Browsing by Subject "amorphous"
Now showing items 1-9 of 9
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(2022)In this thesis, sputtering of several low- and high-index tungsten surface crystal directions are investigated. The molecular dynamics study is conducted using the primary knock-on atom method, which allows for an equal energy deposition for all surface orientations. The energy is introduced into the system on two different depths, on the surface and on a depth of 1 nm. Additionally to the sputtering yield of each surface orientation, the underlying sputtering process is investigated. Amorphous target materials are often used to compare sputtering yields of polycrystalline materials with simulations. Therefore, an amorphous surface is also investigated to compare it's sputtering yield and process with crystalline surface orientations. When the primary knock-on atom was placed on the surface all surface orientations had a cosine shaped angular distribution with little variation in the sputtering yield for most of the surface orientations. Linear collision sequences were observed to have a large impact on the sputtering yield when the energy was introduced deeper inside the material. In these linear collision sequences the recoils are traveling along the most close packed atom rows in the material. The distance from the origin of the collision cascade to the surface in the direction of the most close packed row is therefore crucial for the sputtering yield of the surface. Surface directions with high angles between this direction and the surface normal hence show a reduction in the sputtering yield. The amorphous material had a little lower sputtering yield than the crystalline materials when the primary knock-on atoms was placed on the surface whereas the difference rose into several orders of magnitude when the energy was given at 1 nm. It is impossible for linear collision sequences to propagate long distances in the amorphous material and therefore the angular distribution in both cases is cosine shaped. The amorphous material has no long range order and was therefore unable to reproduce the linear collision sequences, which are characteristic for the crystalline materials. The difference in the sputtering yield was hence up to several orders of magnitude as a result when the energy was introduced at 1 nm depth.
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(2012)Solid materials can exist in two major forms: in crystalline or amorphous form. Amorphous form is defined as no long term order existing in solid structure in molecular scale. Amorphous materials have different physicochemical properties compared crystalline forms of same substance. Amorphous materials doesn't have sharp melting point as crystalline materials. When heated above so called glass transition temperature amorphous materials become rubbery (plasticization) and when cooled below they become glassy (hard and brittle). Amorphous forms can also have different dissolution properties which makes them useful in formulation of poorly soluble drugs. Amorphous forms are less stable compared to crystalline form. That's due amount of free energy stored in it's structures. Amorphous materials can be manufactured in many ways including quench cooling, hot-melt-extrusion, spray drying and lyophilisation (freeze drying). In experimental section effect of grinding method in properties of amorphous indomethacin was studied. Amorphous indomethacin was prepared by quenching of melt in liquid nitrogen. Properties of amorphous indomethacin was studied by x-ray powder diffraction and differential scanning calorimetry. Measurements were performed in different time stamps varied form 0 to 92 days. Measured properties were crystalline content, glass transition temperature, change in heath capacity, heat of crystallization, heat of melting and melting points of crystallized forms. Calorimetry data was recorded only from totally amorphous samples. It can be seen in results that different patches are not comparable statistically but when comparing room temperature ground and liquid nitrogen ground samples to each other differences can be found in every set. Difference is observed in initial time of crystallization (time when crystallinity can be measured first time) and in thermodynamical properties such as change in heat capacity, glass transition temperature and heat of melting. Solid dispersions of indomethacin and xylitol were prepared in 3 different compositions (5%, 10% and 20% xylitol in indomethacin). XRPD and DSC data were measured at different time stamps (aged 1 to 63 days). 5% and 10% dispersions found to be stabile and being amorphous in all time stamps. 20% dispersion was already partly crystallized at 63 days (especially liquid nitrogen ground sample).
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(2022)Amorphous metal oxides have proven to deform in a plastic manner at microscopic scale. In this study the plastic deformation and elastic properties of amorphous metal oxides are studied at microscopic scale using classical molecular dynamics simulations. Amorphous solids differ from crystalline solids by not having a regular lattice nor long range order. In this study the amorphous materials were created in simulations by melt-quenching. The glass transition temperature (Tg) depends on the material and cooling rate. The effect of cooling rate was studied with aluminiumoxide (Al2O3) by creating a simulation cell of 115 200 atoms and melt-quenching it with cooling rates of 1011 , 1012 and 1013 K/s. It was observed that faster cooling rates yield higher Tg. The Al2O3 was cooled to 300 K and 50 K after which the material was stretched. The stress-strain curve of the material showed that samples with higher Tg deforms in plastic manner with smaller stresses. The system stretched at 50 K had higher ultimate tensile strength than the system stretched at 300 K and thus confirming the hypothesis proposed by Frankberg about activating plastic flow with work. In order to see if the plastic phenomena can be generalized to other amorphous metal oxides the tensile simulation was performed also with a-Ga2O3 by creating a simulation cell of 105 000 atoms, melt-quenching it and then stretching. Due to the lack of parameters for Buckingham potential these parameters were fitted with GULP using the elastic properties and crystalline structure of Ga2O3. The elastic properties of Ga2O3 with the fitted potential parameters agreed very well with the literature values. The elongated a-Ga2O3 behaved in a very similar fashion compared to a-Al2O3 cooled with the same cooling rate. Further work is needed to establish the Buckingham potential parameters of a-Ga2O3 by experimen tal work. The potential can also be developed further by using the elastic constants and structures of amorphous a-Ga2O3 in the fitting process, although the potential shows already very promising results.
