A Systematic Investigation of Process Parameters for Small-Volume Aqueous Suspension Production by the Use of Focused Ultrasonication.

Aqueous suspensions containing crystalline drug in the sub-micron range is a favorable platform for long-acting injectables where particle size can be used to obtain a desired plasma-concentration profile. Stabilizers are added to the suspensions and screened extensively to define the optimal formulation composition. In the initial formulation screening the amount of drug compound can be limited, necessitating milling methods for small-volume screening predictable for scale-up. Hence, adaptive focused ultrasound was investigated as a potential milling method for rapid small-volume suspensions by identifying the critical process parameters during preparation. Suspensions containing drug compounds with different mechanical properties and thereby grindability, i.e., cinnarizine, haloperidol, and indomethacin with brittle, elastic, and plastic properties, respectively, were investigated to gain an understanding of the manufacturing with adaptive focused acoustics as well as comparison to already established milling techniques. Using a DoE-design, peak incident power was identified as the most crucial process parameter impacting the milling process for all three compounds. It was possible to decrease the sizes of drug particles to micron range after one minute of focused ultrasound exposure which was superior compared to other milling techniques (e.g., non-focused ultrasound exposure). The addition of milling beads decreased the drug particle sizes even further, thus to a lower degree than other already established milling techniques such as milling by dual centrifugation. This study thereby demonstrated that adaptive focused ultrasonication was a promising method for rapid homogenization and particle size reduction to micron range for different compounds varying in grindability without altering the crystalline structure.

Physico-Chemical and Biological Features of Fluorine-Substituted Hydroxyapatite Suspensions.

Infections related to orthopedic/stomatology surgery are widely recognized as a significant health concern. Therefore, the development of new materials with superior biological properties and good stability could represent a valuable alternative to the classical treatments. In this paper, the fluorine-substituted hydroxyapatite (FHAp) suspension, with the chemical formula Ca10(PO4)6(OH)2-2xF2x (where x = 0.05), was prepared using a modified coprecipitation technique. Stability studies were conducted by zeta potential and ultrasound measurements for the first time. The X-ray diffraction (XRD) patterns of FHAp powders displayed a hexagonal structure akin to that of pure hydroxyapatite (HAp). The XPS general spectrum revealed peaks corresponding to the constituent elements of fluorine-substituted hydroxyapatite such as calcium, phosphorus, oxygen, and fluorine. The purity of the obtained FHAp samples was confirmed by energy-dispersive X-ray spectroscopy (EDS) studies. The FHAp morphology was evaluated by scanning electron microscopy (SEM) measurements. Fourier-transform infrared spectroscopy (FTIR) studies were performed in order to study the vibrational properties of the FHAp samples. The FHAp suspensions were tested for antibacterial activity against reference strains such as Staphylococcus aureus 25923 ATCC, Escherichia coli ATCC 25922, and Candida albicans ATCC 10231. Additionally, the biocompatibility of the FHAp suspensions was assessed using human fetal osteoblastic cells (hFOB 1.19 cell line). The results of our biological tests suggest that FHAp suspensions are promising candidates for the future development of new biocompatible and antimicrobial agents for use in the biomedical field.

The Rheology of Polyether Ether Ketone Concentrated Suspensions for Powder Molding and 3D Printing.

The main goal of the work was to use rheological methods for assessing the properties of a composition based on polyether ether ketone (PEEK) to determine the concentration limits of the polymer in the composition and select the optimal content of this composition for powder molding. The rheological properties of highly filled suspensions based on PEEK and paraffin, as well as in paraffin-polyethylene mixtures at various component ratios, were studied. These materials are designed for powder injection molding and 3D printing. Suspensions with a PEEK powder content above 50% are not capable of flow and, with increasing pressure, slide along the surface of the channel. For compositions with a higher content (60 and 70 vol.%) PEEK, independence of the storage modulus from frequency is observed, which is typical for solids and confirms the assignment of such suspensions to elastic-plastic media. The introduction of high-density polyethylene into the composition helps improve the technological properties of suspensions, expanding the range of fluidity, although it leads to an increase in viscosity. In suspensions with a mixed composition of the liquid phase, with increasing temperature, a decrease in the storage modulus is observed at 120 °C and, on the contrary, an increase at 180 °C. The latter may be a consequence of the evaporation of paraffin and the softening of PEEK due to the approach to the glass transition temperature of the polymer. Suspensions with 40% PEEK content have an optimal set of rheological properties for powder injection molding. A 3D printing filament was also obtained from a composition with 40% PEEK, which had good technological properties for FDM 3D printing. Products of satisfactory quality from suspensions with 50% PEEK can be produced by powder injection molding, but not by 3D printing. The selected compositions were used to obtain real PEEK products for practical applications.

