Breakage Assessment of Lath-Like Crystals in a Novel Laboratory-Scale Agitated Filter Bed Dryer.

Agitated filter bed dryer is often the equipment of choice in the pharmaceutical industry for the isolation of potent active pharmaceutical ingredients (API) from the mother liquor and subsequent drying through intermittent agitation. The use of an impeller to promote homogeneous drying could lead to undesirable size reduction of the crystal product due to shear deformation induced by the impeller blades during agitation, potentially causing off-specification product and further downstream processing issues. An evaluation of the breakage propensity of crystals during the initial development stage is therefore critical. A new versatile scale-down agitated filter bed dryer (AFBD) has been developed for this purpose. Carbamazepine dihydrate crystals that are prone to breakage have been used as model particles. The extent of particle breakage as a function of impeller rotational speed, size of clearance between the impeller and containing walls and base, and solvent content has been evaluated. A transition of breakage behaviour is observed, where carbamazepine dihydrate crystals undergo fragmentation first along the crystallographic plane [00l]. As the crystals become smaller and more equant, the breakage pattern switches to chipping. Unbound solvent content has a strong influence on the breakage, as particles break more readily at high solvent contents. The laboratory-scale instrument developed here provides a tool for comparative assessment of the propensity of particle attrition under agitated filter bed drying conditions.

Triboelectric Charging Properties of the Functional Groups of Common Pharmaceutical Materials Using Density Functional Theory Calculations.

Triboelectrification is a ubiquitous and poorly understood phenomenon in powder processing, particularly for pharmaceutical powders. Charged particles can adhere to vessel walls, causing sheeting; they can also cause agglomeration, threatening the stability of powder formulations, and in extreme cases electrostatic discharges, which present a serious fire and explosion hazard. Triboelectrification is highly sensitive to environmental and material conditions, which makes it very difficult to compare experimental results from different publications. In this work, density functional theory (DFT) is used to investigate the charge transfer characteristics of several functional groups of paracetamol in order to better understand the mechanisms of charging at the nanoscale and the influence of the environmental and material properties on charge transfer. This is achieved by studying the structure and electronic properties at the molecule-substrate interface. Using this molecule-substrate approach, the charging contributions of individual functional groups are explored by examining the Hirschfeld charges, the charge density difference between the molecule and substrate, the density of states, and the location of the frontier orbitals (HOMO and LUMO) of a paracetamol molecule. Charge density difference calculations indicate a significant transfer of charge from the molecule to the surface. Observable regions of electron density enrichment and depletion are evident around the electron-donating and -withdrawing groups, respectively. The density of states for the paracetamol molecule evolves as it approaches the surface, and the band gap disappears upon contact with the substrate. Hirshfeld charge analysis reveals asymmetry in the charge redistribution around the molecule, highlighting the varying charging tendencies of different atoms.

Prediction of the Effective Work Function of Aspirin and Paracetamol Crystals by Density Functional Theory-A First-Principles Study.

Crystals of active pharmaceutical ingredients (API) are prone to triboelectric charging due to their dielectric nature. This characteristic, coupled with their typically low density and often large aspect ratio, poses significant challenges in the manufacturing process. The pharmaceutical industry frequently encounters issues during the secondary processing of APIs, such as particle adhesion to walls, clump formation, unreliable flow, and the need for careful handling to mitigate the risk of fire and explosions. These challenges are further intensified by the limited availability of powder quantities for testing, particularly in the early stages of drug development. Therefore, it is highly desirable to develop predictive tools that can assess the triboelectric propensity of APIs. In this study, Density Functional Theory calculations are employed to predict the effective work function of different facets of aspirin and paracetamol crystals, both in a vacuum and in the presence of water molecules on their surfaces. The calculations reveal significant variations in the work function across different facets and materials. Moreover, the adsorption of water molecules induces a shift in the work function. These findings underscore the considerable impact of distinct surface terminations and the presence of molecular water on the calculated effective work function of pharmaceuticals. Consequently, this approach offers a valuable predictive tool for determining the triboelectric propensity of APIs.

Effect of Mixer Type on Particle Coating by Magnesium Stearate for Friction and Adhesion Modification.

