Mixing of pharmaceutical solids. I. Effect of particle size on mixing in cylindrical shear and V-shaped tumbling mixers

The mixing of a cohesive drug with a cohesive, non-cohesive and free-flowing excipient was studied using two types of mixers, cylindrical shear and V-shaped tumbling. Two mixing indices, one based on complete random mixing, s/σ_R, and the other based on standard specifications, s/σ_A, were used to evaluate the data. Both indices gave similar results for mixing cohesive drug with a free-flowing or non-cohesive excipient and were suitable for evaluating homogeneity. However, for mixing a cohesive drug with a cohesive excipient, s/σ_R was not a suitable index, while s/σ_A could be used. The ‘mixing margin’, a concept proposed by Hersey [3], is not a very useful tool in assessing mix-ability of powders having too large or too small particle size distributions. Because of electrostatic charging, preferential sticking of the drug to the walls of the mixer resulted in a lower mean value of the drug in the mixture. Although the mixing indices suggested that the desired mixedness was reached, it is proposed that the mean percent of the active ingredient should be checked in addition to the mixing indices for ensuring the uniformity and potency of the drug content in solid state mixtures.     

Mixing of pharmaceutical solids. IV. Effects of concentration and material properties on multicomponent mixing of cohesive powders

The results of mixing three cohesive drugs in different concentrations with a fixed concentration of a cohesive excipient were compared. The mixing index, s/σ_A, which is based on setting standard specifications was used to analyze the data. The results suggested that the homogeneity of the three drug components with similar individual concentrations (6 – 7%) approached acceptable homogeneity at a faster rate compared to the mixture where the concentration of drugs varied over a wider range (2 – 12%). However, the mixing of the three drugs in similar concentrations indicated that the rate of mixing of the drug components was dependent on the material properties, such as tensile strength of the drugs and the excipient.     

Assessing distribution of nanosmears due to mutual interaction of additives in high shear mixing of pharmaceutical blends

The objective of this study was to investigate the mutual interaction behavior of magnesium stearate (MgSt) and colloidal silica (CS) affecting their smear coating phenomena on excipient and active ingredient particles during shear mixing of pharmaceutical blends. Multiple pharmaceutical blends were processed in a v-blender under high shear condition by simultaneously varying the mixing orders of blends and concentration of additives. Uniformity of smeared patterns of additives was found to be affected by the physical and chemical nature of excipient surfaces. Although, an increase in concentration of lubricant in the formulation increased the amount of smeared lubricant coating on surrounding particles, the hydrophobic behavior was found to be predominantly dependent upon the order of mixing of constituent components of additives. More interestingly, prior mixing of the blend with MgSt followed by other components although increased the smearing area, surprisingly decreased the hydrophobic behavior, indicating a strong interaction parametric effect of MgSt with CS. For the first time, this work successfully demonstrated the limits of additive concentration in the blends governing the smearing at nanoscale. A phenomenal increase in nanosmearing area of CS compared to MgSt also prolonged the dissolution of tablets, indicating a strong interaction effect of both additives at nanoscale.     

Assessment of adhesion and autoadhesion forces between particles and surfaces. Part II. The investigation of adhesion phenomena of Salmeterol Xinafoate and lactose monohydrate particles in particle-on-particle and particle-on-surface contact

The centrifuge technique has been used to compare particle-on-particle and particle-on-surface adhesion with Salmeterol Xinafoate particles on single lactose particles or compacted lactose surfaces. The results from particle-on-particle and particle-on-surface adhesion measurements are not equivalent in terms of median adhesion force. The assessment of adhesion using either particle-on-particle or particle-on-surface systems depends on the process on which information is required: e.g. mixing problems are better investigated by applying the particle-on-particle technique, whereas surface transport problems such as powder compaction or flow can be more appropriately studied using particle-on-surface measurements. Taking autoadhesion measurements from the previous study into account, adhesion and autoadhesion forces were found to allow the prediction and choice of mixture components for powder blends. The results suggest that the homogeneity of such a powder blend depends both on thermodynamic properties and on the adhesion and autoadhesion properties of the single components.     