The efficacy and safety of autologous epidermal cell suspensions for re-epithelialization of skin lesions: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Successful usage of autologous skin cell suspension (ASCS) has been demonstrated in some clinical trials. However, its efficacy and safety have not been verified. This latest systematic review and meta-analysis aim to examine the effects of autologous epidermal cell suspensions in re-epithelialization of skin lesions. METHODS: Relevant articles were retrieved from PubMed, Embase, Cochrane Database, Web of Science, International Clinical Trials Registry Platform, China National Knowledge Infrastructureris, VIP Database for Chinese Technical Periodicals and Wanfang database. The primary output measure was the healing time, and the secondary outputs were effective rate, size of donor site for treatment, size of study treatment area, operation time, pain scores, repigmentation, complications, scar scale scores and satisfaction scores. Data were pooled and expressed as relative risk (RR), mean difference (MD) and standardized mean difference (SMD) with a 95% confidence interval (CI). RESULTS: Thirty-one studies were included in this systematic review and meta-analysis, with 914 patients who received autologous epidermal cell suspensions (treatment group) and 883 patients who received standard care or placebo (control group). The pooled data from all included studies demonstrated that the treatment group has significantly reduced healing time (SMD = -0.86; 95% CI: -1.59-0.14; p = 0.02, I2 = 95%), size of donar site for treatment (MD = -115.41; 95% CI: -128.74-102.09; p<0.001, I2 = 89%), operation time (MD = 25.35; 95% CI: 23.42-27.29; p<0.001, I2 = 100%), pain scores (SMD = -1.88; 95% CI: -2.86-0.90; p = 0.0002, I2 = 89%) and complications (RR = 0.59; 95% CI: 0.36-0.96; p = 0.03, I2 = 66%), as well as significantly increased effective rate (RR = 1.20; 95% CI: 1.01-1.42; p = 0.04, I2 = 77%). There were no significant differences in the size of study treatment area, repigmentation, scar scale scores and satisfaction scores between the two groups. CONCLUSION: Our meta-analysis showed that autologous epidermal cell suspensions is beneficial for re-epithelialization of skin lesions as they significantly reduce the healing time, size of donar site for treatment, operation time, pain scores and complications, as well as increased effective rate. However, this intervention has minimal impact on size of treatment area, repigmentation, scar scale scores and satisfaction scores.

Positive student-teacher relationships and exclusionary discipline practices.

Teacher-student relationships are beneficial for students and especially important in the middle school context. Suspensions are critical to reduce as it can be detrimental to the educational trajectory of students, particularly for marginalized students in underfunded schools. This study looked at the relations between teacher-student relationships and suspensions across the academic year in a sample of students (N = 541) and teachers (N = 51) in two urban school districts in the Midwest. A brief measure of teachers' perceptions of relationships with students completed in the fall of the academic year predicted the odds of receiving in-school suspension (ISS; odds ratio [OR] = 0.65) and out-of-school suspension (OSS; OR = 0.72) by the end of the school year. Student reports of the relationships were also associated with ISS (OR = 0.94), but not OSS. On average, teachers' report on the scale improved over the course of the school year (d = 0.11); however, student report of the relationships worsened (d = 0.30). The difference in the student report of the relationships from fall to spring was also associated with the odds of receiving ISS and OSS (ORs = 0.94). These findings suggest that student and teacher perceptions together are associated with harsh discipline practices that can negatively impact students' developmental trajectories. Relationships can change but direct action is necessary to develop, maintain, and repair relationships during the academic year.

