Enabling formulations are growing in popularity due to the large number of drugs within the pharmaceutical development pipeline that possess poor water solubility. These sophisticated formulation techniques can increase the solubility of the drug in aqueous media and/or aid in their dissolution. Amorphous solid dispersions (ASDs) are of particular interest due to their ability to generate highly supersaturated solutions upon dissolution. Typically, an ASD consists of amorphous drug homogenously blended with an amphiphilic polymer. The polymer has several roles including to facilitate drug release, as well as to inhibit crystallization of the drug from the solid matrix and from the supersaturated solution generated following dissolution. A phenomenon termed liquid-liquid phase separation (LLPS) or glass-liquid phase separation (GLPS) can occur during ASD dissolution when the amorphous solubility is exceeded. Here the drug attains its maximum thermodynamic activity in solution with the excess drug forming a second phase consisting of colloidal amorphous aggregates. It has been hypothesized that the presence of the colloidal amorphous aggregates could be advantageous in vivo since they can act as a drug reservoir and subsequently maintain the drug at its maximum thermodynamic activity in the gastro-intestinal fluid following solution depletion arising from permeation across the gastrointestinal membrane. However, there are few in vivo studies which test this hypothesis. If colloids form, the polymer must also inhibit crystallization from the drug-rich phase. Hence, the polymer has many roles during ASD dissolution making rational polymer selection for ASD formulation a complex process. While many studies, both past and present, probe drug release during dissolution, a limited number of studies address a mechanistic understanding of the polymer role during dissolution. The purpose of this study was to 1) investigate the interplay of the polymer’s ability to inhibit crystallization (thought to be primarily through hydrophobic interactions) and to facilitate drug release (via hydrophilic interaction with the aqueous media) on ASD performance and 2) determine the in vivo relevance of colloidal amorphous aggregates. Herein, a preliminary correlation was established between in vitro diffusion cell experiments and the amount of drug absorbed in rats. Further, it was found that rapid drug release through use of a relatively hydrophilic polymer is essential, and that the best crystallization inhibitors may be too hydrophobic to achieve adequate release. Therefore, a polymer needs to be an adequate crystallization inhibitor, but be able to release the drug upon oral administration. The implications from this study provides the necessary foundation for assessing ASD phase behavior and performance in vitro in order to make improved in vivo predictions. Ultimately, this research is expected to improve the speed of life-saving drugs progressing through the development pipeline and reduce drug development costs by reducing the need for animal testing.

Proteins are commonly found molecules in biological systems: our fingernails, hair, skin, blood, muscle, and eyes are all made of protein. Many diseases simply arise because a protein is not folded properly. Therefore, knowledge of protein structure is considered a prerequisite to understanding protein function and, by extension, a cornerstone for drug design and for the development of therapeutic agents. Protein crystallography is a tool that allows structural biologists to discern protein structures to the highest degree of detail possible in three dimensions. The recording of x-ray diffraction data from the protein crystal is a central part of protein crystallography. As such, an important challenge in protein crystallography research is to design x-ray detectors to accurately determine the structures of proteins. This research presents the design and evaluation of a solid-state large area at panel detector for protein crystallography based on an amorphous selenium (a-Se) x-ray sensitive photoconductor operating in avalanche mode integrated with an amorphous silicon (a-Si:H) charge storage and readout pixel. The advantages of the proposed detector over the existing imaging plate (IP) and charge coupled device (CCD) detectors are large area, high dynamic range coupled to single x-ray detection capability, fast readout, high spatial resolution, and inexpensive manufacturing process. The requirement of high dynamic range is crucial for protein crystallography since both weak and strong diffraction spots need to be imaged. The main disadvantage of a-Si:H thin film transistor (TFT) array is its high electronic noise which prohibits quantum noise limited operation for the weak diffraction spots. To overcome the problem, the x-ray to charge conversion gain of a-Se is increased by using its internal avalanche multiplication gain. Since the detector can be made approximately the same size as the diffraction pattern, it eliminates the need for image demagnification. The readout time of the detector is usually within the ms range, so it is appropriate for crystallographic application. The optimal detector parameters (such as, detector size, pixel size, thickness of a-Se layer), and operating parameters (such as, electric field across the a-Se layer) are determined based on the requirements for protein crystallography. A complete model of detective quantum efficiency (DQE) of the detector is developed to predict and optimize the performance of the detector. The performance of the detector is evaluated in terms of readout time (< 1 s), dynamic range (~10^5), and sensitivity (~ 1 x-ray photon), thus validating the detector's efficacy for protein crystallography. The design of an in-house a-Si:H TFT pixel array for integration with an avalanche a-Se layer is detailed. Results obtained using single pixel are promising and highlight the feasibility of a-Si:H pixels coupled with avalanche a-Se layer for protein crystallography application.

