A Tight-binding Molecular Dynamics Study of the Dissociation of Boron Clusters in c-Si

Boron clusters with silicon self-interstitials have been implicated in the phenomenon of transient enhanced diffusion (TED) following ion implantation of boron and subsequent annealing steps. This paper explores possible dissolution mechanisms for boron-interstitial clusters during the simulation of a typical annealing process. Using tight-binding molecular dynamics (TBMD) and employing a Goodwin-Skinner-Pettifor sp-based TB model, we have been able to observe the complete dissolution of a B 4 I 4 cluster into the surrounding crystalline silicon matrix. Many unsuccessful attempts to observe dissolution are also presented, highlighting the effect of cluster stability, temperature and the role of vacancies in cluster dissolution. Though we can make no unambiguous statements on the definitive dissolution mechanism of boron-defect clusters based on one successful dissolution event, we can hint at key events that appear to be important, such as the diffusion of self-interstitials (presciently predicted by Pelaz et al. ), the "stranding" of boron atoms in their wake, and the importance of mobile boron-self-interstitial (B-I) pairs. The intrinsic diffusivity of boron in a c-Si lattice and its retardation of the diffusivity of Si self-interstitials is also discussed.     

The kinetics of siderophore‐mediated olivine dissolution

Silicate minerals represent an important reservoir of nutrients at Earth's surface and a source of alkalinity that modulates long‐term geochemical cycles. Due to the slow kinetics of primary silicate mineral dissolution and the potential for nutrient immobilization by secondary mineral precipitation, the bioavailability of many silicate‐bound nutrients may be limited by the ability of micro‐organisms to actively scavenge these nutrients via redox alteration and/or organic ligand production. In this study, we use targeted laboratory experiments with olivine and the siderophore deferoxamine B to explore how microbial ligands affect nutrient (Fe) release and the overall rate of mineral dissolution. Our results show that olivine dissolution rates are accelerated in the presence of micromolar concentrations of deferoxamine B. Based on the non‐linear decrease in rates with time and formation of a Fe³⁺‐ligand complex, we attribute this acceleration in dissolution rates to the removal of an oxidized surface coating that forms during the dissolution of olivine at circum‐neutral pH in the presence of O₂ and the absence of organic ligands. While increases in dissolution rates are observed with micromolar concentrations of siderophores, it remains unclear whether such conditions could be realized in natural environments due to the strong physiological control on microbial siderophore production. So, to contextualize our experimental results, we also developed a feedback model, which considers how microbial physiology and ligand‐promoted mineral dissolution kinetics interact to control the extent of biotic enhancement of dissolution rates expected for different environments. The model predicts that physiological feedbacks severely limit the extent to which dissolution rates may be enhanced by microbial activity, though the rate of physical transport modulates this limitation.     

New Approach for the Application of USP Apparatus 3 in Dissolution Tests: Case Studies of Three Antihypertensive Immediate-Release Tablets

The USP Apparatus 3 is a compendial dissolution Apparatus that has been mainly used to assess the performance of modified-release drug products. However, this Apparatus can be applied to dissolution testing of immediate-release tablets as well, with several advantages such as lower consumption of dissolution media, reduced setup time in quality control routine, and minimized hydrodynamic issues. In this work, three immediate-release (IR) tablets containing antihypertensive drugs of different Biopharmaceutic Classification System (BCS) classes were evaluated in order to assess the possible interchangeability between the official dissolution method using typical USP Apparatus 1 or 2 and the proposed methods using USP Apparatus 3. Depending on the selection of the appropriate operational conditions, such as dip rate and sieve mesh size, it was observed that USP Apparatus 3 could provide similar dissolution profiles compared to USP Apparatus 1 or 2 to the drug products tested. In addition, USP Apparatus 3 avoided conning issues related to USP Apparatus 2. The successful application of USP Apparatus 3 in dissolution tests for IR drug products depends on the definition of specific test conditions for each product, considering all the equipment variables, as well as drug and formulation characteristics.     