Assembly of uniform photoluminescent microcomposites using a novel micro‐fluidic‐jet‐spray‐dryer

Generation of uniform micro‐particles containing (i) pure lactose; (ii) silica nanoparticles and lactose; (iii) silica nanoparticles/lactose doped with Eu(III) have been successfully achieved using a novel spray dryer with a uniquely designed microfluidic aerosol nozzle as the monodisperse droplet generator. Here we investigate the impacts of precursor compositions and concentrations, as well as the drying temperature profile on particle size, morphology, and surface element distribution. Distinct morphologies are observed with different precursor compositions, ranging from smooth spherical lactose microparticles to the buckled shape for composites containing silica nanoparticles. The formation of such morphology is qualitatively interpreted by using Peclet number, indicating that the presence of the suspended silica nanoparticles facilitates shell formation at the early stage of the drying process. As the drying continue, such shell is subject to buckling, induced by the capillary force due to the lower mechanical integrity inside the droplet. Post calcination, transmission electron micrographs of Eu(III)/silica nanoparticles/lactose microcomposites confirm the formation of nano‐sized Eu₂O₃ homogeneously embedded on the silica shell. Photoluminescence spectra of these particles indicate that enhancement of photoluminescence intensity is directly related to the europium loading, which could be adjusted from the precursor composition. This work demonstrates a scalable route to assemble relatively complex composites with uniform properties, without extensive conjugation or purification steps commonly required in wet chemistry‐based processes. © 2011 American Institute of Chemical Engineers AIChE J, 2011     

The relationship between particulate properties of carrier materials and the adhesion force of drug particles in interactive powder mixtures

The influence of particle size, shape, and particle surface roughness of lactose monohydrate carrier particles on the adhesion properties of drug particles in interactive powder mixtures similar in quality of a commercial product (Serevent Diskhaler^®) has been investigated. None of the ten lactose monohydrate batches tested was found to be similar in terms of particle size. To obtain more information about particle shape and surface roughness, mathematical analysis was undertaken to structure the data. The lactose monohydrate batches could be split into four different types of particle shape. In terms of particle surface roughness, as measured by a laser profilometer, three different roughness categories were identified. Two sets of mixtures were prepared to relate the physical properties of the lactose monohydrate particles to the adhesion properties of the drug formulations: (a) constant mixing time and speed (25 min, 42 rpm), and (b) optimal mixing time (speed 42 rpm) to match the adhesion properties of the Serevent Diskhaler^®. All ten lactose monohydrate batches provided different adhesion properties under test condition (a) and the optimum mixing time [test condition (b)] was also different for each batch. Multivariate data analysis showed that the adhesion force between drug and lactose monohydrate increases with a decrease in particle size and for more irregularly shaped, elongated carrier particles. The effect of surface roughness could only be qualitatively assessed and thus no definitive conclusions can be drawn to judge whether adhesion will increase or decrease as surface roughness changes.     

Polymer powders mixing part II: Multi-component mixing dynamics using RGB color analysis

In this work, the mixing quality of a multi-component blend of particles is determined using Multivariate Image Analysis of RGB images combined with the Grey Level Co-occurrence Matrix (GLCM) texture analysis. The mixing dynamics and flow behavior are studied in terms of mixing homogeneity and time to achieve equilibrium for binary, ternary and quaternary mixtures of equal size particles. The parameters studied are rotational speed, filling ratio, initial powder composition and particle sizes. Using the experimental data in the rolling regime, a second order model is proposed to predict the mixing curve as a function of time.     

Role of some technological parameters during carburizing titanium dioxide

The influence of technological parameters is followed during the carbothermal synthesis of titanium carbide from the dioxide. The carbon grain size, the homogeneity of the carbon/oxide mixtures and the ventilation of the powders' beds are the most important conditions for a rapid reaction. The oxide grain size, the mixing method and the compactness of the mixture has no influence, or very little. These results are explained by the carburizing mechanism where the Boudouard's reaction: C+CO₂→2CO plays a central role. This reaction is more rapid when fine carbon is used and when the carbon monoxide is eliminated as soon as formed. These conditions are those required for a complete synthesis of the carbide by: TiO₂+3C→TiC+2CO for mixtures having the stoichiometric composition.     

