Preparation and Evaluation of High Drug Content Particles

Abstract

To determine how to prepare high drug content particles using a Wurster fluidized bed to determine realizing the miniaturization of solid dosage forms, aspirin was selected as the model drug and granulated without any additive. In this study, the emphasis was on evaluating the key operation factors of airflow rate and atomizing flow volume. The properties of the resulting particles, such as the average diameter, particle strength, appearance, and compressibility using different airflow rates and atomizing flow volumes, were investigated. Furthermore, detailed optimization of the operation conditions was conducted by artificial neural network (ANN) analysis. The relationship between the controlling factors (powder supplied, concentration of spray liquid, the amount of consumed spray liquid, and spray rate) and the response variables (product yield, median diameter, angle of repose, and degradation of aspirin) was investigated after evaluating the airflow rate and atomizing flow volume effects. The resulting granules under optimum operation conditions showed excellent physicochemical properties such as particle size uniformity, flowability, and compressibility.     

热喷涂液相合成粉末的雾化喷嘴设计

为了形成尺寸基本一致且在空间呈均匀分布的雾滴,以利于制备均匀性好、粒径分布窄的纳米颗粒,通过对单相流和两相流雾化喷嘴的对比,以及液滴的雾化过程分析,根据相关实验结果和经验公式,设计出了用于热喷涂液相合成粉末的雾化喷嘴,其雾化气输送管径为0.2mm,液料输送管径为2.0mm,二者夹角为90°。此雾化喷嘴在等离子喷涂制备TiO2纳米颗粒的实验中得到了成功应用。     

An experimental study of fluidized-bed coating: influence of operating conditions on growth rate and mechanism

This study investigates the influence of fluidizing gas velocity, atomizing air, and liquid flow rates, liquid concentration, initial bed mass, and particle size on the mechanism of growth of sand particles in a batch fluidized-bed coater. An aqueous solution of NaCl was used as the coating liquid and sprayed in the bed by means of a pneumatic atomizer. The results showed that for a given particle size, the fluidizing air velocity was the most important factor affecting the coating kinetics and stability. The dominant mechanism was the onion-ring layering, especially at excess gas velocities higher than 0.27 m/s. For a fixed value of the mass ratio of solute introduced in the bed to the initial particle mass, binder concentration, liquid flow rate, and the initial bed weight had no effect on the growth mechanism. The deposition quality was found to be affected by the droplet size. A decrease of droplet size resulting from increasing the atomizing air flow rate permitted homogenous coating of the solid surface.     

Microstructure and electrical conductivity of Al-SiCp composites produced by spray forming process

Al- SiC_p composites have been synthesized by spray forming process with variation in particle flow rate, size of reinforcement particles and their volume fraction. The microstructure of composites and their electrical conductivity have been investigated. The results showed a uniform dispersion of large size particulate phase in the matrix of the primary α- phase with its equiaxed grain morphology. However, clustering of small size particles was observed at the grain boundary and grain junctions. The grain size of the composite materials was observed to be lower than that of the base Al- alloy. The composite materials invariably indicated their lower electrical conductivity compared to that of the monolithic Al- alloy. The electrical conductivity of composites decreased with increase in the volume fraction and decrease in size of the reinforcement particles. A high flow rate of particles during spray deposition resulted in a decrease in its conductivity. These results are explained in the light of thermal mismatch between the matrix and the reinforcement phases resulting in generation of high dislocation density. The droplet- particle interaction and resulting microstructure evolution during the spray deposition of the composites are discussed.     