Proteins are commonly found molecules in biological systems: our fingernails, hair, skin, blood, muscle, and eyes are all made of protein. Many diseases simply arise because a protein is not folded properly. Therefore, knowledge of protein structure is considered a prerequisite to understanding protein function and, by extension, a cornerstone for drug design and for the development of therapeutic agents. Protein crystallography is a tool that allows structural biologists to discern protein structures to the highest degree of detail possible in three dimensions. The recording of x-ray diffraction data from the protein crystal is a central part of protein crystallography. As such, an important challenge in protein crystallography research is to design x-ray detectors to accurately determine the structures of proteins. This research presents the design and evaluation of a solid-state large area at panel detector for protein crystallography based on an amorphous selenium (a-Se) x-ray sensitive photoconductor operating in avalanche mode integrated with an amorphous silicon (a-Si:H) charge storage and readout pixel. The advantages of the proposed detector over the existing imaging plate (IP) and charge coupled device (CCD) detectors are large area, high dynamic range coupled to single x-ray detection capability, fast readout, high spatial resolution, and inexpensive manufacturing process. The requirement of high dynamic range is crucial for protein crystallography since both weak and strong diffraction spots need to be imaged. The main disadvantage of a-Si:H thin film transistor (TFT) array is its high electronic noise which prohibits quantum noise limited operation for the weak diffraction spots. To overcome the problem, the x-ray to charge conversion gain of a-Se is increased by using its internal avalanche multiplication gain. Since the detector can be made approximately the same size as the diffraction pattern, it eliminates the need for image demagnification. The readout time of the detector is usually within the ms range, so it is appropriate for crystallographic application. The optimal detector parameters (such as, detector size, pixel size, thickness of a-Se layer), and operating parameters (such as, electric field across the a-Se layer) are determined based on the requirements for protein crystallography. A complete model of detective quantum efficiency (DQE) of the detector is developed to predict and optimize the performance of the detector. The performance of the detector is evaluated in terms of readout time (< 1 s), dynamic range (~10^5), and sensitivity (~ 1 x-ray photon), thus validating the detector's efficacy for protein crystallography. The design of an in-house a-Si:H TFT pixel array for integration with an avalanche a-Se layer is detailed. Results obtained using single pixel are promising and highlight the feasibility of a-Si:H pixels coupled with avalanche a-Se layer for protein crystallography application.

An onset coarsening-coalescence event based on the incubation time of cylindrical mesopore formation and a significant decrease of specific surface area by a certain fraction relative to the dry pressed samples was determined by N2 adsorption-desorption hysteresis isotherm for amorphous SiO2 nanoparticles (ca. 40 nm in size). In the temperature range of 1150-1300oC, the nanoparticles with binder (PVA) additive underwent onset sintering coupled with coarsening-coalescence without appreciable crystallization. The apparent activation energy of such a rapid process for amorphous SiO2 nanoparticles was estimated as 177 ¡Ó 31.5 kJ/mol, based on 30% change of specific surface area. As a comparison, in much lower temperature range of 600-900oC, the amorphous Zn2SiO4 nanoparticles underwent onset sintering coupled with coarsening-coalescence accompanied more or less with the formation of ZnO The apparent activation energy of such a rapid process for a amorphous Zn2SiO4 was estimated as 105 ¡Ó 3.8 kJ/mol based on 50% change of specific surface area. The minimum temperatures for sintering/coarsening/coalescence of the amorphous SiO2 and Zn2SiO4 are 1120¢J and 635oC, respectively based on the extrapolation of steady specific surface area reduction rates to null. PLA fragmentation of amorphous and nearly spherical SiO2 nanoparticles (40 nm in size) in water (i.e. PLAL process) with optional NaCl addition was conducted under Q-switch mode (532 nm, 400 mJ per pulse) having laser focal point fixed at ca. 10 mm beneath the water level for an accumulation time of 20 and 30 min at 10 Hz. The 532 nm laser incidence suffered little water absorption and was effective to produce irregular shaped amorphous nanocondensates as small as 10nm~20nm in diameter with accompanied change of medium range order (MRO) as indicated by single rather than two broad x-ray diffractions at low 2theta angle. Whereas the Na+ uptake in the amorphous silica from the salty water account for a lower wave number of FTIR bands. The combined effects of nanosize, MRO change and H+ -signature may cause a lower minimum band gap of the amorphous products (analogous to opal-A) which become partially crystallized as £]-cristobalite (analogous to opal-CT) with additional £\-tridymite when Na+ is present.

