Screening of sugars and cyclodextrins as carriers in montelukast dry powder inhalers processed by spray freeze drying

The purpose of this study was to develop a site targeting montelukast sodium (MTK) microparticles as a respiratory drug delivery system using the spray freeze drying (SFD) process. A range of sugars and cyclodextrins (CDs) were screened as carrier in order to find compatible excipients for the preparation of dry powder inhalers (DPIs). The physical characteristics of collected powders were studied by scanning electron microscopy (SEM), laser light scattering, differential scanning calorimetry (DSC), and X-ray diffraction (XRD). The aerodynamic behavior of the particles was also assessed using twin stage impinge (TSI). In the presence of simple sugars as carriers, highly porous particles in irregular shapes were produced. The use of CDs resulted in the formation of spherical particles with high porosity. Among all carriers that were used during the preparation of powders, raffinose had the best aerodynamic behavior with a fine particle fraction (FPF) of 60 % in sugar groups, while the lowest FPF was related to trehalose as carrier. Powders containing CDs mostly showed proper aerodynamic behavior, especially in formulations containing alfa-cyclodextrin (A-CD), beta-cyclodextrin (β-CD), and highly branched cyclic dextrin (HBCD). Overall, data indicated that the CDs were excellent excipients for use with MTK for respiratory drug delivery.     

Machine learning aided nanoindentation: A review of the current state and future perspectives

The solution of instrumented indentation inverse problems by physically-based models still represents a complex challenge yet to be solved in metallurgy and materials science. In recent years, Machine Learning (ML) tools have emerged as a feasible and more efficient alternative to extract complex microstructure-property correlations from instrumented indentation data in advanced materials. On this basis, the main objective of this review article is to summarize the extent to which different ML tools have been recently employed in the analysis of both numerical and experimental data obtained by instrumented indentation testing, either using spherical or sharp indenters, particularly by nanoindentation. Also, the impact of using ML could have in better understanding the microstructure-mechanical properties-performance relationships of a wide range of materials tested at this length scale has been addressed.The analysis of the recent literature indicates that a combination of advanced nanomechanical/microstructural characterization with finite element simulation and different ML algorithms constitutes a powerful tool to bring ground-breaking innovation in materials science. These research means can be employed not only for extracting mechanical properties of both homogeneous and heterogeneous materials at multiple length scales, but also could assist in understanding how these properties change with the compositional and microstructural in-service modifications. Furthermore, they can be used for design and synthesis of novel multi-phase materials.     

Influence of the solvent evaporation rate on the β-Phase content of electrosprayed PVDF particles and films studied by a fast Multi-Overtone QCM

A combination of an electrospray setup and a quartz crystal microbalance with dissipation monitoring (QCM-D) was employed to study the drying of droplets of poly(vinylidene fluoride) (PVDF) dissolved in dimethylformamide (DMF). A novel variant of the QCM was used, which interrogates the resonance frequency and the resonance bandwidth on four overtones at the same time, achieving a time resolution of 2 ms. This instrument allowed to elucidate the mechanism of β-phase formation in electrospray deposition of PVDF. When the distance between the nozzle and the substrate was small, the droplets landed in a partially wet state, as evidenced from an increase in the resonance bandwidth. No such increase in bandwidth was observed when the distance was large. From the flight time (milliseconds) and the drying time on the substrate (seconds), one concludes that drying in the plume is faster than drying on the substrate. IR spectra show that the β–phase content is close to 100 % for particles, which dried in the plume. It is less than 50 % for particles having dried on the substrate. Fast drying promotes the formation of the β-phase. Follow-up experiments with thicker films on steel substrates also show increased β-phase content for larger distances.     

Investigation of the molecular state of 4-aminosalicylic acid in matrix formulations for dry powder inhalers using solid-state fluorescence spectroscopy of 4-dimethylaminobenzonitrile