Experimental investigation of bubble and particle motion behaviors in a gas-solid fluidized bed with side wall liquid spray

Bubble and particle motion behaviors are investigated experimentally in a gas solid fluidized bed with liquid spray on the side wall. The particles used in the experiment are classified as Geldart B particles. The results reveal that when the fluid drag force is less than the liquid bridge force between particles, liquid distribute all over the bed. Bubble size increases as the increase of inter-particle force, then decreases owing to the increase of particle weight with increasing liquid flow rate. When the fluid drag force is greater than the liquid bridge force, liquid mainly distribute in the upper part of the bed. And it is difficult for the wet particles to form agglomerates. Bubble size decreases with increasing liquid flow rate due to the increasing of minimum fluidization velocity. Besides, the acoustic emission (AE) measurements illustrate that the liquid adhesion and evaporation on particles could enhance the particles motion intensity. Consequently, the bubble and particle behaviors change due to the variation in fluidized gas velocity and liquid flow rate should be seriously considered when attempting to successfully design and operate the side wall liquid spray gas solid fluidized bed.     

Study of airflow induced by regular particles in freefall through tubes

Airflow induced by falling particles can be a significant factor in causing dust emission during the conveyance of bulk materials. Heretofore, there have been few experimental studies on the effect of the particle size and the diameter of the tubes through which they are falling on the induced airflow. This study involved the experimental analysis of the correlation between those two factors and the induced airflow. The results were as follows: within the range of the total drag coefficient (0.62–0.94) of the experimental setup, the induced airflow velocity increased with an increment of the mass flow rate of the particles and drop height, and the power exponents of a fitted curve were approximately 0.35 and 1.29, respectively. Within the particle diameter range of 3.247–9.223 mm, the power coefficients and power exponents of a fitted curve for induced airflow velocity increased from 0.224 and 0.269 to 0.458 and 0.384, respectively, with the increase in particle size. As the tube diameter decreased from 200 mm to 120 mm, both the induced airflow velocity and the quantity of specific induced airflow increased, while the quantities decreased when the tube diameter decreased from 120 mm to 75 mm. The semi-empirical equation of the induced airflow velocity was established to predict the quantity of induced airflow under various operation conditions.     

Evaluation of the Granulation of a Hydrophilic Matrix Sustained Release Tablet

Wet granulation of a hydrophilic sustained release matrix tablet formulation has been studied. A fractional factorial experimental design was employed to identify principal influences and interacting factors from the following : granulation fluid volume, mixing time, mixer speed and inclusion of a wet screening step. Fluid volume and mixing time were primary factors affecting mean granule size. Fines in the granulation were reduced at higher fluid levels and by inclusion of a wet screening operation. There were several interacting factors influencing the particle size properties of the granulation. The factors studied had little influence on the bulk density of the granulation.

The influence of granule mean particle size on flow, compressibility and drug release from finished tablets was evaluated. Flow and compressibility were influenced by granule properties and the data generated suggested that should final tablet properties deteriorate on scale up it may be possible to ameliorate the effect by modification of granulation fluid volume or mixing time or both.

The factors studies had no influence on release of drug from finished tablets.     

Protein micro and nanoencapsulation within glycol-chitosan/Ca²+/alginate matrix by spray drying

Encapsulation of therapeutic peptides and proteins into polymeric micro and nanoparticulates has been proposed as a strategy to overcome limitations to oral protein administration. Particles having diameter less than 5 μm are able to be taken up by the M cells of Peyer's patches found in intestinal mucosa. Current formulation methodologies involve organic solvents and several time consuming steps. In this study, spray drying was investigated to produce protein loaded micro/nanoparticles, as it offers the potential for single step operation, producing dry active-loaded particles within the micro to nano-range. Spherical, smooth surfaced particles were produced from alginate/protein feed solutions. The effect of operational parameters on particle properties such as recovery, residual activity and particle size was studied using subtilisin as model protein. Particle recovery depended on the inlet temperature of the drying air, and mean particle size ranged from 2.2 to 4.5 μm, affected by the feed rate and the alginate concentration in the feed solution. Increase in alginate:protein ratio increased protein stability. Presence of 0.2?g trehalose/g particle increased the residual activity up to 90%. Glycol-chitosan-Ca(2+)alginate particles were produced in a single step operation, with resulting mean diameter of 3.5 μm. Particles showed fluorescein isothiocyanate labeled bovine serum albumin (BSA)-protein entrapment with increasing concentration toward the particle surface. Similar, limited release profiles of BSA, subtilisin and lysozyme were observed in gastric simulation, with ultimate full release of the proteins in gastrointestinal simulation.     

