Search

3D printing has been applied in numerous research fields ranging from biomedical, mechanical engineering and chemistry to material science. 3D printing applications have driven innovations in particle technology, especially through tackling particle-related issues arising from the development of particle-based printing feedstocks across such application areas. Therefore, in this review, established 3D printing processes are described to include their prototyping mechanisms, advantages and limitations. Various particulate systems, including dry and wet systems, as printing feedstock materials are introduced. The main motivation for this paper is to outline the current state of particulate feedstock systems and to attempt to outline future directions for enhancing these particle applications. This paper would be valuable for individuals, researchers and companies who need adequate and comparative information regarding the state of particle applications in the AM industry.

Binder jetting is an additive manufacturing technique that creates three-dimensional constructs from a powder feedstock. It is used by several industries, including pharmaceuticals. This additive approach to manufacture provides several functional benefits that are not easily achievable using conventional manufacturing methods. There is currently only limited publicly available knowledge that details the requirements of an effective binder jetting powder. Specifically in the pharmaceutical industry, since the 2015 release of Spritam®, a binder-jetted tablet containing levetiracetam, no new pharmaceutical tablets have been produced using such methods. There appears to be gap in powder technology expertise and the development of 3D printing processes. Our goal is to enhance our knowledge in terms of powder flow, powder wetting and powder binding to link particles with process and build the capability to create a greater range of powders suitable to be binder-jetted into new products. After initially screening several standard pharmaceutical excipient powders for their relevant properties, two candidates showed best fit potential for use in binder jetting, specifically microcrystalline cellulose (Pharmacel 101 and 102) and lactose (Lactohale 200). Using simple formulations of these pharmaceutical excipient powders as a model, we analysed for printability and powder performance using a range of quantitative parameters including dimensional accuracy, construct hardness, friability, porosity and surface finish. In general, formulations of these powders showed good printability, but some powder blends produced constructs with more obvious manufacturing imperfections. Several routes to improve the printability of these pharmaceutical powders are proposed for future works. Ultimately, this work provides a fundamental basis to start to quantitatively assess the potential of standard pharmaceutical excipient powders in binder jetting printers using powder characterisation techniques and print quality outcomes.

The current study presents a novel and reliable method for producing 3D printed agglomerates with different colour distributions and material properties with 2-fold aims: providing feasible and accurate control on compression of agglomerates under different compression angles, and better tracking of individual particle position after agglomerate breakage. Multi-coloured agglomerates in cubic tetrahedral and random sphere shapes were printed with both rigid and soft bonds. The printed agglomerates were analysed thoroughly of their surface and structural properties including surface roughness and printing accuracy. The agglomerate breakage behaviours under static compression were analysed as a function of bond strength, loading rate and loading directions, with strain distribution plotted over the random sphere agglomerate structure. In addition, agglomerate structures with designed internal macro-voids in different positions and sizes were also created for breakage study, in an effort to better understand parameters governing the mechanical properties of agglomerates with cavities and voids which is inevitable in particle industry but poorly understood at present.

Simulation of pharmaceutical unit operations by the discrete element method (DEM) has elevated our understanding of the impact of single-particle interactions on themselves, and on the entire tablets/powder. Studies in the past have shown how this knowledge helps to mitigate/solve multiple challenges during conventional formulation and process development/modernization/troubleshooting, with minimal use of active drug material. This communication adds to this- highlighting the tool's potential for a rapid preliminary assessment of the mechanistic attributes of multiple unit particle system (MUPS) based tablet and capsule drug products.

Mechanofusion is a dry coating method that can be used to improve the flowability of cohesive powder by coating host particles with a lubricant, for example magnesium stearate (MgSt). It has been shown previously that fragmenting material can under some circumstances be mechanofused with MgSt without impairing compactibility of the powder and without reducing the dissolution rate of the resulting tablets. However, the effects on material with viscoelastic behaviour, known to be sensitive for the negative effects of MgSt, is not known. Therefore, mechanofusion of microcrystalline cellulose (MCC) with MgSt was investigated in this study. Four MCC grades were mechanofused with different MgSt concentrations and process parameters, and the resulting flowability and compactibility were studied. Starting materials and low-shear blended binary mixtures were studied as a reference. Mechanofusion improved the flow properties of small particle size MCC powders (d50 78 μm) substantially, but increasing the MgSt content consequently resulted in weaker tablets. Larger particle size MCC grades, however, fractured under the shear forces during the mechanofusion process and hence their flow properties were decreased. Improvement of the flow properties but also the negative effects on compactibility of small particle size grades were observed even at relatively mild mechanofusion parameters and low lubricant concentrations.

The determination of the surface energy of free-flowing fine powders through IGC analysis can be technically challenging. These powders can have high packing efficiencies that can often lead to excessive gas pressure build up as the mobile phase passes through the stationary phase. As such, free-flowing fine powders may not necessarily be readily suitable to form the stationary phase of an IGC system. To alleviate this challenge, large carrier particles, in the form of silanized glass powders, can be blended with the free-flowing fine powder, in a manner that aids in disrupting the packing efficiency. However, the major concern here is that the introduced foreign material can potentially interfere with the probing of the sample of interest. This research found that blending 250 μm silanized glass beads with a free-flowing fine powder can effectively reduce the pressure build up to prevent the system from over-pressuring. Additionally, it was observed that there is a critical mass for the sample of interest. Below this critical mass, the introduction of the carrier particles can interfere with the determination of the surface energy of the sample, where the surface energy was underestimated. However, above this critical mass, the introduction of the carrier particle does not significantly influence the surface energy determination of the sample of interest. It is therefore concluded that blending free-flowing fine powders with large carrier particles is a potential approach to resolve the challenge of over-pressured systems, provided the mass of the powder of interest is above the critical mass for that powder.

This study aims at testing the feasibility of a single-step coating process to produce a powder formulation of active and inactive ingredients for direct compression. A cohesive ibuprofen powder was coprocessed with a coating material, a binder (polyvinylpyrrolidone K25), and a superdisintegrant (crospovidone). Magnesium stearate (MgSt), l-leucine, and silica were selected as coating materials (1% w/w). A coprocessed powder without any coating material was employed as a control. Coating with MgSt, l-leucine, or silica produced significantly improved powder flow in comparison to the control batch. Robust tablets were produced from the processed powders for each coating material. The tablets compacted using the coated powders with MgSt or l-leucine also exhibited significantly lower tablet ejection forces than the control batch, demonstrating their lubrication effect. Furthermore, the disintegration time and dissolution rates of these tablets made of the formulations coprocessed with lubricants were enhanced, even for those coated with the hydrophobic material such as MgSt that has been previously reported to inhibit dissolution. However, the tablets made with silica-coated powders would not disintegrate. This study indicated the feasibility of a single-step dry coating process to produce powders with both flow-aid and lubrication effects, which are suitable for direct compression.

