The Impact of a Manufacturing Process on the Stability of Microcrystalline Long-Acting Injections: A Case Study on Aripiprazole Monohydrate

An Image-based method for evaluating changes in particle size and morphology distributions of aggregate materials after vibratory compaction test

Aggregation and deposition kinetics of carboxymethyl cellulose-modified zero-valent iron nanoparticles in porous media

An increased worldwide protein demand for food and feed and the necessity to release the water soluble proteins in the first stage of the cascade biorefinery require the development of mild protein extraction technologies. Cell disintegration is the first hurdle and is considered as one of the most energy consuming steps. Therefore, this thesis focused on the development of a mild, scalable and energy efficient disintegration technology for green microalgae and macroalgae (seaweed) aimed on extraction of water soluble components (like proteins and carbohydrates). For microalgae disintegration, two main technologies were investigated. First of all the conventional technology bead milling and second a novel approach using Pulsed Electric Field (PEF). In Chapter 2 a benchmark was set by means of bead milling for the release of water soluble protein from the green microalgae Chlorella vulgaris. Overall, protein yields between 32 and 42% were achieved, while the energy consumption was reduced with 85% by selective protein extraction to values as low as 0.81 kWh kgDW-1. Remarkably, the benchmark was much better than expected. In Chapter 3 the bead mill was further optimized by decreasing the applied bead size, furthermore the applicability of bead milling on two additional microalgae species (Neochloris oleoabundans, Tetraselmis suecica) was shown. In addition, to be able to better understand the disintegration mechanism, the so-called stress model was applied. This model describes the comminution process in a bead mill as function of the amount of bead contacts and the force of each impact. The release kinetics could be improved and thereby the specific energy consumption could be reduced to 0.45‒0.47 kWh kgDW-1 by using 0.3 mm beads for all algae. Chapter 4 describes a screening on the applicability of PEF, over a broad range of operating conditions, for the extraction of water soluble proteins from the microalgae C. vulgaris and N. oleoabundans. No substantial protein yields were observed under the investigated conditions. This led to the conclusion that PEF is not suitable to release water soluble proteins, not even at specific energy consumptions much higher than those for the benchmark, bead milling. In Chapter 5 it was attempted to improve the performance of PEF by investigating the synergistic effect with the processing temperature. The PEF experiments were performed using a pilot scale continuous flow electroporation unit in which the processing temperature was controlled between 25 – 65 °C. The results showed that under the tested conditions, the combined PEF-Temperature treatment did not cause substantial disintegration of the algal cells to effectively release water soluble proteins. In addition to the microalgae, macroalgae were subject of investigation in the search for new protein sources in Chapter 6. Four batch technologies were used to disintegrate the green macroalgae Ulva lactuca, being; osmotic shock, enzyme incubation, PEF and High Shear Homogenization (HSH). In descending order the highest protein yields per treatment; HSH (~40%) > enzyme degradation (~25%) > osmotic shock (~20%) > PEF (~15%). In the final chapter the main results and remaining bottlenecks are discussed and a future outlook on microalgae disintegration is presented. To date, bead milling is the only technology able to disintegrate fresh microalgae at specific energy consumptions below 10% of the total energy available from the algae and release substantial amounts of water soluble protein. The future outlook was based on a techno-economic evaluation, which showed that the cultivation costs are limiting the economic feasibility of microalgae biorefinery. Future focus should be on the cultivation.

Emulsion stability—theoretical studies on simultaneous flocculation and creaming

Long acting injectables for the treatment of prostate cancer

BackgroundTo overcome nonadherence in patients with psychosis switch to long-acting injectable (LAI) antipsychotic formulations is adopted. Most oral versus LAI comparisons showed similar antipsychotic responses. Psychoses often overlap with substance use disorder (SUD). Head-to-head LAI comparisons have hitherto focused only on non-comorbid populations.ObjectiveThe objective of this study was to compare two LAIs, administered for 12 months, in initially hospitalized patients with psychosis comorbid with SUD in their clinical and quality of life (QoL) outcomes.Patients and methodsInpatients were recruited during 2016 and switched randomly to 400 mg intramuscular aripiprazole monohydrate (AM) (N=50) or to 100 mg intramuscular paliperidone palmitate (PP) once-monthly (N=51); patients were discharged and followed up for 12 months. Patients were rated at baseline and after 1 year through the Clinical Global Impression scale – severity (CGIs), substance craving intensity was rated through a visual analog scale for substance craving, and QoL through the World Health Organization (WHOQOL-BREF) scale. We addressed confounders with backward stepwise logistic regression and three-way analysis of variance.ResultsPP were older and had more cases of schizophrenia spectrum and less bipolar disorders than AM, but AM had a stronger craving for substances at baseline. Both LAIs were associated with significant improvements in all outcomes, with AM displaying stronger effect sizes than PP. The two groups did not differ on baseline WHOQOL-BREF scores in any domain, but at the 1-year follow-up, AM fared better on all domains. The two groups did not differ in final severity, but PP scored higher than AM in craving at the 1-year endpoint.Limitation: The CGIs is not a refined tool for severity and the substance craving may be subject to recall bias.Conclusion1-year AM and PP was followed by improved clinical status and QoL and reduced substance craving in a population with psychosis and SUD comorbidity. AM, compared to PP, improved craving and QoL at the 1-year follow-up.