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(2011)Generation of raw materials for dry powder inhalers by different size reduction methods can be expected to influence physical and chemical properties of the powders. This can cause differences in particle size, size distribution, shape, crystalline properties, surface texture and energy. These physical properties of powders influence the behaviour of particles before and after inhalation. Materials with an amorphous surface have different surface energy compared to materials with crystalline surface. This can affect the adhesion and cohesion of particles. Changes in the surface nature of the drug particles results in a change in product performance. By stabilization of the raw materials the amorphous surfaces are converted into crystalline surfaces. The primary aim of the study was to investigate the influence of the surface properties of the inhalation particles on the quality of the product. The quality of the inhalation product is evaluated by measuring the fine particle dose (FPD). FDP is the total dose of particles with aerodynamic diameters smaller than 5,0 µm. The secondary aim of this study was to achieve the target level of the FPD and the stability of the FPD. This study was also used to evaluate the importance of the stabilization of the inhalation powders. The study included manufacturing and analysing drug substance 200 µg/dose inhalation powder batches using non-stabilized or stabilized raw materials. The inhaler formulation consisted of micronized drug substance, lactose <100µm and micronized lactose <10µm. The inhaler device was Easyhaler®. Stabilization of the raw materials was done in different relative humidity, temperature and time. Surface properties of the raw materials were studied by dynamic vapour sorption, scanning electron microscopy and three-point nitrogen adsorption technique. Particle size was studied by laser diffraction particle size analyzer. Aerodynamic particle size distribution from inhalers was measured by new generation impactor. Stabilization of all three raw materials was successful. A clear difference between nonstabilized and stabilized raw materials was achieved for drug substance and lactose <10µm. However for lactose <100µm the difference wasn't as clear as wanted. The surface of the non-stabilized drug substance was more irregular and the particles had more roughness on the surface compared to the stabilized drug substances particles surface. The surface of the stabilized drug particles was more regular and smoother than non-stabilized. Even though a good difference between stabilized and non-stabilized raw materials was achieved, a clear evidence of the effect of the surface properties of the inhalation particles on the quality of the product was not observed. Stabilization of the raw materials didn't lead to a higher FPD. Possible explanations for the unexpected result might be too rough conditions in the stabilization of the drug substance or smaller than wanted difference in the degree of stabilization of the main component of the product <100µm. Despite positive effects on the quality of the product were not seen there appears to be some evidence that stabilized drug substance results in smaller particle size of dry powder inhalers.
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(2012)In pharmaceuticals amorphous state can be obtained either intentionally or unintentionally. Intentional production is used, for example, to improve the dissolution of poorly soluble compounds, to stabilize the structure of proteins, or to improve the mechanical properties of excipients (e.g., lactose). Unintentional introduction of amorphous phases can result from general manufacturing procedures of pharmaceuticals, such as coating, granulation, drying, milling, and compression. The presence of amorphous regions, even in small quantities, can exhibit a significant influence on the physical and chemical stability of pharmaceutical products. Molecular mobility in formulation with amorphous content is believed to be the key factor of their stability. Therefore, evaluating of molecular mobility is an important step in pharmaceutical product development. The aim of this study was to estimate molecular motions in amorphous disaccharides using calorimetric approach at temperatures below the glass transition temperature (Tg), where relaxation process is very slow as compared to the time of experiment. When temperature is low enough, the initial relaxation time parameter (τi) can be used as an estimate for relaxation process on the timescale of pharmaceutical product shelf life. The results of the present study revealed similar trend in stability of amorphous forms for the disaccharides (sucrose experiencing the fastest structural relaxation), which can be assumed on the basis of Tg alone, where higher Tg would result in more stable glassy state (Tg of sucrose is the lowest). Storage temperature of Tg - 55oC or lower would suffice for amorphous trehalose, melibiose and cellobiose to achieve at least 2 year's relaxation time, while for sucrose the temperature is Tg - 70oC. Fragility has been used as a helpful mean for classifying amorphous materials. All the compounds can be classified as fragile. Fragility ranking in the present study contains some degree of uncertainty, while 3 different approaches revealed somewhat different results for ranking the disaccharides. The variation in the results can be attributed to the overall sensitivity of DSC. The method described in the present study is quite difficult to apply without supportive information from other techniques. The results, obtained with the method, are very dependent on the slope in plotting ln q vs. 1/Tg, and even small fluctuations in the estimation can lead to different fragility values and consequently to different relaxation times. However, the final results reveal values for relaxation times well below Tg, which are in reasonable agreement with modern theoretical understanding of glassy state dynamics.
