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.     

Setting the bar for powder flow properties in successful high speed tableting

An inadequate powder flow leads to problems in tablet manufacturing. The knowledge of minimum flow properties required for successful tableting on a high speed press is critically important to the efficient development of pharmaceutical tablets. This may be achieved by identifying a powder that exhibits minimally acceptable flow properties on a high speed tablet press. A grade of a common tablet excipient, microcrystalline cellulose (Avicel PH102) lies near the borderline between acceptable and poor flow regions during high speed tableting. It can therefore serve as a reference material for judging adequacy of flow properties of prototype formulations by the way of comparison. A powder exhibiting poorer flow properties than Avicel PH102 likely exhibits flow problems and should be avoided. An implementation of this simple approach in formulation development can minimize potential flow problems during large scale tablet manufacture.     

Slow and intermediate flow of a frictional bulk powder in the Couette geometry

Most current research in the field of dry, non-aerated powder flows is directed toward rapid granular flows of large particles. Slow, frictional, dense flows of powders in the so-called quasi-static regime were also studied extensively using Soil Mechanics principles. The present paper describes the rheological behavior of powders in the “intermediate” regime lying between the slow and rapid flow regimes. Flows in this regime have direct industrial relevance. Such flows occur when powders move relative to solid walls in hoppers, bins and around inserts or are mixed in high and low shear mixers using moving paddles. A simple geometry that of a Couette device is used as a benchmark of more complicated flows.The constitutive equations derived by Schaeffer [J. Differ. Equ. 66 (1987) 19] for slow, incompressible powder flows were used in a new approach proposed by Savage [J. Fluid Mech. 377 (1998) 1] to describe flows in the intermediate regime. The theory is based on the assumption that both stress and strain-rate fluctuations are present in the powder. Using Savage's approach, we derive an expression for the average stress that reduces to the quasi-static flow limit when fluctuations go to zero while, in the limit of large fluctuations, a “liquid-like”, “viscous” character is manifested by the bulk powder.An analytical solution of the averaged equations for the specific geometry of the Couette device is presented. We calculate both the velocity profile in the powder and the shear stress in the sheared layer and compare these results to experimental data. We show that normal stresses in the sheared layer depend linearly on depth (somewhat like in a fluid) and that the shear stress in the powder is shear rate dependent. We also find that the velocity of the powder in the vicinity of a rough, moving boundary, decays exponentially so that the flow is restricted to a small area adjacent to the wall. The width of this area is of the order of 10-13 particle diameters. In the limit of very small particles, this is tantamount to a shear band-type behavior near the wall.     

Shear and flow behavior of pharmaceutical blends — Method comparison study

A method comparison study was undertaken to characterize the effects of the formulation composition on the flow and shear properties of pharmaceutically relevant powders. Fourteen blends with various concentrations of an active ingredient, magnesium stearate as a lubricant and silica as a glidant were prepared. These blends were characterized with two very different techniques: the gravitational displacement rheometer (GDR), and a rotational shear cell. The values of GDR flow index were compared to the values of principal stresses and cohesion obtained with the shear cell. These measurements are different in that the GDR operates in the gravity-driven flow regime while the shear cell utilizes an imposed normal force, which leads to a much more pronounced powder consolidation. In spite of these differences, the study demonstrated a significant correlation between the two methods, although some discrepancies were observed due to differences in the consolidation state for each technique. This observation was confirmed by measuring compressibility of these formulations with the FT4 Powder Rheometer; the presence of a cohesive component influenced the values of the shear cell principal stresses (and therefore, the shear cell flow factor) in a non-linear manner, contributing to the discrepancies in the correlation between the flow factor and the GDR flow index. Conversely, the correlation between the shear cell cohesion parameter and the GDR flow index was significantly better, as both indices test the materials at similar degree of consolidation. The study examined the limits and the ranges of applicability of each technique, offered recommendations on applications, where the use of each method was more reliable, as well as provided reasons for the methods' failure.     