Aqueous re-dispersibility characterization of spray-dried hollow spherical silica nano-aggregates

Hollow spherical aggregates of biocompatible silica nanoparticles are produced by the spray drying technique to facilitate the delivery of the nanoparticles to the lung for potential drug delivery applications. The large geometric size (d_G > 5 µm) and the low density (ρ_eff ≈ 0.3 g/cm³) of the nano-aggregates are specifically formulated to achieve high aerosolization efficiency and an effective lung deposition. The nano-aggregates must readily re-disperse into the primary nanoparticles in an aqueous medium for the nanoparticles to perform their intended therapeutic functions. An aqueous re-dispersibility characterization technique based on the turbidity level measurement is developed for this purpose. A water-soluble excipient (i.e. mannitol), which forms “excipient bridges” interconnecting the nanoparticles, is included in the spray-drying formulation to produce readily re-dispersible nano-aggregates. The nano-aggregate aqueous re-dispersibility depends on (1) the silica: mannitol concentration ratio and (2) the degree of hollowness, where nano-aggregates with a higher shell thickness to particle radius ratio exhibit weaker re-dispersibility due to the poor particle wetting. The spray-drying condition and the silica: mannitol ratio, which lead to the production of highly re-dispersible nano-aggregates having the desired morphology, are determined. The promising results signify the potential application of hollow spherical silica nano-aggregates as an inhaled drug delivery vehicle.     

Influence of solvent and nanoparticles on the morphology and gas separation properties of copolyimide membranes

In this study, the effect of solvent type and nanoparticles of silica and zeolite 4A on the gas separation properties of polyimide (PI) membranes were investigated. Gas separation of the membranes based on pure solvents of dimethylformamide (DMF), n-methyl-2-pirrolidone (NMP), dimethylacetamide (DMAc), and dimethylsulfoxide (DMSO) were studied. The prepared PI membranes using DMAc and DMSO showed the highest selectivity and permeability, respectively. In this regard, the influence of their mixing on transport properties of the PI was evaluated. The prepared membrane using the mixture of DMSO/DMAc with the volume ratio of 1:3 showed the best gas separation performance in comparison to the Robeson's upper bound. Incorporation of 20 wt% of silica and zeolite 4A nanoparticles into the PI membrane indicated that the selectivity of CO₂/CH₄ increased from 39.4 to 57.6 and 68.5, respectively. Besides, gas transport properties of the PI-based mixed matrix membranes were satisfactory predicted by modified Maxwell model. Furthermore, characteristic parameters of the encapsulated particles by interfacial layer were determined.     

Phase behavior of water-insoluble simvastatin drug in supercritical mixtures of chlorodifluoromethane and carbon dioxide

Phase behavior data are presented for simvastatin, a water-insoluble drug, in supercritical solvent mixtures of chlorodifluoromethane (CHClF₂) and carbon dioxide (CO₂). The solubilities of the simvastatin drug in the solvent mixtures of CHClF₂ and CO₂ were determined by measuring the cloud point pressures using a variable-volume view cell apparatus as functions of temperature, solvent composition, and amount of the drug loaded into the solution. The cloud point pressure increased with increasing the system temperature. As the CHClF₂ composition in the solvent mixture increased, the cloud point pressure at a fixed temperature decreased. Addition of CHClF₂ to CO₂ caused an increase of the dissolving power of the mixed solvent for the simvastatin drug due to the increase of the solvent polarity. CHClF₂ acted as a solvent for simvastatin, while CO₂ acted as an anti-solvent. The cloud point pressure increased as the amount of the simvastatin drug in the solvent mixture increased. Consequently, the solubility of the simvastatin drug in the solvent mixture of CHClF₂ and CO₂ decreased with increasing the CO₂ content in the solvent mixture as well as with increasing the system temperature.     

Structural and transport properties of polydimethylsiloxane based polyurethane/silica particles mixed matrix membranes for gas separation

Mixed matrix membranes of synthesized polyurethane (PU) based on toluene diisocyanate (TDI), polydimethylsiloxane (PDMS) and polytetramethylene glycol (PTMG) with polyvinyl alcohol based polar silica particles were prepared by solution casting technique. The homogeneity and thermal properties of the prepared PDMS-PU/silica membranes were characterized using scanning electron microscope (SEM), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). The SEM micrographs confirmed the distribution of silica particles in the polymer matrix without agglomerations. Gas permeation properties of membranes with different silica contents were studied for pure CO₂, CH₄, O₂, He and N₂ gases. The obtained results indicated the permeability of the condensable and polar CO₂ gas was enhanced whereas permeability of other gases decreased upon increasing the silica content of the mixed matrix membranes. The permeability of CO₂ and its selectivity over N₂ was increased from 68.4 Barrer and 22 in pure PDMS-PU to 96.7 Barrer and 64.4 in the mixed matrix membranes containing 10 wt% of the silica particles.     

