Particle Technology Research Articles

Compaction and tableting properties of composite particles of microcrystalline cellulose and crospovidone engineered for direct compression

BackgroundExcipients with improved functionality have continued to be developed by the particle engineering strategy of co-processing. The aim of this study was to evaluate the compaction and tableting properties of composite particles of microcrystalline cellulose (MCC) and crospovidone (CPV) engineered by co-processing.ResultsHeckel analysis of the compaction behavior revealed a decrease in plasticity of co-processed excipient (CPE) when compared to MCC due to an increase in Heckel yield pressure from 144 to 172 MPa. The compressibility-tabletability-compactibility (CTC) profile revealed a decrease in individual parameters for CPE when compared to MCC. CPE was found to be more sensitive to the lubricant effect of sodium stearyl fumarate (SSF) when compared to MCC and less sensitive to magnesium stearate (MST) when compared to MCC. A higher dilution potential was obtained for MCC (60%) compared to 44% for CPE when metronidazole was used as model drug. Tableting properties revealed that metronidazole tablets generated with CPE by direct compression disintegrated within 15 min and gave a rapid drug release when compared to MCC as a direct compression (DC) excipient.ConclusionThe compaction and tableting properties of CPE were characterized and yielded tablets with better disintegration and drug release profile when compared to MCC. This study, therefore, confirms the suitability of co-processing as a proven strategy in engineering the performance of excipients.

Unraveling Particle Formation: From Single Droplet Drying to Spray Drying and Electrospraying.

Spray drying and electrospraying are well-established drying processes that already have proven their value in the pharmaceutical field. However, there is currently still a lack of knowledge on the fundamentals of the particle formation process, thereby hampering fast and cost-effective particle engineering. To get a better understanding of how functional particles are formed with respect to process and formulation parameters, it is indispensable to offer a comprehensive overview of critical aspects of the droplet drying and particle formation process. This review therefore closely relates single droplet drying to pharmaceutical applications. Although excellent reviews exist of the different aspects, there is, to the best of our knowledge, no single review that describes all steps that one should consider when trying to engineer a certain type of particle morphology. The findings presented in this article have strengthened the predictive value of single droplet drying for pharmaceutical drying applications like spray drying and electrospraying. Continuous follow-up of the particle formation process in single droplet drying experiments hence allows optimization of manufacturing processes and particle engineering approaches and acceleration of process development.

Polyphenol-Mediated Assembly for Particle Engineering.

Polyphenols are naturally occurring compounds that are ubiquitous in plants and display a spectrum of physical, chemical, and biological properties. For example, they are antioxidants, have therapeutic properties, absorb UV radiation, and complex with metal ions. Additionally, polyphenols display high adherence, which has been exploited for assembling nanostructured materials. We previously reviewed the assembly of different phenolic materials and their applications (Angew. Chem. Int. Ed. 2019, 58, 1904-1927); however, there is a need for a summary of the fundamental interactions that govern the assembly, stability, and function of polyphenol-based materials. A detailed understanding of interactions between polyphenols and various other building blocks will facilitate the rational design and assembly of advanced polyphenol particles for specific applications. This Account discusses how different interactions and bonding (i.e., hydrogen, π, hydrophobic, metal coordination, covalent, and electrostatic) can be leveraged to assemble and stabilize polyphenol-based particles for diverse applications. In polyphenol-mediated assembly strategies, the polyphenols typically exert more than one type of stabilizing attractive force. However, one interaction often dominates the assembly process and dictates the physicochemical behavior of the particles, which in turn influences potential applications. This Account is thus divided into sections that each focus on a key interaction with relevant examples of applications to highlight structure-function relationships. For example, metal coordination generally becomes weaker at lower pH, which makes it possible to engineer metal-phenolic materials with a pH-responsive disassembly profile suitable for drug delivery. Engineered particles, such as hollow capsules, mesoporous and core-shell particles, and self-assembled nanoparticles are some of the systems that are covered to highlight how polyphenols interact with other building blocks and therefore make up the major focus of this Account. Some of the applications of these materials exemplified in this Account include drug delivery, catalysis, environmental remediation, and forensics. Finally, a perspective is provided on the current challenges and trends in polyphenol-mediated particle assembly, and viable near-term strategies for further elucidating the interplay of various competing interactions in particle formation are discussed. This Account is also expected to serve as a reference to guide fundamental research and facilitate the rational design of polyphenol-based materials for diverse emerging applications.

