微米TiC-TiN-WC-Mo-Ni-C金属陶瓷复合粉，并烧结成亚微米晶粒Ti(C,N）基金属陶瓷；研究了原始粉末粒度，磨球大小，球磨时间对复合粉粒度的影响，研究了球磨过程中氧和铁元素对粉末的污染情况；并对烧结合金的组织，性能进行了分析，表明亚微米晶粒Ti(C,N）金属陶瓷的性能优良。     

Spray drying of drug-swellable dispersant suspensions for preparation of fast-dissolving,high drug-loaded,surfactant-free nanocomposites

Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles (NCMPs). Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete recovery and slow dissolution. The aim of this study is to investigate the impact of various classes of dispersants on drug dissolution from drug NCMPs, with the ultimate goal of enhancing the bioavailability of poorly water-soluble drugs via high drug nanoparticle loaded, surfactant-free NCMPs. Precursor suspensions of griseofulvin (GF, model drug) nanoparticles in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form the NCMPs. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as a base-line stabilizer/dispersant during milling. Two swellable crosslinked polymers, croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a conventional soluble matrix former, Mannitol, were used in addition to HPC. Besides being used as-received, CCS was also wet co-milled with GF for two different durations to examine the impact of CCS particle size. Laser diffraction, scanning electron microscopy, powder X-ray diffraction (XRD), UV spectroscopy, NCMP redispersion and dissolution tests were used for characterization. The results show that incorporation of CCS/SSG, preferably wet-milled to a wide particle size distribution, into the spray-dried NCMPs resulted in fast release and dispersion of drug nanoparticle clusters. The swellable dispersants were superior to Mannitol in dissolution enhancement, and could achieve fast release comparable to SDS, demonstrating the feasibility of spray drying to prepare high drug-loaded, surfactant-free nanocomposites.     

pH-independent dissolution enhancement for multiple poorly water-soluble drugs by nano-sized solid dispersions based on hydrophobic–hydrophilic conjugates

The objective of this study was to achieve an optimal formulation of hydrophilic–hydrophobic conjugates for nano-sized solid dispersions (SDs) with enhanced dissolution of multiple drugs in different gastrointestinal (GI) tract environments. A new conjugate powder with an optimized process was used to fabricate SDs that contained three poorly water-soluble drugs that were also poorly soluble in different dissolution media. The self-assembled nanoparticle formation, drug crystallinity and SD molecular interactions were investigated by measuring the particle size during dissolution testing and physicochemical property analysis (powder X-ray diffraction and Fourier transform infrared spectroscopy). Drug release studies indicated that SD containing conjugated powder significantly improved the dissolution rates of these poorly water-soluble drugs in the GI tract. In addition, particle size analysis showed nano-sized particles in the dissolution media in the early stage with a tendency to reduce smaller particles over time. Physicochemical characterizations demonstrated almost amorphous drug states and hydrogen bonding interactions between the drugs and conjugates in the SD. This study optimized a promising material for SD, and the material was shown to have a promising performance under various pH medium conditions with poorly water-soluble drugs.     

Mechanomaking of nanostructured hypereutectic white irons: powder fabrication

Abstract

White irons containing 5·7 wt-%C were produced by room temperature, high energy milling from iron and carbon elemental powders. Both iron and cementite phases have crystal sizes of less than 10 nm in the powders which have fully dense particles of 50 μm mean size. The gas content is 0·5 wt-% and the powder is stable up to 550°C. Above 550°C decomposition of cementite occurs, involving a decrease in combined carbon content from 5·7 to 3·5 wt-% (annealing at 1050°C). The crystal growth kinetics has two temperature regions with lower activation energies in the high temperature (above 800°C) region. Crystal sizes still below 100 nm were observed for annealing up to 800°C. The size distribution in mechanosynthesised powders was modified by tumbling (dry) and attritor (wet) milling down to mean sizes of 4 μm and 1·4 μm respectively. Whereas tumbling milling does not alter the properties of MS powders, wet attritor milling produced higher gas content (7 wt-%) and much decreased thermal stability. Mechanosynthesised and tumbling milled powders can be degassed prior to consolidation, while wet attritor milled ones cannot.     

