Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill.

Organic compounds can crystallize in different forms known as polymorphs. Discovery and control of polymorphism is crucial to the pharmaceutical industry since different polymorphs can have significantly different physical properties which impacts their utilization in drug delivery. Certain polymorphs have been reported to 'disappear' from the physical world, irreversibly converting to new ones. These unwanted polymorph conversions, initially prevented by slow nucleation kinetics, are eventually observed driven by significant gains in thermodynamic stabilities. The most infamous of these cases is that of the HIV drug ritonavir (RVR): Once its reluctant form was unwillingly nucleated for the first time, its desired form could no longer be produced with the same manufacturing process. Here we show that RVR's extraordinary disappearing polymorph as well as its reluctant form can be consistently produced by ball-milling under different environmental conditions. We demonstrate that the significant difference in stability between its polymorphs can be changed and reversed in the mill-a process we show is driven by crystal size as well as crystal shape and conformational effects. We also show that those effects can be controlled through careful design of milling conditions since they dictate the kinetics of crystal breakage, dissolution, and growth processes that eventually lead to steady-state crystal sizes and shapes in the mill. This work highlights the huge potential of mechanochemistry in polymorph discovery of forms initially difficult to nucleate, recovery of disappearing polymorphs, and polymorph control of complex flexible drug compounds such as RVR.

Chemoselectivity Inversion of Responsive Metal-Organic Frameworks by Particle Size Tuning in the Micrometer Regime.

Gated adsorption is one of the unique physical properties of flexible metal-organic frameworks with high application potential in selective adsorption and sensing of molecules. Despite recent studies that have provided some guidelines in understanding and designing structural flexibility for controlling gate opening by chemical modification of the secondary building units, currently, there is no established strategy to design a flexible MOF showing selective gated adsorption for a specific guest molecule. In a present contribution it is demonstrated for the first time, that the selectivity in the gate opening of a particular compound can be tuned, changed, and even reversed using particle size engineering DUT-8(Zn) ([Zn2(2,6-ndc)2(dabco)]n, 2,6-ndc = 2,6-naphthalenedicarboxylate, dabco = 1,4-diazabicyclo-[2.2.2]-octane, DUT = Dresden University of Technology) experiences phase transition from open (op) to closed (cp) pore phase upon removal of solvent from the pores. Microcrystals show selective reopening in the presence of dichloromethane (DCM) over alcohols. Crystal downsizing to micron size unexpectedly reverses the gate opening selectivity, causing DUT-8(Zn) to open its nanosized pores for alcohols but suppressing the responsivity toward DCM.

Effect of particle size on liver MRI R 2 * relaxometry: Monte Carlo simulation and phantom studies.

PURPOSE: To investigate the effect of particle size on liver R 2 * $$ {\mathrm{R}}_2^{\ast } $$ by Monte Carlo simulation and phantom studies at both 1.5 T and 3.0 T. METHODS: Two kinds of particles (i.e., iron sphere and fat droplet) with varying sizes were considered separately in simulation and phantom studies. MRI signals were synthesized and analyzed for predicting R 2 * $$ {\mathrm{R}}_2^{\ast } $$ , based on simulations by incorporating virtual liver model, particle distribution, magnetic field generation, and proton movement into phase accrual. In the phantom study, iron-water and fat-water phantoms were constructed, and each phantom contained 15 separate vials with combinations of five particle concentrations and three particle sizes. R 2 * $$ {\mathrm{R}}_2^{\ast } $$ measurements in the phantom were made at both 1.5 T and 3.0 T. Finally, differences in R 2 * $$ {\mathrm{R}}_2^{\ast } $$ predictions or measurements were evaluated across varying particle sizes. RESULTS: In the simulation study, strong linear and positively correlated relationships were observed between R 2 * $$ {\mathrm{R}}_2^{\ast } $$ predictions and particle concentrations across varying particle sizes and magnetic field strengths ( r ≥ 0.988 $$ r\ge 0.988 $$ ). The relationships were affected by iron sphere size ( p < 0.001 $$ p<0.001 $$ ), where smaller iron sphere size yielded higher predicted R 2 * $$ {\mathrm{R}}_2^{\ast } $$ , whereas fat droplet size had no effect on R 2 * $$ {\mathrm{R}}_2^{\ast } $$ predictions ( p ≥ 0.617 $$ p\ge 0.617 $$ ) for constant total fat concentration. Similarly, the phantom study showed that R 2 * $$ {\mathrm{R}}_2^{\ast } $$ measurements were relatively sensitive to iron sphere size ( p ≤ 0.004 $$ p\le 0.004 $$ ) unlike fat droplet size ( p ≥ 0.223 $$ p\ge 0.223 $$ ). CONCLUSION: Liver R 2 * $$ {\mathrm{R}}_2^{\ast } $$ is affected by iron sphere size, but is relatively unaffected by fat droplet size. These findings may lead to an improved understanding of the underlying mechanisms of R 2 * $$ {\mathrm{R}}_2^{\ast } $$ relaxometry in vivo, and enable improved quantitative MRI phantom design.