Glidants and lubricants are often used to modify interparticle friction and adhesion in order to improve powder characteristics, such as flowability and compactability. Magnesium stearate (MgSt) powder is widely used as a lubricant. Shear straining causes MgSt particles to break, delaminate, and adhere to the surfaces of the host particles. In this work, a comparison is made of the effect of three mixer types on the lubricating role of MgSt particles. The flow behaviour of α-lactose monohydrate, coated with MgSt at different mass percentages of 0.2, 0.5, 1, and 5 is characterised. The mixing and coating process is carried out by dry blending using Turbula, ProCepT, and Mechanofusion. Measures have been taken to operate under equivalent mixing conditions, as reported in the literature. The flow resistance of the coated samples is measured using the FT4 rheometer. The results indicate that the flow characteristics of the processed powders are remarkably similar in the cases of samples treated by Turbula and Mechanofusion, despite extreme conditions of shear strain rate. The least flow resistance of samples is observed in the case of samples treated by the ProCepT mixer. High-velocity collisions of particles round off the sharp corners and edges, making them less resistant to flow. The optimal percentage of magnesium stearate is found to be approximately 1% by weight for all mixer types, as the addition of higher amounts of lubricant does not further improve the flowability of the material.

Particle breakability assessment using an Aero S disperser.

Milling is widely used in various industries to tailor the particle size distribution for desired attributes. The ability to predict milling behaviour by testing the breakability of a small quantity of material is of great interest. In this paper, a widely available aerodynamic dispersion method, i.e. the Aero S disperser of Malvern Mastersizer 3000 has been evaluated for this purpose. This device is commonly used for dispersion of fine and cohesive powders, as the particles are accelerated and impacted at a bend, but here its use for assessing particle breakability is explored. The fluid flow field is modelled using one-way coupled Computational Fluid Dynamics approach, as the particle concentration is low, following which the particle impact velocity is calculated by Lagrangian tracking and used in the analysis of particle breakage. Experimental work on the breakability is carried out using aspirin, paracetamol, sucrose and α-lactose monohydrate particles. The relative shift in the specific surface area is determined and together with the calculated particle impact velocity and physical properties, they are used to calculate the breakability index. A good agreement is obtained with the single particle impact testing and aerodynamic dispersion by Scirocco disperser, indicating the breakability could also be inferred from this method.

Numerical Simulation of Particle Dynamics in a Spiral Jet Mill via Coupled CFD-DEM.

Spiral jet mills are ubiquitous in the pharmaceutical industry. Breakage and classification in spiral jet mills occur due to complex interactions between the fluid and the solid phases. The study of these interactions requires the use of computational fluid dynamics (CFD) for the fluid phase coupled with discrete element models (DEM) for the particle phase. In this study, we investigate particle dynamics in a 50-mm spiral jet mill through coupled CFD-DEM simulations. The simulations showed that the fluid was significantly decelerated by the presence of the particles in the milling chamber. Furthermore, we study the particle dynamics and collision statistics at two different operating conditions and three different particle loadings. As expected, the particle velocity was affected by both the particle loading and operating pressure. The particles moved slower at low pressures and high loadings. We also found that particle-particle collisions outnumbered particle-wall collisions.

Understanding stress-induced disorder and breakage in organic crystals: beyond crystal structure anisotropy.

Crystal engineering has advanced the strategies for design and synthesis of organic solids with the main focus being on customising the properties of the materials. Research in this area has a significant impact on large-scale manufacturing, as industrial processes may lead to the deterioration of such properties due to stress-induced transformations and breakage. In this work, we investigate the mechanical properties of structurally related labile multicomponent solids of carbamazepine (CBZ), namely the dihydrate (CBZ·2H2O), a cocrystal of CBZ with 1,4-benzoquinone (2CBZ·BZQ) and the solvates with formamide and 1,4-dioxane (CBZ·FORM and 2CBZ·DIOX, respectively). The effect of factors that are external (e.g. impact stressing) and/or internal (e.g. phase transformations and thermal motion) to the crystals are evaluated. In comparison to the other CBZ multicomponent crystal forms, CBZ·2H2O crystals tolerate less stress and are more susceptible to breakage. It is shown that this poor resistance to fracture may be a consequence of the packing of CBZ molecules and the orientation of the principal molecular axes in the structure relative to the cleavage plane. It is concluded, however, that the CBZ lattice alone is not accountable for the formation of cracks in the crystals of CBZ·2H2O. The strength and the temperature-dependence of electrostatic interactions, such as hydrogen bonds between CBZ and coformer, appear to influence the levels of stress to which the crystals are subjected that lead to fracture. Our findings show that the appropriate selection of coformer in multicomponent crystal forms, targetting superior mechanical properties, needs to account for the intrinsic stress generated by molecular vibrations and not solely by crystal anisotropy. Structural defects within the crystal lattice, although highly influenced by the crystallisation conditions and which are especially difficult to control in organic solids, may also affect breakage.

