Examining solution and solid state composition for the solution mediated polymorphic transformation of carbamazepine and piracetam

peer-reviewedSolution mediated polymorphic transformations (SMPT) of the pharmaceutical compounds carbamazepine and piracetam have been investigated. Seeded transformation experiments were performed, and the solution concentration was monitored by in situ infra-red spectroscopy using a calibration free method. Solid samples were also taken over time, and the percentage of metastable and stable polymorphic phases were determined using off line quantitative powder X-ray diffraction analysis. Solution and solid state data were compared for each compound. In the case of carbamazepine, the SMPT from FI to FIII was identified as being controlled by the growth of the stable FIII polymorph. For piracetam, the SMPT was also identified as being controlled by growth of the stable polymorph, but with a more considerable induction time for nucleation of the stable phase. This paper demonstrates how the rate determining steps of the SMPT can be identified if both solution and solid phase data are recorded. The results are compared with other studies reported in the literature and rationalized into four principal scenarios

Analysis of mesoscale effects in high-shear granulation through a computational fluid dynamics-population balance coupled compartment model

There is a need for mesoscale resolution and coupling between flow-field information and the evolution of particle properties in high-shear granulation. We have developed a modelling framework that compartmentalizes the high-shear granulation process based on relevant process parameters in time and space. The model comprises a coupled-flow-field and population-balance solver and is used to resolve and analyze the effects of mesoscales on the evolution of particle properties. A Diosna high-shear mixer was modelled with microcrystalline cellulose powder as the granulation material. An analysis of the flow-field solution and compartmentalization allows for a resolution of the stress and collision peak at the impeller blades. Different compartmentalizations showed the importance of resolving the impeller region, for aggregating systems and systems with breakage. An independent study investigated the time evolution of the flow field by changing the particle properties in three discrete steps that represent powder mixing, the initial granulation stage mixing and the late stage granular mixing. The results of the temporal resolution study show clear changes in collision behavior, especially from powder to granular mixing, which indicates the importance of resolving mesoscale phenomena in time and space

Global monitoring of fluidized-bed processes by means of microwave cavity resonances

We present an electromagnetic measurement system for monitoring of the effective permittivity in closed metal vessels, which are commonly used in the process industry. The measurement system exploits the process vessel as a microwave cavity resonator and the relative change in its complex resonance frequencies is related to the complex effective permittivity inside the vessel. Also, thermal expansion of the process vessel is taken into account and we compensate for its influence on the resonance frequencies by means of a priori information derived from a set of temperature measurements. The sensitivities, that relate the process state to the measured resonance frequencies, are computed by means of a detailed finite element model. The usefulness of the proposed measurement system is successfully demonstrated for a pharmaceutical fluidized-bed process, where the water and solid contents inside the process vessel is of interest

Integrated Initiating Event Performance Indicators

The U.S. Nuclear Regulatory Commission Industry Trends Program (ITP) collects and analyses industry-wide data, assesses the safety significance of results, and communicates results to Congress and other stakeholders. This paper outlines potential enhancements in the ITP to comprehensively cover the Initiating Events Cornerstone of Safety. Future work will address other cornerstones of safety. The proposed Tier 1 activity involves collecting data on ten categories of risk-significant initiating events, trending the results, and comparing early performance with prediction limits (allowable numbers of events, above which NRC action may occur). Tier 1 results would be used to monitor industry performance at the level of individual categories of initiating events. The proposed Tier 2 activity involves integrating the information for individual categories of initiating events into a single risk-based indicator, termed the Baseline Risk Index for Initiating Events or BRIIE. The BRIIE would be evaluated yearly and compared against a threshold. BRIIE results would be reported to Congress on a yearly basis

Estimating Loss-of-Coolant Accident Frequencies for the Standardized Plant Analysis Risk Models

The U.S. Nuclear Regulatory Commission maintains a set of risk models covering the U.S. commercial nuclear power plants. These standardized plant analysis risk (SPAR) models include several loss-of-coolant accident (LOCA) initiating events such as small (SLOCA), medium (MLOCA), and large (LLOCA). All of these events involve a loss of coolant inventory from the reactor coolant system. In order to maintain a level of consistency across these models, initiating event frequencies generally are based on plant-type average performance, where the plant types are boiling water reactors and pressurized water reactors. For certain risk analyses, these plant-type initiating event frequencies may be replaced by plant-specific estimates. Frequencies for SPAR LOCA initiating events previously were based on results presented in NUREG/CR-5750, but the newest models use results documented in NUREG/CR-6928. The estimates in NUREG/CR-6928 are based on historical data from the initiating events database for pressurized water reactor SLOCA or an interpretation of results presented in the draft version of NUREG-1829. The information in NUREG-1829 can be used several ways, resulting in different estimates for the various LOCA frequencies. Various ways NUREG-1829 information can be used to estimate LOCA frequencies were investigated and this paper presents two methods for the SPAR model standard inputs, which differ from the method used in NUREG/CR-6928. In addition, results obtained from NUREG-1829 are compared with actual operating experience as contained in the initiating events database