The increase of particle size shifts the biogeochemical cycle functions of mineral-associated microorganisms and weakens the mineral-associated organic carbon sink in mangrove soils.

Mineral-organic matter-microbe interactions greatly impact the biogeochemical processes and biodiversity in soils. An increasing trend of particle size (PS) in mangrove soils has been observed because of the relative sea level rise. However, the impacts of PS increase on the microbial biogeochemical functions and carbon sink in the mineral-associated microcosms are exceedingly nebulous. This work showed a remarkable difference in the communities of mineral-associated microorganisms (MMOs) in various PS fractions. Heavy metal contents and urease activity were the factors that mostly driven the MMO community variation in different PS fractions. Large PS fraction attenuated the stability of MMO communities according to the co-occurrence network characteristics. The PS increase significantly (P < 0.05) lowered the gene abundances for carbon input (e.g., carbon fixation) and raised the gene abundances for carbon loss (e.g., aerobic respiration). Combined with the significant decrease of mineral-associated organic carbon (MOC) in large PS fraction (P < 0.05), this work inferred that the PS increase could weaken the MOC sink partially due to the MMO function shift for carbon cycle. The current work indicated unhealthy changes of MMO communities and MOC storage in mangrove soils, and PS was of significance as an indicator for predicting the carbon sink function, especially for the stable form, such as MOC, in the soils of mangroves under the ecological background of climate migration. IMPORTANCE: Carbon with stable forms, such as mineral-associated organic carbon (MOC), is crucial for the sink capabilities in mangrove soils, and mineral-associated microorganisms (MMOs) are important players for the formation and metabolism of MOC. Therefore, the future successions of the MMO functions and MOC contents under the background of climate change are of value for a deeper understanding of mangrove ecology. The relative sea level rise caused by the global warming results in the increase of mangrove soil particle size (PS), which provides distinct microcosms for MMOs and MOC. However, the responses of MMO functions and MOC content to the PS increase of mangrove soils are unknown. The current study aims to reveal the succession regulations of MMO functions and their potential ecological impacts for the storages of MOC in different PS fractions, therefore widening our knowledge of future function migration and promoting the research development of mangrove.

Nebulization and In Vitro Upper Airway Deposition of Liposomal Carrier Systems.

