Investigating the molecular structures of solid dispersions by the simulated annealing method

Knowledge of the molecular structures of solid dispersions is vital, yet, despite thousands of reports in this area, it remains unclear. The aim of this research is to investigate the molecular structure of solid dispersions with hot melt preparation method by the simulated annealing method. Simulation results showed linear polymer chains form the random coils under heat and the drug molecules stick on the surface of polymer coils, while drug molecules are dispersed molecularly but irregularly within the amorphous low molecular weight carriers. This research presents more reasonable molecular images of solid dispersions than the existed theory.

The use of binary polymeric networks in stabilising polyethylene oxide solid dispersions

The objective of this study was to determine if a high Tg polymer (Eudragit® S100) could be used to stabilize amorphous domains of polyethylene oxide (PEO) and hence improve the stability of binary polymer systems containing celecoxib (CX). We propose a novel method of stabilizing the amorphous PEO solid dispersion through inclusion of a miscible, high Tg polymer, namely, that can form strong inter-polymer interactions. The effects of inter-polymer interactions and miscibility between PEO and Eudragit S100 are considered. Polymer blends were first manufactured via hot-melt extrusion at different PEO/S100 ratios (70/30, 50/50, and 30/70 wt/wt). Differential scanning calorimetry and dynamic mechanical thermal analysis data suggested a good miscibility between PEO and S100 polymer blends, particularly at the 50/50 ratio. To further evaluate the system, CX/PEO/S100 ternary mixtures were extruded. Immediately after hot-melt extrusion, a single Tg that increased with increasing S100 content (anti-plasticization) was observed in all ternary systems. The absence of powder X-ray diffractometry crystalline Bragg’s peaks also suggested amorphization of CX. Upon storage (40°C/75% relative humidity), the formulation containing PEO/S100 at a ratio of 50:50 was shown to be most stable. Fourier transform infrared studies confirmed the presence of hydrogen bonding between Eudragit S100 and PEO suggesting this was the principle reason for stabilization of the amorphous CX/PEO solid dispersion system.

Co-melt fluidised bed granulation of pharmaceutical powders: Improvements in drug bioavailability

This study investigates the use of co-melt fluidised bed granulation for the agglomeration of model pharmaceutical powders, namely, lactose mono-hydrate, PEG 10000, poly-vinyl pyrolidone and ibuprofen as a model drug. Granulation within the co-melt system was found to follow a nucleationâ??steady growthâ??coating regime profile. Using high molecular weight PEG binder, the granulation mechanism and thus the extent of granulation was found to be significantly influenced by binder viscosity. The compression properties of the granulate within the hot fluidised bed were correlated using a novel high temperature experimental procedure. It was found that the fracture stress and fractural modulus of the materials under hot processing conditions were orders of magnitude lower than those measured under ambient conditions. A range of particle velocities within the granulator were considered based on theoretical models. After an initial period of nucleation, the Stokes deformation number analysis indicated that only velocities within the high shear region of the fluidised bed were sufficient to promote significant granule deformation and therefore, coalescence. The data also indicated that larger granules de-fluidised preventing agglomeration by coalescence. Furthermore, experimental data indicated that dissipation of the viscous molten binder to the surface was the most important factor in the latter stages of the granulation process. From a pharmaceutical perspective the inclusion of the model drug, ibuprofen, combined with PVP in the co-melt process proved to be highly significant. It was found that using DSC analysis on the formulations that the decrease in the heat of fusion associated with the melting of ibuprofen within the FHMG systems may be attributed to interaction between PVP and ibuprofen through inter-molecular hydrogen bonding. This interaction decreases the crystallinity of ibuprofen and facilitates solubilisation and bioavailability within the solid matrix.

Process Analytical Technology Approach on Fluid Bed Granulation and Drying : Identifying Critical Relationships and Constructing the Design Space