In situ Image Processing and Data Binning Strategy for Particle Engineering Applications

AbstractCrystallization control can be improved through real‐time monitoring technologies. Here, a workflow is demonstrated on rapid batch cooling crystallization of L‐glutamic acid. First, in situ images were generated using video microscopy sensors and analyzed, by employing a single, rapid macro code to extract particle data descriptors. A binning procedure (over time) was performed, where every data point represented the counts of particles within a specific size or shape range per 100 images. This binning method was found more informative in tracking of the populations compared to whole image averages or individual particle datapoints. This study provides a step‐by‐step guide towards improving mechanistic modeling, control via feedback, automation, and continuous manufacturing for Industry 4.0.

Effect of formulation and inhaler parameters on the dispersion of spray freeze dried voriconazole particles.

Spray freeze drying is a particle engineering technique that allows the production of porous particles of low density with excellent aerosol performance for inhalation. There are a number of operating parameters that can be manipulated in order to optimise the powder properties. In this study, a two-fluid nozzle was used to prepare spray freeze dried formulation of voriconazole, a triazole antifungal agent for the treatment of pulmonary aspergillosis. A full factorial design approach was adopted to explore the effects of drug concentration, atomisation gas flow rate and primary drying temperature. The aerosol performance of the spray freeze dried powder was evaluated using the next generation impactor (NGI) operated with different inhaler devices and flow rates. The results showed that the primary drying temperature played an important role in determining the aerosol properties of the powder. In general, the higher the primary drying temperature, the lower the emitted fraction (EF) and the higher the fine particle fraction (FPF). Formulations that contained the highest voriconazole concentration (80% w/w) and prepared at a high primary drying temperature (-10°C) exhibited the best aerosol performance under different experimental conditions. The high concentration of the hydrophobic voriconazole reduced surface energy and cohesion, hence better powder dispersibility. The powders produced with higher primary drying temperature had a smaller particle size after dispersion and improved aerosol property, possibly due to the faster sublimation rate in the freeze-drying step that led to the formation of less aggregating or more fragile particles. Moreover, Breezhaler®, which has a low intrinsic resistance, was able to generate the best aerosol performance of the spray freeze dried voriconazole powders in terms of FPF.

Conformable self-assembling amyloid protein coatings with genetically programmable functionality.

Functional coating materials have found broad technological applications in diverse fields. Despite recent advances, few coating materials simultaneously achieve robustness and substrate independence while still retaining the capacity for genetically encodable functionalities. Here, we report Escherichia coli biofilm-inspired protein nanofiber coatings that simultaneously exhibit substrate independence, resistance to organic solvents, and programmable functionalities. The intrinsic surface adherence of CsgA amyloid proteins, along with a benign solution-based fabrication approach, facilitates forming nanofiber coatings on virtually any surface with varied compositions, sizes, shapes, and structures. In addition, the typical amyloid structures endow the nanofiber coatings with outstanding robustness. On the basis of their genetically engineerable functionality, our nanofiber coatings can also seamlessly participate in functionalization processes, including gold enhancement, diverse protein conjugations, and DNA binding, thus enabling a variety of proof-of-concept applications, including electronic devices, enzyme immobilization, and microfluidic bacterial sensors. We envision that our coatings can drive advances in electronics, biocatalysis, particle engineering, and biomedicine.

