Static Powder Bed Research Articles

Formulation in a drop - Templated granulation and compaction analysis

Binder-powder interactions were investigated using single drop penetration on pharmaceutically relevant static powder beds. Experimental effects included polymer binder type, binder concentration, drug load, and pre-wetting of the powder bed. These screening effects are relevant to formulations requiring binder granulation, especially challenging formulations having high levels of micronized active ingredients. Interactions were explored using dynamic droplet imaging to measure drop penetration, contact angle, and drop diameter. The structure of the templated granules was analyzed via uniaxial compaction, focusing on the intermediate range of the compaction curve (granule deformation and closure of interstitial porosity in the compact). The results provide guidance in pharmaceutical formulation including the dynamics of granule formation and resulting compaction behavior. The approach is especially useful for early-stage development when only small quantities of drug substance are available.

Sequential fixed-fluidized bed foam granulation (SFFBFG) and drying: Multivariate model development for water content monitoring with near–infrared spectroscopy

Foam granulation (FG) is a non-conventional technique in which a binding solution is sprayed as aqueous foam. The main objectives of this work are, converting a lab-scale fluidized bed dryer into a fluidized bed foam granulator and dryer. Second, developing a partial least squares regression model for monitoring granules water content during this process, and third, bringing forward sufficient evidence of the fluidized bed foam granulation process feasibility. In this work, a mini-Glatt fluidized bed apparatus was used and aqueous foam was produced through an internal mixing nozzle located above the static powder bed, which is fluidized after foam dispensing. A micro-NIR probe was inserted across the powder container and gather spectral data during granulation and drying. The calibration model was built using the spectral data by Random Subset Cross-Validation and validated externally. Concerning the results, an Rcal2 and RMSECV of 0.945 and 1.67% w/w were obtained respectively. Model validation gave an Rval2 and RMSEP of 0.9 and 2.7% w/w respectively, demonstrating the ability of NIR spectroscopy to predict granules water content. The scanning electron microscopy (SEM) pictures validated the process feasibility.

Discrete element simulation of powder flow in revolution powder analyser: Effects of shape factor, friction and adhesion

Through discrete element method (DEM) simulations in Revolution Powder Analyser (RPA), we found a strong correlation between the static powder bed packing density and the avalanche flow. A wider powder size distribution and a higher fraction of non-spherical powders caused larger misfits in the static packing of powders, and thereby enhanced the powder mobility during revolution, leading to an earlier avalanche. It performs a gradual avalanche under low friction, and an abrupt avalanche under high friction. The rolling motion of non-spherical powders was found to cause an instantaneous disturbance to the flow of neighbouring powders. It was also found that other factors, such as the filling degree, drum rotation speed and inter-powder adhesion, can also influence the measurement results and hence they must be controlled or standardized in order to achieve reliable and consistent measurements. Furthermore, based on the experimental measurements of avalanche angle and packing fraction, we extracted the intrinsic powder friction coefficient and adhesion energy. • DEM powder flow models with realistic powder size and shape distributions. • Performed DEM simulations to study powder flow profiles and avalanche phenomena. • Examined and identified the effects of system factors for reliable RPA measurements. • Extracted the rolling COF and adhesion energy by including powder non-sphericity.

Powder bed packing and API content homogeneity of granules in single drop granule formation

Single drop granule formation on a static powder bed of pharmaceutical mixtures was studied to investigate the effects of hydrophobicity and primary particle size distribution on the powder bed packing structure and the content homogeneity of active pharmaceutical ingredient (API) in granules formed. The granule formation mechanisms, drop penetration time, granule morphology and internal structure have been previously investigated in a mixture of coarse microcrystalline cellulose (MCC) and fine acetaminophen (APAP). When the APAP amount increased (decreasing particle size and increasing hydrophobicity), drop penetration time increased, formation mechanisms transitioned from Spreading to Tunneling, the granules became smaller in size, and the internal porosity of the granules decreased (Gao et al., 2018). In the current study, single drop granulation on mixtures of MCC and APAP with different particle sizes were investigated for formation mechanisms and granule morphology. Additionally, the powder bed packing structure was characterized by X-ray micro-CT and the API content uniformity was measured by UV–vis spectrometry. It was found that in the mixture made from coarse MCC and fine APAP, the internal structure became heterogeneous and there were dense aggregate regions in both the powder bed and granules from 25% APAP proportion, where the transition from Spreading to Tunneling occurs. The content uniformities of granules from fine powder beds are much more compromised (indicating a discrepancy between the actual value and theoretical value) than those from coarse powder beds. This content discrepancy becomes much larger when the APAP proportion in the powder bed is higher (above 50%). This was previously observed by other researchers (Nguyen et al., 2010) and was attributed to the preferential wetting of the ingredients. It is believed that the primary particle size of the powder bed is more significant than the hydrophobicity in affecting the formation mechanism, granule internal structure, and content uniformity.