Liposomal carrier systems have emerged as a promising technology for pulmonary drug delivery. This study focuses on two selected liposomal systems, namely, dipalmitoylphosphatidylcholine stabilized by phosphatidic acid and cholesterol (DPPC-PA-Chol) and dipalmitoylphosphatidylcholine stabilized by polyethylene glycol and cholesterol (DPPC-PEG-Chol). First, the research investigates the stability of these liposomal systems during the atomization process using different kinds of nebulizers (air-jet, vibrating mesh, and ultrasonic). The study further explores the aerodynamic particle size distribution of the aerosol generated by the nebulizers. The nebulizer that demonstrated optimal stability and particle size was selected for more detailed investigation, including Andersen cascade impactor measurements, an assessment of the influence of flow rate and breathing profiles on aerosol particle size, and an in vitro deposition study on a realistic replica of the upper airways. The most suitable combination of a nebulizer and liposomal system was DPPC-PA-Chol nebulized by a Pari LC Sprint Star in terms of stability and particle size. The influence of the inspiration flow rate on the particle size was not very strong but was not negligible either (decrease of Dv50 by 1.34 µm with the flow rate increase from 8 to 60 L/min). A similar effect was observed for realistic transient inhalation. According to the in vitro deposition measurement, approximately 90% and 70% of the aerosol penetrated downstream of the trachea using the stationary flow rate and the realistic breathing profile, respectively. These data provide an image of the potential applicability of liposomal carrier systems for nebulizer therapy. Regional lung drug deposition is patient-specific; therefore, deposition results might vary for different airway geometries. However, deposition measurement with realistic boundary conditions (airway geometry, breathing profile) brings a more realistic image of the drug delivery by the selected technology. Our results show how much data from cascade impactor testing or estimates from the fine fraction concept differ from those of a more realistic case.

Particle Size, Dose, and Confinement Affect Passive Diffusion Flux through the Membrane Concentration Boundary Layer.

The authors present a steady-state-, particle-size-, and dose-dependent dissolution-permeation model that describes particle dissolution within the concentration boundary layer (CBL) adjacent to a semipermeable surface. It is critical to understand how particle size and dose affect the behavior of dissolving particles in the presence of a CBL adjacent to a semipermeable surface both in vivo and in vitro. Control of particle size is ubiquitous in the pharmaceutical industry; however, traditional pharmaceutical assumptions of particle dissolution typically ignore particle dissolution within the length scale of the CBL. The CBL does not physically prevent particles from traveling to the semipermeable surface (mucus, epithelial barrier, synthetic membrane, etc.), and particle dissolution can occur within the CBL thickness (δC) if the particle is sufficiently small (∼dparticle ≤ δC). The total flux (the time rate transport of molecules across the membrane surface per unit area) was chosen as a surrogate parameter for measuring the additional mass generated by particles dissolving within the donor CBL. Mass transfer experiments aimed to measure the total flux of drug using an ultrathin large-area membrane diffusion cell described by Sinko et al. with a silicone-based membrane ( Mol. Pharmaceutics 2020, 17, (7) 2319-2328, DOI: 10.1021/acs.molpharmaceut.0c00040). Suspensions of ibuprofen, a model weak-acid drug, with three different particle-size distributions with average particle diameters of 6.6, 37.4, and 240 µm at multiple doses corresponding to a range of suspension concentrations with dimensionless dose numbers of 2.94, 14.7, 147, and 588 were used to test the model. Experimentally measured total flux across the semipermeable membrane/CBL region agreed with the predictions from the proposed model, and at a range of relatively low suspension concentrations, dependent on the average particle size, there was a measurable effect on the flux due to the difference in δC that formed at the membrane surface. Additionally, the dose-dependent total flux across the membrane was up to 10% higher than the flux predicted by the standard Higuchi-Hiestand dissolution model where the effects of confinement were ignored as described by Wang et al. ( Mol. Pharmaceutics 2012, 9 (5), 1052-1066, DOI: 10.1021/mp2002818).

Effect of reinforcement particle size on the corrosion and mechanical properties of spark plasma sintered aluminium matrix composites.

