Browsing by Subject "Crystallization"

Now showing 1 - 7 of 7
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    Effects of additives on the molecular-level behavior of disordered pharamceuticals
    (2020-12) Amponsah-Efah, Kweku
    Amorphous solid dispersions (ASDs) can improve the oral bioavailability of poorly water-soluble drugs. However, the physical instability of the amorphous form, denoted by the propensity to recrystallize, is a major barrier to the use of ASDs. The overarching goal of this thesis was to understand the mechanisms by which two major classes of additives – antiplasticizers (various polymers) and plasticizers (mainly glycerol) – affect the physical stability of amorphous formulations, in the dry solid form, as well as in aqueous solution. In the first project, we investigated the impact of the strength of drug–polymer interactions, on the dissolution performance of ASDs. With ketoconazole and three polymers as model compounds, we observed that the interactions that stabilize amorphous drugs in the solid state, can also be relevant and important in sustaining the level of supersaturation in aqueous solution. The second project explored the use of analytical ultracentrifugation as a novel technique for characterizing drug–polymer interactions in aqueous buffers. It was possible to quantify the “free” versus “bound” fractions of drug in aqueous solution, and to semi-quantitatively assess the impact of interactions on the dissolution performance of ASDs. The third and fourth projects evaluated the effects of glycerol on the molecular mobility and physical stability of amorphous itraconazole (ITZ), in the “solid” state. It is well-known that small molecule plasticizers, such as water or glycerol, increase the molecular mobility and accelerate the crystallization of amorphous drugs. In the case of amorphized ITZ, however, glycerol at low concentrations did not cause physical instability. Rather, the smectic state (one of the intermediate liquid-crystalline phases of ITZ) was selectively stabilized. The mechanism by which glycerol stabilized the smectic state was investigated with high resolution techniques (synchrotron diffractometry, differential and adiabatic scanning calorimetry, and spectroscopy). The results revealed that additives with fast dynamics, can drive weak first-order (or second-order) intermediate liquid-crystalline phase transitions, to strong first-order transitions, by a possible coupling of the additive concentration to the order parameter. We also demonstrated that the stabilized smectic state can perform the dual role of maintaining good physical stability while achieving adequate dissolution performance.
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    An Engineered Approach to Specialty Chemicals Purification
    (2016-08) Morgan, Nathan
    High purity is a near-universal requirement throughout the specialty chemicals industry, essential for many of the applications we take for granted in our daily life. The purification process is often a significant portion of the manufacturing cost for many specialty chemicals, including organic semiconductors and pharmaceuticals. Reducing this manufacturing cost is a key step in the effort to efficiently produce the necessary materials for our modern world. This dissertation examines two key purification processes, thermal gradient sublimation and crystallization, in order to offer potential routes for process improvement. Thermal gradient sublimation is examined through the lens of organic semiconductors, which are often purified using this technique at the industrial scale. Interestingly, the sublimation process is limited by vapor phase transport and deposition, not solid phase mechanisms. A model for this process is developed, suggesting potential routes to efficient scale-up and separation improvements. This dissertation also proposes a new method for crystallization control, pressure-swing. In this approach, rapid changes in pressure are used to control solubility during the crystallization process. A model describing the changes in solubility due to these pressure changes is developed, and several process validation experiments are performed using pharmaceutical molecules as model systems. While these tests show an enhanced control of solubility, attempts to replicate experimental results obtained using traditional crystallization control are only partially successful when using the pressure-swing technique.
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    Formation of salt crystal whiskers on nanoporous coatings and coating onto open celled foam.