Characterisation of the flow behaviour of pharmaceutical powders using a model die-shoe filling system

In the pharmaceutical industry it is important to understand the factors that influence the flowability of a powder and to identify suitable experimental procedures which can be used to evaluate powders and guide the selection of process parameters. This paper determines the flowability of seven pharmaceutical powders using a model die-shoe filling rig. Dimensional analysis is employed to provide a framework for the interpretation of experimental results and to guide the development of procedures to extrapolate the results to other die and shoe geometries. It is demonstrated that the variation of mass delivered into a standard die as a function of shoe velocity provides a measure of flowability. Qualitative and quantitative studies were undertaken using a high-speed video system and by determining the critical shoe velocity, i.e. the shoe velocity above which incomplete filling occurs.     

Visualization of the shear region in a cohesive powder by scanning with a polarized neutron beam

The flow of cohesive powder occurs by the formation of shear planes or zones. How these form and how particles microscopically behave in a shear zone is fundamental for understanding powder flow. In this work Neutron Depolarization has been used to study in-line particles in a powder sample. The Neutron Depolarization technique gives a unique insight in the particle rotations and width of the shear zone. It has been shown that rotation of particles during a normal consolidation becomes less when the sample is more compacted. Shear displacement experiments showed that particles rotate in a preferred direction. The width of the region in which the preferred rotation takes place is found to be at least 1000 to 2000 particle diameters.     

Time and cost effective methods for testing chemical resistance of aluminium metallic pigmented powder coatings

Polyester based powder coatings containing different types of aluminium metallic flake pigments have been investigated with respect to their chemical stability in acid environments. The metallic flakes are made chemically stable by covering them in silica. The degree of silica coverage and the silica morphology are far more important for the chemical stability of the pigments than the silica thickness. The acid resistance of the final powder coating is found to depend on the pigment embedment depth, on the chemical composition and morphology of the powder coating, and on the silica coating of the pigment. The latter being the single most important factor in our study.     

Influence of thermo-analytical and rheological properties of an epoxy powder coating resin on the quality of coatings on medium density fibreboards (MDF) using in-mould technology

Powder coating of engineered wood panels such as medium density fibreboards (MDF) is gaining industrial interest due to ecological and economic advantages of powder coating technology. For transferring powder coating technology to temperature-sensitive substrates like MDF, a thorough understanding of the melting, flowing and curing behaviour of the used low-bake resins is required. In the present study, thermo-analysis in combination with iso-conversional kinetic data analysis as well as rheometry is applied to characterise the properties of an epoxy-based powder coating. Neat resin and cured powder coating films are examined in order to define an ideal production window within which the resin is preferably applied and processed to yield satisfactory surface performance on the one hand and without exposing the carrier MDF too high a temperature load on the other hand to prevent the panel from deteriorating in mechanical strength. In order to produce powder coated films of high surface gloss – a feature that has not yet successfully been realized on MDF with powder coatings – a new curing technology, in-mould surface finishing, has been applied.     

Synthesis and properties of semi-crystalline hyperbranched poly(ester-amide) grafted with long alkyl chains used for UV-curable powder coatings

A series of semi-crystalline hyperbranched poly(ester-amide)s by modifying hydroxyl end groups of hyperbranched poly(ester-amide) (HP) with IPDI-C18 and IPDI-HEA in different ratios were synthesized and characterized by FTIR, NMR and GPC. Their crystallization behaviors and thermal properties determined by X-ray diffraction (XRD) and differential scanning calorimetry (DSC) showed that the high substitution degree of hydroxyl groups of hyperbranched poly(ester-amide) (HP) with IPDI-C18 resulted in higher degree of crystallization and thus glass transition temperature (T_g) up to 43 °C. The photopolymerization kinetics investigated by photo-DSC showed that the obtained semi-crystalline hyperbranched resins have high photopolymerization rate and final unsaturation conversion, which is very promising for UV-curable powder coating applications.     