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(2022)Indomethacin is in a BCS-classification class two drug, meaning it has poor solubility but good permeability. Because of this solubility is a limiting factor for it reaching bloodcirculation. Amorphous form has better solubility than crystalline form. Most common problems with amorphous form are poor stability and process technical problems. In this study Indomethacin was combined with two different kind of polymers that were prepared by hot-melt extrusion. By hot-melt extrusion we can get more stable product than pure amorphous drug. These polymers were polyvinylpyrrolidone (PVPK179 and polyvinylpyrrolidonevinylacetate (PVPVA). They were prepared with Indomethacin 1:1 mass ratio. The aim was to study these extrudates and their stability, cumulative release and especially permeability. By using differential scanning calorimetry, X-ray diffraction and polarized light microscopy it was possible to analyze whether the drug was amorphous or crystalline. In the study it was found that by using hot-melt extrusion it was possible to make amorphous combinations of Indomethacin and polymers. Their permeability was between crystalline and amorphous form. PVPK17-Indomethacin combination had better permeability than PVPVA-Indomethacin combination. On the other hand PVPVA-Indomethacin had better cumulative release than PVPK17-Indomethacin combination
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(2011)Nearly one fourth of new medicinal molecules are biopharmaceutical (protein, antibody or nucleic acid derivative) based. However, the administration of these compounds is not always that straightforward due to the fragile nature of aforementioned domains in GI-tract. In addition, these molecules often exhibit poor bioavailability when administered orally. As a result, parenteral administration is commonly preferred. In addition, shelf-life of these molecules in aqueous environments is poor, unless stored in low temperatures. Another approach is to bring these molecules to anhydrous form via lyophilization resulting in enhanced stability during storage. Proteins cannot most commonly be freeze dried by themselves so some kind of excipients are nearly always necessary. Disaccharides are commonly utilized excipients in freeze-dried formulations since they provide a rigid glassy matrix to maintain the native conformation of the protein domain. They also act as "sink"-agents, which basically mean that they can absorb some moisture from the environment and still help to protect the API itself to retain its activity and therefore offer a way to robust formulation. The aim of the present study was to investigate how four amorphous disaccharides (cellobiose, melibiose, sucrose and trehalose) behave when they are brought to different relative humidity levels. At first, solutions of each disaccharide were prepared, filled into scintillation vials and freeze dried. Initial information on how the moisture induced transformations take place, the lyophilized amorphous disaccharide cakes were placed in vacuum desiccators containing different relative humidity levels for defined period, after which selected analyzing methods were utilized to further examine the occurred transformations. Affinity to crystallization, water sorption of the disaccharides, the effect of moisture on glass transition and crystallization temperature were studied. In addition FT-IR microscopy was utilized to map the moisture distribution on a piece of lyophilized cake. Observations made during the experiments backed up the data mentioned in a previous study: melibiose and trehalose were shown to be superior over sucrose and cellobiose what comes to the ability to withstand elevated humidity and temperature, and to avoid crystallization with pharmaceutically relevant moisture contents. The difference was made evident with every utilized analyzing method. In addition, melibiose showed interesting anomalies during DVS runs, which were absent with other amorphous disaccharides. Particularly fascinating was the observation made with polarized light microscope, which revealed a possible small-scale crystallization that cannot be observed with XRPD. As a result, a suggestion can safely be made that a robust formulation is most likely obtained by utilizing either melibiose or trehalose as a stabilizing agent for biopharmaceutical freeze-dried formulations. On the other hand, more experiments should be conducted to obtain more accurate information on why these disaccharides have better tolerance for elevating humidities than others.