Granule formation and structure from single drop impact on heterogeneous powder beds

Single drop impact of liquid on a static powder bed was studied to investigate the granule formation mechanism, droplet penetration time, as well as the characterization of granules (morphology, surface structure and internal structure). Water was used as the liquid and two pharmaceutical powders, microcrystalline cellulose (MCC) and acetaminophen (APAP), were mixed to make heterogeneous powder beds. The complete drop impact and penetration was recorded by a high speed camera. Two granule formation mechanisms that have been identified previously occurred: Spreading and Tunneling. Spreading occurred for mixtures with an APAP amount of less than 20%, while Tunneling started to occur when the APAP amount increased above 20%. With an increase of APAP concentration, the mean particle size decreased, drop penetration time increased, and the granules formed became smaller in size, which was in good agreement with previous literature. The granule morphology, surface structure, and internal structure were characterized by a prism method with image analysis, scanning electron microscopy (SEM), and X-ray microtomography, respectively. The Spreading mechanism produced flat disks with a porous internal structure, while the Tunneling mechanism produced round granules with a dense internal structure. There is a clear trend of decreasing porosity and increasing roundness of granules made from heterogeneous mixtures within the transition from Spreading to Tunneling. It is believed that the mean particle size of the powder bed and the powder-liquid contact angle are the predominant factors in influencing the formation mechanism, drop penetration time, and granule properties.

Kinetics of immersion nucleation driven by surface tension

Immersion nucleation is the nuclei formation mechanism for wet granulation systems where the liquid drops are large relative to the primary particles. The process of immersion nucleation has been examined in many studies, however the kinetics of nuclei formation are not well understood, and there is a distinct lack of experimentally validated models for this process.A kinetic model has been proposed by Hounslow et al. (2009) which describes surface tension driven immersion nucleation. This paper presents the results from a series of experiments measuring the kinetics of immersion nucleation, and these results are compared with the model predictions. Drops of model liquids (aqueous HPMC solution and silicone oil) are placed on static powder beds of zeolite and lactose. Nuclei granules are carefully excavated at different times and the change in granule mass with time is measured. As predicted by Hounslow et al.'s model, the granule mass increases with the square root of time to a maximum granule size at a time tmax after an initial adjustment period. The critical packing factor is shown to be a function of powder properties, and not dependent on the liquid properties. The model captures well the measured effects of liquid and powder properties. However, the kinetics of the nucleation process are much slower than predicted by the model. It is believed this is due to continued percolation of the liquid within the powder bed, after the liquid drop is fully immersed. This secondary liquid movement may have an important effect on granule growth kinetics, and influence final granule product properties.

Hydrophobic/hydrophilic static powder beds: Competing horizontal spreading and vertical imbibition mechanisms of a single droplet

There are two competing mechanisms of a single liquid droplet impacting on static powder beds. The dh spreading describes the length the liquid droplet travels horizontally across the powder bed, whereas the dv imbibition is the length the liquid droplet travels vertically into the powder bed.In this work, results are presented from an experimental study of single liquid droplets of varying viscosities impacting static hydrophilic and hydrophobic powder beds. By using a high-speed video camera, the dynamics of the droplet spreading behaviour on static powder bed compacts was captured. The resultant nuclei were then analysed. Results show that the measured maximum dh spreading diameter is less than the diameter of the resultant nuclei. This indicates that the dh spreading of the liquid droplet continues to spread after complete imbibition in a late-diffusive intra-spreading process. This process refers to liquid movement driven by capillary forces in the powder beds and showed a higher degree of dependency on the liquid binder viscosity. The dv imbibition length was found to be dependent on the interfacial tension between the solid and the liquid droplet. This transition in the liquid spreading and imbibition behaviour is explained based on the transportation of a liquid droplet occurring increasingly via site percolation theory with increase in powder bed hydrophobicity. The liquid droplet imbibition rates are described in terms of Darcy's law scaling behaviour. Understanding of single droplet spreading mechanisms provides a basis to select the optimal binder for granulation to form more uniform and robust granules when using hydrophilic and hydrophobic formulations.