Understanding the influence of temperature change and cosolvent addition on conversion rate of enzymatic suspension reactions based on regime analysis

It is a commonly held belief that enzymatic conversions of substrate in aqueous suspensions can be speeded up by raising the temperature or adding organic solvents to promote dissolution of the substrate. To quantify the impact of such changes, we studied the alpha-chymotrypsin-catalyzed hydrolysis of dimethyl benzylmethylmalonate as a model system. It was found that, upon addition of organic cosolvents, longer process times were actually required, even though the substrate solubility increased severalfold as expected. Upon raising the temperature from 25 degrees C to 37 degrees C, on the other hand, both the substrate solubility, the substrate dissolution rate, and the enzymatic reaction rate increased, leading to shorter process times. A dissolution-reaction model incorporating the kinetics of enzyme deactivation could be developed. A simple relation for the prediction of the overall process time was established by evaluating the time constants for the subprocesses: substrate dissolution; enzymatic conversion; and enzyme deactivation. Using regime analysis, rules of thumb for the optimization of an enzymatic suspension reaction were derived.     

The HRDC domain of BLM is required for the dissolution of double Holliday junctions

Bloom's syndrome is a hereditary cancer-predisposition disorder resulting from mutations in the BLM gene. In humans, BLM encodes one of five members of the RecQ helicase family. One function of BLM is to act in concert with topoisomerase IIIalpha (TOPO IIIalpha) to resolve recombination intermediates containing double Holliday junctions by a process called double Holliday junction dissolution, herein termed dissolution. Here, we show that dissolution is highly specific for BLM among human RecQ helicases and critically depends upon a functional HRDC domain in BLM. We show that the HRDC domain confers DNA structure specificity, and is required for the efficient binding to and unwinding of double Holliday junctions, but not for the unwinding of a simple partial duplex substrate. Furthermore, we show that lysine-1270 of BLM, which resides in the HRDC domain and is predicted to play a role in mediating interactions with DNA, is required for efficient dissolution.     

Effect of N-trimethyl chitosan enhancing the dissolution properties of the lipophilic drug cyclosporin A

The aim was to evaluate the influence of N-trimethyl chitosan chloride (TMC) as a carrier for solid dispersion on the dissolution of poorly water-soluble drugs. In this study, we used cyclosporin A(CyA) as a model drug and TMC as a carrier. The effect of various formulation and process variables including TMC-to-CyA mixing weight ratio, weigh molecular(M_w) of TMC and methods used to disperse CyA along with the TMC on the drug dissolution was investigated. The nature of CyA dispersed in the matrix was studied by powder X-ray diffractometry (PXRD), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), and dissolution rate analyses. It was proved that all solid mixtures of CyA with TMCs showed a significantly rapid dissolution rate compared to pure drug and physical mixture. The greater the TMC content the higher the drug dissolution was, up to a maximum corresponding to a polymer: drug ratio of 3:1. The lower the M_w of TMC, the more important the polymer effect was. The dissolution of CyA was remarkably improved by the solid dispersion. The drug dissolution enhancement was attributed to the decreased drug crystallinity and size and polymer wetting effect. There was no significant difference in the efficiency of improving the drug dissolution between the solid dispersions prepared by solvent dispersing and by co-grinding. It was suggested that the TMC with a lower molecular weight is a useful carrier for solid dispersion.     

On the estimation of minimum mechanical loss during an in situ biogenic silica dissolution experiment

Maximum dissolution rates of biogenic silica as a function of depth in the ocean were calculated as a function of the variables temperature, pH, dissolved silicon concentration, and the measured surface area of radiolarian skeletons of a single species. These rates when compared with observed weight losses during an in situ dissolution experiment suggest a mechanical weight loss of about 50%. The relationship between mechanical weight loss and total weight loss is linear, suggesting the usefulness of this mathematical approach to dissolution experiments as well as the need for caution in trying to apply such loss data directly to the environment.     

