Particle Technology Research Articles

The applications of Machine learning (ML) in designing dry powder for inhalation by using thin-film-freezing technology

Dry powder inhalers (DPIs) are one of the most widely used devices for treating respiratory diseases. Thin--film--freezing (TFF) is a particle engineering technology that has been demonstrated to prepare dry powder for inhalation with enhanced physicochemical properties. Aerosol performance, which is indicated by fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD), is an important consideration during the product development process. However, the conventional approach for formulation development requires many trial-and-error experiments, which is both laborious and time consuming. As a state-of-the art technique, machine learning has gained more attention in pharmaceutical science and has been widely applied in different settings. In this study, we have successfully built a prediction model for aerosol performance by using both tabular data and scanning electron microscopy (SEM) images. TFF technology was used to prepare 134 dry powder formulations which were collected as a tabular dataset. After testing many machine learning models, we determined that the Random Forest (RF) model was best for FPF prediction with a mean absolute error of ± 7.251%, and artificial neural networks (ANNs) performed the best in estimating MMAD with a mean absolute error of ± 0.393 μm. In addition, a convolutional neural network was employed for SEM image classification and has demonstrated high accuracy (>83.86%) and adaptability in predicting 316 SEM images of three different drug formulations. In conclusion, the machine learning models using both tabular data and image classification were successfully established to evaluate the aerosol performance of dry powder for inhalation. These machine learning models facilitate the product development process of dry powder for inhalation manufactured by TFF technology and have the potential to significantly reduce the product development workload. The machine learning methodology can also be applied to other formulation design and development processes in the future.

Advancements in Particle Engineering for Inhalation Delivery of Small Molecules and Biotherapeutics

Dry powder inhalation formulations have become increasingly popular for local and systemic delivery of small molecules and biotherapeutics. Powder formulations provide distinct advantages over liquid formulations such as elimination of cold chain due to room temperature stability, improved portability, and the potential for increasing patient adherence. To become a viable product, it is essential to develop formulations that are stable (physically, chemically and/or biologically) and inhalable over the shelf-life. Physical particulate properties such as particle size, morphology and density, as well as chemical properties can significantly impact aerosol performance of the powder. This review will cover these critical attributes that can be engineered to enhance the dispersibility of inhalation powder formulations. Challenges in particle engineering for biotherapeutics will be assessed, followed by formulation strategies for overcoming the hurdles. Finally, the review will discuss recent examples of successful dry powder biotherapeutic formulations for inhalation delivery that have been clinically assessed.

Application of CO2 Supercritical Fluid to Optimize the Solubility of Oxaprozin: Development of Novel Machine Learning Predictive Models.

Over the last years, extensive motivation has emerged towards the application of supercritical carbon dioxide (SCCO2) for particle engineering. SCCO2 has great potential for application as a green and eco-friendly technique to reach small crystalline particles with narrow particle size distribution. In this paper, an artificial intelligence (AI) method has been used as an efficient and versatile tool to predict and consequently optimize the solubility of oxaprozin in SCCO2 systems. Three learning methods, including multi-layer perceptron (MLP), Kriging or Gaussian process regression (GPR), and k-nearest neighbors (KNN) are selected to make models on the tiny dataset. The dataset includes 32 data points with two input parameters (temperature and pressure) and one output (solubility). The optimized models were tested with standard metrics. MLP, GPR, and KNN have error rates of 2.079 × 10−8, 2.173 × 10−9, and 1.372 × 10−8, respectively, using MSE metrics. Additionally, in terms of R-squared, they have scores of 0.868, 0.997, and 0.999, respectively. The optimal inputs are the same as the maximum possible values and are paired with a solubility of 1.26 × 10−3 as an output.