Objective In this study, we investigated the applicability of cohesive–adhesive balance (CAB) model to predict the interactive mixing behaviour of small excipient particles. Further, we also investigated the application of this CAB model to predict the flow and compactibility of resultant blends. Methods Excipients created by co-spraying polyvinylpyrrolidone (PVP, a model pharmaceutical binder) with various l -leucine concentrations were used for this study. Paracetamol was used as model active pharmaceutical ingredient (API). The surface energy was used to derive the work of cohesion ( w co ) and work of adhesion ( w ad ) to predict the interactive mixing behaviour of the excipients with paracetamol. The blends were visualised under a scanning electron microscopy microscope to assess the interactive mixing behaviour. In addition, the flow performance and tabletting behaviour of various blends were characterised. Results The surface-energy derived work of adhesion ( w ad ) between excipient and paracetamol particles increased, while the corresponding work of cohesion ( w co ) between excipient particles decreased, with increasing l -leucine concentrations. In blends for which the work of cohesion was higher than the work of adhesion ( w co > w ad ), small excipient particles were apparent as agglomerates. For excipients with 5% and higher l -leucine concentrations, the work of adhesion between excipient and paracetamol particles was higher than or equivalent to the work of cohesion between excipient particles ( w ad ⩾ w co ) and agglomerates were less apparent. This is an indicator of formation of homogeneous interactive mixtures. At 5% (w/w) excipient proportions, blends for which w ad ⩾ w co demonstrated higher compactibility than other blends. Furthermore, at 10% (w/w) and higher excipient proportions, these blends also demonstrated better flow performance than other blends. Conclusion In conclusion, this is the first study to demonstrate that surface-energy derived CAB data effectively predict the interactive mixing behaviour of small excipient particles. Furthermore, at certain proportions of small excipient particles the CAB model also predicts the flow and compaction behaviour of the API/excipient blends.

This study aimed to investigate the surface energy factors behind improved aerosolization performance of spray-dried colistin powder formulations compared with those produced by jet milling. Inhalable colistin powder formulations were produced by jet milling or spray drying (with or without l-leucine). Scanning electron micrographs showed the jet-milled particles had irregularly angular shapes, whereas the spray-dried particles were more spherical. Significantly higher fine particle fractions were measured for the spray-dried (43.8%-49.6%) versus the jet-milled formulation (28.4%) from a Rotahaler at 60 L/min; albeit the size distribution of the jet-milled powder was smaller. Surprisingly, addition of l-leucine in the spray drying feed solution gave no significant improvement in fine particle fraction. As measured by inverse gas chromatography, spray-dried formulations had significantly (p < 0.001) lower dispersive, specific, and total surface energy values and more uniform surface energy distributions than the jet-milled powder. Interestingly, no significant difference was measured in the specific and total surface energy values between the spray-dried formulation with or without l-leucine. Based on our previous findings in the self-assembling behavior of colistin in aqueous solution and the surface energy data obtained here, we propose the self-assembly of colistin molecules during spray drying contributed significantly to the reduction of surface free energy and the superior aerosolization performance.

PURPOSE: Dissolution behavior of dry powder inhaler (DPI) antibiotic formulations in the airways may affect their efficacy especially for poorly-soluble antibiotics such as azithromycin. The main objective of this study was to understand the effects of surface composition on the dissolution of spray dried azithromycin powders by itself and in combination with colistin. METHODS: Composite formulations of azithromycin (a poorly water-soluble molecule) and colistin (a water-soluble molecule) were produced by spray drying. The resultant formulations were characterized for particle size, morphology, surface composition, solid-state properties, solubility and dissolution. RESULTS: The results demonstrate that surfaces composition has critical impacts on the dissolution of composite formulations. Colistin was shown to increase the solubility of azithromycin. For composite formulations with no surface colistin, azithromycin released at a similar dissolution rate as the spray-dried azithromycin alone. An increase in surface colistin concentration was shown to accelerate the dissolution of azithromycin. The dissolution of colistin from the composite formulations was significantly slower than the spray-dried pure colistin. In addition, FTIR spectrum showed intermolecular interactions between azithromycin and colistin in the composite formulations, which could contribute to the enhanced solubility and dissolution of azithromycin. CONCLUSIONS: Our study provides fundamental understanding of the effects of surface concentration of colistin on azithromycin dissolution of co-spray-dried composite powder formulations.

In this study a carrier-free dry powder inhalation (DPI) containing L-arginine (ARG) was developed. As such, it is proposed that ARG could be used for adjunctive treatment of cystic fibrosis and/or tuberculosis. Various processing methods were used to manufacture high-dose formulation batches consisting various amounts of ARG and excipients. The formulations were evaluated using several analytical methods to assess suitability for further investigation. Several batches had enhanced in vitro aerolization properties. Significant future challenges include the highly hygroscopic nature of unformulated ARG powder and identifying the scale of dose of ARG required to achieve the response in lungs.

Tablets represent the preferred and most commonly dispensed pharmaceutical dosage form for administering active pharmaceutical ingredients (APIs). Minimizing the cost of goods and improving manufacturing output efficiency has motivated companies to use direct compression as a preferred method of tablet manufacturing. Excipients dictate the success of direct compression, notably by optimizing powder formulation compactability and flow, thus there has been a surge in creating excipients specifically designed to meet these needs for direct compression. Greater scientific understanding of tablet manufacturing coupled with effective application of the principles of material science and particle engineering has resulted in a number of improved direct compression excipients. Despite this, significant practical disadvantages of direct compression remain relative to granulation, and this is partly due to the limitations of direct compression excipients. For instance, in formulating high-dose APIs, a much higher level of excipient is required relative to wet or dry granulation and so tablets are much bigger. Creating excipients to enable direct compression of high-dose APIs requires the knowledge of the relationship between fundamental material properties and excipient functionalities. In this paper, we review the current understanding of the relationship between fundamental material properties and excipient functionality for direct compression.