In this study, the effects of different sizes of reinforcing particles on the corrosion behaviour and mechanical properties of aluminium (Al)-based composites produced by spark plasma sintering (SPS) are analysed. In the study, the effects of SPS parameters, including electrical power, applied pressure and sintering temperature, on the consolidation process and microstructure evolution of the composite are closely investigated. The results reveal a nuanced relationship between the sintering conditions and the properties of the particles, which in turn determine the sintering dynamics and the formation of the microstructural features. The evaluation of mechanical properties indicates a remarkable influence of particle size distribution on the hardness of the composites, showing an initial improvement with the introduction of nanoparticles, followed by a slight decrease as the balance between nano- and micron-sized Al2O3 particles shifts. A scanning electron microscopy (SEM) study demonstrates the influence of particle dimensions on the change of grain boundaries and the spatial arrangement of the composite matrix. Electrochemical experiments in a 0.1 M NaCl solution show a consistent corrosion potential (Ecorr) across all samples, while the current densities associated with corrosion (icorr) show considerable variation. The presence of nano-sized Al2O3 particles was found to increase corrosion resistance, in contrast to the detrimental effects observed with larger microparticles. In particular, composites with a bimodal distribution of particle sizes showed a 3.5-fold increase in corrosion resistance compared to pure Al. The specific Al-2n8mAl2O3 composite that exhibited active electrochemical properties at elevated potentials without a defined passivation range emphasises the significant role of particle size. This study draws attention to bimodal microstructures as a promising route to achieving uniformity and improved corrosion resistance in Al matrix composites, while pointing to the need for further research to fully elucidate the operative mechanisms.

Modelling Drug Delivery to the Small Airways: Optimization Using Response Surface Methodology.

AIM: The aim of this in silico study was to investigate the effect of particle size, flow rate, and tidal volume on drug targeting to small airways in patients with mild COPD. METHOD: Design of Experiments (DoE) was used with an in silico whole lung particle deposition model for bolus administration to investigate whether controlling inhalation can improve drug delivery to the small conducting airways. The range of particle aerodynamic diameters studied was 0.4 - 10 µm for flow rates between 100 - 2000 mL/s (i.e., low to very high), and tidal volumes between 40 - 1500 mL. RESULTS: The model accurately predicted the relationship between independent variables and lung deposition, as confirmed by comparison with published experimental data. It was found that large particles (~ 5 µm) require very low flow rate (~ 100 mL/s) and very small tidal volume (~ 110 mL) to target small conducting airways, whereas fine particles (~ 2 µm) achieve drug targeting in the region at a relatively higher flow rate (~ 500 mL/s) and similar tidal volume (~ 110 mL). CONCLUSION: The simulation results indicated that controlling tidal volume and flow rate can achieve targeted delivery to the small airways (i.e., > 50% of emitted dose was predicted to deposit in the small airways), and the optimal parameters depend on the particle size. It is hoped that this finding could provide a means of improving drug targeting to the small conducting airways and improve prognosis in COPD management.

Development and Validation of Matrix of Chemistry, Manufacturing, and Control (MoCMC) System for Intramammary Drug Products (IMM).

PURPOSE: Products formulated for intramammary (IMM) infusion are intended for the delivery of therapeutic moieties directly into the udder through the teat canal to maximize drug exposure at the targeted clinical site, the mammary gland, with little to no systemic drug exposure. Currently, to our knowledge, there has been no in-vitro matrix system available to differentiate between IMM formulations. Our goal is to develop A custom tailored in-vitro "Matrix of Chemistry, Manufacturing and Control" (MoCMC) System to be a promising future tool for identifying inequivalent IMM formulations. MoCMC can detect inter and intra batch variabilities, thereby identifying potential generics versus brand product similarities or differences with a single numeric value and a specific & distinctive fingerprint. METHODS: The FDA-approved IMM formulation, SPECTRAMASTⓇ LC, was selected as the reference product for the MoCMC. Twelve in-house test formulations containing ceftiofur hydrochloride were formulated and characterized. The MoCMC was developed to include six input parameters and three output parameters. The MoCMC system was used to evaluate and compare SPECTRAMASTⓇ LC with its in-house formulations. RESULTS: Based on the MoCMC generated parameters, the distinctive fingerprints of MoCMC for each IMM formulations, and the statistical analyses of MCI and PPI values, in-house formulations, F-01 and F-02 showed consistency while the rest of in-house formulations (F-03-F-12) were significantly different as compared to SPECTRAMASTⓇ LC. CONCLUSION: This research showed that the MoCMC approach can be used as a tool for intra batch variabilities, generics versus brand products comparisons, post-approval formulations changes, manufacturing changes, and formulation variabilities.