Cardiopulmonary involvement in Puumala hantavirus infection

Abstract Background: Hantavirus infections cause potentially life-threatening disease in humans world-wide. Infections with American hantaviruses may lead to hantavirus pulmonary syndrome characterised by severe cardiopulmonary distress with high mortality. Pulmonary involvement in European Puumala hantavirus (PUUV) infection has been reported, whereas knowledge of potential cardiac manifestations is limited. We aimed to comprehensively investigate cardiopulmonary involvement in patients with PUUV-infection

An Overview of the Reliability and Availability Data System (RADS)

The Reliability and Availability Data System (RADS) is a database and analysis code, developed by the Idaho National Engineering and Environmental Laboratory (INEEL) for the U.S. Nuclear Regulatory Commission (USNRC). The code is designed to estimate industry and plant-specific reliability and availability parameters for selected components in risk-important systems and initiating events for use in risk-informed applications. The RADS tool contains data and information based on actual operating experience from U.S. commercial nuclear power plants. The data contained in RADS is kept up-to-date by loading the most current quarter's Equipment Performance and Information Exchange (EPIX) data and by yearly lods of initiating event data from licensee event reports (LERS). The reliability parameters estimated by RADS are (1) probability of failure on demand, (2) failure rate during operation (used to calculate failure to run probability) and (3) time trends in reliability parameters

Experimental Determination of the Key Heat Transfer Mechanisms in Pharmaceutical Freeze Drying

Freeze-drying is often used in manufacture of pharmaceuticals to remove a solvent in such a way that the sensitive molecular structure of the active substance of a drug is least disturbed, and to provide a sterile powder that can be quickly and completely rehydrated. In this work heat transfer rates in a laboratory-scale freeze-dryer have been measured to investigate the contribution of different heat transfer modes. Pure water was partially dried under low-pressure conditions and sublimation rates were determined gravimetrically. The heat transfer rates were observed to be independent of the separation distance between a product vial and a dryer shelf and linearly dependent on the pressure in the free molecular limit. However, under higher pressures the heat transfer rates were independent of pressure and inversely proportional to the separation distance. Previous heat transfer studies in conventional freeze-drying cycles have attributed a dominant portion of the total heat transfer to radiation, the rest to conduction, whereas the convection has been found insignificant. While the measurements revealed the significance of the radiative and gas conduction components, the convective component was found to be comparable to the gas conduction contribution at pressures greater than 100mTorr. The current investigation suggests that the convective component of the heat transfer cannot be ignored at typical laboratory-scale freeze-drying conditions

Atlantic bluefin tuna spawn at suboptimal temperatures for their offspring

Life-history traits such as spawning migrations and timing of reproduction are adaptations to specific environmental constraints and seasonal cycles in many organisms’ annual routines. In this study we analyse how offspring fitness constrains spawning phenology in a large migratory apex predator, the Atlantic bluefin tuna. The reproductive schedule of Atlantic bluefin tuna varies between spawning sites, suggesting plasticity to local environ- mental conditions. Generally, temperature is considered to be the main constraint on tuna spawning phenology. We combine evidence from long- term field data, temperature-controlled rearing experiments on eggs and larvae, and a model of egg fitness, and show that Atlantic bluefin tuna do not spawn to optimize egg and larval temperature exposure. The timing of spawning leads to temperature exposure considerably lower than optimal at all spawning grounds across the Atlantic Ocean. The early spawning is constrained by thermal inhibition of egg hatching and larval growth rates, but some other factors must prevent later spawning. Matching offspring with ocean productivity and the prey peak might be an important driver for bluefin tuna spawning phenology. This finding is important for predictions of reproductive timing in future climate warming scenarios for bluefin tuna.Versión del edito

Pelagic habitat and offspring survival in the eastern stock of Atlantic bluefin tuna

In this manuscript, we test how an understanding of geographical variation in larval fitness in relation to temperature and habitat use could be a useful method to improve our understanding of recruitment and develop better indices of annual recruitment. On the basis of the assumption that growth and survival of tuna larvae are influenced by temperature, we have developed a potential larval survival index for Atlantic bluefin tuna (Thunnus thynnus) by combining empirical data from egg and larval rearing experiments with temperature data from hydrodynamic models. The experiments were designed to test the full range of temperature variability that bluefin larvae would experience in the field and provide a mechanistic understanding of the processes driving egg and larval survival. We then developed a biological model using the temperature-related growth expressions and a size-dependent survival function for the larvae. The biological model was applied to a time-series of spatially explicit temperature data for the western Mediterranean from the Strait of Gibraltar to 6 E, which includes the major recognized bluefin tuna eastern stock spawning area, the Balearic Sea. Our results show that areas with high probabilities of larval survival coincide with those that would be considered as optimal based on other data sources (ichthyoplankton surveys, spawning female locations from commercial fisheries data, and adult tracking data). However, evidence of spawning has been found in areas with suboptimal thermal habitats, as predicted by the model, which we discuss regarding sampling effort and salinity fronts. There was a good match between the survival index and recruitment indices from standardized CPUE fisheries data. These results have implications for our understanding of the recruitment process of the eastern stock of Atlantic bluefin tuna, since they suggest that the combined effects of temporal and spatial variability of the environment drive recruitment success, which has important implications for the management of the species.Versión del editor2,27