Pulmonary immunization has recently gained increased interest as a means to induce both systemic and mucosal immunity while eliminating issues associated with the use of needles in parenteral vaccination. However, in contrast to the inhaled delivery of small molecule drugs, a dry powder carrier platform that is readily adaptable to the incorporation of biomacromolecules (e.g., vaccine antigens) as a common standard is lacking. Spray-dried trehalose with leucine has previously been characterized and demonstrated to produce highly aerosolizable powders containing an amorphous glassy matrix suitable for stabilization of biomacromolecules. This study aimed to further extend the understanding in the use of this formulation as a dry powder carrier platform in an in vivo setting, using influenza antigen as a model, for pulmonary delivery of biomacromolecules.Spray-dried influenza vaccine was produced using previously established spray-drying conditions. The formulations were characterized to examine the impact of influenza antigen on the solid-state properties of the spray-dried powders. The optimal vaccine formulation was then selected for in vivo immunogenicity study in rats to evaluate the efficacy of the reconstituted spray-dried vaccine compared to liquid vaccine administered via pulmonary and subcutaneous routes.The formation of amorphous glassy matrix and morphology of the spray-dried particles, within the protein concentration range used in the study, was not affected by the incorporation of the influenza antigen. However, the amount of proteins incorporated increased water content and reduced the glass transition temperature (Tg) of the formulation. Nevertheless, the spray-dried vaccine induced strong mucosal and systemic immunity comparable to liquid vaccine after pulmonary and subcutaneous immunization without causing any inflammation to the lung parenchyma.The study demonstrated the usability of the spray-dried carrier as a promising platform for pulmonary delivery of influenza vaccine. The potential utility of this delivery system for other biomacromolecules may also be further explored.

In this study, polyvinylpyrrolidone (PVP) was spray dried with l -leucine (PVP-Leu) to create a prototype multifunctional interactive excipient. The physico-chemical and bulk properties such as particle size, surface composition, surface energy and bulk cohesion of PVP-Leu was measured and compared against pure spray dried PVP (PVP-SD). The mixing behaviour of these excipients and their effect on flow and binder activity of paracetamol was assessed. The mean particle sizes of PVP-Leu PVP-SD and PVP were 2.5, 2.1 and 21.9 μm, respectively. Surface composition characterization indicated that l -leucine achieved higher concentrations on the surface compared to the bulk of the PVP-Leu particles. The surface energy of PVP-Leu was significantly lower compared to PVP-SD. In addition, PVP-Leu exhibited a significantly lower bulk cohesion compared PVP-SD. The excipients were blended with paracetamol and qualitative characterization indicated that PVP-Leu blended more homogeneously with paracetamol compared to PVP-SD. Both PVP-Leu and PVP-SD then exhibited a significantly improved binder activity compared to PVP. The flow of the paracetamol was markedly improved with PVP-Leu while PVP-SD and PVP had negligible effect on its flow. This study reveals how physico-chemical and bulk properties of such prototype interactive excipients can play a key role in determining multi-factorial excipient performance.

Silk particles of different sizes and shapes were produced by milling and interactions with a series of polar and non-polar gaseous probes were investigated using an inverse gas chromatography technique. The surface energy of all silk materials is mostly determined by long range dispersive interactions such as van der Waals forces. The surface energy increases and surface energy heterogeneity widens after milling. All samples have amphoteric surfaces and the concentration of acidic groups increases after milling while the surfaces remain predominantly basic. We also examined powder compression and flow behaviours using a rheometer. Increase in surface energy, surface area, and static charges in sub-micron air jet milled particles contributed to their aggregation and therefore improved flowability. However they collapse under large pressures and form highly cohesive powder. Alkaline hydrolysis resulted in more crystalline fibres which on milling produced particles with higher density, lower surface energy and improved flowability. The compressibility, bulk density and cohesion of the powders depend on the surface energy as well as on particle size, surface area, aggregation state and the testing conditions, notably the consolidated and unconsolidated states. The study has helped in understanding how surface energy and flowability of particles can be changed via different fabrication approaches.

Tablets make up approximately one third of all drug dosage forms which makes tablet manufacture a common process in the pharmaceutical industry. The unified compaction curve [1] is a model developed initially to look at the impact of the roller compaction conditions on the tablet strength. The tensile strength of the tablets made from formulations containing at least 50% microcrystalline cellulose produced at roller compaction pressures were measured and the profiles were collapsed into a single master “unified compaction curve” (UCC). This allowed for the tablet strength to be predicted from the roller compaction condition and formulations and target the required tablet strength criterion set by standards or specifications [1] . The unified compaction curve was applied to investigate the effects of the wet granulation conditions in a 5L Key granulator on the tablet tensile strength. The study was based on a placebo formulation comprising of 50wt% microcrystalline cellulose, 50wt% lactose and a 5w/v% PVP (K90) binder solution. The effects of the liquid level (20-50wt%), wet massing time (0-10 minutes), binder flow rate (130 g/min and 280 g/min) and impeller speed (150, 285 and 600 rpm) on the tablet strength were explored. Scale-down experiments to a 1L mixer bowl were also conducted. Tablets were produced on a single station carver press with controlled force. A series of compaction profiles were created to represent the relationship between the tablet tensile strength, compaction pressure and the granulation condition. By fitting the unified compaction curve model to the data using a shifting intercept approach, the profiles exploring each granulation condition collapsed onto a single master curve which predicts the tablet strength as a function of the liquid level, wet massing time or the binder flow rate. Increasing the liquid level and/or wet massing time caused a reduction in the tablet hardness when compressed at the same compaction force, and the reduction is postulated to be proportional to the effective compaction forces experienced during granulation, PWGC. The PWGC data further collapses onto a single master curve which is solely a function of the total number of impeller revolutions. Further characterization of the granules produced at these conditions showed that the UCC intercept parameter, PWGC was inversely proportional to the granule porosity, linking the granule microstructure directly and quantitatively to the tablet strength during compaction. This is a significant finding that will allow formulators to optimize tablet hardness via a simple adjustment to the granulation conditions.

The identification and optimisation of operating conditions and selection of an appropriate mixer for the manufacturing of pharmaceutical dry powders is extremely challenging, and has relied largely on empirical trial-and-error approaches. A novel extension to a previous method has been proposed, which can be used to quickly and effectively evaluate the progression of a dry powder mixing using a mixing-sensitive coloured tracer powder. A series of lactose powders (white) with 1 wt.% sub-micronised iron oxide tracer (dark red) by weight were blended with three different mixing technologies under a range of processing conditions. Measurement of the hue and hue intensity of the powder blend as a function of time shows two distinct mixing behaviours: dispersion of tracer aggregates through the bulk powder (increase in blend hue intensity) and tracer de-agglomeration into primary particles (hue transition from red to orange). The colourimetric values of samples taken at blending times of up to 1 h were assembled to create a series of formulation-specific colour curves which were able to clearly distinguish and group mixers into low and high intensities given their range of values along the same formulation curves. This iron oxide tracer method provides the basis for a novel quantitative approach for ensuring equivalent blending conditions between mixer types, scales and operating conditions for a given formulation. The approach also shows the potential to identify conditions which may cause unintentional and undesirable particle attrition during powder blending.