The influence of cavitation on the flow characteristics of liquid nitrogen through spray nozzles: A CFD study

Spray cooling with cryogen could achieve lower temperature level than refrigerant spray. The internal flow conditions within spray nozzles have crucial impacts on the mass flow rate, particle size, spray angle and spray penetration, thereby influencing the cooling performance. In this paper, CFD simulations based on mixture model are performed to study the cavitating flow of liquid nitrogen in spray nozzles. The cavitation model is verified using the experimental results of liquid nitrogen flow over hydrofoil. The numerical models of spray nozzle are validated against the experimental data of the mass flow rate of liquid nitrogen flow through different types of nozzles including the pressure swirl nozzle and the simple convergent nozzle. The numerical studies are performed under a wide range of pressure difference and inflow temperature, and the vapor volume fraction distribution, outlet vapor quality, mass flow rate and discharge coefficient are obtained. The results show that the outlet diameter, the pressure difference, and the inflow temperature significantly influence the mass flow rate of spray nozzles. The increase of the inflow temperature leads to higher saturation pressure, higher cavitation intensity, and more vapor at nozzle outlet, which can significantly reduce mass flow rate. While the discharge coefficient is mainly determined by the inflow temperature and has little dependence on the pressure difference and outlet diameter. Based on the numerical results, correlations of discharge coefficient are proposed for pressure swirl nozzle and simple convergent nozzles, respectively, and the deviation is less than 20% for 93% of data.     

The Production and Evaluation of Orally Administered Insulin Nanoparticles

Abstract

Wet granulation of a hydrophilic sustained release matrix tablet formulation has been studied. A fractional factorial experimental design was employed to identify principal influences and interacting factors from the following : granulation fluid volume, mixing time, mixer speed and inclusion of a wet screening step. Fluid volume and mixing time were primary factors affecting mean granule size. Fines in the granulation were reduced at higher fluid levels and by inclusion of a wet screening operation. There were several interacting factors influencing the particle size properties of the granulation. The factors studied had little influence on the bulk density of the granulation.

The influence of granule mean particle size on flow, compressibility and drug release from finished tablets was evaluated. Flow and compressibility were influenced by granule properties and the data generated suggested that should final tablet properties deteriorate on scale up it may be possible to ameliorate the effect by modification of granulation fluid volume or mixing time or both.

The factors studies had no influence on release of drug from finished tablets.     

Numerical study of cryogenic micro-slush particle production using a two-fluid nozzle

The fundamental characteristics of the atomization behavior of micro-slush nitrogen (SN₂) jet flow through a two-fluid nozzle was numerically investigated and visualized by a new type of integrated simulation technique. Computational fluid dynamics (CFD) analysis is focused on the production mechanism of micro-slush nitrogen particles in a two-fluid nozzle and on the consecutive atomizing spray flow characteristics of the micro-slush jet. Based on the numerically predicted nozzle atomization performance, a new type of superadiabatic two-fluid ejector nozzle is developed. This nozzle is capable of generating and atomizing micro-slush nitrogen by means of liquid-gas impingement of a pressurized subcooled liquid nitrogen (LN₂) flow and a low-temperature, high-speed gaseous helium (GHe) flow. The application of micro-slush as a refrigerant for long-distance high-temperature superconducting cables (HTS) is anticipated, and its production technology is expected to result in an extensive improvement in the effective cooling performance of superconducting systems. Computation indicates that the cryogenic micro-slush atomization rate and the multiphase spraying flow characteristics are affected by rapid LN₂-GHe mixing and turbulence perturbation upstream of the two-fluid nozzle, hydrodynamic instabilities at the gas-liquid interface, and shear stress between the liquid core and periphery of the LN₂ jet. Calculation of the effect of micro-slush atomization on the jet thermal field revealed that high-speed mixing of LN₂-GHe swirling flow extensively enhances the heat transfer between the LN₂-phase and the GHe-phase. Furthermore, the performance of the micro-slush production nozzle was experimentally investigated by particle image velocimetry (PIV), which confirmed that the measurement results were in reasonable agreement with the numerical results.     