Development of inhaled formulation of modified clofazimine as an alternative to treatment of tuberculosis

Inhalation drug delivery provides a possible useful alternative to oral drug delivery in the treatment of tuberculosis (TB). This work evaluated inclusion complexes of clofazimine (CFZ), an anti-TB drug with low aqueous solubility and potential gastric degradation, in β-cyclodextrin (βCD), γ-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin and sulfobutyl-ether-β-cyclodextrin. A phase solubility study indicated that βCD showed the best inclusion capacity for CFZ, so a CFZ:βCD complex (1:7) was selected for further studies. Particle engineering was performed using spray drying to obtain powders with suitable characteristics for pulmonary delivery and l-leucine was added to enhance powder dispersibility. Thermal and spectroscopic analyses indicated the CFZ:βCD integrity after spray drying, and the presence of l-leucine resulted in less hygroscopic and rougher particles, and a less agglomerated powder. All formulations, and especially those containing l-leucine, showed suitable in vitro deposition performance in the Next Generation Impactor and presented higher aqueous solubility compared to the free drug. In vitro studies showed low toxicity against Calu-3 and CFZ retention in the cell monolayer and apical compartment. These results suggest that the inhalation formulation composed of CFZ:βCD plus l-leucine should improve CFZ pulmonary bioavailability and provide an alternative treatment for TB, acting on the main infection site of the disease.

Particle engineering for improved stability and handling properties of carrot concentrate powders using fluidized bed granulation and agglomeration

Carotenoid rich carrot concentrate powders were produced using spray drying, fluidized bed agglomeration and spout fluidized bed spray granulation. The powders were analyzed and compared for their microstructure, encapsulation efficiency, dissolution kinetics, flowability and oxidation stability during storage. Agglomeration and spray granulation resulted in powders with a high encapsulation efficiency (96–99%), oxidation stability and improved flowability compared to spray dried powders. Dissolution in water was fastest for agglomerated powders and significantly slowed down by lump formation in spray dried and spray granulated powders. After 168 days of storage at 35 °C, 92–93% and 86–90% of the initial carotenoids were retained in spray granulated and agglomerated powders respectively, whereas only 68–75% were retained in spray dried particles. The obtained results highlight the potential of targeted particle engineering to achieve food powders with superior functional properties and stability.

Effects of spray behavior and wall impingement on particulate matter emissions in a direct injection spark ignition engine equipped with a high pressure injection system

The effects of injection pressure on spray behaviors governing particulate matter emissions were investigated for various injection timings and engine loads in an optically accessible single cylinder engine equipped with gasoline direct injection system. In a spray visualization and particle number (PN) measurement experiment, injection timing and engine load were varied to examine their effects on the spray behavior including cylinder wetting that causes the emission of particulate matter. The analysis was based on the time-averaged spray images, spray variations between the cycles, combustion, and PN emission characteristics. The spray structure in the cylinder under the engine operating conditions used in the present study was a collapsed spray that was evident at high pressure injection under atmospheric conditions. For an injection timing of before top death center (BTDC) 300 deg, at the initial stage of the intake process, the magnitude of spray deflection formed by the in-cylinder flow interacting with the spray in the reverse direction increased owing to the high pressure injection promoting fuel atomization and increasing the effects of the in-cylinder flow. The spray variations between the cycles caused by the in-cylinder flow in the region of spray deflection were also increased by high pressure injection. When the weak in-cylinder flow was formed in the late intake process (BTDC 210 deg), increasing the injection pressure accelerated the initial droplet velocity and increased the amount of fuel reaching the cylinder wall opposite the injector, thus increasing the wall film and PN emissions. In contrast, for the conditions under which the wall film was formed on the piston top by fuel interaction, the large droplet momentum corresponding to high pressure injection increased in the amount of rebounded droplets at collision, thereby reducing the amount of wall film and PN emissions.

Application of a suitable particle engineering technique by pulsed laser ablation in liquid (PLAL) to modify the physicochemical properties of poorly soluble drugs