This work explores two very different structural systems: n-type hydrogenated amorphous silicon (a-Si:H) and gold nanoparticles (AuNPs) suspended in a matrix of organic ligands. For a-Si:H, examination of the gas-phase concentration of dopant (1-6% PH3/SiH4) and argon diluent effects includes the temperature dependent conductivity, low-frequency electronic noise, and Raman spectroscopy to examine structure. It is found that a-Si:H samples grown with high dopant concentration or with argon dilution exhibit an anomalous hopping conduction mechanism with an exponent of p=0.75. An experimental approach is used to determine correlations between conduction parameters, such as the pre-exponential factor and the characteristic temperature, rather than an analysis of existing models to explain the anomalous conduction. From these results, the anomalous conduction is a result of a change in the shape of the density of states and not a shift of the Fermi level with dopant. Additionally, it is found that argon dilution increases the carrier mobility, reduces the doping efficiency, and causes a degradation of the short-range order. With AuNPs, a comparison of temperature dependent conductivity and low-frequency noise shows that the temperature coefficient of resistance (TCR) is independent of the length of interparticle distance while the noise magnitude decreases.

The success of an amorphous solid dispersion (ASD) formulation, consisting of a homogeneous molecular dispersion of drug and polymer, relies on its ability to create and maintain a supersaturated solution. However, supersaturated solutions are metastable and prone to crystallization. In solution, crystals are expected to serve as a template for crystal growth, depleting achieved supersaturation. Thus, in an ASD product, ideally no crystallinity should be present. However, technical challenges exist in both processing and characterization to routinely ensure this is achieved. The presented studies follow the process design, characterization, and dissolution performance of hot melt extruded amorphous solid dispersions, seeking insight into the significance of critical quality attributes of resulting extrudates, namely residual crystallinity and thermal degradation.<div>Selection of hot melt extrusion (HME) processing conditions to prepare ASDs is governed by thermodynamic and kinetic attributes of the drug and polymer system. Mapping the temperature-composition phase diagram to HME processing conditions provides a processing design strategy to prevent residual crystallinity while simultaneously avoiding thermal degradation. Through processing temperatures below the drug’s melting point (Tm) and above the formulation critical temperature (Tc), fully amorphous systems could be generated if sufficient kinetics were provided. The utility of thermogravimetric analysis was critically examined for prediction of the chemical stability processing window for HME formulations.<br></div><div>For characterization and product performance characterization, residual crystalline content in HME ASDs can be anticipated and tailored to various levels. Several HME ASDs were characterized by a range of analytical techniques, highlighting the sensitivity of available techniques to qualitatively or quantitatively detect crystalline content (depending on limitations which stem from properties of the instrument or sample). Transmission electron microscopy (TEM) was found to identify low levels of crystallinity not observed by other technique and provide insight into crystal dissolution mechanisms. A defect-site driven dissolution and fragmentation model was suggested, and supported by a Monte Carlo simulation, underscoring that crystal defect sites, either intrinsic to the crystals or formed during processing, expedite dissolution rates and generation of new surfaces for dissolution.<br></div><div>Non-sink dissolution was performed for indomethacin/PVPVA HME ASD samples with residual crystallinity ranging from 0-25% crystalline content. Due to effective crystal growth inhibition by the polymer, crystals had little impact on dissolution performance. Achieved supersaturation was reduced approximately by the level of crystallinity present, i.e. a lost solubility advantage. These studies have significance for HME processing design and risk assessment of crystallinity within ASD formulations.<br></div>