Application of PAT Probes in Aluminum Phosphate Adjuvant Manufacturing.

PURPOSE: This study is focused on monitoring process parameters and quality attributes of aluminum phosphate (AlPO4) using multiple in-line probes incorporated into an industrial-scale adjuvant suspension manufacturing unit. METHODS: The manufacturing of aluminum adjuvant suspension was monitored at manufacturing scale using conductivity, turbidity, infrared, and particle sizing and count probes to follow the continuous evolution of particle formation and size distribution, and the reaction kinetics during the synthesis of AlPO4. RESULTS: The data showed that AlPO4 forms large particles at the early stages of mixing, followed by a decrease in size and then stabilization towards the later stages of mixing and pH adjustment. The results provided a complementary view of process events and assisted in optimizing several parameters, e.g., flow rate of reactants AlCl3 and Na3PO4 solutions, mixing rate, pH, and conductivity of AlPO4, as well as adjuvant quality attribute such as particle size, thus streamlining and shortening the process development stage. CONCLUSION: The results of this study showed the usefulness of the in-line probes to automate continuous assessment of AlPO4 batch-to-batch consistency during in-house adjuvant production at the industrial scale.

Larger particle size distribution of environmental RNA compared to environmental DNA: a case study targeting the mitochondrial cytochrome b gene in zebrafish (Danio rerio) using experimental aquariums.

Environmental RNA (eRNA) analysis is conventionally expected to infer physiological information about organisms within their ecosystems, whereas environmental DNA (eDNA) analysis only infers their presence and abundance. Despite the promise of eRNA application, basic research on eRNA characteristics and dynamics is limited. The present study conducted aquarium experiments using zebrafish (Danio rerio) to estimate the particle size distribution (PSD) of eRNA in order to better understand the persistence state of eRNA particles. Rearing water samples were sequentially filtered using different pore-size filters, and the resulting size-fractioned mitochondrial cytochrome b (CytB) eDNA and eRNA data were modeled with the Weibull complementary cumulative distribution function (CCDF) to estimate the parameters characterizing the PSDs. It was revealed that the scale parameter (α) was significantly higher (i.e., the mean particle size was larger) for eRNA than eDNA, while the shape parameter (ß) was not significantly different between them. This result supports the hypothesis that most eRNA particles are likely in a protected, intra-cellular state, which mitigates eRNA degradation in water. Moreover, these findings also imply the heterogeneous dispersion of eRNA relative to eDNA and suggest an efficient method of eRNA collection using a larger pore-size filter. Further studies on the characteristics and dynamics of eRNA particles should be pursued in the future.

Silica Nanoparticle Size Determines the Mechanisms Underlying the Inhibition of Iron Oxide Nanoparticle Uptake by Daphnia magna.

Aquatic environments are complicated systems that contain different types of nanoparticles (NPs). Nevertheless, recent studies of NP toxicity, and especially those that have focused on bioaccumulation have mostly investigated only a single type of NPs. Assessments of the environmental risks of NPs that do not consider co-exposure regimes may lead to inaccurate conclusions and ineffective environmental regulation. Thus, the present study examined the effects of differently sized silica NPs (SiO2 NPs) on the uptake of iron oxide NPs (Fe2O3 NPs) by the zooplankton Daphnia magna. Both SiO2 NPs and Fe2O3 NPs were well dispersed in the experimental medium without significant heteroaggregation. Although all three sizes of SiO2 NPs inhibited the uptake of Fe2O3 NPs, the underlying mechanisms differed. SiO2 NPs smaller than the average mesh size (∼200 nm) of the filtering apparatus of D. magna reduced the accumulation of Fe2O3 NPs through uptake competition, whereas larger SiO2 NPs inhibited the uptake of Fe2O3 NPs mainly by reducing the water filtration rate of the daphnids. Overall, in evaluations of the risks of NPs in the natural environment, the different mechanisms underlying the effects of NPs of different sizes on the uptake of dissimilar NPs should be considered.