Microstructure of single-droplet granules formed from ultra-fine powders

A quantitative analysis of variations in granule microstructure based upon changes in primary particle size and bed preparation is presented. The granule microstructures are obtained using X-Ray Computed Tomography (XRCT). An algorithm is developed to measure the number and size of macro-voids (pore space with volume equivalent size greater than or equal to 30μm or 3 times the primary particle size). Four size fractions of alumina, ranging in primary particle size from 0.5μm to 108μm, are sieved using three different sieve sizes to create static powder beds from which single-droplet granules are produced. The analysis shows that large macro-voids exist in ultra-fine powders (0.1–10μm). The macro-voids take up to 7% of the granule volume and the largest macro-voids are 200–700μm in volume equivalent size. Changing the sieve preparation changes the size and total volume of macro-voids. In contrast, there are very few macro-voids in granules formed from coarser powders. This study shows that micron sized powders have the opportunity to form complex structures during granulation and that the handling history of the materials should receive greater scrutiny than it currently gets.

An insight into powder entrainment and drug delivery mechanisms from a modified Rotahaler®

This study aims to improve understanding of the powder fluidisation and aerosolisation processes unique to a split capsule dry powder inhaler. It uses a combination of dynamic real-time methods and a suite of powder material physicochemical characterisation methods. The study focused on examining the effect of different characteristics of lactose carrier employed, and considered specifically the powder fluidisation, entrainment and de-agglomeration mechanisms. A GSK Rotahaler® was selected as the inhaler device. Powder fluidisation and entrainment were investigated using the ensemble technique of laser diffraction and high-speed imaging. This ensemble technique afforded both the powder entrainment profile and simultaneous visual confirmation of the capsule movement and powder fluidisation within the Rotahaler. The results showed that powder fluidisation from a dynamic split capsule was substantially different to that from a static powder bed. Furthermore, the presence of the split capsule dominated powder emission mechanisms from the Rotahaler, regulated by its impaction on the grid/Rotahaler wall and the rotational movement in the entrained air. Of all the material characterisation metrics, the most significant linear correlation was revealed between powder permeability and the aerosolisation efficiency as measured by fine particle fraction (R2=0.98). This indicates that drug delivery from the Rotahaler was mainly governed by the influence of the cohesive fine particle size component. Powder permeability as a practical test may afford an effective and practical predictive link between the raw excipients and drug delivery performance from the capsule device.

A regime map for granule formation by drop impact on powder beds

“Tunneling,” “Spreading,” and “Crater Formation” are the three granule formation mechanisms known to occur when single drops impact static powder beds. To quantify the conditions under which each mechanism will occur, dimensional analysis was performed, and a new regime map was created that plots the powder bed porosity against the modified granular Bond number (Bog*), which is a ratio of the capillary force to the gravitational force acting on a particle. Tunneling occurred for Bog* > 65,000 for all values of bed porosity, whereas Spreading and Crater Formation occurred when Bog* < 65,000 for all values of bed porosity below the minimum fluidization porosity. The granule formation mechanism regime map provides a useful tool to design and predict wet granulation processes by predicting the granule formation mechanism, and thereby general granule shape, from a few key dimensionless groups involving formulation properties and process parameters that can be calculated a priori. © 2012 American Institute of Chemical Engineers AIChE J, 59: 96–107, 2013

Drug distribution in wet granulation: foam versus spray

Foam granulation technology is a new wet granulation approach for pharmaceutical formulations. This study evaluates the performance of foam and spray granulation in achieving uniform drug distribution using a model formulation. To observe wetting and nuclei formation, single drop/foam penetration experiments were performed on a static powder bed comprised of varying compositions of hydrophilic/hydrophobic glass ballotini, and hydrophilic lactose/hydrophobic salicylic acid respectively. High shear granulation experiments were performed in a 5L mixer using varying compositions of hydrophilic lactose and hydrophobic salicylic acid. Four percent hydroxylpropyl methylcellulose (HPMC) solution was delivered at 90 g/min as either a foam (92% FQ) or an atomized spray whilst recording impeller power consumption. After drying, the granule size distribution was measured and the granule composition was estimated using gravimetric filtration in methanol. Foam penetration was less dependent on the powder hydrophobicity compared to drop penetration. For glass ballotini powder mixtures, foam induced nucleation created nuclei with relatively uniform structure and size regardless of the powder hydrophobicity. For salicylic acid and lactose mixtures, increasing the proportion of salicylic acid reduced the nuclei granule size for both foam and drop binder addition. The granule drug distribution was not significantly affected by the binder addition method. Processing conditions, including liquid binder amount, impeller speed, wet massing, and the wettability properties of the formulation were the dominant factors for delivering homogeneous granules. The study reveals that foam and spray granulation involve different nucleation mechanisms – spray tends to incur early liquid penetration whereas foam granulation operates well in mechanical dispersion.