Extracellular vesicles derived from stored red blood cell suspensions enhance invasion and migration of lung cancer cells by miR1246 and miR150-3p.

BACKGROUND AND OBJECTIVES: Aged red blood cell (RBC) transfusions in lung cancer patients are often related to cancer recurrence and shorter lifespans. Extracellular vesicles (EVs) accumulated in stored RBC suspensions may be one of the important influential factors. This study aims to investigate how EVs derived from RBC suspensions affect the progress of lung cancer through the most enriched microRNAs (miRNAs) previously reported in our research. STUDY DESIGN AND METHODS: EVs derived from stored RBC suspensions in Weeks 1, 3 and 5 were harvested via ultracentrifugation. Lung adenocarcinoma H1975 cells were co-cultured with EVs and transfected with miR1246 and miR150-3p mimics to evaluate alterations in their proliferation, invasion and migration abilities in vitro. Proteomics and bioinformatics were performed to predict the signalling pathway related to invasion and migration of H1975, which were verified by western blotting (WB) and flow cytometry. RESULTS: EVs derived from stored RBC suspensions in Weeks 3 and 5 could significantly enhance the invasion and migration ability of H1975 cells and also increase the expression of miR1246 and miR150-3p. After transfection with miR1246 and miR150-3p mimics, invasion, migration and proliferation of H1975 cells were obviously enhanced. Proteomics analysis demonstrated that EVs co-cultivation and miRNA transfection groups were both enriched in cell adhesion molecules. WB and cytometry indicated that integrin beta-1 (ITGB1) and Rap1b were increased. CONCLUSIONS: EVs derived from stored RBC suspensions can enhance invasion and migration ability of lung cancer cells via the most accumulated miR1246 and miR150-3p, which may increase the expression of ITGB1 through Rap1 signalling pathway.

Perfluorodecalin allows resuspension and prevents sediment solidification of extended-release drug formulations in primary packaging.

In this technical note we show with two simple experiments how Perfluorodecalin (PFD), an injectable perfluorocarbon, can be used as an agent for resuspending microparticulate suspensions in primary packaging containers for injection. Furthermore, we explain how this can be a substantial improvement regarding patient compliance in comparison to the commonly used gas headspace for resuspension. Our experiments are conducted with poly(lactic-co-glycolic acid) particles (often used in extended-release pharmaceutical formulations for injection) and in primary packaging that is commonly used in injection devices (glass cartridges). The results show that our method is feasible for resuspension and moreover even sediment solidification/caking is reduced. The differences between the two datasets collected are statistically significant with p < 0.01 in both cases.

Development and approval of novel injectables: enhancing therapeutic innovations.

INTRODUCTION: Novel injectables possess applications in both local and systemic therapeutics delivery. The advancement in utilized materials for the construction of complex injectables has tremendously upgraded their safety and efficacy. AREAS COVERED: This review focuses on various strategies to produce novel injectables, including oily dispersions, in situ forming implants, injectable suspensions, microspheres, liposomes, and antibody-drug conjugates. We herein present a detailed description of complex injectable technologies and their related drug formulations permitted for clinical use by the United States Food and Drug Administration (USFDA). The excipients used, their purpose and the challenges faced during manufacturing such formulations have been critically discussed. EXPERT OPINION: Novel injectables can deliver therapeutic agents in a controlled way at the desired site. However, several challenges persist with respect to their genericization. Astronomical costs incurred by innovator companies during product development, complexity of the product itself, supply limitations with respect to raw materials, intricate manufacturing processes, patent evergreening, product life-cycle extensions, relatively few and protracted generic approvals contribute to the exorbitant prices and access crunch. Moreover, regulatory guidance are grossly underdeveloped and significant efforts have to be directed toward development of effective characterization techniques.

Development of Mechanistic In Vitro-In Vivo Extrapolation to Support Bioequivalence Assessment of Long-Acting Injectables.