DEM Simulation of Particle Comminutionin Jet Milling

A combined discrete element method (DEM) and CFD numerical model was developed to simulate particle comminution in a jet mill. The DEM was used to simulate the motion of the particles in the gas flow. For this, the compressible Reynolds Averaged Navier-Stokes (RANS) equations were used to describe the gas flow field inside a given size's jet mill. Ghadiri's models for breakage and chipping were implemented in the simulation to define the reduction of the particle's size during jet milling. The size distributions of the particles after grinding were obtained numerically. The prediction of the numerical simulation for the median particle size d 50 after grinding was qualitative compared with experimental results for the different operating conditions (i.e., feed rate, angle of grinding nozzles, volumetric rate of grinding air, etc.). The comparison shows good agreement with the experimental observation. The results shows that the feed rate, angle of feeding nozzle, and feeding air's flow rate have more influence on the breakage and chipping of particles in jet milling. In addition, a parametric study was performed to obtain the desired operation conditions.     

Optimization of aqueous microgrinding processes for fibrous plant materials

Fibrous plant-based materials are characterized by inhomogeneous structure and composition, which further evolve during wet grinding processes and affect the surface functionality of micronized particles. Therefore, the performance of aqueous microgrinding operations in stirred media mills can be optimized by investigating the interaction between process conditions and material properties of heterogeneous fibrous plant materials.In this experimental study it is shown how particle size reduction, tendency of re-agglomeration and stability of the suspension of micronized particles are driven by the specific energy input, residence time, temperature and presence of surfactants during the milling process. A structured experimental approach is described to optimize the achievable particle size reduction, expressed by the top cut diameter d_90,3. It was found that the applied wet milling process determines the stability of particle suspensions throughout further downstream processing, making the grinding process the core unit operation with respect to the performance and formulation of food products containing micronized particles.     

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.     

DEM Simulation of Particle Comminutionin Jet Milling

A combined discrete element method (DEM) and CFD numerical model was developed to simulate particle comminution in a jet mill. The DEM was used to simulate the motion of the particles in the gas flow. For this, the compressible Reynolds Averaged Navier-Stokes (RANS) equations were used to describe the gas flow field inside a given size's jet mill. Ghadiri's models for breakage and chipping were implemented in the simulation to define the reduction of the particle's size during jet milling. The size distributions of the particles after grinding were obtained numerically. The prediction of the numerical simulation for the median particle size d 50 after grinding was qualitative compared with experimental results for the different operating conditions (i.e., feed rate, angle of grinding nozzles, volumetric rate of grinding air, etc.). The comparison shows good agreement with the experimental observation. The results shows that the feed rate, angle of feeding nozzle, and feeding air's flow rate have more influence on the breakage and chipping of particles in jet milling. In addition, a parametric study was performed to obtain the desired operation conditions.     

Fracture mechanisms and particle shape formation during size reduction of a model food material

The importance of particle shape to powder properties warrants examination of the effect of size reduction on particle shape formation. In this study, a model food material (dried gelatinized starch) was comminuted in an impact breakage gun, a hammer mill (with and without a screen) and in a blender. After sieving, particle shape at selected sizes was assessed as deviation from sphericity. Generally, particle shapes were elongated at smaller size, except for those produced by unscreened hammer milling. Particle shapes were unaffected by impact velocity in the gun, but were rounded by increased milling. Fractography was used to demonstrate how elongated particles formed. During fracture, fracture fronts were disturbed by air holes in the material, creating cleavage steps. Subsequent undercutting of the steps as fracture planes spread released the elongated particles. Such particle formation mechanisms may account for anomalous size distribution results at early stages of grinding. Particle shape differences between mills and single impact breakage were ascribed to particle selection mechanisms surmised to be operating in the mill. Both material properties and the size reduction method were shown to affect particle shape, thus fracture progress in a given material should be studied if particles of specific shapes are to be produced by comminution.     