Impact of Vibration and Agitation Speed on Dissolution of USP Prednisone Tablets RS and Various IR Tablet Formulations

Dissolution testing is an in vitro procedure which is widely used in quality control (QC) of solid oral dosage forms and, given that real biorelevant test conditions are applied, can also be used as a predictive tool for the in vivo performance of such formulations. However, if a dissolution method is intended to be used for such purposes, it has to deliver results that are only determined by the quality of the test product, but not by other variables. In the recent past, more and more questions were arising on how to address the effects of vibration on dissolution test results. The present study was performed to screen for the correlation of prednisone dissolution of USP Prednisone Tablets RS with vibration caused by a commercially available vibration source as well as to investigate how drug release from a range of immediate release formulations containing class 1–4 drugs of the biopharmaceutical classification scheme is affected by vibration when performing dissolution experiments at different agitation rates. Results of the present study show that the dissolution process of oral drug formulations can be affected by vibration. However, it also becomes clear that the degree of which a certain level of vibration impacts dissolution is strongly dependent on several factors such as drug properties, formulation parameters, and the design of the dissolution method. To ensure the establishment of robust and predictive dissolution test methods, the impact of variation should thus be considered in method design and validation.KEY WORDS: dissolution, USP prednisone calibrator tablets, variability, vibration meter, vibration source     

Calcite and dolomite dissolution rates in the context of microbe–mineral surface interactions

Although microbes have been shown to alter the dissolution rate of carbonate minerals, a mechanistic understanding of the consequences of microbial surface colonization on carbonate dissolution has yet to be achieved. Here we report the use of vertical scanning interferometry (VSI) to study the effect of Shewanella oneidensis MR‐1 surface colonization on the dissolution rates of calcite (CaCO₃) and dolomite (CaMg(CO₃)₂) through qualitative analysis of etch pit development and quantitative measurements of surface‐normal dissolution rates. By quantifying and comparing the significant processes occurring at the microbe–mineral interface, the dominant mechanism of mineral dissolution during surface colonization was determined. MR‐1 attachment under aerobic conditions was found to influence carbonate dissolution through two distinct mechanistic pathways: (1) inhibition of carbonate dissolution through interference with etch pit development and (2) excavation of carbonate material at the cell–mineral interface during irreversible attachment to the mineral surface. The relative importance of these two competing effects was found to vary with the solubility of the carbonate mineral studied. For the faster‐dissolving calcite substrates, inhibition of dissolution by attachment and subsequent extracellular polysaccharide (EPS) production was the dominant effect associated with MR‐1 surface colonization. This interference with etch pit development resulted in a 40–70% decrease in the surface normal dissolution rate relative to cell‐free controls, depending primarily on the concentration of cells in solution. However, in the case of the slower‐dissolving dolomite substrates, carbonate material displaced during the entrenchment of cells on the surface far outweighed the abiotic dissolution rate. Therefore, during the initial stages of surface colonization, dolomite dissolution rates were actually enhanced by MR‐1 attachment. This study demonstrates the dynamic and competitive relationship between microbial surface colonization and mineral dissolution that may be expected to occur in natural environments.     

Involvement of macroautophagy in the dissolution of neuronal inclusions

Ubiquitinated inclusions are a common feature of many neurodegenerative conditions. We have proposed that, at least in part, such inclusions may be formed due to dysfunction of the proteasome. We have modeled such proteasomal dysfunction by applying pharmacological inhibitors to cultured embryonic rat cortical neurons. This treatment leads to neuronal death and formation of ubiquitin/-synuclein-positive cytoplasmic inclusions. At late time points following proteasomal inhibition such inclusions are no longer discerned. Instead, many neurons accumulate small ubiquitinated aggregates, which may represent remnants of the inclusions. In this work we have examined a potential mechanism for inclusion dissolution. Electron microscopy images showed activation of macroautophagy at late time points after proteasomal inhibition. Labeling with LysoTracker Red, a dye that accumulates in acidic compartments, or immunostaining for the lysosomal enzyme Cathepsin D, showed an increase in globular staining. Cathepsin D co-localized partially with small ubiquitinated aggregates, but not inclusions. Application of an inhibitor of macroautophagy or of the vacuolar ATPase led to an increase in the number of inclusions and a decrease in small aggregates, whereas an activator of autophagy had the opposite effects. There was no significant change in apoptotic death following these manipulations. We conclude that, following proteasomal inhibition of cultured cortical neurons, there is activation of macroautophagy and of the lysosomal pathway. This activation results in dissolution of ubiquitinated inclusions into small aggregates, without directly impacting neuronal cell death. These data further support the idea that in this model inclusions and neuronal cell death are independent processes.     