THE INFLUENCE OF LIQUID FLOW RATE ON NUCLEUS FORMATION IN HIGH SHEAR GRANULATION

This paper looks at the nucleation stage, which is a fundamental stage of the granulation process. In order to clarify this mechanism the penetration time of the liquid into the powder bed was studied in both the cases of static and moving beds. Then the formation of the nuclei was studied by slowing down the binder addition rate. The effect of binder addition rate and viscosity on the size and binder fraction of the nuclei and granules was also demonstrated in this study. It was revealed that the penetration time is second power of drop size. Linear relationships between nucleus size and drop size onto both a static powder bed and a moving bed have also been found. It was shown the significant effect of the viscosity of binder on the drop sizes in both static and moving bed cases and granules keep their integrity; large nuclei produce large granules.

Granulation behaviour of increasingly hydrophobic mixtures

Abstract Wet granulation is the formation of powder particle assemblies bound by a liquid binder. Granules are produced in order to prevent mixture segregation, improve flow characteristics and ease of powder handling. The liquid binder droplets penetrate into, and bind together, powder particles being agitated in a mixer. Real granulation formulations are complex and challenging. The difficulty of achieving controlled water based wet granulation of a formulation containing a hydrophobic component is one such challenge that is receiving increasing attention in academic and industrial research. The present work has focussed on the granulation of multicomponent batches, specifically mixtures of hydrophilic Granulac230 (lactose) and hydrophobic limestone, using different spray droplet sizes and impeller speeds. The granulation behaviour of the batches is assessed in terms of granule size and compositional distributions on increasing the hydrophobic content of the batch. Transitions in granulation behaviour are reported as the hydrophobic content of the batch is increased. The granulation behaviour is linked to static powder bed penetration times by assigning ‘compositional zones’, which could be used as a predictive tool in formulation and process development In addition, a new preferential nucleation and layering mechanism is proposed to describe the experimental data and better understand how the ‘compositional zones’ of granulation behaviour have arisen.

Foam granulation: Liquid penetration or mechanical dispersion?

There have been significant advances in the understanding of wet granulation processes. Foam granulation is the latest development and an emerging area of interest for pharmaceutical manufacturing. Single foam penetration experiments were carried out on static powder beds, followed by short-nucleation experiments (where nuclei are formed by a nucleation-only mechanism) and full foam granulation experiments (where nucleation, growth and breakage are occurring simultaneously). All experiments were performed with lactose monohydrate powder using a 5 L high shear mixer–granulator. The foam penetration/dispersion behaviour was examined and the granule size distributions were investigated as a function of foam quality (83–97% FQ), impeller speed (105–515 rpm) and wet massing period (0–4 min). Nucleation in foam granulation is postulated to undergo either “foam drainage” or “mechanical dispersion” controlled mechanisms. For “foam drainage” mechanism, the foam penetrates the powder bed to form coarse and broad granule size distributions. For “mechanical dispersion” mechanism, the wetting and nucleation conditions are governed by the powder mixing conditions and similar granule size distributions are produced. Regardless of the mechanism, the initial wetting and nucleation behaviour controls the initial nuclei size distribution, and this initial distribution is retained in the final granule size distribution. This work demonstrated the critical importance of the nucleation and binder distribution in determining the granule size distributions for foam granulation process.

Granule formation mechanisms and morphology from single drop impact on powder beds

Single drops impacting static powder beds were studied to explain the different resulting granule structures. Three chemically similar powders with different physical properties formed static beds with porosities of 0.66–0.69, 0.54, and 0.30–0.35 respectively. Three different binder fluids (distilled water and silicone oils with viscosities of 9.3 and 96 mPa s) were released onto these powder beds from two different heights (0.5 and 30 cm). The initial drop impact, as well as complete penetration of the droplet into the bed, was recorded with a high speed camera. The high speed camera videos were analyzed, and three different granule formation mechanisms were identified: Tunneling, Spreading, and Crater Formation. Tunneling occurred for loose, cohesive powder beds. Powder aggregates were sucked into the drop which then tunneled into the beds. For coarser powders, granules were formed by a Spreading mechanism at a low impact velocity. At a high impact velocity, the drop formed a crater in the bed surface and deformed elastically in the crater, coating the drop in a layer of powder before penetrating into the bed by capillary action. Using all three dimensions of the granule, a new shape factor, the vertical aspect ratio (the ratio of the granule's projected area diameter to its maximum vertical height), was proposed as a more accurate descriptor of granule shape than currently used descriptors such as the horizontal aspect ratio. The different granule shapes observed were explained by the granule formation mechanisms. The Tunneling mechanism always produced round granules, the Spreading mechanism always produced flat disks, and the Crater Formation mechanism produced granules of varying shapes that were dependant on liquid binder properties. The results of this study have important implications for being able to predict granule structure from granule formation mechanisms, and to be able to choose the desired granule properties by operating in the appropriate regime.