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(2013)Spray drying is one way to dry protein medicines and it has many advantages compared to other drying methods, for example it is a fast process. In spray drying high temperature and mechanical stress can inactivate the protein. Disaccharides are generally used as protective agents of protein in spray drying because they have an ability to protect the structure of the protein during drying and storage. Aim of this research was to study the stability of the protein during spray drying and storage by using β-galactosidace as a model protein. Aim was also to characterize the physical properties of trehalose and melibiose and to study how well they protect the protein. Some of the central matters to be examined were the glass transition temperature, crystallinity, water activity, yield of the spray dried powder and protein activity. Especially studying the properties of melibiose in spray drying was important because it has not been used before. The study also included the optimization of the process parameters to be suitable for the product. Trehalose and melibiose transformed to an amorphous form during spray drying. Both XRPD and DSC showed an amorfous form. Trehalose and melibiose proved to be good protective agents for the protein during spray drying and storatge probably because they remained their amorphous structure. β-galactosidase remained activity very well. Optimizing of the process parameters was successful because protein remained its activity and still the powder was quite dry and yield was good. The changes in the structure of the protein were studied with FT-IR but the amount of the protein was too small. Problems caused by the spray drier may have an effect to the results, but on the other hand the spray dryer was made to work optimally.
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(2012)Improvements in drug screening technology have resulted in a situation where more poorly soluble compounds enter the drug development pipeline. Poor aqueous solubility is a major issue especially in preclinical toxicity testing, where the generation of high drug loads is needed. For oral delivery, liquid formulations are often used and suspensions are potential options for poorly soluble drugs. While several different techniques to enhance solubility exist, most of them have method specific disadvantages or are not universal. Solid state modification, and especially the use of the high energy amorphous form, offers an efficient technique to enhance dissolution properties of a wide range of compounds. A problem of the amorphous form, however, is its physical instability. Amorphous drug in aqueous suspension can re-crystallize via solid-solid and/or solution-mediated pathways. To maintain the solubility advantage of amorphous forms for sufficient period of time, stabilization is needed. One way to stabilize the amorphous form is to prepare a solid dispersion, where the amorphous drug is dispersed in a stabilizing hydrophilic carrier matrix. Another way to add stabilizing agents is to dissolve them into the suspension medium prior to the amorphous solids. Solubilizing polymers may elevate the equilibrium solubility and reduce the driving force for solution mediated crystallization. The aims of this study were to stabilize amorphous indomethacin in aqueous suspensions and to understand the mechanisms behind stabilization. Indomethacin (IND) was used as a poorly soluble model drug (BCS class II). Four different polymers (PVP, HPMC, HPMC-AS and Soluplus®) were selected as stabilizing agents. Crystallization of solid amorphous IND and the concentration of dissolved IND in water were studied after adding: i) the pure amorphous IND, ii) solid dispersions (SDs) at 1:1 and 9:1 drug:polymer ratios (w/w), and iii) the pure amorphous IND into aqueous medium containing predissolved polymer at concentrations of 10 mg/ml or 1 mg/ml, total drug and polymer concentrations being equivalent to 1:1 and 9:1 drug:polymer ratios (w/w) in the SDs, respectively. For HPMC-AS only a 1 mg/ml polymer concentration was used due to its limited solubility. Both the solid and solution phases of the suspension were analysed at different time points for up to 24 h or until crystallization had occurred. Phase transformations in the solid phase were analysed using ATR-FT-IR spectroscopy combined with principal component analysis. The concentration of dissolved drug over the time was assessed by UV spectroscopy. In general, all the polymers, either in SDs or pre-dissolved in medium delayed the onset of crystallization of amorphous IND. Higher polymer concentrations inhibited the crystallization longer than lower ones. A general trend was that SDs were superior in stabilization of amorphous solids, but pre-dissolved polymer solutions generated and maintained higher IND concentrations in solution. Of the four polymers studied, Soluplus® showed the most promising results: SD of Soluplus® and IND at 1:1 ratio (w/w) stayed amorphous in aqueous medium for more than 28 days. On the other hand, crystallization was quite rapid (30 min) when the amount of polymer was inadequate (9:1 w/w). Soluplus® solution (10 mg/ml) generated a 20-fold higher IND concentration than the corresponding SD, possibly due to micellisation. Different polymers showed different abilities to inhibit crystallization and enhance the drug concentration in solution. The addition method and the drug-polymer ratio had an influence on the stabilization abilities of the polymer. Stabilization mechanisms may be both thermodynamic (type of polymer) and kinetic(method of addition).
Now showing items 1-9 of 9