Modeling and simulation of chemomechanics at the cell-matrix interface

Chemomechanical characteristics of the extracellular materials with which cells interact can have a profound impact on cell adhesion and migration. To understand and modulate such complex multiscale processes, a detailed understanding of the feedback between a cell and the adjacent microenvironment is crucial. Here, we use computational modeling and simulation to examine the cell-matrix interaction at both the molecular and continuum lengthscales. Using steered molecular dynamics, we consider how extracellular matrix (ECM) stiffness and extracellular pH influence the interaction between cell surface adhesion receptors and extracellular matrix ligands, and we predict potential consequences for focal adhesion formation and dissolution. Using continuum-level finite element simulations and analytical methods to model cell-induced ECM deformation as a function of ECM stiffness and thickness, we consider the implications toward design of synthetic substrata for cell biology experiments that intend to decouple chemical and mechanical cues.     

Determining the impacts of fermentative bacteria on wollastonite dissolution kinetics

Silicate minerals can be a source of calcium and alkalinity, enabling CO₂ sequestration in the form of carbonates. For this to occur, the mineral needs to be first dissolved in an acidifying process such as the biological process of anaerobic fermentation. In the present study, the main factors which govern the dissolution process of an alkaline silicate mineral (wollastonite, CaSiO₃) in an anaerobic fermentation process were determined. Wollastonite dissolution kinetics was measured in a series of chemical batch experiments in order to be able to estimate the required amount of alkaline silicate that can neutralize the acidifying fermentation process. An anaerobic fermentation of glucose with wollastonite as the neutralizing agent was consequently performed in a fed-batch reactor. Results of this experiment were compared with an abiotic (control) fed-batch reactor in which the fermentation products (i.e. organic acids and alcohols) were externally supplied to the system at comparable rates and proportions, in order to provide chemical conditions similar to those during the biotic (fermentation) experiment. This procedure enabled us to determine whether dissolution of wollastonite was solely enhanced by production of organic acids or whether there were other impacts that fermentative bacteria could have on the mineral dissolution rate. The established pH profiles, which were the direct indicator of the dissolution rate, were comparable in both experiments suggesting that the mineral dissolution rate was mostly influenced by the quantity of the organic acids produced.     

Enhanced Calcite Dissolution in the Presence of the Aerobic Methanotroph Methylosinus trichosporium

Microbial aerobic methane oxidation (MOx) is intrinsically coupled to the production of carbon dioxide, favoring carbonate dissolution. Recently, microbial organic polymers were shown to be able to induce carbonate dissolution. To discriminate between different mechanisms causing calcite dissolution, experiments were conducted in the presence of solid calcite with (1) actively growing cells (2) starving cells, and (3) dead cells of the methanotrophic bacterium Methylosinus trichosporium under brackish conditions (salinity 10) near calcite saturation (saturation state (Ω) 1.76 to 2.22). Total alkalinity and the amount of dissolved calcium markedly increased in all experiments containing M. trichosporium cells. After initial system equilibration, similar calcite dissolution rates, ranging between 20.16 (dead cells) and 25.68 μmol L^?1 d^?1 (actively growing cells), were observed. Although concentrations of transparent exopolymer particles declined with time in the presence of actively growing and starving cells, they increased in experiments with dead cells. Scanning electron microscopy images of calcite crystals revealed visible surface corrosion after exposure to live and dead M. trichosporium cells. The results of this study indicate a strong potential for microbial MOx to affect calcite stability negatively, facilitating calcite dissolution. In addition to CO₂ production by methanotrophically active cells, we suggest that the release of acidic or Ca²⁺-chelating organic carbon compounds from dead cells could also enhance calcite dissolution.     

Quantifying the biodegradation of phenanthrene by Pseudomonas stutzeri P16 in the presence of a nonionic surfactant.