This short communication describes a scalable new method to produce ultrafine hydrophobic or poorly soluble drug particles. Ultrafine Vitamin D3, Aspirin and Ibuprofen particles in the submicron range were produced. The method is an extension of the antisolvent vapour precipitation technique which exposes a droplet to an antisolvent vapour with reference to the dissolved materials within the droplet. In this work, the drug material was dissolved in ethanol droplets and then exposed to a convective stream of water vapour. Absorption of the water vapour into the droplet resulted in the precipitation of the particles. The precipitated submicron particles showed good dispersion behaviour in water droplets. This work will form the basis for using spray dryers as high-throughput scalable micro-precipitators.

The objective was to investigate the effect of dry coating of salbutamol sulphate (SS) with magnesium stearate (MgSt) on the kinetics of powder de-agglomeration. The relative de-agglomeration of the MgSt coated SS powders was higher than uncoated SS at all air flow rates; the SS coated with 2 % MgSt showed the highest extent of de-agglomeration (> 5 % MgSt coated SS > 1 % MgSt coated SS). Rate of de-agglomeration was described by a cumulative de-agglomerated versus time profile. Profiles fitted a mono-exponential model and the de-agglomeration rate constant (kd) was estimated. No significant differences existed between any of the uncoated and coated powders. The significance of this study relates to the improved aerosolization and de-agglomeration performance of the MgSt coated SS powders with optimum performance of 2 % MgSt coated SS. More significant is the finding that no change existed in de-agglomeration rate constants between the coated and uncoated powders, with the potential implications that their aerosol plume concentration and deposition patterns were similar.

Intensive dry powder coating (mechanofusion) with tablet lubricants has previously been shown to give substantial powder flow improvement. This study explores whether the mechanofusion of magnesium stearate (MgSt), on a fine drug powder can substantially improve flow, without preventing the powder from being directly compacted into tablets. A fine ibuprofen powder, which is both cohesive and possesses a low-melting point, was dry coated via mechanofusion with between 0.1% and 5% (w/w) MgSt. Traditional low-shear blending was also employed as a comparison. No significant difference in particle size or shape was measured following mechanofusion. For the low-shear blended powders, only marginal improvement in flowability was obtained. However, after mechanofusion, substantial improvements in the flow properties were demonstrated. Both XPS and ToF-SIMS demonstrated high degrees of a nano-scale coating coverage of MgSt on the particle surfaces from optimized mechanofusion. The study showed that robust tablets were produced from the selected mechanofused powders, at high-dose concentration and tablet tensile strength was further optimized via addition of a Polyvinylpyrrolidone (PVP) binder (10% w/w). The tablets with the mechanofused powder (with or without PVP) also exhibited significantly lower ejection stress than those made of the raw powder, demonstrating good lubrication. Surprisingly, the release rate of drug from the tablets made with the mechanofused powder was not retarded. This is the first study to demonstrate such a single-step dry coating of model drug with MgSt, with promising flow improvement, flow-aid and lubrication effects, tabletability and also non-inhibited dissolution rate Refereed/Peer-reviewed

The aim of the study was to investigate the specific influence of force control agents (FCAs) (leucine, lecithin and magnesium stearate) on the interfacial properties of a salbutamol sulphate-lactose dry powder inhaler formulation. The influence of FCAs on the cohesive and adhesive force balance was directly assessed via an atomic force microscopy (AFM) colloid probe technique, with a recently developed cohesive-adhesive balance (CAB) graphical analysis procedure. Co-processing of constituent particles was conducted by a novel dry mechanical fusion method (Mechanofusion). The in vitro deposition profile of the model salbutamol sulphate formulations was investigated using a Monohaler® DPI device with a next generation impactor (NGI) apparatus. The CAB-graph analysis of a salbutamol sulphate-lactose binary system suggested a predisposition for an interactive mixture. However, the reduced intermixing coefficient (Fdrug-lactose/Fdrug-drug) suggested that a significant amount of energy would be required to overcome the strong adhesive interaction for efficient dispersion of the drug from a lactose surface. The processing of lactose with leucine, lecithin or magnesium stearate, prior to formulating with the drug, significantly reduced the adhesive interactions of the salbutamol with modified lactose samples. The CAB analyses indicated that the reduced intermixing coefficients shifted to such an extent that cohesive drug interactions dominated. These dramatic shifts in the balance of forces were shown to lead to poor blend homogeneity and potential for significant segregation between drug and carrier particles. Conversely, the conditioning of salbutamol sulphate with leucine, lecithin and magnesium stearate, which modified both the adhesive and cohesive interactions, formed homogenous interactive blends with advantageously weaker drug-lactose interactions. Formulations with pre-conditioned drug, in contrast to conditioned lactose, offered the best drug delivery performances. The use of the colloid AFM technique in combination with the cohesive-adhesive balance (CAB) approach provided a very accurate means of predicting dry powder formulation behaviour and the specific influence of particulate interactions on aerosol performance.

Purpose The purpose of the study was to understand the role of particle size and shape changes in modifying agglomerate strength distribution and de-agglomeration of cohesive lactose powders. Methods The relative de-agglomeration of three lactoses of different particle size distributions (Lactohale 201 or LH201, Lactohale 210 or LH210 and Lactohale 220 or LH220) was determined from laser diffraction particle sizing of the aerosol plume at different air flow rates. The agglomerate strength distributions were estimated by Monte Carlo simulation using the primary particle size, work of cohesion and tapped density distributions determined by laser diffraction, inverse gas chromatography and tapping apparatus, respectively. The morphology and particle shape parameters were determined by scanning electron microscopy and the Morphologi G3. Results The estimated agglomerate strength correlated well with the de-agglomeration of all lactose samples at different air flow rates. While the work of cohesion of the lactose samples was not significantly different, the packing fraction was dependent on the proportion and shape of intermediate-sized, cohesive particles between 5.4 and 14 μm. For example, while the proportion of particles LH210 > LH201. Conclusion The study reinforced the role of agglomerate strength distributions in understanding de-agglomeration of cohesive materials. Modification of particle size distributions and shape characteristics contributed to the agglomerate strength changes in the lactose samples. The study enhanced the fundamental understanding of powder de-agglomeration and provided strategic approaches that could be used to improve inhalation product performance.