Assimilating Size Diversity: Population Balance Equations Applied to the Modeling of Microplastic Transport.

Modeling of microplastic (MP) transport in the aquatic environment is complicated by the diverse properties of the plastic particles. Traditional modeling methods such as Lagrangian particle tracking and Eulerian discrete class (DC) methods have limitations as they are not best placed to account for the diverse characteristics of individual particles, namely, size, density, and shape, which are crucial for determining the transport of MPs. In this work, we address the issue of particle size diversity by using the population balance equations (PBE) method. In addition to the advection-diffusion terms, the PBE transport equation involves a deposition sink term. Seven size classes of MPs are modeled in the DC method, which is compared to the PBE method. The evolution of particle size distribution is compared between the two methods using a simplified test case of a schematized estuary with tidal forcing and river discharge. This work successfully demonstrates the applicability and appropriateness of the PBE model in modeling the transport of MPs to track the dynamic and complete size distribution at a reduced computational cost in comparison to the DC model. With the PBE method, it is possible to address other diversities of the MPs such as the shape and density.

Aerodynamic Size-Dependent Collection and Inactivation of Virus-Laden Aerosol Particles in an Electrostatic Precipitator.

Electrostatic precipitators (ESPs) may enable high particle collection efficiency with minimal pressure drop in HVAC systems. However, studies of pathogen collection and inactivation in ESPs at medium to higher flow rates are limited. Here, a single-stage, wire-plate ESP operated at flow rates of 51 and 85 m3 h-1 was used to study the removal of virus-laden aerosol particles for three different airborne viruses: (1) bovine coronavirus (BCoV), (2) influenza A virus (IAV), and (3) porcine reproductive and respiratory virus (PRRSV). Size-resolved measurements of collection efficiency were obtained using Andersen cascade impactors (ACI) sampling upstream and downstream of the ESP. All measurements were analyzed based on three distinctive but complementary methods: (1) fluorimetry to assess physical collection, (2) RT-qPCR to assess viral RNA concentrations and (3) virus titration to assess virus viability. In general, log reductions by virus titration were highest followed by those from RT-qPCR, and last fluorimetry, suggesting that a portion of virus may be potentially inactivated in flight in the ESP. An effective migration (deposition) velocity ranging from 3.10 to 10.05 cm s-1 was also determined using the spatially resolved measurements of virus collection on the ESP plates.

Characterizing and Predicting nvPM Size Distributions for Aviation Emission Inventories and Environmental Impact.

Concerns about civil aviation's air quality and environmental impacts have led to recent regulations on nonvolatile particulate matter (nvPM) mass and number emissions. Although these regulations do not mandate measuring particle size distribution (PSD), understanding PSDs is vital for assessing the environmental impacts of aviation nvPM. This study introduces a comprehensive data set detailing PSD characteristics of 42 engines across 19 turbofan types, ranging from unregulated small business jets to regulated large commercial aircraft. Emission tests were independently performed by using the European and Swiss reference nvPM sampling and measurement systems with parallel PSD measurements. The geometric mean diameter (GMD) at the engine exit strongly correlated with the nvPM number-to-mass ratio (N/M) and thrust, varying from 7 to 52 nm. The engine-exit geometric standard deviation ranged from 1.7 to 2.5 (mean of 2.05). The study proposes empirical correlations to predict GMD from N/M data of emissions-certified engines. These predictions are expected to be effective for conventional rich-burn engines and might be extended to novel combustor technologies if additional data become available. The findings support the refinement of emission models and help in assessing the aviation non-CO2 climate and air quality impacts.

Foliar Uptake and Distribution of Metallic Oxide Nanoparticles in Maize (Zea mays L.) Leaf.