Amorphous metals have gained a lot of attention since its introduction in the 1960s, and the usage and knowledge are growing rapidly. The underlying reason for this trend is the desire to utilize these materials unique combinationof properties. New manufacturing techniques such as amorphous metal moulding (AMM) have enabled themanufacture of larger and more complex amorphous products in larger production volumes than before. In order to successfully implement AMM into the development and production of products, knowledge regarding its strengths and weaknesses, as well as how to relate to it when designing parts to be manufactured using the technology is needed. The objective in this master thesis was to investigate the implementation and potential gains of using amorphous alloys made with AMM, both in theory using academic research, and in practice by redesigning existing productsto be manufactured using the technology. Processes how to identify products that are suitable to manufacture and then design them for AMM were formulated. The academic research was compiled in a literature study and served as a base together with a dialog with a manufacturer to formulate these processes. The processes were then used toredesign the current fuze holder designs to accommodate the new manufacturing requirements posed by AMM. A 3D-model was designed and later analysed to provide a design with sufficient strength. It was shown that substantial volume reductions were possible but at a penalty of increased weight and cost, due to the higher density and material cost of the amorphous alloys compared to the current aluminium alloy. Furthermore, as of this writing, with the limitations that exists with the technology, it was not possible to design the fuze holders to fulfil all requirements that exist for AMM. But a small piston that is currently made of steel was shown to be possible to manufacture using AMM, which resulted in both reduced volume and weight, but also cost. In order toverify the results in this study and to progress further, a prototype should be manufactured and tested. This in order to verify both the integrity of the analysis, but also to verify that the design meets the other requirements posed onfuze holders, such as environmental and functional demands. / Amorfa metaller har fått mycket uppmärksamhet sedan deras introduktion under 1960-talet och användandet och kunskaperna ökar i snabb takt. Den bakomliggande orsaken för denna trend är viljan att utnyttja dessa materials unika kombination av egenskaper. Nya tillverkningstekniker såsom amorf metallgjutning (AMM) har möjliggjort tillverkningen av större och mer komplexa amorfa produkter i större produktionsvolymer än tidigare. För att framgångsrikt implementera AMM till utvecklingen och produktionen av produkter måste kunskap kring dess styrkor och svagheter utvärderas. Men även kunskap hur man ska förhålla sig till den när man konstruerar AMM detaljer. Målet med detta examensarbete var att undersöka genomförandet och potentiella fördelar av att använda amorfametaller gjorda med AMM både teoretiskt via akademisk forskning och i praktiken genom att omkonstruera en existerande produkt för att tillverkas med teknologin. Processer hur man identifierar produkter som är lämpliga att tillverka med AMM och sedan hur dessa ska konstrueras formulerades. Den akademiska litteraturen samlades i en litteraturstudie och användes tillsammans med en dialog med en tillverkare till att formulera dessa processer. Processerna användes sedan för att omkonstruera den nuvarande tändrörshållardesigner för att tillgodose de nya tillverkningskraven som uppstår från AMM. En 3D-modell konstruerades och analyserades sedan för att säkerställaen konstruktion med tillräcklig hållfasthet. Det visades att betydande volymminskningar var möjliga men till en följd av ökad vikt och kostnad på grund avden amorfa legeringens högre densitet och kostnad jämfört med nuvarande aluminiumlegering. Vidare demonstrerades att det vid skrivande stund inte var möjligt att tillverka tändrörshållarna med AMM på grund av teknologins nuvarande begränsningar. Dock visades att en liten kolv som i dagsläget tillverkas i stål kunde tillverkasmed AMM vilket resulterade i en minskning av volymen, massan och kostnaden. För att bekräfta resultaten i denna studie samt för att gå vidare bör en prototyp tillverkas och testas. Detta för att bekräfta både analysens integritet men även för att bekräfta att konstruktionen når upp till de andra kraven som ställs på tändrörshållare såsom miljö- och funktionskrav.

No description available.

Thesis: Metal. E., Massachusetts Institute of Technology, Department of Materials Science and Engineering, 1978 / Includes bibliographical references. / Metal. E. / Metal. E. Massachusetts Institute of Technology, Department of Materials Science and Engineering

Equiatomic composition of Ni and Ti was cryomilled with varying milling times to create Ni-Ti lamella structures with average spacings of 50 nm, 470 nm, and 583 nm in powder particles to vary the interfacial surface area per volume. These surfaces form interfaces for diffusion that are essential for solid state amorphization during low temperature annealing. To compare solid state amorphization in a relatively defect free multilayer system, elemental Ni and Ti were deposited by electron beam physical vapor deposition on titanium plates with comparable spacing as above. Both milled and deposited multilayers were annealed between 225 and 350°C for up to 50 hours. X-ray diffraction characterization and in situ annealing was conducted on cryomilled and deposited multilayers of Ni-Ti. Based on this characterization, an amorphization model based on the Johnson-Mehl-Avrami nucleation and growth equation has been established to predict the amorphization of both cryomilled and deposited multilayers. Cryomilled powders experienced much larger amorphization rates during annealing than that of deposited multilayer structures, for all layer spacings. This superior amorphization is seen despite the formation of amorphous phase during the milling process; the amount of which increases with increasing milling time. The difference in amorphization rates between cryomilled and deposited multilayers is attributed to excess driving force due to the extensive preexisting defects in the powders caused by cryomilling. Serial 3D reconstruction of cryomilled Ni-Ti powders was done by scanning electron microscopy and focused ion beam. Through 3D reconstruction it was observed that a random and non-linear lamella structure has been formed in cryomilled powders. Furthermore, lamellar spacing was seen to become smaller with increased milling time while at the same time becoming more homogeneous through the material's volume. 3D reconstruction of cryomilled Ni-Ti offers a unique insight into the microstructures and surface areas of cryomilled powder particles that has never been accomplished. / Ph. D.