Production of Nano Talc Material and Its Applicability as Filler in Polymeric Nanocomposites

In the present work, focus is on the production of nano-sized talc particles in a stirred ball mill and their nano talc particles incorporated in the polyamide-6 polymer matrix to form polyamide/talc nanocomposite. The results show that enhancement in the polyamide/talc nanocomposite strength properties such as flexural and tensile strength. The production of nano talc particles is difficult process in wet grinding system; however, the minimum achievable particle size is strongly influenced by the suspension stability. Hence, prior to the wet milling, it is imperative to conduct the ζ potential measurements on the talc sample in order to find out at which pH range a strong repulsive force between the given talc sample particles exists. The desired electrostatic repulsion force is maintained by the adjustment of pH 11 in wet milling. The experiments are conducted at pH 11 conditions which were maintained constant throughout the experiments and nanosized talc particles are obtained consequently.     

Multi-sensor inline measurements of crystal size and shape distributions during high shear wet milling of crystal slurries

Size and shape distributions are among critical quality attributes of particulate products and their inline measurement is crucial for monitoring and control of particle manufacturing processes. This requires advanced tools that can estimate particle size and shape distributions from multi-sensor data captured in situ across various processing steps.In this work, we study changes in size and shape distributions, as well as number of particles during high shear wet milling, which is increasingly being employed for size reduction in crystalline slurries in pharmaceutical processing. Saturated suspensions of benzoic acid, paracetamol and metformin hydrochloride were used in this study. We employ our recently developed tools for estimating particle aspect ratio and particle size distributions from chord length distribution (CLD) measurements and imaging. We also compare estimated particle size distributions from CLD and imaging with corresponding estimates from offline instruments.The results show that these tools are capable of quantitatively capturing changes in particle sizes and shape during wet milling inline. This is the first time that such a capability has been reported in the literature. The ability to quantitatively monitor particle size and shape distributions in real time will enable development of more realistic and accurate population balance models of wet milling and crystallisation, and aid more efficient control of crystallisation processes.     

A quality-by-design study to develop Nifedipine nanosuspension: examining the relative impact of formulation variables,wet media milling process parameters and excipient variability on drug product quality attributes

Abstract

Wet milling is a multifunctional and the most common method to prepare a drug nanosuspension for improving the bioavailability of poorly water soluble drugs. A suitable way of preparing a high drug-loaded nifedipine nanosuspension using wet stirred media milling was investigated in the present study. Nifedipine, a poorly water soluble drug, was selected as a model drug to enhance its dissolution rate and oral bioavailability by preparing an appropriate crystalline nanosuspension. Process parameters, such as milling media volume, milling speed and milling time, were optimized using the one variable at a time (OVAT) approach. A similar method was used to select an appropriate polymeric stabilizer and a surfactant from different categories of polymeric stabilizers (HPC SL, HPC SSL Soluplus®, Kollidon^® VA 64 and HPMC E 15) and surfactants (Poloxamer 407, Kolliphor TPGS and Docusate sodium). A systematic optimization of critical formulation parameters (such as drug concentration, polymer concentration and surfactant concentration) was performed with the aid of the Box-Behnken design. Mean particle size, polydispersity index and zeta potential as critical quality attributes (CQAs) were selected in the design for the evaluation and optimization of the formulation and validation of the improved product. The nifedipine nanosuspension that was prepared using HPC and poloxamer 407 was found to be most stable with the lowest mean particle size as compared with the formulations prepared using other polymeric stabilizers and surfactants. The optimized formulation was further spray-dried and characterized using the Fourier Transform Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), polarized light microscopy (PLM) and in-vitro dissolution study. Results have shown no interaction between the drug particles and stabilizers, nor a reduction in the crystallinity of drug, nor an increase in the saturation solubility and rapid in vitro dissolution as compared with pure nifedipine crystals. Thus, the current study supports the suitability of the wet stirred media milling method and a combination of HPC SSL and poloxamer 407 as stabilizers for the preparation of nifedipine nanosuspension.     