Prediction of Powder Stickiness along Spray Drying Process in Relation to Agglomeration

The spray drying process consists of a fast convective drying of liquid droplets by hot air. Initially, the water activity (a_w) of a drop is close to 1. During drying, the drop surface a_w decreases while viscosity increases until reaching a sticky rubbery state before further drying. This can be observed for products such as carbohydrates, leading to particles sticking on walls (product losses) or to adhesion between particles leading to agglomeration. In this study, particle stickiness was investigated in a cocurrent pilot spray dryer by measuring drying air properties (temperature and relative humidity) at different positions. This allowed describing the evolution of temperature and mean water content of the drying drops. Two model products (maltodextrin DE12 and DE21) were spray dried varying process parameters liquid flow rate (1.8, 3.6, and 5.4 kg/h), air temperature (144°, 174°, and 200°C), airflow rate (80–110 kg/h), and rotary atomizer speed (22,500–30,000 rpm). The two products exhibit different drying behaviors in relation to their affinity towards water (sorption isotherms) and glass transition temperature evolution with a_w (stickiness). Depending on drying conditions and product, the drop stickiness was observed very rapidly, close to the atomizer, or later, along the chamber. This approach can be used to identify conditions and positions corresponding to sticky particles.     

Use of the Electrostatic Classification Method to Size 0.1 μm SRM Particles—A Feasibility Study

The use of the electrostatic classification method for sizing monodisperse 0.1 μm polystyrene latex (PSL) spheres has been investigated experimentally. The objective was to determine the feasibility of using electrostatic classification as a standard method of particle sizing in the development of a 0.1 μm particle diameter Standard Reference Material (SRM). The mean particle diameter was calculated from a measurement of the mean electrical mobility of the PSL spheres as an aerosol using an electrostatic classifier. The performance of the classifier was investigated by measuring its transfer function, conducting a sensitivity analysis to verify the governing theoretical relationships, measuring the repeatability of particle sizing, and sizing NIST SRM 1691, 0.269 μm and NIST SRM 1690, 0.895 μm particles. Investigations of the aerosol generator’s performance focused on the effect of impurities in the particle-suspending liquid on the resulting particle diameter.The uncertainty in particle diameter determined by electrical mobility measurements is found to be −3.3% to +3.0%. The major sources of uncertainty include the flow measurement, the slip correction, and a dependence of particle size on the aerosol flow rate. It was found that the classifier could be calibrated to indicate the correct size to within 0.1% for both SRM particle sizes if the defined classification length is decreased by 1.9%.     

气溶胶在岩体裂隙中迁移特性的实验研究

为得到实际岩体裂隙中气溶胶的穿透行为特性,为山体中存储间的选址及洞室工程防护措施的制定提供精确的数据支持,利用电子低压碰撞器对气溶胶在岩体裂隙中的穿透率进行实验测量,得到气流速度、粒径大小、裂隙长度、裂隙高度等参数对穿透率的影响。结果表明,在较低的流速下,小粒径粒子的穿透率随流速的增大稍微增大,大粒径粒子趋势不明显;随着气溶胶粒径的增大,穿透率先增大后减小,峰值在0.3～1.0μm之间;随着裂隙长度的增加,穿透率呈指数减小,且不同长度裂隙、不同粒径气溶胶粒径的穿透率减小趋势基本一致;裂隙高度的增加使气溶胶的穿透率显著增大,高为1.0 mm的裂隙中,气溶胶的穿透率更大,更接近理论结果;在常温常压下,高为0.1 mm的裂隙中,流速为5.6 m/s时,粒径为0.3μm的气溶胶在0.1 mm宽岩体裂隙中的迁移距离非常有限。粒子除了受重力沉积和扩散沉积作用,还受到碰撞效应等作用。     