Non-reducing sugars such as mannitol are widely studied as excipients for spray-dried pharmaceutical formulations. In contrast, the present study investigated the use of a range of polymers for the production of an amorphous glassy carrier platform for pulmonary delivery of potent biomacromolecules. Two different natural polysaccharides, inulin and dextran, and the synthetic polymer polyvinylpyrrolidone (PVP) were combined with leucine using spray-drying. In addition, the effect of these polymers in combination with mannitol was studied. The results showed that leucine was a very effective particle formation agent that substantially improved processing yields of the spray-dried polymer–leucine-based formulations and formed high-rugosity particles with high fine particle fractions. The work indicated the potential utilities of these multicomponent systems as a novel dry powder formulation platform for pulmonary delivery of various biomacromolecules.

Tablets make up approximately one third of all drug dosage forms which makes tablet manufacture a common process in the pharmaceutical industry. The unified compaction curve [1] is an model developed initially to look at the impact of the roller compaction conditions on the tablet strength. The tensile strength of the tablets made from formulations containing at least 50% microcrystalline cellulose produced at roller compaction pressures were measured and the profiles were collapsed into a single master “unified compaction curve”. This allowed for the tablet strength to be predicted from the roller compaction condition and formulations, and target the required tablet strength criterion set by standards or specifications [1]. In this paper, the unified compaction curve was applied to investigate the effects of the wet granulation conditions on the tablet tensile strength. The study was based on a placebo formulation comprising of 50 wt.% microcrystalline cellulose, 50 wt.% lactose and a 5 w/v% PVP (K90) binder solution. The effects of the liquid level (20–50 wt.%), wet massing time (0–10 min), binder flow rate (130 g/min and 280 g/min) and impeller speed (150, 285 and 600 rpm) on the tablet strength were explored. A compaction profile was created to represent the relationship between the tablet tensile strength, compaction pressure and the granulation condition. By fitting the unified compaction curve model to the data, the profiles exploring each granulation condition collapsed onto a single master curve which predicts the tablet strength as a function of the liquid level, wet massing time or the binder flow rate. Increasing the liquid level and/or wet massing time caused a reduction in the tablet hardness when compressed at the same compaction force, and the reduction is postulated to be proportional to the compaction forces experienced during granulation. The data further collapses onto a single master curve which is solely a function of the total number of impeller revolutions. The unified compaction curve is expected to have important implications for the pharmaceutical industry by enabling the tablet strength to be optimised in advance by adjusting the granulation and compaction conditions.

Wool powder may be utilized in advanced applications, notably composite materials, biomedical and cosmetics depending on the development of a suitable powder fabrication process and understanding of powder properties. This paper discusses a novel approach to mill viscoelastic wool fibres using a combined wet attritor and air jet milling (AJM) process. Results show that 5 h attritor milling followed by spray drying can produce wool powder with a BET surface area of 14.89 m2/g and volume based d(0.5) of 4 μm. Despite absence of any milling pre-treatments, the particles are much smaller than previously prepared wool particles using other methods. Subsequent AJM further reduces d(.5) to 1.5 μm, but creates loose aggregates which results in their low bulk density. The aggregates can be disintegrated using a strong consolidating force and such AJM powder can be compressed to 45% of the original volume. Rheological measurements suggest strong cohesion and poor flowability of wool powders. Consolidated AJM powder is even more cohesive with a flow function of 1.64 compared to spray dried powder without AJM which has a flow function of 3.74. The results are important for processing and applications of these novel organic fibre powders, where ultrafine particles are needed and understanding of powder packing and flow behaviour is important.

For dry powder inhaler formulations, micronized drug powders are commonly mixed with coarse lactose carriers to facilitate powder handling during the manufacturing and powder aerosol delivery during patient use. The performance of such dry powder inhaler formulations strongly depends on the balance of cohesive and adhesive forces experienced by the drug particles under stresses induced in the flow environment during aerosolization. Surface modification with appropriate additives has been proposed as a practical and efficient way to alter the inter-particulate forces, thus potentially controlling the formulation performance, and this strategy has been employed in a number of different ways with varying degrees of success. This paper reviews the main strategies and methodologies published on surface coating of lactose carriers, and considers their effectiveness and impact on the performance of dry powder inhaler formulations.

The purpose of this research was to investigate the influence of dry coating micronized cohesive powders of a poorly water-soluble drug, indomethacin with force control agents, on its dissolution performance. A dry mechanical fusion method (mechanofusion) was used to coat indomethacin powders with magnesium stearate (0.25%,1%,5%) and sodium stearate (5%). After mechanofusion, significantly increased bulk and tapped densities and decreased intrinsic cohesion were observed for all samples. X-ray photoelectron spectroscopy analysis confirmed that a thicker magnesium stearate surface coating was achieved with increasing concentrations of the material. Dissolution was studied using the USP paddle method in buffer pH 5.0; several modelling approaches were used to explore the dissolution mechanisms. Whilst the bi-exponential equation represented dissolution of mechanofused indomethacin powders occurring from dispersed and agglomerated particles, it provided unrealistic parameter estimates for the two coating materials of contrasting properties. Initial increases in indomethacin dissolution were dependent on the concentration of magnesium stearate mechanofused onto the drug powders. The dissolution enhancing effect of indomethacin powders mechanofused with 5% sodium stearate was attributed to its surfactant properties that increased dispersion of indomethacin agglomerates. Initial drug release from the coated powders was described by a matrix-diffusion system according to the Higuchi model.

The purpose of the current investigation is to understand the kinetics of de-agglomeration (k(d)) of micronised salbutamol sulphate (SS) and lactohale 300 (LH300) under varying air flow rates (30-180l min(-1)) from three dry powder inhaler devices (DPIs), Rotahaler (RH), Monodose Inhaler (MI) and Handihaler (HH).Cumulative fine particle mass vs. time profiles were obtained from the powder concentration, emitted mass and volume percent5.4 μm, embedded in the particle size distributions of the aerosol at specific times. The rate of de-agglomeration (k(d)), estimated from non-linear least squares modelling, increased with increasing air flow rates. The k(d)vs. air flow rate profiles of SS and LH300 were significantly different at high air flow rates. The k(d) was highest from RH and lowest from MI. Differences in k(d) between the devices were related to device mode of operation while the differences between the materials were due to the powder bed structure.This approach provided a methodology to measure the rate constant for cohesive powder de-agglomeration following aerosolisation from commercial devices and an initial understanding of the influence of device, air flow rate and material on these rate constants.