Several disintegration procedures are well known in the field of pharmaceutical technology to improve the solubility, dissolution rate and bioavailability. Only a few, organic materials were applied for micro/nanoparticle generation by pulsed laser ablation in liquid (PLAL), however in the last decade, several studies presented successful production from different active agents. PLAL could be a non-conventional approach by the preformulation of the drug, as a simple, clean (no additional chemicals are needed) and a rapid wet grinding metho d. It can be stated about the novelty of the work that a poorly water-soluble meloxicam was milled first time by pulsed laser ablation in liquid, where the effect of three different wavelengths, fluence values (energy density) and polymer type (PVP, PVA, Poloxamer) on the habit, structure, solubility and in vitro properties of the drug were investigated. Nearly spherical amorphous micro- and nanoparticles could be reached in a size range between 60 and 700 nm.Fourier-transform infrared spectroscopy (FT-IR) was applied to check the purity, secondary interaction and High performance liquid chromatography (HPLC) method was used for the determination of the presence of the meloxicam content and the final yield. The results suggest that laser ablation a useful approach to modify the physicochemical properties of the active agents, introduced a novel preparation method in drug preformulation with improved solubility (from 0.0203 mg/mL to 0.0797 mg/mL), dissolution rate (~85%) and also to produce a suitable intermediate product for traditional and alternative drug administration (e.g. pulmonary, nasal, transdermal).

Surface Functional Group Engineering of CeO2 Particles for Enhanced Phosphate Adsorption.

Surface functional groups play a dominating role in determining the adsorption performance of metal oxide particles. The ability to manipulate the surface functional groups is vital in designing an effective adsorbent for water decontamination. In this study, a facile method is proposed for tuning the amount of the surface hydroxyl groups of CeO2 particles. The volume of water added during the ethylene glycol-mediated solvothermal synthesis of CeO2 particles can be used to adjust the amount of surface hydroxyl groups. By simple reduction in the volume of water, the number of surface hydroxyl groups of CeO2 particles can be increased and the phosphate adsorption capacity can be greatly improved. Our results show that the obtained CeO2 particles have high phosphate adsorption capacity at low phosphate concentrations, fast adsorption kinetics, and the ability to achieve an ultralow phosphate concentration in the real sewage effluent. This study provides an effective strategy for designing highly effective metal oxide adsorbents through surface functional group engineering.

Quantifying redox heterogeneity in single-crystalline LiCoO2 cathode particles.

Active cathode particles are fundamental architectural units for the composite electrode of Li-ion batteries. The microstructure of the particles has a profound impact on their behavior and, consequently, on the cell-level electrochemical performance. LiCoO2 (LCO, a dominant cathode material) is often in the form of well-shaped particles, a few micrometres in size, with good crystallinity. In contrast to secondary particles (an agglomeration of many fine primary grains), which are the other common form of battery particles populated with structural and chemical defects, it is often anticipated that good particle crystallinity leads to superior mechanical robustness and suppressed charge heterogeneity. Yet, sub-particle level charge inhomogeneity in LCO particles has been widely reported inthe literature, posing a frontier challenge in this field. Herein, this topic isrevisited and it is demonstrated that X-ray absorption spectra on single-crystalline particles with highly anisotropic lattice structures are sensitive to thepolarization configuration of the incident X-rays, causing some degree of ambiguity in analyzing the local spectroscopic fingerprint. To tackle this issue, a methodology is developed that extracts the white-line peak energy in the X-ray absorption near-edge structure spectra as a key data attribute for representing the local state of charge in the LCO crystal. This method demonstrates significantly improved accuracy and reveals the mesoscale chemical complexity in LCO particles with better fidelity. In addition to the implications on the importance of particle engineering for LCO cathodes, the method developed herein also has significant impact on spectro-microscopic studies of single-crystalline materials at synchrotron facilities, which is broadly applicable to a wide range of scientific disciplines well beyond battery research.

Particle technology education in the 21st century – Outcomes from the IFPRI sponsored workshop in Sheffield, April 2017

In April 2017, IFPRI sponsored a workshop at the University of Sheffield to assess the current state of global particle technology education and chart a course forward. There is a clearly demonstrated need for trained graduates at all levels across a broad spectrum of industries. Workshop participants recommended a top down approach for curriculum renewal and developed key high-level learning attributes for undergraduate education in particle science and engineering. Participants further identified a variety of barriers to integrating particle technology into undergraduate engineering curricula such as the crowded engineering curriculum, a perception that particle technology is more an art than a science, and that it is an orphan subject that fits uncomfortably in standard engineering disciplines. Nevertheless, change is possible with better underlying science, new textbooks and software tools, examples of excellent programs and courses, and increasing demand from employers for skills in the area, as compared to 25 years ago. Suggestions for how to do this are reported. It will take persistence and cooperation between both academia and industry to achieve a significantly higher percentage of engineers trained in particle science and engineering. This education will benefit society in solving the world's current and future technological grand challenges.