Assessment of impact breakage of carbamazepine dihydrate due to aerodynamic dispersion.

Acicular crystals are very common in pharmaceutical manufacturing. They are very prone to breakage, causing unwanted particle size degradation and problems such as segregation and lump formation. We investigate the breakage pattern of carbamazepine dihydrate, an acicular and platy crystal with cleavage planes. It readily undergoes attrition during isolation and drying stage, causing processing difficulties. We use the aerodynamic dispersion of a very small quantity of powder sample to induce breakage by applying a pulse of pressurised air. The dispersion unit of Morphologi G3 is used for this purpose. The broken particles settle in a chamber and are subsequently analysed using the built-in image analysis software. The shift in the particle size and shape distributions is quantified through which the extent of breakage is determined as a function of the dispersion pressure. The analysis reveals a change of breakage mechanism as the dispersion pressure is increased from primarily snapping along the crystal length to one in which chipping has also a notable contribution. The breakage data are analysed using a modified impact-based breakage model and the breakability index of the carbamazepine dihydrate is determined for the two breakage regimes. The method provides a quick and easy testing of particle breakability, a useful tool for assessing attrition in process plant and grindability in milling operations.

Analysis of pin milling of pharmaceutical materials.

Milling is an important process for tailoring the particle size distribution for enhanced dissolution, content uniformity, tableting, etc., specially for active pharmaceutical ingredients and excipient in pharmaceutical industries. Milling performance of particulate solids depends on the equipment operating conditions (geometry, process conditions and input energy etc.) as well as material properties (particle size, shape, and mechanical properties, such as Young's modulus, hardness and fracture toughness). In this work, a newly developed approach to assess the breakability of pharmaceutical materials using an aerodynamic dispersion method has been combined with the Discrete Element Method (DEM) to simulate the dynamic behaviour of a number of pharmaceutical materials in a pin mill. A sensitivity analysis is carried out addressing the effect of the milling conditions (rotational speed of the mill and feed particle flow rate) and feed properties on the milled products in terms of the shift in the specific surface area of the milled particles. The outcome of the work is used as a method to predict the breakage of the particles for the milling conditions where chipping takes place.

Promising solid electrolyte material for an IT-SOFC: crystal structure of the cerium gadolinium holmium oxide Ce0.8Gd0.1Ho0.1O1.9 between 295 and 1023†K.

The crystal structure of Ce0.8Gd0.1Ho0.1O1.9 (cerium gadolinium holmium oxide) has been determined from powder X-ray diffraction data. This is a promising material for application as a solid electrolyte for intermediate-temperature solid oxide fuel cells (IT-SOFCs). Nanoparticles were prepared using a novel sodium alginate sol-gel method, where the sodium ion was exchanged with ions of interest and, after washing, the gel was calcined at 723 K in air. The crystallographic features of Gd and Ho co-doped cerium oxide were investigated around the desired operating temperatures of IT-SOFCs, i.e. 573 ≤ T ≤ 1023 K. We find that the crystal structure is a stable fluorite structure with the space group Fm-3m in the entire temperature range. In addition, the trend in lattice parameters shows that there is a monotonic increase with increasing temperature.

Triboelectrification of pharmaceutical powders by particle impact.