Computational simulation of thermally sprayed WC–Co powder

WC–Co cemented carbides are a class of hard composite materials of great technological importance. They are widely used as tool materials in a large variety of applications that have high demands on hardness and toughness, including mining, turning, cutting and milling. The HVOF (high velocity oxygen fuel) technology has been very successful in spraying wear resistant WC–Co coatings with higher density, superior bond strengths and less decarburization than many other thermal spray processes, attributed mainly to its high particle impact velocities and relatively low peak particle temperatures. The degree of decomposition and bond strength is directly related to relevant particle parameters such as velocity, temperature and state of melting or solidification. These are consecutively related to process parameters such as powder particle size distribution, carrier gas flow rate, and fuel type employed. To obtain detailed particle data important for thermal spraying, mathematical models are developed in the present paper to predict the particle dynamic behavior in a liquid fuelled HVOF thermal spray gun. The particle transport equations are coupled with the three-dimensional, chemically reacting, turbulent gas flow, and solved in a Lagrangian manner. The melting and solidification within the particles as a result of heat exchange with the surrounding gas flow is solved numerically. The in-flight characteristics of WC–Co particles are studied and the effects of carrier gas parameters on particle behavior are examined. The results demonstrate that WC–Co particles smaller than 5 μm in diameter undergo melting and solidification prior to impact while most particles never reach liquid state during the HVOF thermal spraying. The flow rate of carrier gas has considerable influence on particle dynamics as well as deposition on substrate. At higher flow rate the powder particles are redirected further away from the substrate center, while smaller flow rate results in better heating, higher impact velocity and deposition closer to the substrate center.     

颗粒尺寸对颗粒增强型金属基复合材料动态特性的影响

利用有限元模型分析了颗粒增强型金属基复合材料 ( PMMCs ) Al/SiC的颗粒尺寸对复合材料在不同应变率下的动态特性的影响。采用有限元三维立方体单胞模型嵌入单个和多个球形增强颗粒,颗粒直径分别为16 μ m和7.5 μ m,多颗粒模型内部颗粒随机分布。基体材料假设为弹塑性,应变强化及应变率强化均符合指数规律。模拟结果表明:颗粒尺寸、颗粒体积含量及应变率对金属基复合材料的动态特性的影响是相互耦合的。颗粒体积含量一定时,颗粒尺寸越小,复合材料流动应力越高;颗粒含量越高,材料流动应力越高;应变率越高,材料流动应力越高。      

Synthesis of solid NMC622 particles by spray drying,post-annealing and lithiation

Layered lithium-nickel-manganese-cobalt oxide (NMC) cathode materials are widely used in Li-ion batteries that require high energy densities, such as those used in plug-in hybrid electric vehicles (PHEVs) and electric vehicles (EVs). Here we studied the synthesis of NMC622 particles by spray pyrolysis, which is a simple one-step process for production of spherical particles. However, synthesising NMC powder using spray pyrolysis has a tendency to produce hollow NMC particles. To gain insight into the mechanism behind the formation of the hollow particles, one dimensional numerical simulation of the physical and chemical phenomena taking place during spray drying were carried out. The effects of several process parameters, including drying air temperature, drying air mass flow rate, and liquid feed mass flow rate, on the evaporation and particle formation process were studied. The increased evaporation rate at higher temperatures was found to result in crust formation on the droplet surface during the particle formation, and thus, in lower solid volume fractions in the dried particles. However, by optimizing the process parameters production of solid NMC622 sulphate particles by spray drying was achieved. The produced NMC622 sulphate particles were then oxidised and lithiated in air at 850 °C via the conventional thermal treatment process. Four lithium precursors, LiOH, Li₂CO₃, Li₂SO₄ and LiNO_3, were tested for the lithiation of the oxidized NMC particles. The degree of lithiation and the crystalline phase of the powders were determined using ICP-OES and XRD, respectively.     