The purpose of this study was to understand the kinetics of emptying of micronised salbutamol sulphate (SS) and lactohale 300 (LH300) under varying air flow rates (30–180 L min −1 ) from three dry powder inhaler devices, Rotahaler ® (RH), Monodose Inhaler ® (MI) and Handihaler ® (HH). Aerosol concentration vs. time profiles, determined through real-time laser diffraction particle sizing, demonstrated that the majority of the powder from RH was emitted within one second while a more prolonged aerosolisation was observed from MI and HH. Peak aerosol concentrations were achieved more rapidly from RH compared to MI for both SS and LH300. Calculated cumulative emitted mass (CCEM) vs. time profiles were obtained from the aerosol concentration vs. time profiles and the emitted mass and the rate of CCEM ( k CCEM ), estimated from a modelling approach, increased with increasing air flow rates. The k CCEM vs. air flow rate profiles of SS and LH300 were significantly different at high air flow rates. The k CCEM was highest from RH and lowest from MI. Differences in k CCEM between the devices were related to capsule aperture size while the differences between the materials were due to the powder bed structure. This approach provided an understanding of the rate at which powder mass emptied from dry powder inhaler devices and was proposed to be a powerful development tool for the future powder inhalers.

The objective of this study was to investigate if the coating extent created by a mechanofusion process corresponded with observed changes in bulk powder properties. A fine lactose powder (approximate median diameter 20 μm) was dry coated with magnesium stearate using from 0.1 to 5% (w/w) content. An ultra-thin coating layer of magnesium stearate was anticipated, but previous attempts to determine such thin layers on these fine particles have had limited success, with poor resolution. In this study, the surface coating was examined using the state-of-the-art XPS and ToF-SIMS systems. The powder flow was characterized by Carr index and shear cell testing. XPS was successfully applied to demonstrate variations in surface coverage, as a function of additive levels, and indicated near complete coating coverage at additive levels of 1% (w/w) and above. ToF-SIMS results supported such coating coverage assessment, and indicated coating uniformly across the fine particle surfaces. The flow metrics employed could then be related to the coating coverage metrics. The mechanofusion process also modified the apparent surface roughness observed by SEM and BET. It was suggested that the changes in the surface chemical composition exerted a more evident and direct impact on the powder cohesion and flow characteristics than the changes in the surface morphological properties after the mechanofusion in this study.

The purpose was to employ a new finite dilution approach to determine total surface energy distributions of mechanofused powders by inverse gas chromatography (IGC) to contribute to the understanding of their improved flow properties and to help optimise the magnesium stearate (MgSt) coating. Pharmatose 450M was mechanofused with between 0.1 and 8% (w/w) of MgSt. The non-polar, polar and total surface energies and work of cohesion at infinite dilution and the energy distributions at finite dilution were constructed using IGC. Brunauer-Emmet-Teller (BET) surface area and particle morphology were determined by IGC and scanning electron microscope, respectively. Surface energies determined at finite dilution appeared more consistent with the observed flow behaviour of mechanofused powders than comparative surface energy determination at infinite dilution. Polar and total surface energy distributions together with BET surface area measurements were the lowest when lactose was mechanofused with 1-2% MgSt (w/w). In conclusion, the surface energy distribution profiles measured at finite dilution were argued to be more informative and useful in reporting the surface energy changes during mechanofusion, optimising MgSt concentration in the mechanofusion process, and the flow behaviour of mechanofused powders.

Pulmonary immunization has gained increased recognition as a means of triggering both a mucosal and systemic immune response without the use of needles. The appropriate formulation of antigens in a dry, solid state can result in improved stability, thereby removing cold-chain storage complications associated with conventional liquid-based vaccines. The particulate nature of dry powder vaccines could also induce a better immune response. This review describes our current understanding of pulmonary immunization, including possible barriers facing the development of pulmonary vaccines, and discusses recent advances in spray-drying technologies applicable to the production of dry powder formulations for pulmonary vaccine delivery.

The purpose of this study was to characterise the cohesive behaviour of powders by measuring aerosolisation at a sequence of different flow rates, i.e. flow titration. Salbutamol sulphate and Lactohale 300 were model cohesive materials. Laser diffraction particle sizing of the aerosolised plume provided in-situ, real time particle size distributions of the aerosolised powder dispersed at increasing flow rates, from 30 to 180 L min −1 . Relative de-agglomeration was determined from the cumulative particle size of the aerosolised powder less than 5.4 μm compared with the full availability of particles in that size range. Relative de-agglomeration-flow rate profiles were modelled using a non-linear least squares regression to fit an empirical 3-parameter sigmoidal equation; the parameters of the sigmoid were estimated from the data. Relative de-agglomeration–flow rate titration profiles and their estimated parameters were obtained to define the different de-agglomeration mechanisms of the two cohesive powders. Salbutamol sulphate showed a maximum percent de-agglomeration of 54.9%, compared with Lactohale 300 which was only 29.5%. Lactohale 300 gave 50% of its maximum de-agglomeration at a flow rate of 48.0 L min −1 while the equivalent for Salbutamol sulphate was 113.8 L min −1 . Salbutamol sulphate and Lactohale 300 demonstrated different patterns of dispersion in relation to de-agglomeration mechanism. This approach to characterising the aerosolisation processes has significant application in designing formulation and processing strategies for pharmaceutical inhalation drug delivery.

The aim of this study was to evaluate the effect of an intensive dry coating process on the improvement in flow behaviours for fine cohesive lactose powders as a function of size distribution and coating process parameters. Various commercial fine lactose powders with particle size range from approximately 4 to 120 μm were dry coated with magnesium stearate using a recently optimised mechanofusion approach. The bulk densities for all cohesive powders increased and flow behaviours were improved substantially except for the already free-flowing powder of R010 (with VMD approximately 120 μm). Of particular note, the originally non-flowing cohesive powder P450 with VMD approximately 20 μm achieved free-flowing characteristics and was as flowable as R010 after mechanofusion. The improvement in powder flow behaviours was shown to be dependent on coating parameters such as coating speed and coating time duration. At an appropriate coating speed, optimal coating can be achieved after processing for 5 min for P450. This study demonstrated that an optimised mechanofusion process is an efficient and effective approach for substantially improving flow of fine cohesive powders to achieve equivalent flow behaviours of much larger sized powders.