On the Effect of Secondary Nucleation on Deracemization through Temperature Cycles

Herein, the pivotal role of secondary nucleation in a crystallization-enhanced deracemization process is reported. During this process, complete and rapid deracemization of chiral conglomerate crystals of an isoindolinone is attained through fast microwave-assisted temperature cycling. A parametric study of the main factors that affect the occurrence of secondary nucleation in this process, namely agitation rate, suspension density, and solute supersaturation, confirms that an enhanced stereoselective secondary nucleation rate maximizes the deracemization rate. Analysis of the system during a single temperature cycle showed that, although stereoselective particle production during the crystallization stage leads to enantiomeric enrichment, undesired kinetic dissolution of smaller particles of the preferred enantiomer occurs during the dissolution step. Therefore, secondary nucleation is crucial for the enhancement of deracemization through temperature cycles and as such should be considered in further design and optimization of this process, as well as in other temperature cycling processes commonly applied in particle engineering.

Shape engineering of polystyrene particles from spherical to raspberry-like to hollow flower-like via one-step non-surfactant self-templating polymerization of styrene in ethanol-water mixtures.

We report a facile method for preparation of polystyrene (PS) particles with spherical, raspberry-like, and hollow flower-like structures by single-step non-surfactant self-templating polymerization of styrene in ethanol–water mixtures. PS particles with diverse morphologies could be easily obtained by simply adjusting the volume ratios of the styrene/water/ethanol mixture and initiator-ethanol–water mixture. By decreasing this ratio, the particles with spherical, raspberry-like, and hollow flower-like structures were obtained in sequence. The wettability of the coatings changing from hydrophilicity to hydrophobicity was easily tuned by the PS particles with different roughnesses. A competitive mechanism of interfacial polymerization and exudation was proposed to interpret the formation of PS particles with diverse morphologies.

Morphology engineering of silicon nanoparticles for better performance in Li-ion battery anodes.

Amorphous silicon nanoparticles were synthesized through pyrolysis of silane gas at temperatures ranging from 575 to 675 °C. According to the used temperature and silane concentration, two distinct types of particles can be obtained: at 625 °C, spherical particles with smooth surface and a low degree of aggregation, but at a higher temperature (650 °C) and lower silane concentration, particles with extremely rough surfaces and high degree of aggregation are found. This demonstrates the importance of the synthesis temperature on the morphology of silicon particles. The two types of silicon nanoparticles were subsequently used as active materials in a lithium half cell configuration, using LiPF6 in an alkylcarbonate-based electrolyte, in order to investigate the impact of the particles morphology on the cycling performances of silicon anode material. The difference in morphology of the particles resulted in different volume expansions, which impacts the solid electrolyte interface (SEI) formation and, as a consequence, the lifetime of the electrode. Half-cells fabricated from spherical particles demonstrated almost 70% capacity retention for over 300 cycles, while the cells made from the rough, aggregated particles showed a sharp decrease in capacity after the 20th cycle. The cycling results underline the importance of Si particle engineering and its influence on the lifetime of Si-based materials.

Feasibility of electrospraying fully aqueous bovine serum albumin solutions

Electrospraying or electrohydrodynamic atomisation, i.e. the formation of tiny droplets from a jet of conductive liquid under the influence of an electric field, has been gaining in popularity as a particle engineering technique in recent years. In addition to general benefits for particle engineering, e.g. the ability to generate nanometre sized particles with a very narrow size distribution, electrospraying also possesses a number of characteristics, like its applicability at ambient conditions, which could make it especially interesting for formulating therapeutic proteins. However, as fully aqueous solutions of proteins tend to have relatively high electrical conductivities and surface tensions, obtaining a stable Taylor cone-jet mode for these solutions is inherently challenging. This is why in the majority of studies reporting the successful electrospraying of proteins, either emulsions, aqueous suspensions or a mixture of water and one or more organic solvents were used instead of fully aqueous solutions. Therefore, an ab initio electrospraying formulation development study was conducted, using only fully aqueous feed solutions containing protein stabilising excipients commonly used in spray- and freeze-drying of therapeutic proteins. The study included bovine serum albumin (BSA) as a model protein and consisted out of two parts: (1) a one parameter at a time screening study, designed to improve the understanding of how various formulation components influence relevant physicochemical properties and the electrospraying process and (2) two subsequent mixture design of experiments (DoE) studies, designed to aid in the statistical description and prediction of the influence of different protein-excipient combinations on the electrospraying process. Additionally, the influence of physicochemical properties relevant to the electrospraying process, i.e. the volumetric mass density, electrical conductivity, kinematic viscosity and surface tension, was assessed for all feed solutions included in the study.