The foliar uptake of Fe3O4, Cr2O3, CuO, and ZnO nanoparticles (NPs) by maize (Zea mays L.) was studied in a lab-scale experiment. The significant increase of Fe concentrations in leaves exposed to Fe3O4 was observed in both stomatal closing and stomatal opening treatments, suggesting the presence of a nonstomatal uptake. In parallel treatments with equal doses of Fe3O4 (∼200 nm), Cr2O3 (∼300 nm), CuO (∼30 nm), and ZnO (∼40 nm) (20-200 µg), the retention percentage of Fe in the leaves (21.0-69.0%) was higher than that of Cr, Cu, and Zn (0.5-14.0%). The steric hindrance effect seems more important for NPs of >200 nm, while hydrophobic surface and negative charge promote the foliar uptake of NPs smaller than 200 nm. The accumulation of NPs in the cuticle was observed through dark-field hyperspectral microscopy. Cr2O3, Fe3O4, and CuO NPs were difficult to penetrate the cuticle. In comparison, ZnO further migrated and distributed within the extracellular space of epidermal and mesophyll cells of the exposed leaf, possibly due to its comparatively higher solubility and hydrophilicity. The findings highlight the potential of the nonstomatal uptake, which might be a critical route for metallic oxide NPs to enter the food chain.

Finer Particle Size Distribution and Potential Higher Toxicity of Elemental Carbon and Polycyclic Aromatic Hydrocarbons Emitted by Ships after Fuel Oil Quality Improvement.

Ship emissions are a significant source of air pollution, and the primary policy to control is fuel oil quality improvement. However, the impact of this policy on particle size distribution and composition characteristics remains unclear. Measurements were conducted on nine different vessels (ocean-going vessels, coastal cargo ships, and inland cargo ships) to determine the impact of fuel upgrading (S < 0.1% m/m marine gas oil (MGO) vs S < 0.5% m/m heavy fuel oil (HFO)) on elemental carbon (EC) and polycyclic aromatic hydrocarbons (PAHs) emitted by ships. (1) Fuel improvement significantly reduced EC and PAH emission, by 31 ± 25 and 45 ± 38%, respectively. However, particle size distributions showed a trend toward finer particles, with the peak size decreasing from DP = 0.38-0.60 µm (HFO) to DP = 0.15-0.25 µm (MGO), and the emission factor of DP < 100 nm increased. (2) Changes in emission characteristics led to an increase in the toxicity of ultrafine particulate matter. (3) Ship types and engine conditions affected the EC and PAH particle size distributions. Inland ships have a more concentrated particle size distribution. Higher loads result in higher emissions. (4) The composition and engine conditions of fuel oils jointly affected pollutant formation mechanisms. MGO and HFO exhibited opposite EC emissions when emitting the same level of PAHs.

Development of an advanced separation and characterization platform for mRNA and lipid nanoparticles using multi-detector asymmetrical flow field-flow fractionation.

In recent years, the use of lipid nanoparticles (LNPs) for delivery of messenger RNA (mRNA)-based therapies has gained substantial attention in the field of drug development. In such an application, multiple LNP attributes have to be carefully characterized to ensure product safety and quality, whereas accurate and efficient characterization of these complex mRNA-LNP formulations remains a challenging endeavor. Here, we present the development and application of an online separation and characterization platform designed for the isolation and in-depth analysis of mRNAs and mRNA-loaded LNPs. Our asymmetrical flow field-flow fractionation with a multi-detector (MD-AF4) method has demonstrated exceptional resolution between mRNA-LNPs and mRNAs, delivering excellent recoveries (over 70%) for both analytes and exceptional repeatability. Notably, this platform allows for comprehensive and multi-attribute LNP characterization, including online particle sizing, morphology characterization, and determination of encapsulation efficiency, all within a single injection. Furthermore, real-time online sizing by synchronizing multi-angle light scattering (MALS) and dynamic light scattering (DLS) presented higher resolution over traditional batch-mode DLS, particularly in differentiating heterogeneous samples with a low abundance of large-sized particles. Additionally, our method proves to be a valuable tool for monitoring LNP stability under varying stress conditions. Our work introduces a robust and versatile analytical platform using MD-AF4 that not only efficiently provides multi-attribute characterizations of mRNA-LNPs but also holds promise in advancing studies related to formulation screening, quality control, and stability assessment in the evolving field of nanoparticle delivery systems for mRNAs.