Application of powder coatings: Viscosity and density measurements in a conventional fluidized bed

The values of dynamic viscosity characteristic of the different stages in a fluidized bed were determined using a torsional viscometer (Dragge Eppretch Rheometer type STVK) with a specially designed cup. Experiments were made with three kinds of rotor: a full paddle, a cylinder and a split paddle. Apparent densities have been determined by measuring differential pressures across known heights in an experimental fluidized bed. A modified Matheson equation has been developed to determine the values of maximum bed density and minimum bed porosity, associated with the inset of fluidization. The experimental determinations were made with a white powder coating in which the granulometric distribution and composition were previously established.     

Simultaneous particulate design of primary and agglomerated crystals of steroid by spherical agglomeration in liquid for dry powder inhalation

Spherical agglomerates of steroid KSR-592, consisting of fine primary drug crystals suitable for dry powder inhalation (DPI), were prepared by the spherical agglomeration method in liquid with a bridging liquid. It was found that the particle size of primary crystals increased until the dispersing medium was saturated with the bridging liquid, whereas the spherical agglomeration of primary crystals was continued even after the saturation of medium with the bridging liquid. The growth rates of primary crystals and agglomerates increased with an increase in the temperature and/or a reduction in the agitation speed of the system. The agglomerates were easily disintegrated into the primary crystals depositing ideally on carrier lactose particles for DPI by mixing. The in vitro efficiency of the mixed system of lactose and disintegrated primary crystals of drug was 2 to 3 times higher than that of crystals prepared conventionally. Furthermore, the soft agglomerates disintegrated easily into respirable particles in air stream when emitted from the inhalation device were prepared by reducing the agitation speed after the dispersing medium was saturated with the bridging liquid.     

Detailed analysis of air flow and spray loss in a pharmaceutical coating process

In the pharmaceutical industry, more than half of all tablets receive a film coating. A commonly used technique is drum coating, where a film solution is applied to the moving tablets by a spray nozzle. Important process parameters include the amount and temperature of drying air, as well as spray nozzle position. Among other influences, the proper adjustment of these parameters has a great impact on spray loss, defined as the fraction of spray liquid that does not form a film on the tablets. Often, the lack of scientific data hinders a process setup based on engineering principles, resulting in operational conditions based on trial‐and‐error approaches. Here, we show how a coating system can be numerically modeled by means of computational fluid dynamics (CFD) techniques. Furthermore, we present how different parameters affect the efficiency of the process, leading to a deeper understanding of the coating device. © 2011 American Institute of Chemical Engineers AIChE J, 2012     

Gas-powder flow and powder accumulation in a packed bed: II: Numerical study

A mathematical model is proposed to describe gas-powder flow in a bed packed with particles. The model is the same as the two fluid model developed on the basis of the space-averaged theorem in terms of the governing equations but extended to consider the interactions between gas, powder and packed particles, as well as the static and dynamic holdups of powder. In particular, a method is proposed to determine the boundary between dynamic and stagnant zones with respect to powder phase, i.e., the profile of the powder accumulation zone. The validity of numerical modeling is confirmed by comparing the predicted and measured distributions of powder flow and accumulation under various flow conditions. On this basis, the role of gas-powder and powder-particle forces relative to the gravity force in controlling the powder flow and accumulation is analyzed.     

Oscillatory power number,power density model,and effect of restriction size for a moving-baffle oscillatory baffled column using CFD modelling

Although single-hole oscillatory columns have been studied since the 1990s, to this day there is an absence of appropriate dimensionless groups to express the hydrodynamic conditions and power requirement for the moving-baffle oscillatory baffled column (OBC). This paper uses computational fluid dynamic (CFD) software coupled with moving overset meshing to aid in the derivation of the first dimensionless oscillatory power number for OBCs. In terms of the moving-baffle OBC, this work marks the first time a power density equation has been derived specifically to account for this column's unique hydrodynamic profile. Equations for period-averaged Reynolds number and period-averaged Strouhal numbers were developed to better estimate the fluid intensity within these moving-baffle columns. This work serves as an example of how complex and challenging flow regimes, such as periodically oscillating flow, can be simplified and analyzed to produce appropriate design equations.     