The particle size distribution (PSD) of soil plays a vital role in wind erosion prediction. However, the impact of different pretreatments to remove binding agents for PSD and consequences for wind erosion modelling have not been tested. We collected 90 topsoil samples of Chernozems and Kastanozems from different test sites in Kazakhstan. Soil samples covered typical land-use types and farming methods with calcium carbonate contents reaching from 2.2 to 117.3 g kg−1 and soil organic carbon content from 11.2 to 48.7 g kg−1. Prior to particle size analysis by laser diffraction, samples were chemically pretreated separately and successively with 10% hydrochloric acid (HCl), to dissolve carbonates and 30% hydrogen peroxide (H2O2), to oxidise organic binding material. The HCl pretreatment resulted in incomplete dispersion or even aggregation due to calcium ions released by the dissolution of carbonates, while removing organic matter with H2O2 caused complete sample dispersion. The associated changes in PSD were overall minor, and only a few of our samples were assigned to a different texture class. Obtained PSD data was used to calculate texture-based properties, such as the geometric mean diameter (GMD), with a pedotransfer function. Calculated and measured input data were applied to the Single–event Wind Erosion Evaluation Program (SWEEP) to estimate potential soil losses. As a result, SWEEP's simulations showed substantial variations if the GMD is calculated based on PSD under the influence of different pretreatments. At the same time, there was no variation if the GMD was independently measured. We suggest that for standard particle size analysis of calcareous soils, pretreatment with HCl should be avoided because it might cause misleading results. Considering the variation induced by PSD analysis and resulting potential soil losses, pretreatments for laser diffraction analysis can be omitted for the investigated, silt-dominated Chernozems and Kastanozems if additional texture-based parameters are measured.

A study on the fragmentation of saltating particles along the fetch distance during wind erosion

Scattering theory predictions of the changes in the attenuation of sound at frequencies between 100 Hz and 100 kHz due to changes in the (spherical) particle size distributions in airborne particulate suspensions with characteristics typical of pulverized fuel flows are considered. These predictions are compared with a criterion for the detectability of insertion loss changes, assuming a sensor separation of 100 mm. It is concluded that, for such a separation, at frequencies greater than 30 kHz and concentrations greater than 0.5 kg/kg, it is feasible to monitor changes in the fraction of particles with radii above 37.5 μm by measuring cross-pipe sound attenuation.

Optical techniques for the particle size characterization of metered dose inhaler (MDI) suspensions have been developed as an alternative to the labor-intensive and time-consuming impaction method. In this study, a laser diffraction (LD) apparatus with a liquid cell (“wet cell” method) and a “time-of-flight” apparatus named aerodynamic particle sizer (APS) were utilized to assess MDI suspensions with varied formulation compositions and storage conditions. The results were compared with the conventional Anderson cascade impaction (ACI) data. The two optical methods were able to detect the changes in particle size distributions between formulations, yet to a lesser extent than those observed using the cascade impaction methodology. The median aerodynamic particle size measured by the APS method and the median geometric particle size obtained from the LD method were linearly correlated with the corresponding ACI results in the range of 2–5 µm. It was also found that the APS measurement was biased towards the finer particle size region and resulted in overestimated fine particle fraction (FPF) values which were 2–3 times folds of the ACI results. In conclusion, the optical particle sizing techniques may, under some circumstances, be viable techniques for the rapid assessment of MDI suspensions. The “wet cell” LD method, in particular, is found to be a valuable means of detecting active pharmaceutical ingredient (API) particle size changes in an MDI suspension. Using both the LD and the APS methods in early formulation screening followed by a final assessment with cascade impaction analysis can improve the efficiency of MDI formulation development.

IntroductionSchizophrenia is a chronic mental disorder that worsens with each relapse. Long-acting injectable (LAI) antipsychotics may prevent the exacerbation of symptoms and occurrence of relapses through improved continuity of care. Different dose regimens are available for the LAIs aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL), but their cost effectiveness is unclear.ObjectivesThe study aim was to compare costs and effects (relapses) of the different aripiprazole LAI dose regimens to inform clinical and US payer decisions.MethodsA state-transition model calculated the outcomes of eight LAI dose regimens based on their relapse rates. As effectiveness data from randomized controlled trials were unavailable, relapse rates were modeled using pharmacokinetic and pharmacodynamic evidence. These described blood plasma levels of aripiprazole as a function of AM and AL dose regimens and described the probability of relapse as a function of aripiprazole blood plasma levels. The analysis had a time horizon of 1 year and took the US healthcare payer perspective. The incremental cost per relapse avoided and the probability of cost effectiveness were calculated in deterministic and probabilistic analyses. Scenario analyses explored the model’s main assumptions, and results were validated against external data and other cost-effectiveness analyses.ResultsMonthly administration of AM 400 mg consistently yielded the lowest predicted number of relapses across deterministic, probabilistic, and scenario analyses. The costs of treatment and relapses were projected to be the lowest with a monthly administration of AL 441 mg. The incremental cost per relapse avoided with AM 400 mg ranged from AM 400 mg being dominant to $US83,300. From willingness-to-pay thresholds of $US30,000 per relapse avoided, the probability of cost effectiveness was highest for AM 400 mg. The validation showed alignment with external data.ConclusionThe analysis highlighted the robustness of the novel framework based on pharmacokinetic and pharmacodynamic evidence and demonstrated an application in a postmarketing setting.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-021-01077-8.