Real-Time Monitoring of Particle Size in Emulsion Polymerization: Simultaneous Turbidity and Photon Density Wave Spectroscopy.

Particle size evolution in seeded semibatch emulsion polymerization is monitored by two real-time monitoring techniques: online turbidity spectroscopy (TUS) and inline photon density wave spectroscopy (PDWS). An automatic dilution system that withdraws a sample from the reactor and upon dilution transfers to the measurement cell is used for the online TUS analysis. A PDWS probe is immersed in the reactor and collects inline the scattered light directly from the reacting latex. The particle sizes retrieved from TUS and PDWS are compared to offline dynamic light scattering (DLS) values. The particle size obtained by TUS is close to the intensity-average particle size obtained offline by DLS, while the particle size obtained by PDWS lies closer to the number-average particle size from DLS.

Associations of diet quality and food consumption with serum biomarkers for lipid and amino acid metabolism in Finnish children: the PANIC study.

PURPOSE: To investigate the associations of overall diet quality and dietary factors with serum biomarkers for lipid and amino acid metabolism in a general population of children. METHODS: We studied 194 girls and 209 boys aged 6-8 years participating in the Physical Activity and Nutrition in Children study. Food consumption was assessed by 4-day food records and diet quality was quantified by the Finnish Children Healthy Eating Index (FCHEI). Fasting serum fatty acids, amino acids, apolipoproteins, as well as lipoprotein particle sizes were analyzed with high-throughput nuclear magnetic resonance spectroscopy. Data were analyzed using linear regression adjusted for age, sex, and body fat percentage. RESULTS: FCHEI was directly associated with the ratio of polyunsaturated (PUFA) to saturated fatty acids (SFA) (PUFA/SFA), the ratio of PUFA to monounsaturated fatty acids (MUFA) (PUFA/MUFA), the ratio of PUFA to total fatty acids (FA) (PUFA%), the ratio of omega-3-fatty acids to total FA (omega-3 FA%), and inversely associated with the ratio of MUFA to total FA (MUFA%), alanine, glycine, histidine and very-low density lipoprotein (VLDL) particle size. Consumption of vegetable oils and vegetable-oil-based margarine (≥ 60% fat) was directly associated with PUFA/SFA, PUFA/MUFA, PUFA%, the ratio of omega-6 FA to total FA (omega-6 FA%), and inversely associated with SFA, MUFA, SFA to total FA (SFA%), MUFA%, alanine and VLDL particle size. Consumption of high-fiber grain products directly associated with PUFA/SFA, PUFA/MUFA, omega-3 FA%, omega-6 FA%, PUFA% and inversely associated with SFA and SFA%. Fish consumption directly related to omega-3 FA and omega-3 FA%. Consumption of sugary products was directly associated with histidine and VLDL particle size. Vegetable, fruit, and berry consumption had direct associations with VLDL particle size and the ratio of apolipoprotein B to apolipoprotein A1. Consumption of low fat (< 1%) milk was directly associated with phenylalanine. A higher consumption of high-fat (≥ 1%) milk was associated with lower serum MUFA/SFA and higher SFA%. Sausage consumption was directly related to SFA% and histidine. Red meat consumption was inversely associated with glycine. CONCLUSIONS: Better diet quality, higher in intake of dietary sources of unsaturated fat and fiber, and lower in sugary product intake were associated with more favorable levels of serum biomarkers for lipid and amino acid metabolism independent of adiposity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01803776, registered March 3, 2013.