Improved processability of ethambutol hydrochloride by spherical agglomeration

Ethambutol hydrochloride (ETB), high dose anti-tubercular drug exhibits poor micromeritics and compressibility. The current study aimed to enhance flow, compressibility and packing characteristics, thereby improving processability of ETB by spherical agglomeration. Quasi emulsion solvent diffusion method was used for agglomeration process in which saturated aqueous ETB solution was prepared and the crystallization was carried out subsequently at different ratios of acetone and ethyl acetate which act as anti-solvent. Further the process was optimised statistically using 32 factorial design keeping ‘speed of stirring’ and ‘ratio acetone and ethyl acetate’ as independent variables and particle size as dependent variable. Optimised batch of ethambutol hydrochloride spherical agglomerates (ETB-SA) was characterised for sieve analysis, solid state characteristics and Kawakita analysis. The uniformity of ETB-SA was observed with SEM while XRPD studies revealed reduction in crystallinity for ETB-SA. DSC and FTIR indicated no polymeric or chemical alteration during crystallization process. The flow properties of ETB-SA were found superior and its Kawakita parameters indicated improved packability and flowability compared to ETB. ETB has high solubility in water therefore was no significant difference was observed in in vitro dissolution of ETB and ETB-SA. Thus spherical agglomeration, a revered particle engineering technique, continues to be a salient approach for enhancing processability of high-dose drugs like ETB.

Spray Dried Formulations for Inhalation-Meaningful Characterisation of Powder Properties.

Spray drying as a particle engineering technique is of increasing interest in the field of inhalation and is already being utilised e.g., for the PulmoSphereTM products. As spray dried particles tend to agglomerate and are mechanically instable, low dose filling processes can be difficult. This study correlates powder flowability tests of spray dried formulations with filling processes with drum and dosator systems. Four pulmonary and four nasal powders with different characteristics in terms of shape, composition, and surface polarity were prepared and characterised for powder flowability according to Ph. Eur. and by powder rheometry. All formulations were filled with a manual drum TT and a dosator system. The classical flowability tests according to the Ph. Eur. showed a bad flow behaviour for hydrophilic pulmonary powders (x50 ~ 3 µm), whereas hydrophobic pulmonary particles and nasal particles (x50 ~ 25 µm) showed a better flowing behaviour. Powder rheometry supports this finding but can better differentiate flow behaviours.

All the small things: How virus-like particles and liposomes modulate allergic immune responses.

Recent years have seen a dramatic increase in the range of applications of virus‐like nanoparticle (VNP)‐ and liposome‐based antigen delivery systems for the treatment of allergies. These platforms rely on a growing number of inert virus‐backbones or distinct lipid formulations and intend to engage the host's innate and/or adaptive immune system by virtue of their co‐delivered immunogens. Due to their particulate nature, VNP and liposomal preparations are also capable of breaking tolerance against endogenous cytokines, Igs, and their receptors, allowing for the facile induction of anti‐cytokine, anti‐IgE, or anti‐FcεR antibodies in the host. We here discuss the “pros and cons” of inducing such neutralizing autoantibodies. Moreover, we cover another major theme of the last years, i.e., the engineering of non‐anaphylactogenic particles and the elucidation of the parameters relevant for the specific trafficking and processing of such particles in vivo. Finally, we put the various technical advances in VNP‐ and liposome‐research into (pre‐)clinical context by referring and critically discussing the relevant studies performed to treat allergic diseases.