Long-acting injectable (LAI) formulations provide sustained drug release over an extended period ranging from weeks to several months to improve efficacy, safety, and compliance. Nevertheless, many challenges arise in the development and regulatory assessment of LAI drug products due to a limited understanding of the tissue response to injected particles (e.g., inflammation) impacting in vivo performance. Mechanism-based in silico methods may support the understanding of LAI-physiology interactions. The objectives of this study were as follows: (1) to use a mechanistic modeling approach to delineate the in vivo performance of DepoSubQ Provera® and formulation variants in preclinical species; (2) to predict human exposure based on the knowledge gained from the animal model. The PBPK model evaluated different elements involved in LAI administration and showed that (1) the effective in vivo particle size is potentially larger than the measured in vitro particle size, which could be due to particle aggregation at the injection site, and (2) local inflammation is a key process at the injection site that results in a transient increase in depot volume. This work highlights how a mechanistic modeling approach can identify critical physiological events and product attributes that may affect the in vivo performance of LAIs.

Bottom-up production of injectable itraconazole suspensions using membrane technology.

Bottom-up production of active pharmaceutical ingredient (API) crystal suspensions offers advantages in surface property control and operational ease over top-down methods. However, downstream separation and concentration pose challenges. This proof-of-concept study explores membrane diafiltration as a comprehensive solution for downstream processing of API crystal suspensions produced via anti-solvent crystallization. It involves switching the residual solvent (N-methyl-2-pyrrolidone, NMP) with water, adjusting the excipient (d-α-Tocopherol polyethylene glycol 1000 succinate, TPGS) quantity, and enhancing API loading (solid concentration) in itraconazole crystal suspensions. NMP concentration was decreased from 9 wt% to below 0.05 wt% (in compliance with European Medicine Agency guidelines), while the TPGS concentration was decreased from 0.475 wt% to 0.07 wt%. This reduced the TPGS-to-itraconazole ratio from 1:2 to less than 1:50 and raised the itraconazole loading from 1 wt% to 35.6 wt%. Importantly, these changes did not adversely affect the itraconazole crystal stability in suspension. This study presents membrane diafiltration as a one-step solution to address downstream challenges in bottom-up API crystal suspension production. These findings contribute to optimizing pharmaceutical manufacturing processes and hold promise for advancing the development of long-acting API crystal suspensions via bottom-up production techniques at a commercial scale.

Enhanced contact flexibility from nanoparticles in capillary suspensions.

HYPOTHESIS: Sample-spanning particle networks are used to induce structure and a yield stress, necessary for 3D printing of porous ceramics and paints. In capillary suspensions, a small quantity of immiscible secondary fluid is incorporated into a suspension. By further adding nanoparticles with a range of hydrophobicities, the structure of the bridges and microparticle-microparticle contacts is expected to be modified, resulting in a tunable yield stress and shear moduli. Moreover, the compressibility of these samples, important in many processing and application steps, is expected to be sensitive to these changes. EXPERIMENT: The nanoparticle hydrophobicity was altered and their position relative to the microparticles and the bridges was examined using confocal microscopy where the correlation between bridge size and network structure was observed. A step-wise uniaxial compression test on the confocal was conducted to monitor the microparticle movement and structural changes between capillary suspension networks with and without nanoparticles. FINDINGS: Our observation suggests that nanoparticles induce the formation of thin liquid films on the surface of the microparticles, mitigating contact line pinning and promoting internal liquid exchange. Additionally, nanoparticles at microparticle contact regions further diminish Hertzian contact, enhancing the capacity for rearrangement. These effects enhance microparticle movement, narrowing the bridge size distribution.

Dataset on exposure conditions to Fe2O3 and SiO2 colloidal suspension and airborne particulate matter (PM) suspensions: crude NIST1648a and with reduced content of organic matter, LAp120.