Fluid bed granulation is a key pharmaceutical process which improves many of the powder properties for tablet compression. Dry mixing, wetting and drying phases are included in the fluid bed granulation process. Granules of high quality can be obtained by understanding and controlling the critical process parameters by timely measurements. Physical process measurements and particle size data of a fluid bed granulator that are analysed in an integrated manner are included in process analytical technologies (PAT). Recent regulatory guidelines strongly encourage the pharmaceutical industry to apply scientific and risk management approaches to the development of a product and its manufacturing process. The aim of this study was to utilise PAT tools to increase the process understanding of fluid bed granulation and drying. Inlet air humidity levels and granulation liquid feed affect powder moisture during fluid bed granulation. Moisture influences on many process, granule and tablet qualities. The approach in this thesis was to identify sources of variation that are mainly related to moisture. The aim was to determine correlations and relationships, and utilise the PAT and design space concepts for the fluid bed granulation and drying. Monitoring the material behaviour in a fluidised bed has traditionally relied on the observational ability and experience of an operator. There has been a lack of good criteria for characterising material behaviour during spraying and drying phases, even though the entire performance of a process and end product quality are dependent on it. The granules were produced in an instrumented bench-scale Glatt WSG5 fluid bed granulator. The effect of inlet air humidity and granulation liquid feed on the temperature measurements at different locations of a fluid bed granulator system were determined. This revealed dynamic changes in the measurements and enabled finding the most optimal sites for process control. The moisture originating from the granulation liquid and inlet air affected the temperature of the mass and pressure difference over granules. Moreover, the effects of inlet air humidity and granulation liquid feed rate on granule size were evaluated and compensatory techniques used to optimize particle size. Various end-point indication techniques of drying were compared. The ∆T method, which is based on thermodynamic principles, eliminated the effects of humidity variations and resulted in the most precise estimation of the drying end-point. The influence of fluidisation behaviour on drying end-point detection was determined. The feasibility of the ∆T method and thus the similarities of end-point moisture contents were found to be dependent on the variation in fluidisation between manufacturing batches. A novel parameter that describes behaviour of material in a fluid bed was developed. Flow rate of the process air and turbine fan speed were used to calculate this parameter and it was compared to the fluidisation behaviour and the particle size results. The design space process trajectories for smooth fluidisation based on the fluidisation parameters were determined. With this design space it is possible to avoid excessive fluidisation and improper fluidisation and bed collapse. Furthermore, various process phenomena and failure modes were observed with the in-line particle size analyser. Both rapid increase and a decrease in granule size could be monitored in a timely manner. The fluidisation parameter and the pressure difference over filters were also discovered to express particle size when the granules had been formed. The various physical parameters evaluated in this thesis give valuable information of fluid bed process performance and increase the process understanding.

Hot corrosion of γ-Y2Si2O7 in strongly basic Na2CO3 molten salt environment

γ-Y2Si2O7 is a promising candidate both for high temperature structural applications and as thermal barrier coatings due to its unique combination of properties, such as high melting point, good machinability, high thermal stability, low linear thermal expansion coefficient (3.9 × 10-6 K-1, 25-1400 °C) and low thermal conductivity (<3 W/m K above 300 °C). In this work, the hot corrosion behavior of γ-Y2Si2O7 in strongly basic Na2CO3 molten salt at 850-1000 °C for 20 h in flowing air was investigated. In the employed conditions, multi-layer corrosion scales with total thickness less than 90 μm were formed. At 850-900 °C, the outmost layer of the scale was composed of the reprecipitation of Y2O3, the bottom of a Si-rich Na2O·xSiO2 (x > 3.65) melt layer, and the middle of a NaYSiO4 layer. At 1000 °C, the corrosion products turned out to be a mixture of NaY9Si6O26 and Si-rich Na2O·xSiO2 (x > 3.65). In all cases, a thin layer of protective SiO2 formed under the Na2O·xSiO2 melt and protected the bulk material from further corrosion.

Structural, thermal and electrical properties of poly(methyl methacrylate)/CaCu3Ti4O12 composite sheets fabricated via melt mixing

Poly(methyl methacrylate) (PMMA) and CaCu3Ti4O12 (CCTO) composites were fabricated via melt mixing followed by hot pressing technique. These were characterized using X-ray diffraction, thermo gravimetric, thermo mechanical, differential scanning calorimetry, fourier transform infrared (FTIR) and Impedance analyser for their structural, thermal and dielectric properties. Composites were found to have better thermal stability than that of pure PMMA. However, there was no significant difference in the glass transition (T (g) ) temperature between the polymer and the composite. The appearance of additional vibrational frequencies in the range 400-600 cm(-1) in FTIR spectra indicated a possible interaction between PMMA and CCTO. The composite, with 38 vol% of CCTO (in PMMA), exhibited remarkably low dielectric loss at high frequencies and the low-frequency relaxation is attributed to the interfacial polarization/MWS effect. The origin of AC conductivity particularly in the high-frequency region was attributed to the electronic polarization.