The Study of Spray-Freeze-Drying Technique for Development of Novel Combination pMDIs, Part I: Study on the Preparation Method

AbstractClinically available pressurized metered-dose inhalers (pMDIs) mainly directly use micronized drugs as inhalable microparticles. Although technology for preparing pMDIs has proven to obtain clinically appropriate aerosol performance, the fine particle fraction and delivered dose content uniformity (DDCU) of pMDIs still need to be improved. DDCU problem is usually exacerbated by patients' handling errors prior to taking a dose. In this study, novel phospholipid microparticle inhalation pMDIs were prepared by a spray-freeze-drying process using mometasone furoate and formoterol fumarate dihydrate as model drugs and distearoylphosphatidylcholine as an excipient. Combined with the material composition, the atomization and freeze-drying processes were also studied. Our data showed that both atomization parameters of gas–liquid ratio and freeze-drying curve settings met the requirements of drug design. According to aerodynamic performance in vitro and DDCU evaluation, the performance of the phospholipid microparticle inhalation pMDI was better than that of the micronized drug microparticle pMDI. In conclusion, preparing pMDIs with particle engineering has the potential to ensure accuracy of quantification and to improve the efficiency of drug deposition in lungs in clinical practice.

Biopolymer coating for particle surface engineering and their biomedical applications.

Surface engineering of particles based on a polymeric coating is of great interest in materials design and applications. Due to the disadvantages of non-biodegradability and undesirable biocompatibility, the application of petroleum-based synthetic polymers coating in the biomedical field has been greatly limited. In addition, there is lack of a universal surface modification method to functionalize particles of different compositions, sizes, shapes, and structures. Thus, it is imperative to develop a versatile biopolymeric coating with good biocompatibility and tunable biodegradability for the preparation of functional particle materials regardless of their surface chemical and physical structures. Recently, the natural polysaccharide polymers (e.g. chitosan and cellulose), polyphenol-based biopolymers (e.g. polydopamine and tannic acid), and proteins (e.g. amyloid-like aggregates) have been utilized in surface modification of particles, and applications of these modified particles in the field of biomedicine have been also intensively exploited. In this review, the preparation of the above three coatings on particles surface are summarized, and the applications of these materials in drug loading/release, biomineralization, cell immobilization/protection, enzyme immobilization/protection, and antibacterial/antiviral are exemplified. Finally, the challenges and the future research directions on biopolymer coating for particles surface engineering are prospected.

Oyster shell reuse: A particle engineering perspective for the use as emulsion stabilizers

Oyster shells are an important bioresource that causes serious environmental problems and is currently only partially repurposed. Its versatile nature is reflected in the manifold studies already proposed for the material. In this study, we add to this effort by first grinding the material with a hammer mill, beater disc mill, pin mill and wet media mill, treating part of it in a muffle furnace, noting the shift in its properties such as particle size, morphology, surface free energy, specific surface area and choosing a fraction to incorporate in a particle stabilized emulsion. The particle stabilized emulsions were prepared with oyster shells grinded by the agitated wet media mill at 2000 rpm for 30 min, with a media at x 50 = 0.79 μm, a SSA at 17.16 m 2 /g, a SFE at 32.53 mN/m and with particles resembling a spherical shape. The emulsion was studied in terms of particle concentration, ranging from 2 to 10 wt% with the 8 wt% showing the best stability. The 8 wt% oyster shell formulation was tested and compared with a formulation using 2 wt% Aerosil particles and a surfactant store-bought product. The oyster shell particle formulation exhibited minor viscosity changes in the studied period of 8 weeks, a constant LVE range and promising behaviour in the proposed application. • Description of applications suggested for waste oyster shells in different sectors. • Grinding experiments for oyster shells performed with four different types of mills. • Characterization of the physicochemical properties of the grinded fractions including size, shape and surface interactions. • Proposition of an innovative application for oyster shells as emulsion stabilizers. • Rheological analysis to support suitability of the particles as stabilizers.

Metallopolymer Particle Engineering via Etching of Boronate Polymers toward High-Performance Overall Water Splitting Catalysts.

Metallopolymers combine the property features of both metallic compounds and organic polymers, representing a typical direction for the design of high-performance hybrid materials. Here, a highly adaptive etching method to create pores and cavities in the metallopolymer particles is established. Starting from boronate polymer (BP) and inorganic@BP core-shell particles, porous, hollow, and yolk-shell metallopolymer particles can be fabricated, respectively. By taking advantage of the easy control over composition and pore/cavity structure, these metallopolymer particles provide a universal platform for the fabrication of nitrogen, boron co-doped carbon nanocomposites loaded with metals (M-NBCs). The as-prepared M-NBCs exhibit remarkable catalytic activities toward oxygen evolution reaction and hydrogen evolution reaction. An alkaline overall water splitting cell assembled by using M-NBCs as the anode and cathode can be driven by a single AAA battery. The proposed strategy for the construction of metallopolymer composites may enlighten for the design of complex hybrid nanomaterials.