Particulate matter (PM) present in the air pollution increases morbidity and mortality due to several reasons. The dataset presents a comparative analysis of nebulization process of Fe2O3 and SiO2 nanoparticles or crude PM (NIST1648a) and that with reduced content of organic matter (LAp120). Nebulization tests were carried out to determine concentrations of nanoparticle and PM suspensions, in order to create an atmosphere with a concentration of PM particles about 1000 µg/m3 of air in the exposure chambers. It is important to properly recreate environmental conditions during further research on animals. The absorbance spectrum of the suspensions of the tested materials was measured in the range of 300-700 nm. The changes in the absorbance of these suspensions depending on the concentration after their passage through the nebulizers were examined. Based on the absorbance, it was determined to what extent the suspensions are passed out and dispersed by the nebulizers. The operating mode of the nebulizers and the concentration of suspensions were determined in order to establish the optimal exposure conditions and the microclimate of the chambers for further studies with mice. The dataset can help in optimization of nebulization process for all researchers exploring the further issue of the influence of the air pollution on the broadly understood animal functions, behavioral parameters and biochemical aspects.

Exact Results for Non-Newtonian Transport Properties in Sheared Granular Suspensions: Inelastic Maxwell Models and BGK-Type Kinetic Model.

The Boltzmann kinetic equation for dilute granular suspensions under simple (or uniform) shear flow (USF) is considered to determine the non-Newtonian transport properties of the system. In contrast to previous attempts based on a coarse-grained description, our suspension model accounts for the real collisions between grains and particles of the surrounding molecular gas. The latter is modeled as a bath (or thermostat) of elastic hard spheres at a given temperature. Two independent but complementary approaches are followed to reach exact expressions for the rheological properties. First, the Boltzmann equation for the so-called inelastic Maxwell models (IMM) is considered. The fact that the collision rate of IMM is independent of the relative velocity of the colliding spheres allows us to exactly compute the collisional moments of the Boltzmann operator without the knowledge of the distribution function. Thanks to this property, the transport properties of the sheared granular suspension can be exactly determined. As a second approach, a Bhatnagar-Gross-Krook (BGK)-type kinetic model adapted to granular suspensions is solved to compute the velocity moments and the velocity distribution function of the system. The theoretical results (which are given in terms of the coefficient of restitution, the reduced shear rate, the reduced background temperature, and the diameter and mass ratios) show, in general, a good agreement with the approximate analytical results derived for inelastic hard spheres (IHS) by means of Grad's moment method and with computer simulations performed in the Brownian limiting case (m/mg→∞, where mg and m are the masses of the particles of the molecular and granular gases, respectively). In addition, as expected, the IMM and BGK results show that the temperature and non-Newtonian viscosity exhibit an S shape in a plane of stress-strain rate (discontinuous shear thickening, DST). The DST effect becomes more pronounced as the mass ratio m/mg increases.

Rheology of Highly Filled Polymer Compositions-Limits of Filling, Structure, and Transport Phenomena.

The current state of the rheology of various polymeric and other materials containing a high concentration of spherical solid filler is considered. The physics of the critical points on the concentration scale are discussed in detail. These points determine the features of the rheological behavior of the highly filled materials corresponding to transitions from a liquid to a yielding medium, elastic-plastic state, and finally to an elastic solid-like state of suspensions. Theoretical and experimental data are summarized, showing the limits of the most dense packing of solid particles, which is of key importance for applications and obtaining high-quality products. The results of model and fine structural studies of physical phenomena that occur when approaching the point of filling the volume, including the occurrence of instabilities, are considered. The occurrence of heterogeneity in the form of individual clusters is also described. These heterogeneous objects begin to move as a whole that leads to the appearance of discontinuities in the suspension volume or wall slip. Understanding these phenomena is a key for particle technology and multiphase processing.

Evaluation of the Effect of Polyethylenimine on Boron Adsorption by Soil Minerals.

The removal of hazardous ions from water is crucial for safeguarding both the environment and human health. Soil minerals, integral components of soil, play a vital role as adsorbents for various contaminants, including heavy metal ions, organic dyes, and detergents. This study investigates the interaction between boron ions and soil minerals (gibbsite, kaolinite, and montmorillonite) in the presence of polyethylenimine (PEI). The minerals underwent characterization based on specific surface area, particle size distribution, zeta potential, and the presence of functional groups. The influence of PEI addition on the stability of the soil mineral suspension was evaluated by turbidimetry. Mineral-boron and mineral-boron-PEI interactions were explored under varying conditions, including pH, initial boron concentration, and mineral quantity, with all adsorption experiments conducted over 24 hours. Using the Langmuir isotherm, the maximum adsorption capacity of the studied minerals was determined for boron both without and in the presence of PEI. For gibbsite, kaolinite and montmorillonite, it was 30.63, 24.55 and 26.62 mg g-1, respectively, while in the presence of PEI, it increased to 33.11, 26.61 and 45.47 mg g-1, respectively. The addition of PEI enhanced boron adsorption from aqueous solutions, increasing the removal efficiency from 65 % to about 80 %.