Carrier-free method is an alternative approach for dry powder inhaler (DPI) formulations, which overcome poor drug mobility and distribution. Here we investigated the properties of an active pharmaceutical ingredient (API) within composite particles. We used highly-branched cyclic dextrin (HBCD) as the excipient matrix that was prepared using a spray-drying technique. 4-Aminosalicylic acid (4-ASA) and 4-dimethylaminobenzonitrile (DMABN) were selected as a hydrophilic second-line antitubercular agent and a surrogate for 4-ASA as a model compound, respectively. The spray-dried particles (SDPs) containing 4-ASA or DMABN with HBCD had geometric median diameters (D₅₀) of 2.34 ± 0.07 μm and 2.26 ± 0.10 μm, respectively. Further, the in vitro aerodynamic properties were similar for SDPs containing 4-ASA and DMABN with HBCD. To determine the properties of APIs within composite particles, we performed solid-state fluorescence spectroscopy of DMABN. As a candidate excipient, hydroxypropyl methylcellulose (HPMC) was compared to HBCD. We determined the intensity ratio of twisted intramolecular charge transfer (TICT) emission to locally excited emission within the excipient matrix environment. The HBCD matrix environment was better than HPMC to trigger a more robust TICT reaction of DMABN. A potent state-changing interaction of APIs occurred in the HBCD matrix environment versus another excipient environment.     

Three-dimensional periodic structures of gold nanoclusters in the interstices of sub-100 nm polymer particles toward surface-enhanced Raman scattering

Regularly ordered polymer nanoparticle (PNP) assemblies incorporating gold nanoparticle (Au NP) clusters into the PNP interstices were fabricated by a simultaneous deposition of PNPs and Au NPs on a glass substrate. Monodisperse PNPs with an average size of 66 nm were employed as a template in the co-assembly to create the sub-100 nm periodic Au nanostructures on the substrate. First, mono-layering of PNP array with incorporation of 14 nm Au NPs was performed by a drop-casting to examine the number ratio of Au NPs to PNPs for multi-layering. Absorption spectra of the mono-layered co-assemblies of PNPs and Au NPs were employed to characterize the clustered state of Au NPs in the interstices of mono-layered PNPs. The number ratio suitable for homogeneous incorporation of Au NPs clustered in the interstice was found to be ranged from 6 to 8 in the characterization. Then, multi-layered co-assemblies of PNPs and clustered Au NPs were fabricated by a vertical deposition method with the Au NP number ratio of 8 to PNPs. Lifting rate of the substrate on which the PNPs were deposited was varied in the vertical deposition method to tune the film thickness of NP co-assembly. A decrease in the lifting rate to 1 μm/s could thicken the film to 0.71 μm corresponding to 13 layers of PNPs, resulting in the fabrication of periodic structures of Au NP clusters with a high packing density. Signal-to-noise ratio in the Raman measurement using p-mercaptobenzoic acid as a target molecule was successfully enhanced by multi-layering of the co-assembly, indicating that Au NP clusters were homogeneously incorporated into the interstices of PNPs in the co-assemblies.     

Granulation of ibuprofen/isonicotinamide co-crystals by continuous spray granulator (CTS-SGR)

The importance of granulation is paramount for tablet manufacturing, and is based on the fact that granulated powders are characterized by improved flowability, compressibility, segregation, and dust reduction. The aim of this study was to prepare and characterize continuous granules of high drug content by using a continuous-spray granulator (CTS-SGR). Ibuprofen (IBU), a drug of low-flowability, was selected as the model drug. As IBU has a low melting point and cannot easily granulate on its own, we employed isonicotinamide (INA) as a coformer that would allow us to prepare co-crystal granules containing 60 % IBU. The results of the undertaken differential scanning calorimetry and powder X-ray diffraction revealed that the IBU and the INA in the granules formed co-crystals. The granulation conditions affected the particle size and the yield of the granules; in fact, a low air supply temperature, a low atomizing air rate, and a high solution flow rate ensured a high granulation efficiency. Moreover, continuous granulation increased the yields of the formulations compared to those obtained through a short-run granulation, and high yields were obtained after applying a low atomizing air rate. The circularity of the granules exceeded 90 %, and their flowability improved when compared to that of the IBU bulk. The undertaking of dissolution studies revealed no change in the elution amount of IBU as a result of the co-crystallization. Our study shows that it is possible to produce high-content IBU granules in a direct and continuous manner through the co-crystallization of IBU and the use of a CTS-SGR.     