(Invited) Mesoscale Reaction Kinetics Modulated By Structural and Compositional Heterogeneity in Battery Cathode Materials

Doping, coating, and particle engineering for cathode materials are broadly adopted by both academia and industry to improve the battery performance. The lack of an in-depth understanding for the underlying mechanism, however, makes it a largely try-and-error process with unsatisfactory efficiency and effectiveness. This is particularly true for the electrochemical reaction kinetics that is heterogeneous over a broad range of length scales and is determined collectively by the cathode’s electronic structure, lattice configuration, and micro-morphology.In this presentation, I will talk about the use of advanced synchrotron techniques for imaging the cathode particles with structural, chemical and compositional sensitivities. We will talk about the mutual modulation between the surface chemistry and the bulk charge distribution and mechanical cracking. As an example, we will discuss how a facet-dependent dopant segregation in Zr-modified single-crystal LiNi0.6Co0.2Mn0.2O2 cathode would modulate its mesoscale reaction kinetics. This study suggests that a delicately controlled dopant distribution is a viable strategy for designing the next-generation battery cathode with superior structural and chemical robustness.

Research the Effect of Oxidation Catalytic Converter on Reducing Diesel Engine Particulate Emission Based on Artificial Intelligence

Research the Effect of Oxidation Catalytic Converter on Reducing Diesel Engine Particulate Emission Based on Artificial Intelligence

Decoding Fine API Agglomeration as a Key Indicator of Powder Flowability and Dissolution: Impact of Particle Engineering.

Fine API agglomeration and its mitigation via particle engineering, i.e., dry coating, remains underexplored. The purpose was to investigate agglomeration before and after dry coating of fine cohesive APIs and impact on powder processability, i.e., flowability (FFC), bulk density (BD), and dissolution of BCS Class II drugs. Ibuprofen (three sizes), fenofibrate, and griseofulvin (5-20µm), before and after dry coating with varying amounts of hydrophobic (R972P) or hydrophilic (A200) nano- silica, were assessed for agglomeration, FFC, BD, surface energy, wettability, and dissolution. The granular Bond number (Bog), a dimensionless parameter, evaluated through material-sparing particle-scale measures and particle-contact models, was used to express relative powder cohesion. Significant powder processability improvements after dry coating were observed: FFC increased by multiple flow regimes, BD increased by 25-100%, agglomerate ratio (AR) reduction by over an order of magnitude, and greatly enhanced API dissolution rate even with hydrophobic (R972P) silica coating. Scrutiny of particle-contact models revealed non-triviality in estimating API surface roughness, which was managed through the assessment of measured bulk properties. A power-law correlation was identified between AR and Bog and subsequently, between AR and FFC & bulk density; AR below 5 ensured improved processability and dissolution. Agglomeration, an overlooked material-sparing measure for powder cohesiveness, was a key indicator of powder processability and dissolution. The significant agglomerate reduction was possible via dry coating with either silica type at adequate surface area coverage. Reduced agglomeration after dry coating also countered the adverse impact of increased surface hydrophobicity on dissolution.

Application of design of experiments for development and characterization of coprocessed excipients using Lapidium Sativum

The development of novel excipients with enhanced functionality has been explored using particle engineering by co-processing. The aim of this study was to improve the functionality of Lapidium Sativum for direct compression by co-processing with MCC pH 101 and PVP K30 in optimized proportions. Design of Experiment (DoE) was employed to optimize the composition of the co-processed excipient using the desirability function and other supporting studies as a basis for selecting the optimized formulation. The co-processed excipient was thereafter developed by the method of spraydrying. Flow and compaction studies of coprocessed excipient were carried out in comparison to its parent component and physical mixture. Tablets were prepared by direct compression (DC) containing Venlafaxine hydrochloride (100 mg) as a model for poor compressibility. Tablets produced with CPE were satisfactory and conformed to USP specifications for acceptable tablets. The application of DoE was successful in optimizing and developing a starch-based co-processed excipient that can be considered for direct compression tableting.