Pharmaceutical powders are very prone to electrostatic charging by colliding and sliding contacts with walls and other particles. In pharmaceutical formulation processes, particle charging is often a nuisance and can cause problems in the manufacture of products, such as affecting powder flow, and reducing fill and dose uniformity. For a fundamental understanding of the powder triboelectrification, it is essential to study charge transfer due to a single contact of a particle with a target plane under well-defined physical, mechanical and electrical conditions. In this study, charge transfer due to a single impact of a particle against a stainless steel target was measured for alpha-lactose monohydrate, aspirin, sugar granules and ethylcellulose. The amount of transferred charge is expressed as a function of impact velocity and impact angle as well as the initial charge. The maximum contact area during impact between a particle and a target plane is estimated by an elastic-plastic deformation model. It is found that the transferred charge is a linear function of the contact area. For a given material, there is an initial particle charge for which no charge transfer occurs due to impact. This is found to be independent of impact velocity and angle, and is hence viewed as a characteristic property, which is related to the contact potential difference and tribo-electric series of the sample powders.

New instrument for tribocharge measurement due to single particle impacts.

During particulate solid processing, particle-particle and particle-wall collisions can generate electrostatic charges. This may lead to a variety of problems ranging from fire and explosion hazards to segregation, caking, and blocking. A fundamental understanding of the particle charging in such situations is therefore essential. For this purpose we have developed a new device that can measure charge transfer due to impact between a single particle and a metal plate. The device consists of an impact test system and two sets of Faraday cage and preamplifier for charge measurement. With current amplifiers, high-resolution measurements of particle charges of approximately 1 and 10 fC have been achieved before and after the impact, respectively. The device allows charge measurements of single particles with a size as small as approximately 100 microm impacting on the target at different incident angles with a velocity up to about 80 m/s. Further analyses of the charge transfer as a function of particle initial charge define an equilibrium charge, i.e., an initial charge level prior to impact for which no net charge transfer would occur as a result of impact.

Assessment of surface caking of powders using the ball indentation method.

Powder caking is a ubiquitous problem, which could significantly decrease product quality and lead to economic losses. Hence it is important to know the conditions under which it occurs. The caking behaviour of three powder materials (PVP, HPC and CaHPO4) has been investigated by the ball indentation method (BIM) as affected by relative humidity (RH), temperature and time. The resistance to powder flow, as indicated by the hardness is measured by a ball indenting the powder bed surface. The surface hardness increases with increasing RH and temperature, indicating caking of the powder bed. Moreover, the temperature and RH show a coupled effect on powder caking. Irreversible caking is formed in PVP and HPC at 75% RH; the particles coalesce and the volume of powder bed is significantly reduced with time. However, the caking of CaHPO4 is reversible. To examine the caking mechanism of PVP and HPC, the critical glass transition RH is determined at 25°C and 45°C. The values are 63% and 53% RH for PVP and 61% and 50% RH for HPC, respectively. The glass transition moisture content in the ball indentation experiments is comparable with that determined by the dynamic vapor sorption measurement. BIM could be a fast and effective method for the assessment of powder surface caking.

A method for grindability testing using the Scirocco disperser.

In the early stages of development of a new Active Pharmaceutical Ingredient (API), insufficient material quantity is available for addressing processing issues, and it is highly desirable to be able to assess processability issues using the smallest possible powder sample quantity. A good example is milling of new active pharmaceutical ingredients. For particle breakage that is sensitive to strain rate, impact testing is the most appropriate method. However, there is no commercially available single particle impact tester for fine particulate solids. In contrast, dry powder dispersers, such as the Scirocco disperser of the Malvern Mastersizer 2000, are widely available, and can be used for this purpose, provided particle impact velocity is known. However, the distance within which the particles can accelerate before impacting on the bend is very short and different particle sizes accelerate to different velocities before impact. As the breakage is proportional to the square of impact velocity, the interpretation of breakage data is not straightforward and requires an analysis of particle velocity as a function of size, density and shape. We report our work using an integrated experimental and CFD modelling approach to evaluate the suitability of this device as a grindability testing device, with the particle sizing being done immediately following dispersion by laser diffraction. Aspirin, sucrose and α-lactose monohydrate are tested using narrow sieve cuts in order to minimise variations in impact velocity. The tests are carried out at eight different air nozzle pressures. As intuitively expected, smaller particles accelerate faster and impact the wall at a higher velocity compared to the larger particles. However, for a given velocity the extent of breakage of larger particles is larger. Using a numerical simulation based on CFD, the relationship between impact velocity and particle size and density has been established assuming a spherical shape, and using one-way coupling, as the particle concentration is very low. Taking account of these dependencies, a clear unification of the change in the specific surface area as a function of particle size, density and impact velocity is observed, and the slope of the fitted line gives a measure of grindability for each material. The trend of data obtained here matches the one obtained by single particle impact testing. Hence aerodynamic dispersion of solids by the Scirocco disperser can be used to evaluate the ease of grindability of different materials.