    (2012-02) Zhang, Heng
    Salt crystal whiskers were grown from salt solution saturated nanoporous silica coatings. Coated substrates were partially immersed into an aqueous potassium chloride solution and then kept in a controlled relative humidity chamber for whisker growth. The salt solution was first wicked into the coating by capillary action, and then evaporation ensued and a supersaturated condition was reached. Crystals grew from the surface by a base growth mechanism in which salt ions were added to the surface of the crystal that was in contact with the nanoporous coating. Optical microscopy and SEM results demonstrated this mechanism. Crystals with whisker morphologies, typically 2 - 50 µm in lateral dimension and up to ~1 cm in length, emerged from the coating surface at a position above the original liquid level. Sheet-like crystals also formed from whiskers that had fallen flat onto the porous coating surface. Inspired by the sheet formation mechanism and liquid transportation phenomenon, a seeding technique was developed to reduce whisker width. Attritor ground salt particles were placed on the nanoporous coating surface to initiate simultaneous whiskers growth and salt nano-whiskers with lateral dimension as small as 50 nm were obtained on the surface of the coating. This crystal growth method can be applied to different materials, namely water soluble materials, and creates whisker crystals with controllable size and location on the nanoporous coating. Open celled foam is a three dimensional structure. In some applications, other materials are coated on internal surface of the foam to provide desired final product functionality. Because of their complicated 3D structures, coating onto foam is challenging. A new coating process that combines dip coating and spin coating was developed. Dip coating step was used to load the solution into the foam and a spin treatment step was added to remove the trapped liquid and redistribute the liquid to obtain uniform coating. The dip and spin process was also used to create -alumina and zeolite coatings, which are of interest for catalysis applications.
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    Kinetics of nonisothermal phase change with arbitrary temperature–time history and initial transformed phase distributions
    (2022-09-08) Kangas, Joseph; Bischof, John; Hogan, Christopher; hogan108@umn.edu; Hogan, Christopher; University of Minnesota Hogan's Lab; University of Minnesota Bioheat and Mass Transfer Laboratory
    This paper describes the extension of the classic Avrami equation to nonisothermal systems with arbitrary temperature–time history and arbitrary initial distributions of transformed phase. We start by showing that through examination of phase change in Fourier space, we can decouple the nucleation rate, growth rate, and transformed fraction, leading to the derivation of a nonlinear differential equation relating these three properties. We then consider a population balance partial differential equation (PDE) on the phase size distribution and solve it analytically. Then, by relating this PDE solution to the transformed fraction of phase, we are able to derive initial conditions to the differential equation relating nucleation rate, growth rate, and transformed fraction.
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    Novel microfluidic technologies: toward a low-cost system for protein crystallization.
    (2009-12) Hattan, Paul J
    The three-dimensional structure of folded proteins is of enormous interest to the scientific community. The structure is best determined with x-ray diffraction through a protein crystal, but it has proven extremely difficult to grow crystals large enough for this process [1, 2]. Significant challenges faced by protein crystallographers include the inability to sufficiently control the crystallization environment and the scarcity of protein available [3]. Microfluidic devices, which allow ultra-precise fluid management and require significantly less reagent than traditional methods, constitute an ideal technology with which to overcome these crystallization challenges [4-7]. A microfluidic system has been designed to give a crystallographer precise management of the concentrations of several reagents (such as protein and a suitable precipitant salt) over time. To create components of the microfluidic system, two novel fabrication methods were developed: photopolymer mold making and three-dimensional plate tectonics. These methods are rapid, inexpensive, and do not require any special equipment. A novel micropump and channel network suitable for the crystallization system were successfully created using these techniques.
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    Recognition and assembly at multiple length-scales.
    (2010-05) Olmsted, Brian Keith
    Many molecular materials capable of crystallizing into an ordered solid state may assume multiple packing arrangements. This behavior is called polymorphism and is common among organic molecules such as pharmaceuticals and dyes. Controlling the nucleation of specific polymorphic crystals is not well understood, but is tantamount to the development and manufacture of new industrial products. One phenomena that has been observed to influence crystal orientation, growth rate, and morphology is epitaxy. Epitaxy refers to a condition by which a crystalline substrate presents a similar two-dimensional lattice to a crystalline plane of a nucleating species, resulting in a condition that lowers the energy barrier to nucleation and results in a preferential orientation of crystal growth on the substrate. Therefore, epitaxial nucleation may provide routes to selectively nucleate polymorphs and attain control over otherwise unpredictable crystallization events. The literature provides several examples of epitaxial relationships between a substrate and a crystal overlayer in fields involving inorganic crystals as well as organic crystals, and because epitaxy relies on geometric comparisons between lattice parameters, computational prediction of epitaxy is an active area of