Simultaneous Spray Drying for Combination Dry Powder Inhaler Formulations.

Spray drying is a particle engineering technique used to manufacture respirable pharmaceutical powders that are suitable for delivery to the deep lung. It is amenable to processing both small molecules and biologic actives, including proteins. In this work, a simultaneous spray-drying process, termed simul-spray, is described; the process involves two different active pharmaceutical ingredient (API) solutions that are simultaneously atomized through separate nozzles into a single-spray dryer. Collected by a single cyclone, simul-spray produces a uniform mixture of two different active particles in a single-unit operation. While combination therapies for dry powder inhalers containing milled small molecule API are commercially approved, limited options exist for preparing combination treatments that contain both small molecule APIs and biotherapeutic molecules. Simul-spray drying is also ideal for actives which cannot withstand a milling-based particle engineering process, or which require a high dose that is incompatible with a carrier-based formulation. Three combination case studies are demonstrated here, in which bevacizumab is paired with erlotinib, cisplatin, or paclitaxel in a dry powder inhaler formulation. These model systems were chosen for their potential relevance to the local treatment of lung cancer. The resulting formulations preserved the biologic activity of the antibody, achieved target drug concentration, and had aerosol properties suitable for pulmonary delivery.

Pharmacotechnical Evaluation by SeDeM Expert System to Develop Orodispersible Tablets.

Sediment delivery model (SeDeM) system is innovative tool to correlate micromeritic properties of powders with compressibility. It involves computation of indices which facilitate direct compressibility of solids and enable corrective measures through particle engineering. Study had multiple objectives, viz, (i) to enhance solubility of BCS class II, nevirapine using solid dispersions; (ii) SeDeM analyses of excipients and solid dispersions to analyze direct compressibility; and (iii) prepare orodispersible tablets (ODT). Solid dispersions were prepared by solvent evaporation. Superdisintegrants and solid dispersions were analyzed for primary indices of dimension, compressibility, flowability, stability, and disgregability derived from micromeritic properties. Radar diagrams were constructed to provide visual clues to deficient properties for direct compressibility. ODTs were prepared using excipients which passed criteria for direct compressibility and evaluated for tablet properties. Solid dispersions with Eudragit S100 revealed 6 to 10 fold increase in solubility in various dissolution media including biorelevant media in comparison with plain drug. Solubility was found to be pH dependent. SeDeM analyses facilitated identification of superdisintegrants and excipients with unfavorable compressibility. Radar diagrams provided a clear pictorial evidence of lacunae in powder properties. Based on SeDeM results, tablets were formulated by direct compression using crosspovidone, croscarmellose sodium, and mannitol. All batches showed 40% release in first minute in simulated salivary fluid.

Printed asymmetric microcapsules: Facile loading and multiple stimuli-responsiveness.

Engineering of colloidal particles and capsules despite substantial progress is still facing a number of unsolved issues including low loading capacity, non-uniform size and shape of carriers, tailoring different functionalities and versatility to encapsulated cargo. In this work, we propose a method for defined-shaped functionally asymmetric polymer capsule fabrication based on a soft lithography approach. The developed capsules consist of two classes of polymers - the main part "cup" is made out of polyelectrolyte multilayers (PAH-PSS) and "lid" is made of biodegradable polyether (PLGA). Asymmetric capsules combine advantages from both traditional layer-by-layer capsules and recently developed printed "pelmeni" capsules. This combination provides stimuli-responsiveness due to polyelectrolyte multilayer properties differing from PLGA. The inner volume of capsules can be loaded with a variety of active compounds and the capsule's geometry is defined due to the soft-lithography method. Capsules have a core-shell structure and monodisperse size distribution. Three methods to trigger cargo release have been demonstrated, namely temperature treatment, ultrasonication and pH shift. Steroidal drug dexamethasone was used to illustrate the applicability of the systems for triggered drug release. The application of proposed asymmetric capsules includes but is not limited to pharmacology, diagnostics, sensors, micro- and nanoreactors and chemical actuators.

Proof-of-Concept for Adjusted Surface Energies and Modified Fines as a Novel Concept in Particle Engineering for DPI Formulations.