A comparison of mechanochemical methods for the synthesis of nanoparticulate nickel oxide

In this study, mechanochemical processing has been investigated as a means of manufacturing nanoparticulate powders of NiO. Two different reactant mixtures were examined and compared. The first system was based on mechanical milling of Ni(OH)₂ with NaCl diluent. Milling of this reactant mixture resulted in disintegration of the Ni(OH)₂ precursor and its progressive dispersal into the NaCl matrix. Subsequent heat treatment and washing yielded a nanocrystalline powder of NiO, which contained a significant proportion of particles with an unusual platelike morphology. The second system that was examined was based on mechanically activated reaction of NiCl₂ + Na₂CO₃ + 4NaCl. Milling resulted in mixing and microstructural refinement of the reactant mixture. Chemical reaction during post-milling heat treatment resulted in the formation of a powder consisting of nanocrystalline NiO grains embedded in NaCl. Removal of the NaCl by washing with water yielded NiO nanoparticles with an equiaxed particle shape.     

硅溶胶硅酸钾混合物微量热法研究

在25.0℃及搅拌条件下,采用等温热导微量热法研究了硅溶胶与硅酸钾的混合过程。结果表明,硅溶胶与硅酸钾混合,立刻发生了SiO2溶解和复杂的化学反应,并产生了完全不同于硅溶胶和硅酸钾的SiO2胶体粒子和化学成分以及热效应,热效应受硅溶胶所占的相对重量百分比的影响。其反应的特征是硅溶胶和硅酸钾的反应级数从低到高时刻都在快速不断交替变化;随着硅溶胶所占比例的提高,热谱曲线峰高、硅溶胶与硅酸钾的混合化学反应完全的曲线总面积(总焓变QT)和热力学焓变(ΔH)数值都表现出不断增大的趋势。     

Particle design for dry powder inhalation via binderless powder coating by pressure swing granulation

Novel formulation for dry powder inhalation (DPI) particularly appropriate for very dilute drug concentration was developed based on the pressure swing granulation (PSG) technology. PSG was applied to the granulation of excipient lactose particles and to the coating/dusting of lactose granules with fine model drug particles. Size distribution and granule strength as well as the dispersibility of the drug particles for DPI were found to be successful for practical use. The drug particles dispersed into the respirable aerodynamic size range of 1-7 μm from the E-haler® was 53.9% for 1% coating/dusting (i.e. 1% drug in product granules) and 46.3% for 2%. E-haler® was capable of emitting 89.8% and 83.2% of drug particles charged for cases for 1% and 2% coatings, respectively.     

Aqueous re-dispersibility of spray-dried antibiotic-loaded polycaprolactone nanoparticle aggregates for inhaled anti-biofilm therapy

Antibiotic-loaded nanoparticles have emerged as one of the most promising inhaled antibiotic formulations for treating bacterial biofilm infections in the lung. To effectively deliver the nanoparticles by inhalation, the nanoparticles are transformed into micro-scale dry-powder structures in the form of nanoparticle aggregates that can be easily aerosolized off the inhaler. Moreover, the nano-aggregates must readily reconstitute into the primary nanoparticles to be therapeutically effective upon their deposition in the lung. In the present work, respirable dry-powder aggregates of antibiotic-loaded polycaprolactone nanoparticles are produced by the spray-drying technique. The effects of the excipient formulation and drying temperature on the aqueous re-dispersibility, morphology, production yield, and flowability of the nano-aggregates are investigated. Three excipients commonly used in inhaled dosage formulation (i.e. mannitol, lactose, and leucine) and their combinations are examined. The results indicate that the nano-aggregate morphology is not greatly influenced by the excipient formulation, where low-density spherical nano-aggregates are consistently produced. The inclusion of hydrophobic leucine is mandatory to produce free-flowing particles, which however leads to decreased production yields. The aqueous re-dispersibility is strongly dependent on the excipient formulation, where only lactose-leucine formulations at particular nanoparticle to excipient concentration ratios are capable of producing re-dispersible nano-aggregates.     