Selection of a Digitalis purpurea Cell Line with Improved Bioconversion Capacity of Hydroquinone into Arbutin.

This study aimed to investigate the biotransformation capabilities of a hydroquinone-tolerant Digitalis purpurea cell line (DpHQ) for bioconverting hydroquinone (HQ) into arbutin, a compound with significant therapeutic and cosmetic applications. The research evaluated the influence of various HQ concentrations, feeding protocols, and carbon sources on arbutin bioconversion yield. By using HPLC-MS for the quantification of arbutin in biomass and medium, the study revealed that higher precursor (HQ) concentration led to a more pronounced growth inhibition under single dosing than sequential dosing. At lower sugar (3%) and precursor (4 mM HQ) levels, arbutin predominantly remained within the cells, whereas higher sugar (6%) and HQ (5-6 mM) levels promoted its release into the medium. Arbutin production ranged from 591 mg/L under single dosing to 3049 mg/L with sequential dosing, with the highest yield being achieved with 5 mM HQ in divided doses and 6% glucose. This study holds novelty for being the first to demonstrate the DpHQ's tolerance to high concentrations of HQ and its efficient capabilities to bioconvert HQ to arbutin, indicating that D. purpurea is equipped with the enzymes required for this process. These aspects highlight its potential as a biotechnological source for arbutin synthesis.

Tailoring the use of excipients in bottom-up production of naproxen crystal suspensions via membrane technology.

Long-acting crystal suspensions of active pharmaceutical ingredients (API) mostly comprised of an API, a suspension media (water) and excipients and provide sustained API release over time. Excipients are crucial for controlling particle size and to achieve the stability of the API crystals in suspension. A bottom-up process was designed to produce long-acting crystal suspensions whilst investigating the excipient requirements during the production process and the subsequent storage. PVP K30 emerged as the most effective excipient for generating stable naproxen crystals with the desired size of 1 to 15 µm, using ethanol as solvent and water as anti-solvent. Calculations, performed based on the crystal properties and assuming complete PVP K30 adsorption on the crystal surface, revealed lower PVP K30 requirements during storage compared to initial crystal generation. Consequently, a membrane-based diafiltration process was used to determine and fine-tune PVP K30 concentration in the suspension post-crystallization. A seven-stage diafiltration process removed 98 % of the PVP K30 present in the suspension thereby reducing the PVP-to-naproxen ratio from 1:2 to 1:39 without impacting the stability of naproxen crystals in suspension. This work provides insights into the excipient requirements at various production stages and introduce the membrane-based diafiltration for precise excipient control after crystallization.

Intramuscularly injected long-acting testosterone-cholesterol prodrug suspension with three different particle sizes: extended in vitro release and enhanced in vivo safety.

The testosterone undecanoate oil solution is the most widely used injection of testosterone for long-acting effects on the market, whereas the formulation carries the potential risk of causing pulmonary vascular embolism, inflammation, and pain at the injection site. Therefore, a sustained-released long-acting injection of testosterone with strong security is urgently exploited. Herein, a poorly water-soluble testosterone-cholesterol prodrug (TST-Chol) was synthesized by esterification. The water solubility of TST-Chol was decreased by 644 folds in comparison to that of testosterone (TST). Moreover, suspensions of TST and TST-Chol were prepared and analyzed in vitro, utilizing three distinct particle sizes: small-sized nanocrystals (SNCs) measuring 300 nm, medium-sized microcrystals (MMCs) measuring 12 µm, and large-sized microcrystals (LMCs) measuring 20 µm. The findings from the in vitro release study indicated that the sustained release of the drug was significantly influenced by the solubility and particle sizes of the suspension. Notably, the suspensions with low water solubility and larger particle sizes exhibited a more desirable sustained-release effect in vitro. Furthermore, the study on pharmacokinetics exhibited that TST-Chol SNCs produced a sustained TST plasma concentration in vivo for up to 40 days and no obvious pathological changes in lung tissue were found. Our study indicated that solubility and particle sizes of suspensions had made a difference in pharmacokinetics and provided a valuable reference for the advancement of long-acting injections.