Currently marketed dry powder inhaler (DPI) medicine lacks drug delivery performance due to insufficient powder dispersion. In carrier-based blends, incomplete drug detachment is typically attributed to excessive adhesion forces between carrier and drug particles. Adding force control agents (FCA) is known to increase drug detachment. Several researchers accounted this effect to a decrease in carrier surface energy (SE). In turn, an increase in SE should impede drug detachment. In this proof-of-concept study, we investigated the influence of the SE of the carrier material in binary blends by intentionally inverting the FCA approach. We increased SEs by dry particle coating utilising high-shear mixing, which resulted in decreased respirable fractions of the respective blends. Thus, we confirmed the SE of the carrier influences drug delivery and should be considered in formulation approaches. Complementing engineering techniques on the carrier level, we evaluated a method to modify the SE of extrinsic fines in ternary powder blends for inhalation. By the co-milling of fine lactose and an additive, we tailored the SE and hence the adhesiveness of additional fine excipients. Thus, the extent and the strength of drug–fines agglomerates may be controllable. For ternary DPI formulations, this work highlights the potential benefits of matching the SE of both fines and drugs.

Nanoscale engineering of gold particles in 18th century Böttger lusters and glazes

SignificanceThe exploration of gold-based colorants in glass and glazes led Nobel Laureate Richard Zsigmondy to the study of colloids, and to the development, with Henry Siedentopf, of the earliest microscopes capable of resolving such small length scales. Zsigmondy's studies were preceded by alchemical investigations starting in the 17th century that yielded the gold-based Purple of Cassius, and experiments in the early 18th century resulting in an unusual purple iridescent porcelain overglaze, called Böttger luster, at the Meissen Manufactory. We discuss the first nano-scale characterization of Böttger luster, its successful replication, and propose an explanation for its optical properties based on the physics of scattering and interference of nanoparticle arrays.

Particle Engineering by Nano Spray Drying: Optimization of Process Parameters with Hydroethanolic versus Aqueous Solutions.

Nano spray drying has emerged as an outstanding platform for engineering micro- and nanoparticles, with growing applications in various areas of drug delivery. As a new technology involving distinct technical design, parameters of the nano spray drying process are not fully elucidated. In a quality-by-design approach, the aim of the current study was to gain thorough understanding of critical determinants of product characteristics in the Büchi Nano Spray Dryer B-90. Following a factorial experimental design, a series of spray drying experiments were conducted to gain new insights into the influences of the inlet temperature, the spray solvent, and the solute concentration in the spray solution on the yield, the moisture content, and the particle size of the nano spray-dried powder material. Special consideration was given to the potential of using hydroethanolic in comparison with aqueous solvent systems and to particle engineering for pulmonary drug delivery. Lactose and mannitol, widely used as excipients in dry powder inhalation formulations, were used as model materials. Lactose and mannitol are known to spray dry in amorphous and crystalline forms, respectively. The yields of spray drying of lactose and mannitol amounted generally to 71.1 ± 6.6% w/w and 66.1 ± 3.5% w/w, respectively. The spray-dried materials exhibited generally a number-weighted median particle diameter of 1.6 ± 0.2 μm and a volume-weighted median particle diameter of 5.1 ± 1.0 μm. A detailed analysis of the results improved understanding of the interplay between process parameters in the Nano Spray Dryer. The results demonstrate that optimization of spray generation is the key to yield optimization. On the other hand, particle size is determined by the spray mesh pore size and the spray solution degree of saturation. Selection of an appropriate spray solvent and using spray solution additives could optimize spray flow. In parallel, the spray solvent and the solute concentration in the spray solution determine the degree of saturation. Guidance on optimization of particle engineering by nano spray drying is provided.