Assessment of flow and heat transfer characteristics for proposed solid density distributions in dilute laminar slurry upflows through a concentric annulus

A computational model is developed to predict the hydrodynamic and heat transfer characteristics of dilute liquid-solid laminar upflows through a concentric annulus. The dilute slurry is treated as a single phase Newtonian fluid of locally variable physical and thermal properties. Available experimental data of radial solid density distributions in dilute water-feldspar annular upflows is used in the model. Various important characteristics of laminar slurry flows were successfully predicted. It was also shown mathematically that in the limiting case of zero average solid loading, the solution reduces to that of the single phase. The radial location of maximum slurry density in the annular gap was found to be an important factor in determining both the flow and heat transfer behavior of the present system; also, the higher heat transfer enhancement ratios were predicted at the lower slurry Reynolds numbers.     

Application of electrochemical techniques to study the effect on the anticorrosive properties of the addition of ytterbium and erbium triflates as catalysts on a powder epoxy network

New low curing temperature epoxy powder coatings cured with o-tolylbiguanide and catalyzed by the use of erbium(III) and ytterbium(III) trifluoromethanesulfonates have been formulated. Their curing kinetics and anticorrosive properties have been studied and compared with a system commonly used in industry (o-tolylbiguanide/epoxy resin). Three different tests for measuring anticorrosive properties (EIS, AC/DC/AC, and salt fog spray) have been used together with an adherence test, in order to establish the ideal system. Results show that a system using 1 phr of ytterbium triflate presents good anticorrosive properties. The technique AC/DC/AC has shown its ability to evaluate properly and much faster than other techniques the anticorrosive properties of powder coatings with similar results.     

Development of a new experimental method to determine critical pigment-volume-concentrations using impedance spectroscopy : Part II: Solvent based coatings with components typical for commercial organic anticorrosion coatings or with nanoparticles

Electrochemical impedance spectroscopy (EIS), which has been previously demonstrated to be a suitable method to determine the CPVC coatings [R.E. Lobnig, W. Villalba, K. Goll, J. Vogelsang, I. Winkels, R. Schmidt, P. Zanger, J. Soetemann, Development of a new experimental method to determine critical pigment-volume-concentrations using impedance spectroscopy, Prog. Org. Coat. 55 (2006) 363–374.], was applied to four series of coatings with components typical for solvent based commercial organic anticorrosion coatings, and to three series of coatings with nanopigments. For all coatings, the CPVC determined using EIS correlated very well with the CPVC determined from cross-sections with electron microscopy (SEM). The EIS method was also useful for the coatings with nanopigments, for which pores were too small to be detected by SEM-analysis of cross-sections.     

Experimental and CFD studies on using coil wire insert in a proton exchange membrane fuel cell

In this paper a study on the role of wire coils inserted in the oxygen supply channels of a proton exchange membrane fuel cell (PEMFC) is reported. Different power densities have been obtained at different oxygen flow rates with and without insert. The experimental results clearly reveal that inserting a wire coil can increase the generated power density up to 41% in some layouts. The CFD modeling is carried out to explain and to analyze the observed results. The generated circumferential flow close to the gas diffusion layer (GDL) is found to be the main reason for the obtained experimental results.     

Development of a new experimental method to determine critical pigment-volume-concentrations using impedance spectroscopy: Part III: Water-based coatings with components typical for commercial organic anticorrosion coatings

Electrochemical impedance spectroscopy (EIS), which has been previously demonstrated to be a suitable method to determine the CPVC of organic coatings [R.E. Lobnig, W. Villalba, K. Goll, J. Vogelsang, I. Winkels, R. Schmidt, P. Zanger, J. Soetemann, Development of a new experimental method to determine critical pigment-volume-concentrations using impedance spectroscopy, Prog. Org. Coat. 55 (2006) 363–374], was applied to three series of coatings with components typical for water-based commercial organic anticorrosion coatings and to one with components typical for a wall paint. The new method led to CPVC-values for all four coating series, but up to 5–10% higher than those determined from cross sections with scanning electron microscopy (SEM), for one coating series to the exact reference value. The CPVC could be identified best from EIS data by visual comparison of the shape of Bode plots or from pore resistance (R_p)-time plots. The constant phase element (CPE), that characterizes the coating, was less useful for the determination of the CPVC of most water-based coatings.