Single-Bubble Sonoluminescence of Colloidal Suspensions of Europium(II) Salt Nanoparticles.

Colloidal suspensions of EuCl2, EuBr2, and EuSO4 nanoparticles (<50 nm) in dodecane and EuSO4 in 70% H2SO4 were synthesized. Moving single-bubble sonoluminescence (m-SBSL) spectra were obtained for a bubble performing radial oscillations in these suspensions and translational motions at the antinode of a standing ultrasonic wave with a frequency of about 27 kHz. In these spectra (at a spectral resolution of 10 nm), the sono-excited luminescence bands of the Eu2+ ion were detected for the first time, coinciding in the shape and position of the maxima (404, 413, and 377 nm for EuCl2, EuBr2, and EuSO4, respectively) with the bands of Eu2+ located in a crystalline environment in the photoluminescence spectra of nanoparticles of europium salts in suspensions. The detected sonoluminescence of Eu2+ arises due to the injection of nanoparticles into a bubble deformed during motion and excitation of a lanthanide ion at the periphery of the bubble volume during collisions of nanoparticles with charged particles, mainly electrons, coming from a hot nonequilibrium plasma, which periodically arises during bubble compression. Evidence for the excitation of the europium ion in the bubble is the absence of its luminescence bands in the SBSL spectra of the translationally immobile bubble, in which nanoparticles are unlikely to enter. The nanoparticles that enter the bubble also undergo decomposition in the plasma into fragments, in particular, with the formation of Eu, Eu+ in the excited state. The atomic lines of these fragments were recorded for the first time in the m-SBSL spectrum with a resolution of 1 nm for a suspension of EuSO4 nanoparticles in 70% H2SO4. The resulting m-SBSL spectra will add to the library of characteristic spectra of objects of sonoluminescent spectroscopic analysis and will make it possible to identify and determine the content of Eu or Eu2+ in these objects.

Paving the way for new and challenging matrix reference materials-particle suspensions at the core of material processing providing RMs for method development and method validation.

Sufficient homogeneity of the certified parameter(s) over the whole fill series of a matrix reference material (RM) is a fundamental quality criterion. In practice, the heterogeneity of the target parameter is evaluated, whereby a relative value can be calculated of how much the target parameter is varying over the RM-batch. A high degree of homogeneity (low heterogeneity) is an inherent quality mark of a good RM. Here, we report how challenging matrix RMs were produced by using particle suspensions at the core of the material processing step. The examples of matrix RMs produced span from whole water reference materials for persistent organic pollutants, PM2.5-like atmospheric dust certified for specific ions to microplastic RMs. Most of these RMs were subsequently used in different phases of analytical method development or for method validation. Common to all these matrices is that they cannot be easily mixed, handled, or dosed to prepare larger sample batches. In all cases, a continuously stirred suspension of particles was used during material processing. In general, relative between-bottle heterogeneities from 1.6 to 6% were achieved for the target parameters in these matrix presentations. Concerning developments of new CRMs in emerging fields, the co-dependence between the availability of validated analytical methods with good repeatability and testing materials with a known and high homogeneity of the target parameter(s) becomes particularly challenging. This situation is an RM/Method causality dilemma. To overcome that hurdle, strategies are proposed for stepwise processes where RM producers and a network of analytical method developers could work hand in hand. In addition, development of a portfolio of inexpensive and well-homogenised common samples coupled with a reporting interface is suggested. This would benefit method developers and RM producers alike. As more and more data is compiled for a specific matrix, it paves the way for new and challenging RMs that can later be used by a wider community.