Drop impact and agglomeration under static powder bed conditions

AbstractThe influence of impact conditions (reported in terms of Weber and Reynolds numbers) on nucleus formation was studied for single drops striking a static glass bead bed. Results from high speed images showed that the nucleation rate is not influenced by liquid physical properties (density, surface tension, viscosity) for drops that spread significantly (30 < We < 233). Results also showed that nucleus size is determined by how much liquid penetrates into the bed during drop spreading, so does depend on surface tension and liquid density. A corresponding analytical model, derived from first principles, predicts nucleus size to with 1.5% using only liquid physical and powder bed properties, plus the experimentally measured drop spreading behavior. © 2011 American Institute of Chemical Engineers AIChE J, 2012

Physical Characterization of Component Particles Included in Dry Powder Inhalers. II. Dynamic Characteristics

Characteristics of particles included in dry powder inhalers is extended from our previous report (in this journal) to include properties related to their dynamic performance. The performance of dry powder aerosols for pulmonary delivery is known to depend on fluidization and dispersion which reflects particle interactions in static powder beds. Since the solid state, surface/interfacial chemistry and static bulk properties were assessed previously, it remains to describe dynamic performance with a view to interpreting the integrated database. These studies result in complex data matrices from which correlations between specific properties and performance may be deduced. Lactose particles were characterized in terms of their dynamic flow, powder and aerosol electrostatics, and aerodynamic performance with respect to albuterol aerosol dispersion. There were clear correlations between flow properties and aerosol dispersion that would allow selection of lactose particles for formulation. Moreover, these properties can be related to data reported earlier on the morphological and surface properties of the carrier lactose particles. The proposed series of analytical approaches to the evaluation of powders for inclusion in aerosol products has merit and may be the basis for screening and ultimately predicting particle performance with a view to formulation optimization.

Powder specific active dispersion for generation of pharmaceutical aerosols

Dry powder inhalers are increasingly employed to deliver pharmaceutical aerosols. Efficient mechanisms of particle dispersion are central to their success in disease therapy. Creation of a powder aerosol requires the input of energy to transition the static powder bed into an entrained aerosol. The purpose of this study was to investigate the effects of input of vibrational energy into a powder on aerosol entrainment. Rotating drum characterization of powder flow was performed on lactose and maltodextrin excipients blended with albuterol sulfate. Dispersion experiments were conducted using an entrainment tube and a vibration actuator, vibrational energy input being derived from analysis of powder flow data from rotating drum analysis. Results of analysis of the rotating drum data showed that with increasing rotational speed powders reached a constant state of fluidization with a mean avalanche time dependent on the powder. Dispersion experiments demonstrated that the input of vibrational energy increased the dose emission while the input of frequencies specific to the powders improved the reproducibility. Frequency analysis of the vibration signals indicated that the reproducibility was determined by the bandwidth of the signal. This work suggests that an ability to tailor energy input to match the flow properties of a given powder formulation may significantly improve reproducibility of dose delivery from active dry powder inhalers.

Fluidization of ferromagnetic particles in a magnetic field Part 2: Field effects on preliminarily gas fluidized bed

The bed behaviour of preliminarily fluidized beds has been investigated in the presence of an external magnetic field, using different ferromagnetic materials which are non-cohesive in the absence of a magnetic field. The field was applied at fixed gas velocity on particles which are already fluidized. This mode of operation is known as ‘magnetization LAST’. Homogeneous magnetic fields in two limiting orientations axial and transverse — were used. The results are compared with those obtained when the field was applied to a static powder bed before fluidization, i.e. the ‘magnetization FIRST’ mode. The terms used to describe the regimes in both modes are reviewed.

Effect of powder bed on critical heating rates for thermolysis of ceramic injection moldings

AbstractThe mass transport during pyrolysis of the degradation product of a polymeric binder used for ceramic molding is analyzed. Two series resistances to transport are incorporated: the diffusion of the product of degradation through its parent polymer during decomposition and the permeation of vapor through a static powder bed used to support the molding. The model predicts the critical rate of heating, Zc, above which defects caused by boiling of the organic phase occur at the center of the molding. For the system modeled, the permeability of the powder bed has little effect on Zcif the moldings are small but this is not the case for large moldings where well‐packed fine powders should be avoided and the thickness of the powder bed should be kept to a minimum.