Purpose The purpose of this study was to understand the behaviour of cohesive powder mixtures of salbutamol sulphate (SS) and micronized lactose (LH300) at ratios of SS:LH300 of 1:1, 1:2, 1:4 and 1:8 under varying air flow conditions. Methods Aerosolisation of particles less than 5.4 μm at air flow rates from 30 to 180 l min−1 was investigated by determining particle size distributions of the aerosolised particles using laser diffraction and fine particle fractions of SS using the twin stage impinger modified for different air flow rates using a Rotahaler®. The de-agglomeration data were best fitted by a 3-parameter sigmoidal equation using non-linear least squares regression and characterised by the estimated parameters. Results De-agglomeration air flow rate profiles showed that SS:LH300 mixtures with increased lactose content (1:4 and 1:8) improved powder aerosolisation, but lactose had negligible effect on SS aerosolisation at the higher and lower limits of air flow rates studied. De-agglomeration flow rate profiles of SS–LH300 mixtures with increased lactose content (1:4 and 1:8) were greater than theoretically expected based on weighted individual SS and LH300 profiles. This indicated that interactions between the cohesive components led to enhanced de-agglomeration. The composition of the aerosol plume changed with air flow rate. Conclusion This approach to characterising aerosolisation behaviour has significant applications in understanding powder structures and in formulation design for optimal aerosolisation properties.

The aim of this study was to investigate the effect of coating on the aerosolization of three model micronized powders. Three model powder materials (salbutamol sulphate, salmeterol xinafoate, triamcinolone acetonide) were chosen not only for their different chemical properties but also for their different physical properties such as shape and size distribution. Each powder was coated with 5% (w/w) magnesium stearate using two different dry mechanofusion approaches. After mechanofusion, both poured and tapped densities for all three model drug powders significantly increased. There were significant improvements in aerosolization behavior from an inhaler device for all model powders after mechanofusion. Such improvements in aerosolization were attributed to the reduction in agglomerate strength caused by decreasing powder intrinsic cohesion via surface modification. The work also indicated that the effect of the coating was dependant on the initial particle properties.

Since the 1950s, ultrasonic nebulizers have played an important role in pulmonary drug delivery. As the process in which aerosol droplets are generated is independent and does not require breath-actuation, ultrasonic nebulizers, in principle, offer the potential for instantaneously fine-tuning the dose administered to the specific requirements of a patient, taking into account the patient's breathing pattern, physiological profile and disease state. Nevertheless, owing to the difficulties and limitations associated with conventional designs and technologies, ultrasonic nebulizers have never been widely adopted, and have in recent years been in a state of decline.An overview is provided on the advances in new miniature ultrasonic nebulization platforms in which large increases in lung dose efficiency have been reported.In addition to a discussion of the underlying mechanisms governing ultrasonic nebulization, in which there appears to be widely differing views, the advantages and shortcomings of conventional ultrasonic nebulization technology are reviewed and advanced state-of-the-art technologies that have been developed recently are discussed.Recent advances in ultrasonic nebulization technology demonstrate significant potential for the development of smart, portable inhalation therapy platforms for the future. Nevertheless, there remain considerable challenges that need to be addressed before such personalized delivery systems can be realized. These have to be addressed across the spectrum from fundamental physics through to in vivo device testing and dealing with the relevant regulatory framework.

Our previous work demonstrated that the powder flowability of a cohesive lactose sample can be improved substantially using a dry coating technique. Our study reported here aims to investigate the influence of host particle size on the modification of powder flowability following dry coating process. Four commercial lactose monohydrate powders with different particle sizes were coated by an intensive mechanical process or mixed using a conventional tumbling process, both with magnesium stearate. All four untreated lactose samples showed a relatively poor powder flow. After dry coating, poured and tapped densities of all the lactose samples increased, while Carr indices and Hausner ratios decreased substantially. The angle of repose values were reduced to a notable extent only for particles with a median size larger than about 7 μm after dry coating. Both specific energy (SE) and cohesion values of lactose samples, measured by a powder rheometer system, decreased substantially after coating. In contrast, no apparent changes in powder flow were evident for conventionally mixed batches, except that in the dynamic powder rheometry measurement, a relatively small change in SE was observed. This study demonstrated that for the finer particles examined, cohesive forces were more influential in the powder bed after the surface treatment and resulted in a relatively poor flow. However, for the larger powders studied, the cohesive inter-particle forces could be overcome after this dry coating, whereby satisfactory flow could be obtained. This study indicated that the host particle size was a critical factor in influencing the modification of cohesive powder flowability.

The aim of this study was to determine the aerosolisation and aerodynamic properties of model inhalation particles (salbutamol sulphate and budesonide) upon coprocessing with force control agents (FCAs)-leucine, lecithin and magnesium stearate. Coprocessing of the drug particles with FCAs (5%, w/w) was conducted using mechanofusion-a novel dry mechanical fusion process. The influence of mechanofused FCAs on the entrainment and deaggregation behaviour of the drug-only formulations was investigated using a next generation impactor (NGI) and an in-line Spraytec laser diffraction particle sizer. In vitro measurements of salbutamol sulphate coprocessed with FCAs indicated a significant (p0.001) improvement of the fine particle fraction (FPF). The coprocessing of salbutamol sulphate with magnesium stearate produced the highest FPF, with an increase from 29.18% to 79.42% of the emitted dose. Coprocessing of budesonide particles only led to a small increase in fine particle delivery but a greater reduction in device retention. Aerosolisation analysis of the aerosolised powders indicated more effective aerosolisation and a considerable time reduction in powder bed fluidisation and entrainment upon coprocessing of the APIs with FCAs. From these data, it can be postulated that processing of drug actives with FCAs using mechanofusion is an effective means of improving the deagglomeration and aerosolisation properties of cohesive powders in DPI systems.

In this study, we aimed to investigate the effects cohesion of small surface-engineered guest binder particles on the flow behaviour of interactive mixtures. Polyvinylpyrrolidone (PVP) – a model pharmaceutical binder – was spray-dried with varying l -leucine feed concentrations to create small surface-engineered binder particles with varying cohesion. These spray-dried formulations were characterised by their particle size distribution, morphology and cohesion. Interactive mixtures were produced by blending these spray-dried formulations with paracetamol. The resultant blends were visualised under scanning electron microscope to confirm formation of interactive mixtures. Surface coverage of paracetamol by guest particles as well as the flow behaviour of these mixtures were examined. The flow performance of interactive mixtures was evaluated using measurements of conditioned bulk density, basic flowability energy, aeration energy and compressibility. With higher feed l -leucine concentrations, the surface roughness of small binder particles increased, while their cohesion decreased. Visual inspection of the SEM images of the blends indicated that the guest particles adhered to the surface of paracetamol resulting in effective formation of interactive mixtures. These images also showed that the low-cohesion guest particles were better de-agglomerated that consequently formed a more homogeneous interactive mixture with paracetamol compared with high-cohesion formulations. The flow performance of interactive mixtures changed as a function of the cohesion of the guest particles. Interactive mixtures with low-cohesion guest binder particles showed notably improved bulk flow performance compared with those containing high-cohesion guest binder particles. Thus, our study suggests that the cohesion of guest particles dictates the flow performance of interactive mixtures.