Novel preparation approach with a 2-step process for spherical particles with high drug loading and controlled size distribution using melt granulation: MALCORE®

A novel approach for preparing drug-containing particles (DCPs) with controlled size distribution and high drug loading was developed using melt granulation. This approach comprises two steps. First, melting component adsorbed particles (MAs) were prepared by mixing and heating the melting components with a porous carrier using a high shear granulator. Second, DCPs were prepared by layering the drug on MAs using a fluidized bed rotor granulator. The time taken for both steps was within 30 min. Adding the polymer in the second step remarkably increased the viscosity of the mixture of melting components and the polymer. Therefore, DCPs could be successfully loaded with a high amount of drug (70% w/w). The particle size distribution of the DCPs was narrow, and it depended on that of the MAs. The flowability of the DCPs was excellent, and the sphericity was close to 1. A unique particle formulation mechanism was suggested based on the observation of DCPs using scanning electron microscopy. The manufacturing time and DCP characteristics were not affected by the manufacturing scale. In conclusion, we have successfully developed a highly efficient novel approach for preparing optimal DCPs through melt granulation, named “Melt Adsorption and Layering with Porosity Core” (MALCORE®).     

Immersed-boundary/soft-sphere method for particle–particle-fluid interaction in a viscous flow: An OpenFOAM solver

We developed a stable OpenFOAM solver for Immersed Boundary Method based on direct forcing and regularized delta function. The soft-sphere model and a lubrication model were implemented to consider particle–particle collision in a viscous flow. We proposed a fluid–structure interaction (FSI) coupling method to accurately calculate the fluid forcing term and particle velocity. Our solver was validated for fixed and moving bodies, including rotation. The accuracy of various FSI schemes was evaluated in predicting the solid and fluid flow behavior in a viscous flow. It was demonstrated that neglecting or simplifying the fluid momentum change affects the accuracy of the solid velocity and fluid flow dynamic; for higher solid-to-fluid density ratios, a larger deviation was predicted. Furthermore, the FSI schemes highly influenced the behavior of the formed vortices.The solver was validated to predict the effective restitution coefficient of particles in a viscous flow as a function of the Stokes number. We also thoroughly analyzed the dynamic flow behavior of colliding particles through the pressure and velocity field and fluid force. This analysis helped us accurately determine the rebound velocity of particles in case of high Stokes numbers when the effect of viscous force is significant.     

Characterization of solid-electrolyte/active-material composite particles with different surface morphologies for all-solid-state batteries

In all-solid-state lithium-ion batteries (ASS-LIBs), the electrode structure is an important factor that determines the battery performance; in particular, the formation of contact interface between the active material (AM) and solid electrolyte (SE) is an important issue associated with ASS-LIBs. Although we previously reported the formation of interfacial contacts between AM and SE by dry coating, the influence of the surface morphologies of composite particles on the performance of ASS-LIB was not revealed. In this study, we investigated the effects of the surface morphologies of composite particles on the performance of ASS-LIB. The surface morphologies of composite particles changed from “discrete” to “continuous” as the dry coating progressed. The cell prepared with composite particles showed higher ionic conductivity due to well-percolated ionic path than that prepared with simple mixture. Comparing the composite particles with different surface morphologies, the cell prepared with discrete-coating particles showed lower internal resistance due to higher ionic/electrical conductivity than that prepared with continuous-coating particles. Further, the cells prepared with discrete- and continuous-coating particles showed the highest charge and discharge capabilities, respectively. The results suggest that the contact areas of AM-SE and AM-AM were critical structural factors for the discharge and charge rate capability, respectively.     

pH-responsive dual-functional hydrogel integrating localized delivery and anti-cancer activities for highly effective therapy in PDX of OSCC

As one of the most promising localized drug delivery systems for enhancing therapeutic efficacy and reducing systemic toxicity, supramolecular hydrogels self-assembled from natural products have recently attracted tremendous attention. However, the intricate drug loading process, limited drug entrapment efficacy, and lack of stimulus responsiveness considerably impede their potential for biological applications and raise the need for advanced hydrogel-based delivery systems. Therefore, the development of updated materials that integrate localized delivery and drug activity into a single system is extremely desired and has great potential to overcome the aforementioned shortcomings. In this study, a pH-responsive dual-functional isoG-based supramolecular hydrogel with both localized delivery and anti-cancer activity in one molecule is successfully developed in one pot by following a simple and green procedure. The isoguanosine-phenylboronic-guanosine (isoGPBG) hydrogel exhibits exceptional stability (more than one year), outstanding pH-responsiveness and excellent sustained release capability. Both in vitro and in vivo experiments demonstrate that the isoGPBG hydrogel not only shows acceptable biocompatibility and biodegradability but also significantly inhibit tumor growth (approximately 60% inhibition of tumor growth) and improve overall survival, especially in preclinical patient-derived xenograft (PDX) model of oral squamous cell carcinoma (OSCC). Therefore, the isoGPBG hydrogel, to the best of our knowledge, is the first example of pH-responsive dual-functional isoG-based supramolecular hydrogel integrating localized delivery and anti-cancer activity in one molecule. It is implied that the isoGPBG hydrogel could act as a smart dual-functional localized delivery system in the future for clinical cancer therapy.     