Hot melt mixing and foaming of soluplus® and indomethacin

The hot melt mixing (HMM) process was used to dissolve 30 wt% of a model drug, indomethacin (INM), in Soluplus® a water soluble polymer excipient. Comprehensive characterization of the HMM‐prepared samples, using differential scanning calorimetry, X‐ray diffraction, Fourier Transform Infrared spectroscopy, and optical microscopy, strongly suggests that INM was in amorphous state, forming a solid solution with the polymer. Furthermore, to understand the impact of foaming on INM's release profile, the HMM product was foamed in a batch process using supercritical carbon dioxide (CO₂). Dissolution tests of HMM and reference samples were conducted in aqueous solutions with pH 7.4 and 1.2. In all cases INM's release showed strong pH‐dependency; faster release and a greater amount of INM was released at pH 7.4 than at pH 1.2. For pure INM and the physical mixture, the drug's ionizable character results in the observed pH‐dependency. While for the HMM samples it is also a consequence of theformation of hydrogen bonds between Soluplus® and INM which hinder polymer dissolution at pH 1.2. It was observed that the release rate of INM from different sample types at pH 7.4 decreased in the following sequence: foamed HMM > unfoamed HMM > crystalline INM > physical mixture. POLYM. ENG. SCI., 2012. © 2012 Society of Plastics Engineers     

A perspective on vibration-induced size segregation of granular materials

Segregation of particulate mixtures is a problem of great consequence in industries involved with the handling and processing of granular materials in which homogeneity is generally required. While there are several factors that may be responsible for segregation in bulk solids, it is well accepted that nonuniformity in particle size is a fundamental contributor. When the granular material is exposed to vibrations, the question of whether or not convection is an essential ingredient for size segregation is addressed by distinguishing between the situation where vibrations are not sufficiently energetic to promote a mean flow of the bulk solid, and those cases where a convective flow does occur. Based on experimental and simulation results in the literature, as well as dynamical systems analysis of a recent model of a binary granular mixture, it is proposed that “void-filling” beneath large particles is a universal mechanism promoting segregation, while convection essentially provides a means of mixing enhancement.     

Reinforcing effect of silica on the properties of styrene butadiene rubber–reclaim rubber blend system

Incorporation of silica into styrene butadiene rubber (SBR)–reclaim rubber (RR) blend system was carried out by sol–gel technique and conventional method. A well known silica coupling agent bis(3‐triethoxysilyl propyl) tetrasulfide was found to affect the curing characteristics and mechanical properties of SBR/RR vulcanizate. Here, the effect of RR on silica reinforcement was studied for different SBR/RR blend system. Silica incorporation by conventional mechanical mixing in absence of TESPT showed a much higher tensile properties than that of silica incorporated by the in situ sol–gel reaction of tetraethoxy silane both in presence and absence of TESPT. Studies of equilibrium swelling in a hydrocarbon solvent were also carried out. ATR study indicates that RR forms bond with silica particles due to the presence of active functional site on RR. The amount of silica incorporated by sol–gel reaction was determined through thermogravimetric analysis (TGA). Scanning electron microscopy (SEM) studies further indicate the coherency and homogeneity in the silica filled SBR/RR vulcanizate. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 99: 957–968, 2006     

Complex formation of Ibuprofen and β-Cyclodextrin by controlled particle deposition (CPD) using SC-CO2

Modern therapeutically used drugs are often lipophilic compounds. To reach the target structures, the drugs must be dissolved in physiological fluids and absorbed through entrance ports. In modern medicine, due to costs, convenience and compliance, oral application of solid forms is the preferential way. Since the bioavailability of orally applied drugs depends on the velocity of dissolution and absorption, methods to increase the dissolution of the lipophilic substances are often necessary to obtain significant blood levels. A well suitable way is the reduction of particle size to increase the dissolution velocity. However submicron particles are very difficult to be included in solid dosage forms. To overcome this, the controlled particle deposition (CPD) process was developed. The key idea behind CPD is to dissolve the drug of interest in supercritical CO₂, followed by permeation of the supercritical solution into the pores of the carrier and precipitation of the drug inside the pores. Thus, the attractive feature of CPD is the possibility to produce solvent-free, drug loaded carrier particles in a single processing step. In order to ensure that both, the drug and the carrier, exist as a solid under the conditions of study, the phase behaviour of RS(±)-Ibuprofen and of β-Cyclodextrin in the presence of CO₂ was investigated prior to the inclusion experiments. The results of the present investigations show, that an almost complete inclusion of RS(±)-Ibuprofen in β-Cyclodextrin at the solid state could be achieved. In addition, the dissolution rate of the complex formed by CPD was found to be significantly higher than that of untreated RS(±)-Ibuprofen and its physical mixture with β-Cyclodextrin.