Turbulent coagulation of aerosol particles was studied experimentally by observing the time-dependent changes in particle number concentration and size distribution of aerosol for various intensities of stirring in a stirred tank, using the ultramicroscopic size analysis. From the observed data on the decrease in particle number concentration of aerosol, the rate constants of turbulent coagulation were evaluated and compared with some of the most representative theories, and were found in good agreement with Saffman and Turner''s theory. Further, the changes in particle size distribution observed were confirmed by those obtained by numerically solving the equation of coagulation for polydisperse aerosol, the so-called population balance equation.

Combination of low energy and high energy methods were studied as alternative process to individual spontaneous emulsification and ultrasonication for production of stable nanoemulsions in order to reduce the synthetic surfactant requirement. A three-step procedure was used: The dispersed oil phase containing hydrophilic surfactant (Tween 80) was titrated into an aqueous phase for formation of nanoemulsion by spontaneous method. Then, it was homogenized by a high shear homogenizer and sonicated to form final stable nanoemulsions. Influence of orange oil to sunflower oil ratio, surfactant emulsion ratio (SER), ultrasonication (US) time and temperature and high shear homogenization (HSH) time on particle size and polydispersity index (PDI) of nanoemulsions were determined. Orange oil/sunflower oil ratio, SER, US time and temperature and HSH time all had an appreciable effect on nanoemulsion formation, particle size distribution and stability. Translucent nanoemulsions (70 nm) was obtained under following specific conditions: 10 wt% oil phase (7 wt% orange oil + 3 wt% sunflower oil), 2 wt% SER (Tween 80), 5 min HSH and 10 min US in an ice bath. The selected nanoemulsion was stable for 35-day storage at ambient temperature. These findings demonstrate that stable orange oil nanoemulsions can be produced from food-grade ingredients using combined processing operations (spontaneous homogenization, HSH and US homogenization) and low synthetic surfactant concentration. This study provides important information for design and application of essential oil nanoemulsion-based delivery systems in food, beverage and other applications.

Continuous crystallization of adipic acid with ultrasound

We report a comprehensive strategy based on implementation of orthogonal measurement techniques to provide critical and verifiable material characteristics for functionalized gold nanoparticles (AuNPs) used in biomedical applications. Samples were analyzed before and after ≈50 months of cold storage (≈4 °C). Biomedical applications require long-term storage at cold temperatures, which could have an impact on AuNP therapeutics. Thiolated polyethylene glycol (SH-PEG)-conjugated AuNPs with different terminal groups (methyl-, carboxylic-, and amine-) were chosen as a model system due to their high relevancy in biomedical applications. Electrospray-differential mobility analysis, asymmetric-flow field flow fractionation, transmission electron microscopy, scanning electron microscopy, atomic force microscopy, inductively coupled plasma mass spectrometry, and small-angle X-ray scattering were employed to provide both complementary and orthogonal information on (1) particle size and size distribution, (2) particle concentrations, (3) molecular conjugation properties (i.e., conformation and surface packing density), and (4) colloidal stability. Results show that SH-PEGs were conjugated on the surface of AuNPs to form a brush-like polymer corona. The surface packing density of SH-PEG was ≈0.42 nm(-2) for the methyl-PEG-SH AuNPs, ≈0.26 nm(-2) for the amine-SH-PEG AuNPs, and ≈0.18 nm(-2) for the carboxylic-PEG-SH AuNPs before cold storage, approximately 10 % of its theoretical maximum value. The conformation of surface-bound SH-PEGs was then estimated to be in an intermediate state between brush-like and random-coiled, based on the measured thicknesses in liquid and in dry states. By analyzing the change in particle size distribution and number concentration in suspension following cold storage, the long term colloidal stability of AuNPs was shown to be significantly improved via functionalization with SH-PEG, especially in the case of methyl-PEG-SH and carboxylic-PEG-SH (i.e., we estimate that >80 % of SH-PEG5K remained on the surface of AuNPs during storage). The work described here provides a generic strategy to track and analyze the material properties of functional AuNPs intended for biomedical applications, and highlights the importance of a multi-technique analysis. The effects of long term storage on the physical state of the particles, and on the stability of the ligand-AuNP conjugates, are employed to demonstrate the capacity of this approach to address critical issues relevant to clinical applications.