DEM study on the mixed feeding process of coal and cylindroid biomass particles in a screw feeder

The complex mixed feeding process for the binary mixture of coal and cylindroid biomass particles in a screw feeder was numerically studied by the discrete element method (DEM). The effects of biomass feeding ratio, feeding rate, and screw rotational speed on the feeding performance were investigated with the continuity, uniformity, and stability of the mixed feeding process being emphatically discussed. The results reveal that the stability of real-time mass flow rate and biomass blending ratio performs better at higher biomass feeding ratios. A larger variability of real-time biomass blending ratio is found at low feeding rate, while increasing the feeding rate reduces the stability of real-time mass flow rate and the too high feeding rate would cause some cylindroid biomass particles being hindered by the front wall surface of the hopper. Moreover, increasing the screw rotational speed significantly increases the stability of the mixed feeding process.     

Steel slag waste combined with melamine pyrophosphate as a flame retardant for rigid polyurethane foams

To explore the potential application of industrial waste, steel slag powder in combination with melamine pyrophosphate (MPP) was adopted to improve the flame retardancy of rigid polyurethane foam (RPUF). The incorporation of steel slag slightly reduced the thermal conductivity of the resulting flame-retardant RPUF samples. The addition of MPP and/or steel slag did not significantly alter the thermal stability in terms of T_-10% and T_max but did obviously increase the T_-50% value, suggesting the improved thermal resistance of the residues. The coaddition of MPP and steel slag into RPUF resulted in higher LOI values and lower peak heat release rates than the samples incorporating either MPP or steel slag alone. The superior flame retardancy could be attributed to MPP promoting char formation, which then acted as a barrier at the beginning of RPUF thermal decomposition; simultaneously, the thermally stable inorganics in the steel slag powder strengthened the thermal resistance of this char layer.     

Virus meet metal-organic frameworks: A nanoporous solution to a world-sized problem?

Laboratory diagnosis of pathologies caused by virus plays a critical role in outbreak response efforts and establishing safe and expeditious testing strategies. Detection of pathogenic virus using commercial solutions require specific tools and laborious laboratory procedures. This makes the day-to-day on time detection of virus infections the limiting step in any outbreak. The need for new diagnostic tools easily available to poor and rural underdeveloped areas where health infrastructure and trained personnel are scarce is highly desirable. The widely known intrinsic properties of Metal-Organic Frameworks (MOFs) embody them with the potential to overcome some of the challenges inherent to virus detection. MOFs are already components of functional devices capable of perform an uninterrupted detection of molecular targets in real time. In this review, we summarise the few studies concerning the reported MOFs used as sensors for pathogenic virus. We emphasise the structural and physical properties of these materials which can open the possibility for their use in this type of sensors and conclude on how the field can progress to envisage the usage of MOFs by the pharmaceutical industry to develop new sensors for these sub-microscopic infectious agents.     

Changes in the oxygen content,morphology, and microstructure of Mo-10Nb composite powders during mechanical alloying

The prefabrication of Mo-Nb composite powders is an effective way of improving the homogeneity of Mo-10Nb targets, which have broad application prospects in the photoelectric sensor industry. However, this aspect has been rarely addressed so far. Therefore, we prepared Mo-10Nb composite powders by mechanical alloying (MA), and investigated the effects of the experimental parameters such as the milling speed and duration on the particle morphology, size distribution, compositional homogeneity, crystallite size, inner strain, and oxygen content. High-quality Mo-10Nb composite powders with 3-μm spherical particles of narrow size distribution, homogeneous elemental distribution, and nanometric crystalline structure were obtained by implementing optimum MA parameters, viz., a milling speed of 250 rpm and duration of 36 h using an MITR QM-QX-4L omnidirectional ball mill. The mechanically alloyed Mo-10Nb composite powders were prone to oxidation when exposed to air, which led to a sharp increase in the oxygen content to ~5400 ppm. X-ray photoelectron spectroscopic analysis revealed the presence of Nb₂O₅, MoO₂, and MoO₃ on the surface of the Mo-10Nb particle. We believe that this study demonstrates an interesting strategy for the fabrication of high-quality Mo-10Nb targets.     