Experimental investigation of the impact breakage characteristics between grinding media and iron ore particle in ball mills

The particle breakage of the ball mill is an extremely complicated breakage process. It is difficult to quantify and describe the particle breakage behavior. In this study, a drop-ball experimental setup was developed to demonstrate the impact process of grinding media on ore particles. The quantitative analysis of the effects of particle size, impact energy, and the number of impacts on particle breakage behavior was performed separately. The results show that the breakage probability model and product size distribution model used can be excellent to predict the particle breakage behavior for the single-particle impact experiments. The breakage probability of particles is highly sensitive to impact energy and particle size, exponentially increasing with the increase of impact energy. In addition, the application of the t_n-t₁₀ relationship provides a convenient means to characterize and predict the particle size distribution. In multi-layer particle impact experiments, the captured thickness of ore particles is approximately 2 layers during the crushing process. The broken mass of iron ore particles is proportional to the number of concessive impacts at different impact energies. This paper provides theoretical and methodological support for the evaluation and optimization of particle breakage in ball mills.     

Preparation of concentrated stable fenofibrate suspensions via liquid antisolvent precipitation

A major challenge in achieving size stability for relatively high concentration of fine particles from poorly water-soluble drug fenofibrate (FNB) is addressed through T-mixing based liquid antisolvent precipitation in the presence of ultrasonication and judicious use of stabilizers. Multiple stabilizers were screened in a batch mode prior to their continuous formation via T-mixing. In both cases, the stable suspensions maintained their size after 2 days of storage at room temperature, with the smallest particle size of d₅₀: ～1.2?µm was achieved through a combination of HPMC with SDS or PF-68. The influence of processing parameters, such as sonication energy, sonication probe insert depth and solvent/antisolvent flow rate, on the particle size distribution (PSD) in T-mixing were investigated, to identify optimum processing conditions. Optimal operating and formulation conditions also allowed increase in the drug loading from 0.32% to 4% (w/v), while keeping the median size 2.5?µm. Interestingly, the primary particles observed in the SEM were spherical and under 100?nm in diameter, indicating agglomeration. It was shown that the stabilized particles could be centrifuged and did not show size growth upon resuspension, allowing for increase in the drug loading up to 27% (w/v), which is a significant novel outcome.     

Low-energy bead-milling dispersions of rod-type titania nanoparticles and their optical properties

The low-energy dispersion of nanomaterials in the bead-milling process is examined. The effect of milling parameters including bead size, rotation speed, and milling time on the dispersibility of fragile rod-type titanium dioxide nanoparticles is investigated. From experimental data obtained for the morphological, optical, and crystalline properties of dispersed nanoparticles, an unbroken primary particle dispersion in colloidal suspension was obtained only by conducting the bead-milling process using the optimum milling parameters. Deviation from the optimum conditions (i.e., higher rotation speed and larger bead size) causes re-agglomeration phenomena, produces smaller and ellipsoidal particles, and worsens crystallinity and physicochemical properties, especially the refractive index, of the dispersed nanoparticles. We also found that decreases in refractive index induced by the milling process are related to collisions forming broken particles and the amorphous phase on the surface of the particles. In addition, the present low-energy dispersion method is prospective for industrial applications, confirming almost no impurity (from breakage of the beads) was apparent in the final product.     

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?相似文献   

The synthesis and characterization of polymer coated iron oxide microspheres

For biomedical applications drug carrying polymers are coated around magnetic iron oxide particles to form microspheres. In the present study, the iron oxide powder was ball milled. Microspheres were then synthesized by solvent evaporation, resulting in iron oxide particles encapsulated in a polymer and drug coating. Various parameters, such as the duration of milling and agitation speed as well as the polymer concentration were varied. A milling time of 72 h was found to yield a small size and narrow size distribution of particles; the average particle size was about 600 nm. Measurements of the change in grain size and the magnetic properties of the powder with milling time were performed. It was determined that the size of the microspheres was not sensitive to the initial particle size, but it could be decreased by variation of agitation speed or polymer concentration. The agitation speed and polymer concentration of 400 rpm and 0.04 g poly(l-lactic acid) in 8 g dicholoromethane, respectively, was found to yield small, spherical microspheres with a narrow size distribution. The surface morphology and magnetic properties of the microspheres was also analyzed.