The flow of powders can often play a critical role in the manufacturing of pharmaceutical products. Many of these processes require good, consistent and predictable flow of powders to ensure continuous production of pharmaceutical dosages and to ensure their quality. Therefore, the flow of powders is of paramount importance to the pharmaceutical industry and thus the measuring and evaluating of powder flow is of utmost importance. At present, there are numerous methods in which the flow of powders can be measured. However, due to the complex and environment-dependent nature of powders, no one method exists that is capable of providing a complete picture of the behaviour of powders under dynamic conditions. Some of the most commonly applied methods to measure the flow of powders include: density indices, such as the Carr index and Hausner ratio, powder avalanching, the angle of repose (AOR), flow through an orifice, powder rheometry and shear cell testing.

Cohesive powders are problematic in the manufacturing of pharmaceutical solid dosage forms because they exhibit poor flowability, fluidization and aerosolization. These undesirable bulk properties of cohesive powders represent a fundamental challenge in the design of efficient pharmaceutical manufacturing processes. Recently, mechanical dry coating has attracted increasing attention as it can improve the bulk properties of cohesive powders in a cheaper, simpler, safer and more environment-friendly way than the existing solvent-based counterparts. In this review, mechanical dry coating techniques are outlined and their potential applications in formulation and manufacturing of pharmaceutical solid dosage forms are discussed. Reported data from the literature have shown that mechanical dry coating holds promise for the design of superior pharmaceutical solid formulations or manufacturing processes by engineering the interfaces of cohesive powders in an efficient and economical way.

Laninamivir is a long-acting antiviral requiring only a single dose for the treatment of influenza infection, making it an attractive alternative to existing neuraminidase inhibitors that require multiple doses over many days. Like zanamivir, laninamivir is administered to patients by inhalation of dry powder. To date, studies investigating the effectiveness of laninamivir or zanamivir in a ferret model of influenza infection have administered the drug in a solubilised form. To better mimic the delivery action of laninamivir in humans, we assessed the applicability of a Dry Powder Insufflator™ (DPI) as a delivery method for laninamivir octanoate (LO) in ferrets to determine the effectiveness of this drug in reducing influenza A and B virus infections. In vitro characterisation of the DPI showed that both the small particle sized LO (0.7-6.0μm diameter) and the large particle sized lactose carrier (20-100μm diameter) were effectively discharged. However, LO delivered to ferrets via the DPI prior to infection with either A(H1N1)pdm09 or B viruses had a limited effect on nasal inflammation, clinical symptoms and viral shedding compared to placebo. Our preliminary findings indicate the feasibility of administering powder drugs into ferrets, but a better understanding of the pharmacokinetics and pharmacodynamics of LO in ferrets following delivery by the DPI is warranted prior to further studies.

To obtain a quantitative assessment of the cohesive and adhesive force balance within dry powder inhaler formulations.The atomic force microscope (AFM) colloid probe technique was used to measure the adhesive and cohesive force characteristics of dry powder systems containing an active component (budesonide, salbutamol sulphate) and alpha-lactose monohydrate. To minimize the variations in contact area between colloid probe and substrates, nanometer smooth crystal surfaces of the drugs and the excipient were prepared.The uniformity in contact area allowed accurate and reproducible force measurements. Cohesive-adhesive balance (CAB) graphs were developed to allow direct comparison of the interaction forces occurring in model carrier-based formulations. A salbutamol sulphate-lactose system revealed a significant tendency for the two materials to adhere, suggesting a propensity for the powder to form a homogenous blend. In contrast, the budesonide-lactose system exhibited strong cohesive properties suggesting that the formulation may exhibit poor blend homogeneity and potential for segregation upon processing and handling.The novel approach provides a fundamental insight into the cohesive-adhesive balances in dry powder formulations and further understanding of powder behavior.

The amino acid l -leucine has been demonstrated to act as a lubricant and improve the dispersibility of otherwise cohesive fine particles. It was hypothesized that optimum surface l -leucine concentration is necessary to achieve optimal surface and bulk powder properties. Polyvinylpyrrolidone was spray dried with different concentration of l -leucine and the change in surface composition of the formulations was determined using X-ray photoelectron spectroscopy (XPS) and time of flight-secondary ion mass spectrometry (ToF-SIMS). The formulations were also subjected to powder X-ray diffraction analysis in order to understand the relationship between surface concentration and solid-state properties of l -leucine. In addition, the morphology, surface energy and bulk cohesion of spray dried formulations were also assessed to understand the relation between surface l -leucine concentration and surface and bulk properties. The surface concentration of l -leucine increased with higher feed concentrations and plateaued at about 10% l -leucine. Higher surface l -leucine concentration also resulted in the formation of larger l -leucine crystals and not much change in crystal size was noted above 10% l -leucine. A change in surface morphology of particles from spherical to increasingly corrugated was also observed with increasing surface l -leucine concentration. Specific collapsed/folded over particles were only seen in formulations with 10% or higher l -leucine feed concentration suggesting a change in particle surface formation process. In addition, bulk cohesion also reduced and approached a minimum with 10% l -leucine concentration. Thus, the surface concentration of l -leucine governs particle formation and optimum surface l -leucine concentration results in optimum surface and bulk powder properties.

This study investigates the effects of a variety of coating materials on the flowability and dissolution of dry-coated cohesive ibuprofen powders, with the ultimate aim to use these in oral dosage forms. A mechanofusion approach was employed to apply a 1% (w/w) dry coating onto ibuprofen powder with coating materials including magnesium stearate (MgSt), L-leucine, sodium stearyl fumarate (SSF) and silica-R972. No significant difference in particle size or shape was measured following mechanofusion with any material. Powder flow behaviours characterised by the Freeman FT4 system indicated coatings of MgSt, L-leucine and silica-R972 produced a notable surface modification and substantially improved flow compared to the unprocessed and SSF-mechanofused powders. ToF-SIMS provided a qualitative measure of coating extent, and indicated a near-complete layer on the drug particle surface after dry coating with MgSt or silica-R972. Of particular note, the dissolution rates of all mechanofused powders were enhanced even with a coating of a highly hydrophobic material such as magnesium stearate. This surprising increase in dissolution rate of the mechanofused powders was attributed to the lower cohesion and the reduced agglomeration after mechanical coating. Refereed/Peer-reviewed

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 (R(2)=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.