Optimisation of granola breakfast cereal manufacturing process by wet granulation and pneumatic conveying

This study has considered the optimisation of granola breakfast cereal manufacturing processes by wet granulation and pneumatic conveying. Granola is an aggregated food product used as a breakfast cereal and in cereal bars. Processing of granola involves mixing the dry ingredients (typically oats, nuts, etc.) followed by the addition of a binder which can contain honey, water and/or oil. In this work, the design and operation of two parallel wet granulation processes to produce aggregate granola products were incorporated: a) a high shear mixing granulation process followed by drying/toasting in an oven. b) a continuous fluidised bed followed by drying/toasting in an oven. In high shear granulation the influence of process parameters on key granule aggregate quality attributes such as granule size distribution and textural properties of granola were investigated. The experimental results show that the impeller rotational speed is the single most important process parameter which influences granola physical and textural properties. After that binder addition rate and wet massing time also show significant impacts on granule properties. Increasing the impeller speed and wet massing time increases the median granule size while also presenting a positive correlation with density. The combination of high impeller speed and low binder addition rate resulted in granules with the highest levels of hardness and crispness. In the fluidised bed granulation process the effect of nozzle air pressure and binder spray rate on key aggregate quality attributes were studied. The experimental results show that a decrease in nozzle air pressure leads to larger in mean granule size. The combination of lowest nozzle air pressure and lowest binder spray rate results in granules with the highest levels of hardness and crispness. Overall, the high shear granulation process led to larger, denser, less porous and stronger (less likely to break) aggregates than the fluidised bed process. The study also examined the particle breakage of granola during pneumatic conveying produced by both the high shear granulation and the fluidised bed granulation process. Products were pneumatically conveyed in a purpose built conveying rig designed to mimic product conveying and packaging. Three different conveying rig configurations were employed; a straight pipe, a rig consisting two 45° bends and one with 90° bend. Particle breakage increases with applied pressure drop, and a 90° bend pipe results in more attrition for all conveying velocities relative to other pipe geometry. Additionally for the granules produced in the high shear granulator; those produced at the highest impeller speed, while being the largest also have the lowest levels of proportional breakage while smaller granules produced at the lowest impeller speed have the highest levels of breakage. This effect clearly shows the importance of shear history (during granule production) on breakage during subsequent processing. In terms of the fluidised bed granulation, there was no single operating parameter that was deemed to have a significant effect on breakage during subsequent conveying. Finally, a simple power law breakage model based on process input parameters was developed for both manufacturing processes. It was found suitable for predicting the breakage of granola breakfast cereal at various applied air velocities using a number of pipe configurations, taking into account shear histories.

Fluidised bed characterisation using Raman spectroscopy: Applications to pharmaceutical processing

This study investigates a model system for potential pharmaceutical materials in fluidised bed processes. In particular, this study proposes a novel use of Raman spectroscopy, which allows in situ measurement of the composition of the material within the fluidised bed in three spatial dimensions and as a function of time. This is achieved by recording Raman spectra from specific volumes of space. The work shows that Raman spectroscopy can be used to provide 3D maps of the concentration and chemical structure of the particles in a fluidised bed within a relatively short (120 s) time window. At the most basic level the technique measures particle density via the intensity of the Raman spectra, however this could be used. More importantly the data are also rich in spectroscopic information on the chemical structure of the fluidised particles which is useful either for monitoring a given granulation process or more generally for the analysis of the dynamics of the airflow if the data were incorporated into an appropriate model. The technique has the potential to give detailed in situ information on how the structure and composition of the granules/powders within the fluidised bed (dryer or granulator) vary with the position and evolve with time. (c) 2007 Elsevier Ltd. All rights reserved.