The low water solubility of polycyclic aromatic hydrocarbons is believed to limit their availability to microorganisms, which is a potential problem for bioremediation of polycyclic aromatic hydrocarbon-contaminated sites. Surfactants have been suggested to enhance the bioavailability of hydrophobic compounds, but both negative and positive effects of surfactants on biodegradation have been reported in the literature. Earlier, we presented mechanistic models of the effects of surfactants on phenanthrene dissolution and on the biodegradation kinetics of phenanthrene solubilized in surfactant micelles. In this study, we combined the biodegradation and dissolution models to quantify the influence of the surfactant Tergitol NP-10 on biodegradation of solid-phase phenanthrene by Pseudomonas stutzeri P16. Although micellized phenanthrene does not appear to be available directly to the bacterium, the ability of the surfactant to increase the phenanthrene dissolution rate resulted in an overall increase in bacterial growth rate in the presence of the surfactant. Experimental observations could be predicted well by the derived model with measured biokinetic and dissolution parameters. The proposed model therefore can serve as a base case for understanding the physical-chemical effects of surfactants on nonaqueous hydrocarbon bioavailability.     

Regulation of Par6 by extracellular signals

The critical regulator of polarity, Par6, is a key member of a multi-component polarity complex that controls a variety of cellular processes such as asymmetric cell division, establishment of epithelial apico-basal polarity, and polarized cell migration. Recently, we have come to understand how regulation of the Par6 interactome by extracellular cues such as integrin and transforming growth factor beta signalling regulates cell motility and tight junction dissolution. These studies have begun to elucidate how signalling to the polarity complex might regulate pathological processes such as tumour cell invasion and metastasis.     

Challenges with Developing In Vitro Dissolution Tests for Orally Inhaled Products (OIPs)

The purpose of this article is to review the suitability of the analytical and statistical techniques that have thus far been developed to assess the dissolution behavior of particles in the respirable aerodynamic size range, as generated by orally inhaled products (OIPs) such as metered-dose inhalers and dry powder inhalers. The review encompasses all analytical techniques publicized to date, namely, those using paddle-over-disk USP 2 dissolution apparatus, flow-through cell dissolution apparatus, and diffusion cell apparatus. The available techniques may have research value for both industry and academia, especially when developing modified-release formulations. The choice of a method should be guided by the question(s) that the research strives to answer, as well as by the strengths and weaknesses of the available techniques. There is still insufficient knowledge, however, for translating the dissolution data into statements about quality, performance, safety, or efficacy of OIPs in general. Any attempts to standardize a dissolution method for compendial inclusion or compendial use would therefore be premature. This review reinforces and expands on the 2008 stimulus article of the USP Inhalation Ad Hoc Advisory Panel, which "could not find compelling evidence suggesting that such dissolution testing is kinetically and/or clinically crucial for currently approved inhalation drug products."     

Experimental dissolution of a fossil foraminiferal assemblage (Paleocene–Eocene Thermal Maximum,Dababiya, Egypt): Implications for paleoenvironmental reconstructions

Dissolution experiments were carried out on a foraminiferal assemblage from the Paleocene–Eocene Thermal Maximum (PETM) at Dababiya, Egypt, in order to: 1) reveal the effects of differential dissolution on the composition of the foraminiferal assemblage and 2) develop objective criteria for the evaluation of dissolution in foraminiferal assemblages used in early Paleogene paleoenvironmental reconstructions, particularly with respect to neritic Midway-type assemblages from the Paleocene/Eocene transition. Our results confirm two general observations on modern foraminifera: 1) planktic foraminifera are much more vulnerable to dissolution than benthic foraminifera, leading to depressed P/B ratios and 2) dissolution susceptibility differs between size fractions, with the smaller specimens dissolving more rapidly than the bigger ones, leading to a larger average size of the remaining assemblage. Within a size fraction, wall structure and thickness are considered to be the main factors controlling differential dissolution susceptibility. We propose a ranking scheme for taxa with respect to dissolution resistance. Among the benthic taxa, Lenticulina is most resistant, followed by the agglutinated Gaudryina cf. ellisorae and Alabamina midwayensis. Biserial and triserial hyaline taxa and the porcelaneous Spiroloculina sp. are most susceptible to dissolution, whereas rotaliines, such as Cibicidoides and Anomalinoides have an intermediate susceptibility. This implies that mild dissolution of a Midway-type benthic assemblage leads to a relative enrichment in Lenticulina, Gaudryina and rotaliines. Amongst planktic foraminifera, the muricate taxa Acarinina and Morozovella are most resistant, followed by the cancellate Subbotina. The smooth and generally small Globanomalina and Zeauvigerina are least resistant to dissolution. Our data enable to objectively evaluate various degrees of dissolution in benthic and planktic foraminiferal assemblages retrieved from the lower Paleogene Tethyan outcrops. In this way taphonomic artifacts can be readily distinguished from paleoenvironmental signals affecting the primary composition of the assemblages. More generally, we propose that the combined use of foraminiferal numbers, P/B ratio and relative abundances of non-calcareous agglutinated taxa and Lenticulina may provide a powerful proxy for assessing dissolution in hemipelagic assemblages from Cenozoic and upper Cretaceous continental margins. In order to achieve more robust pre-Quaternary paleoenvironmental reconstructions based on quantitative foraminiferal data, application of dissolution proxies, like proposed here, or in slightly modified form, should become a more widely used micropaleontologic procedure. Particularly continental margin studies dealing with major biotic events (e.g. PETM) or employing P/B ratios for sea-level reconstructions should benefit from such an approach.     