research. Our laboratories have developed software; named GRACE, to attempt to predict epitaxial relationships and this software has been used to verify epitaxy reported in the literature. One particularly useful feature of GRACE is its ability to handle a library of substrates and screen them against a corresponding database of crystal structures available as candidate crystal overlayers. In this capacity GRACE allows large libraries of substrates and crystals to be reduced to an experimentally manageable size, whereby combinatorial crystallizations can be tested for selective nucleation arising from epitaxial interfaces. This research also focuses on other aspects of nucleation that are not yet fully understood. Epitaxial interfaces are by definition, abrupt. However, a specialized class of crystals involving a domain that completely overgrows a core crystal by epitaxial mechanisms has revealed a zone of intermixing spanning close to a micron. In situ Atomic Force Microscopy (AFM) reveals the mechanisms for these observations and provides insight into how epitaxial interfaces behave mechanistically. Notably, it was revealed that process conditions between phases of growth in the formation of core-shroud heterocrystals may yield controllable interfacial thicknesses between crystalline domains, It was also discovered that the propensity for abrupt, epitaxial interfaces may be limited by the thermodynamic behavior of specific crystal interfaces under conditions of near-equilibrium. Although the use of in situ AFM is excellent for the study of crystal growth, the mass-transfer limitations at crystallizing interfaces inside an (AFM) fluid cell are not directly discernable and the assumption is typically made that conditions in the bulk solution are the same inside the cell. By implementing computational fluid dynamic (CFD) simulations for flow and mass transport, in situ AFM was studied to determine how the different conditions at the crystal surface are in comparison to the bulk solution outside the cell. The geometry of the internal volume of the AFM fluid cell imparts specific fluid flow and mass transport limitations on the environment directly at the area of investigation for crystal growth and in some cases may have significant ramifications for the appropriate correlation of bulk solution variables to crystal growth variables. The results of the CFD calculations indicate that differences are significant, though usually minor and these results may prove useful for future fluid cell design. Finally, photolithographic techniques were employed to produce millions of micron-sized particles with shapes mimicking molecular contours and other crystallographically significant contours to study how symmetry and packing originates at the micron length-scale. Although much is known about assembly at the molecular level for symmetry and packing, the assembly of anisotropic particles at longer length scales, which involve different interactive forces, has not been studied. This work concludes by performing preliminary work in elucidating the general behavior towards symmetry and packing in two-dimensions of micron-sized particles by using gravitational gradients and dielectrophoresis.
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    Thermal Analysis of Cryoprotectants for Cryopreservation
    (2017-02) Phatak, Shaunak
    Cryopreservation by vitrification is a promising technique for preservation of biomaterials such as organs for long term storage. Crystallization while cooling and warming is an important hurdle for a successful cryopreservation. This problem can be addressed by the use of cryoprotectant solutions (CPAs) which help in inhibiting crystallization. The cooling and warming rates needed to prevent crystallization in these CPAs are called Critical Cooling Rate (CCR) and Critical Warming Rate (CWR) respectively. Thermal modeling is an important tool which can help to study this process and predict subsequent cooling and warming rates needed to avoid crystallization. Temperature dependent thermal properties such as thermal conductivity, specific heat capacity and density are needed in order to develop an accurate model. This work involved the measurement of specific heat capacity (Cp) of high concentration CPAs (> 6M) that are used to study vitrification. The thermal properties were then used in a numerical model to predict cooling and warming rates encountered in a cylindrical geometry of CPAs. Chapter 1 provides a review of the thermal properties (thermal conductivity and specific heat capacity) of various biomaterials available in the literature in the sub-zero and supra-zero temperature ranges. Thermal properties of biomaterials are highly temperature dependent. In addition to dependence on temperature, these properties are affected by crystallization and vitrification at sub-zero temperatures (<0°C) and protein denaturation and water loss at supra-zero temperatures (>0°C). Finally, a modeling case study (Bischof and Han 2002) has been provided to highlight the significance of using temperature dependent thermal properties for accurately predicting thermal history. Chapter 2 focusses on experimental measurements of specific heat capacity (cp) of five high concentration CPAs (> 6M) — VS55 (with and without sucrose), DP6 (with and without sucrose) and M22. Further, the effect of cooling / warming rate (1, 5 and 10 °C/min) on crystallization and vitrification has been studied. It was observed that the addition of 0.6 M sucrose to two CPAs viz., VS55 and DP6 suppressed their crystallization for all the three cooling and warming rates. Chapter 3 involves thermal modeling of cooling and warming in a COMSOL Multiphysics package. Thermal properties from Chapters 1 & 2 were used in order to predict the cooling and warming rates for three conditions, viz. convective cooling, convective warming and nano warming. These simulations were carried out in a cylindrical geometry for an increasing size, i.e. the radius of the cylinder. The objective was to find the size limit beyond which cooling and warming rates would not exceed the CCR and CWR respectively.