Measurement and analysis of impact dynamics suitable for modelling pneumatic transport of metallic powder flow through a directed energy deposition nozzle

In blown powder directed energy deposition (DED) additive manufacturing powdered metal feedstock is pneumatically conveyed to the meltpool via a nozzle. DED nozzles have been the subject to a growing number of research efforts using computational fluid dynamics (CFD) with multiphase flows to study and optimize powder flow. However, many research papers published to date contain powder – nozzle impact dynamics behavior that is not realistic or not derived from experiments that resemble the powder conveyance process in the DED nozzle being studied. To provide a set of data representative of DED powder flow through a nozzle particle image velocimetry (PIV) experiments were conducted using 316L stainless steel metal powder and flat targets with varying surface roughness made of oxygen free copper, mild steel, P20 tool steel, 316L stainless steel, Inconel 718, and Ti-Al6-V4. Normal coefficients of restitution (COR) were calculated and compared to several analytical and empirical models in literature.     

Full-loop study of a dual fluidized bed cold flow system: Hydrodynamic simulation and validation

The unsteady behaviors of the air-silica sand flow in a lab-scale dual fluidized bed gasification cold flow system have been studied. A two-dimensional computational fluid dynamics full-loop model with poly-size distribution in solid phases was developed as an innovation of this study to investigate the effects of crucial parameters on system hydrodynamics. The results showed a decrease in the mixture static pressure from the bottom to the upper regions of the system, which maintained the system operations stable. The riser air inlet velocity and the gasifier static bed height were found to play considerable roles in enhancing the total sand flow rates. The same tendencies in the prediction and experiment of both the mixture pressure and the sand flow rate showed the feasibility of the proposed model. Besides, the residual evaluation enhanced data reliability and supported model validation. Especially, undesirable phenomena possibly occurring in the system operation under improper conditions could also be predicted. Accordingly, the inventory of bed material and the fluidizing gas flow rates should be suitably regulated to maintain pressure balances, trouble-free continuous flow, optimal sand circulation rate, and low solids loss. Furthermore, the obtained results in this study can be used as a reference for optimizing the designs and operational conditions of large-scale plants.     

Data-driven parameter optimization for the synthesis of high-quality zeolitic imidazolate frameworks via a microdroplet route

As an emerging strategy for the synthesis of metal-organic frameworks (MOFs), a microdroplet-based spray method holds merits of improved heat and mass transfer rates, which allows the formation of MOF crystals in a much faster manner. To optimize the spray route for the MOF synthesis, further exploration is needed to understand the dominant variables controlling the quality of the products. With a series of experiments and advanced computational analysis, we present here general guidance for the synthesis of representative zeolitic imidazolate frameworks (i.e., ZIF-8 and ZIF-67) using the spray route.     

Understanding the formation of ultrafine maltodextrin particles under simultaneous convective drying and antisolvent vapour precipitation

Research on simultaneous antisolvent-vapour-induced precipitation and convective drying of a solute-containing droplet was extensively conducted since this technique was introduced. However, the internal droplet compositions, which were suggested to be related to the formation of particle morphologies, had not been explored. Herein, the ethanol-vapour-induced precipitation of multi-solvent droplets containing maltodextrin as the solute was used to analyse internal droplet compositions. The droplet mass and diameter profiles were obtained via an established single-droplet drying experiment, which mimicked the spray drying of droplets. Analysis revealed that the antisolvent concentration increased with time and was higher than solvent concentration towards the end of the process. It is interesting to find out that the final particle morphology was profoundly impacted by the ambient ethanol humidity and also how spontaneous the subsequent drying was during ethanol-vapour-induced precipitation of the solutes. The formation of the porous structure was favoured with the occurrence of spontaneous vaporization once the ethanol was present for precipitation. Therefore, low ethanol humidity (20% ERH in this study) was sufficient. In contrast, higher ethanol humidity (>70% ERH) was preferable to produce spherical particles. This study provides an insight into particle engineering to unveil the internal droplet conditions and physical phenomena during this unique process.