Polyelectrolyte nanoparticles with high drug loading enhance the oral uptake of hydrophobic compounds

In the pharmaceutical industry, orally active compounds are required to have sufficient water solubility to enable dissolution within the gastrointestinal tract prior to absorption. Limited dissolution within the gastrointestinal tract often reduces the bioavailability of hydrophobic drugs. To improve gastrointestinal tract dissolution, nonaqueous solvents are often used in the form of emulsions and microemulsions. Here, we show that oil-free polyelectrolyte nanosystems (micellar dispersions and 100-300 nm particles) prepared from poly(ethylenimines) derivatized with cetyl chains and quaternary ammonium groups are able to encapsulate high levels of hydrophobic drug (0.20 g of drug per g of polymer) for over 9 months, as demonstrated using cyclosporine A (log P = 4.3). The polyelectrolytes facilitate the absorption of hydrophobic drugs within the gastrointestinal tract by promoting drug dissolution and by a hypothesized mechanism involving paracellular drug transport. Polyelectrolyte nanoparticle drug blood levels are similar to those obtained with commercial microemulsion formulations. The polyelectrolytes do not promote absorption by inhibition of the P-glycoprotein efflux pump.     

Influence of Postprandial Intragastric Pressures on Drug Release from Gastroretentive Dosage Forms

Despite extensive research in the field of gastroretentive dosage forms, this “holy grail” of oral drug delivery yet remained an unmet goal. Especially under fasting conditions, the reproducible retention of dosage forms in the stomach seems to be an impossible task. This is why such systems are often advised to be taken together with food. But also the postprandial motility can contribute significantly to the failure of gastroretentive dosage forms. To investigate the influence of postprandial pressure conditions on drug release from such systems, we used a novel in vitro dissolution tool, the dissolution stress test device. With the aid of this device, we simulated three different intragastric pressure profiles that may occur after postprandial intake. These transit scenarios were based on recently obtained, postprandial SmartPill® data. The tested systems, Glumetza® 1000 and Madopar® HBS 125, are marketed dosage forms that are based on different approaches to achieve proper gastric retention. All three transit scenarios revealed a highly pressure-sensitive drug release behavior, for both drugs. For Madopar® HBS 125, nearly complete drug release was observed even after early occurring pressures. Glumetza® 1000 seemed to be more resistant to these, most likely due to incomplete wetting of the system. On the contrary to these findings, data from standard dissolution tests using the paddle apparatus displayed controlled drug release for both systems for about 6 h. Based on these results, it can be doubted that established gastroretentive systems stay intact over a longer period of time, even under postprandial conditions.     

Enhanced dissolution of silicate minerals by bacteria at near-neutral pH

Previous studies have shown that various microorganisms can enhance the dissolution of silicate minerals at low (<5) or high (>8) pH. However, it was not known if they can have an effect at near-neutral pH. Almost half of 17 isolates examined in this study stimulated bytownite dissolution at near-neutral pH while in a resting state in buffered glucose. Most of the isolates found to stimulate dissolution also oxidized glucose to gluconic acid. More detailed analysis with one of these isolates suggested that this partial oxidation was the predominant, if not sole, mechanism of enhanced dissolution. Enhanced dissolution did not require direct contact between the dissolving mineral and the bacteria. Gluconate-promoted dissolution was also observed with other silicate minerals such as albite, quartz, and kaolinite.Correspondence to: D.L. Kirchman.