Development of a novel approach towards predicting the milling behaviour of pharmaceutical powders.

A novel approach has been developed for evaluating the milling behaviour of pharmaceutical powders based on their material and mechanical properties obtained by single particle impact testing. Milling behaviour of two widely used pharmaceutical excipients, namely microcrystalline cellulose and alpha-lactose monohydrate has been analysed in an oscillatory single ball mill. It is found that the milling behaviour of these two powders can be described by analogy with a first-order rate process except for alphaLM at 18Hz of milling frequency. At the same time, single particle impact testing has been used to infer the material properties that are related to breakage. The milling rate of these powders is found to correlate well with the parameter representing the material properties including the particle size, density, hardness and critical stress intensity factor. This provides the basis for a novel approach towards analyzing the milling behaviour of a material based on a simple and reliable approach.

Steam reforming of crude glycerol with in situ CO(2) sorption.

Steam reforming of the crude glycerol by-product of a biodiesel production plant has been evaluated experimentally at atmospheric pressure, with and without in situ CO(2) sorption, in a continuous flow fixed-bed reactor between 400 degrees C and 700 degrees C. The process outputs were compared to those using pure glycerol. Thermodynamic equilibrium calculations were used to assess the effect on the steam reforming process of the main crude impurities (methanol and four fatty acid methyl esters). The crude glycerol and steam conversions and the H(2) purity reached 100%, 11% and 68%, respectively at 600 degrees C. No CH(4) was found at and above 600 degrees C. Steam reforming of crude glycerol with in situ CO(2) removal is shown to be an effective means of achieving hydrogen purity above 88% in pre-CO(2) breakthrough conditions.

Hydrogen production by sorption-enhanced steam reforming of glycerol.

Catalytic steam reforming of glycerol for H(2) production has been evaluated experimentally in a continuous flow fixed-bed reactor. The experiments were carried out under atmospheric pressure within a temperature range of 400-700 degrees C. A commercial Ni-based catalyst and a dolomite sorbent were used for the steam reforming reactions and in situ CO(2) removal. The product gases were measured by on-line gas analysers. The results show that H(2) productivity is greatly increased with increasing temperature and the formation of methane by-product becomes negligible above 500 degrees C. The results suggest an optimal temperature of approximately 500 degrees C for the glycerol steam reforming with in situ CO(2) removal using calcined dolomite as the sorbent, at which the CO(2) breakthrough time is longest and the H(2) purity is highest. The shrinking core model and the 1D-diffusion model describe well the CO(2) removal under the conditions of this work.

Use of the JKR model for calculating adhesion between rough surfaces.

A simple method for using the JKR model to determine interfacial adhesion between two ideal rough surfaces is demonstrated for individual asperity-asperity and asperity-flat contacts both in air and in water. The model takes into account the effect of a modified contact area at separation due to viscoelastic effects. The equilibrium version of the model significantly underestimates the measured adhesion, whereas the viscoelastic version of the model is much closer to the measured data. The asperity-flat geometry used with the viscoelastic version of the model seems to fit the experimental results best. This was thought to be due to the unlikely occurrence of direct asperity-asperity contacts. Instead, it would seem that the asperities have a far higher chance of fitting between each other on opposing surfaces, leading to correspondingly higher pull-off forces measured on separation. Many possible extensions to the roughness model described here may be made, allowing a much-improved understanding of the contact mechanics between two rough surfaces.