Optimization of the spray-drying process for developing aquasolv lignin particles using response surface methodology

Particle size and morphology are of high industrial importance due to the fact that product properties and performance can be affected by this factors. For instance, bulk properties, processability and appearance of the final product are given by particle size and shape. In this regard, the optimization of process parameters for particle development is required when targeting formulation of specific product and/or particular properties. Response surface methodology (RSM) was used to optimize the spray drying process for the development of aquasolv lignin particles with desired particle size and morphology. The inlet drying temperature X₁: 180–200 °C, atomization pressure X₂: 1.3–1.7 bar and feeding rate X₃: 65–75 mL min⁻¹ were kept as independent variables while the optimizing responses were_: Yield fine of particles with desired particle size and particle size (D₅₀). The quadratic part of the equation and statistical analysis showed substantial effect of the atomizing pressure and feeding rate on the responses and the optimized conditions validated the model. Optimum processing conditions for spray drying of aquasolv lignin were inlet temperature of 173 °C, 1.8 bar atomization pressure and 62 mL/min feeding rate. With this, desired responses of powder were 66% of yield and particle size of D₅₀ < 30 µm were obtained. The experimental values were found to be in agreement with the predicted values indicating the suitability of the model in predicting the particle size and yield of aquasolv lignin.     

Foam granulation: new developments in pharmaceutical solid oral dosage forms using twin screw extrusion machinery

This paper investigates foam granulation in a twin screw extruder as a new continuous wet granulation technique for pharmaceutical powder drug formulations. Foamed aqueous binder has a reportedly lower soak-to-spread ratio than drop or spray liquid addition in batch granulation. This work demonstrates a twin screw extruder configuration for foam granulation and subsequently compares the new approach against liquid injection in the granulation of α-lactose monohydrate with a methylcellulose binder. Trials were conducted at high powder output rates (20-40 kg/h) and high screw speeds (220-320 RPM) with two screw configurations. Process stability improved with the new technique allowing granulation with less binder. The extruded mass maintained a low exit temperature, being insensitive to operating conditions unlike the liquid injection approach, where temperatures rose significantly as flow rate increased. The particle size distribution by foam granulation reflected a more uniformly wetted mass with larger granule growth noted even for conditions where dry powder exited by liquid injection. Other factors were found similar between the two binder delivery methods such as consumed mechanical energy, as well as fracture strength and compressibility of produced granules.     

Particle engineering at the drug substance,drug product interface: a comprehensive platform approach to enabling continuous drug substance to drug product processing with differentiated material properties

Direct compression offers a simple route to generate pharmaceutical dosage units and is core to the growing arena of continuous manufacturing. However, direct compression can be untenable for some active materials. This paper will outline three specific challenges API’s can present to direct (active pharmaceutical ingredients) compression. The first involves API’s having exceedingly high aspect ratio (“needles”) or small particle size resulting in low bulk density and poor flow properties. Two additional cases are relatively newer challenges to direct compression driven by the growing need for solubility enhancing formulations, and involve nano-crystalline materials and spray dried amorphous dispersions. Multiple approaches for managing high aspect ratio or micronized API’s have been implemented during the crystallization process or via particle coating downstream from API isolation. Fewer options have been reported for the successful conversion of nano-crystalline materials or spray dried amorphous dispersions into materials amenable to direct compression as these materials offer another specific set of challenges. One route that has not been explored that stands to allow continuous drug product processing across a broader product portfolio involves evaluating opportunities at the drug substance/drug product interface. Here, the options achieved through targeted introduction of excipients to the drug substance processing steps during product precipitation and/or isolation from a product slurry are discussed. This approach introduces new opportunities for designing multicomponent particles through productive and inherently continuous processes. This also offers a longer-term potential route to integrate across continuous drug substance processing to continuous drug product processing.