Device fabrication for investigating Maxwell's Demon at room-temperature using double quantum dot transistors in silicon

Maxwell's Demon and its development by Szilard to a single particle engine, probe the limits of the 2nd law of thermodynamics and demonstrate a link between entropy and information. With advances in nanofabrication techniques, these thought experiments are becoming feasible. Room temperature (RT) dual-gate double quantum dot (DQD) transistors have been fabricated using electron beam lithography and geometric oxidation. Measurements at RT have shown device operation, where hexagonal patterns have been extracted from the charge stability diagram. These patterns imply ideal underlying characteristics and have been simulated in the form of a series DQD transistor. The boundaries of hexagonal regions correspond to a one-electron exchange between the coupled QDs. Carefully defined gate voltage trajectories crossing these boundaries show the behaviour of Szilard's engine and an identical minimum entropy of − k B ln 2. These results suggest that DQD devices, even those that operate at RT, can be used to investigate the limits of the 2nd law of thermodynamics. • A fabrication process for room temperature double quantum dot (DQD) transistors. • Room temperature electrical measurements of these DQD transistors. • A single-electron Monte Carlo method has been applied to simulate ideal series DQD transistor and to emulate Szilard’s Engine. • Entropy has been calculated for all stages of a gate voltage sweep trajectory correlating to a Szilard Engine. • It is shown that room temperature DQD transistors can be used to investigate the limits of the 2 nd law of thermodynamics.

Development and characterization of a spray-dried inhalable ciprofloxacin-quercetin co-amorphous system

Spray drying is an increasingly used particle engineering technique for the production of dry powders for inhalation. However, the amorphous nature of most spray-dried particles remains a big challenge affecting both the chemical and the physical stability of the dried particles. Here, we study the possibility of producing co-amorphous ciprofloxacin-quercetin inhalable particles with improved amorphous stability compared to the individual amorphous drugs. Ciprofloxacin (CIP), a broad-spectrum antibiotic, was co-spray dried with quercetin (QUE), a compound with antibiofilm properties, from an ethanol–water co-solvent system at 2:1, 1:1 and 1:2 M ratios to investigate the formation of co-amorphous CIP-QUE particles. Differential scanning colorimetry (DSC) and X-ray powder diffraction (XRPD) were used for solid-state characterization; dynamic vapor sorption (DVS) was used for investigating the moisture sorption behaviour. The intermolecular interaction was studied via solution-state nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy; the miscibility of the drugs was predicted via free energy calculations based on the Flory–Huggins interaction parameter (χ). A next generation impactor (NGI) was used to study the in vitro aerosol performance of the spray-dried powders. The physicochemical characteristics such as particle size, density, morphology, cohesion, water content and saturation solubility of the spray-dried powders were also studied. The co-spray-dried CIP-QUE powders prepared at the three molar ratios were predominantly amorphous. However, differences were observed between sample types. It was found that at a molar ratio of 1:1, CIP and QUE form a single co-amorphous system. However, increasing the molar ratio of either drug results in the formation of an additional amorphous phase, formed from the excess of the corresponding drug. Despite these differences, DVS showed that elevated humidity had a much lower influence on all three co-amorphous systems compared with the individual amorphous drugs. In vitro aerosolization study showed co-deposition of the two drugs from CIP-QUE powders with a desirable aerosol performance (ED ∼ 72–94%; FPF ∼ 48–65%) whereas QUE-only amorphous powder had an ED of 36% and a FPF of 22%. In summary, spray-dried CIP-QUE combinations resulted in co-amorphous systems with boosted stability and improved aerosol performance with the 1:1 M ratio exhibiting the greatest improvement.

Particle engineering in dry powders for inhalation

Drug administration by inhalation is a well-established approach to treat respiratory and systemic diseases. To deliver a drug into the lung dry powder inhalation (DPI) is an advantageous, but yet challenging option. A variety of strategies is available for developing DPI formulations. These formulation strategies should address the present disadvantage of insufficient drug delivery and enable therapies in general or to reach new targets (e.g. mucosal vaccination). To increase therapy safety and efficacy scientists challenge the limits of technical feasibility to engineer respiratory medicines.In this review, we provide a concise overview of particle engineering as enabling formulation technique or as an optimisation approach for existing strategies in pulmonary drug delivery. It comprehensively describes different techniques for particle engineering in carrier-based blends for inhalation. This covers considerations on which attributes are beneficial for carriers, followed by methods to modify such attributes or directly manufacture the desired carriers. Furthermore, this work comprises the current state of knowledge on nanocrystal and nanoparticle production as well as other carrier-free technologies and their applications. This review is completed by a glance in the future of carrier engineering using additive manufacturing.