Major and trace element concentration of melt inclusions from Zhupanovsky volcano, Kamchatka

The paper presents data on naturally quenched melt inclusions in olivine (Fo 69-84) from Late Pleistocene pyroclastic rocks of Zhupanovsky volcano in the frontal zone of the Eastern Volcanic Belt of Kamchatka. The composition of the melt inclusions provides insight into the latest crystallization stages (~70% crystallization) of the parental melt (~46.4 wt % SiO2, ~2.5 wt % H2O, ~0.3 wt % S), which proceeded at decompression and started at a depth of approximately 10 km from the surface. The crystallization temperature was estimated at 1100 ± 20°C at an oxygen fugacity of deltaFMQ = 0.9-1.7. The melts evolved due to the simultaneous crystallization of olivine, plagioclase, pyroxene, chromite, and magnetite (Ol: Pl: Cpx : (Crt-Mt) ~ 13 : 54 : 24 : 4) along the tholeiite evolutionary trend and became progressively enriched in FeO, SiO2, Na2O, and K2O and depleted in MgO, CaO, and Al2O3. Melt crystallization was associated with the segregation of fluid rich in S-bearing compounds and, to a lesser extent, in H2O and Cl. The primary melt of Zhupanovsky volcano (whose composition was estimated from data on the most primitive melt inclusions) had a composition of low-Si (~45 wt % SiO2) picrobasalt (~14 wt % MgO), as is typical of parental melts in Kamchatka and other island arcs, and was different from MORB. This primary melt could be derived by ~8% melting of mantle peridotite of composition close to the MORB source, under pressures of 1.5 ± 0.2 GPa and temperatures 20-30°C lower than the solidus temperature of 'dry' peridotite (1230-1240°C). Melting was induced by the interaction of the hot peridotite with a hydrous component that was brought to the mantle from the subducted slab and was also responsible for the enrichment of the Zhupanovsky magmas in LREE, LILE, B, Cl, Th, U, and Pb. The hydrous component in the magma source of Zhupanovsky volcano was produced by the partial slab melting under water-saturated conditions at temperatures of 760-810°C and pressures of ~3.5 GPa. As the depth of the subducted slab beneath Kamchatkan volcanoes varies from 100 to 125 km, the composition of the hydrous component drastically changes from relatively low-temperature H2O-rich fluid to higher temperature H2O-bearing melt. The geothermal gradient at the surface of the slab within the depth range of 100-125 km beneath Kamchatka was estimated at 4°C/km.

Thermal strain in the mushy zone related to hot tearing

A volume-averaged two-phase model addressing the main transport phenomena associated with hot tearing in an isotropic mushy zone during solidification of metallic alloys has recently been presented elsewhere along with a new hot tearing criterion addressing both inadequate melt feeding and excessive deformation at relatively high solid fractions. The viscoplastic deformation in the mushy zone is addressed by a model in which the coherent mush is considered as a porous medium saturated with liquid. The thermal straining of the mush is accounted for by a recently developed model taking into account that there is no thermal strain in the mushy zone at low solid fractions because the dendrites then are free to move in the liquid, and that the thermal strain in the mushy zone tends toward the thermal strain in the fully solidified material when the solid fraction tends toward one. In the present work, the authors determined how variations in the parameters of the constitutive equation for thermal strain influence the hot tearing susceptibility calculated by the criterion. It turns out that varying the parameters in this equation has a significant effect on both liquid pressure drop and viscoplastic strain, which are key parameters in the hot tearing criterion. However, changing the parameters in this constitutive equation will result in changes in the viscoplastic strain and the liquid pressure drop that have opposite effects on the hot tearing susceptibility. The net effect on the hot tearing susceptibility is thus small.

Upgrading of fast pyrolysis oils by hot filtration

A hot filtration unit downstream of a 1kg/h fluidised bed fast pyrolysis reactor was designed and built. The filter unit operates at 450oC and consists of 1 exchangeable filter candle with reverse pulse cleaning system. Hot filtration experiments up to 7 hours were performed with beech wood as feedstock. It was possible to produce fast pyrolysis oils with a solid content below 0.01 wt%. The additional residence time of the pyrolysis vapours and secondary vapour cracking on the filter cake caused an increase of non-condensable gases at the expense of organic liquid yield. The oils produced with hot filtration showed superior quality properties regarding viscosity than standard pyrolysis oils. The oils were analysed by rotational viscosimetry and gel permeation chromatography before and after accelerated aging. During filtration the separated particulates accumulate on the candle surface and build up the filter cake. The filter cake leads to an increase in pressure drop between the raw gas and the clean gas side of the filter candle. At a certain pressure drop the filter cake has to be removed by reverse pulse cleaning to regenerate the pressure drop. The experiments showed that successful pressure drop recovery was possible during the initial filtration cycles, thereafter further cycles showed minor pressure drop recovery and therefore a steady increase in differential pressure. Filtration with pre-coating the candle to form an additional layer between the filter candle and cake resulted in total removal of the dust cake.