Browsing by Subject "Dissolution"
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Item Artificial Gut Simulator for Simultaneous Evaluation of Drug Dissolution and Absorption(2021-08) Harish Jain, KrutikaOver the past three decades, high-throughput screening has resulted in a discovery pipeline consisting mostly of highly potent but lipophilic compounds exhibiting poor aqueous solubility and classified as Biopharmaceutics Classification System (BCS) Class II. Since poor solubility limits absorption and bioavailability, efforts have been made to develop supersaturating delivery systems such as amorphous solid dispersions (ASD) that enhance the apparent solubility of the drug without sacrificing its thermodynamic activity. The performance of these dispersions is often tested in ‘closed’, non-sink compendial dissolution testing apparatus that lacks an absorptive sink. The supersaturated solution generated upon ASD dissolution is metastable with respect to the stable crystalline phase and can undergo amorphous and/or crystalline precipitation. The rate of precipitation depends upon the degree of supersaturation. In the absence of absorption, during non-sink dissolution testing, high supersaturation can drive more precipitation than that which occurs in vivo where continuous drug absorption from the intestinal lumen decreases drug concentration, which in turn decreases the driving force for precipitation. Unsurprisingly, many in vitro studies with non-sink dissolution testing have failed to predict the in vivo performance of formulations of BCS-II drugs, which by definition, have high intestinal permeability. A simultaneous dissolution and absorption testing apparatus called the side-by-side diffusion cell allows drug to diffuse from the donor to a receiver compartment across a membrane that separates the two. However, small surface area of the membrane results in very low rates of drug absorption and very long, unphysiological experimental time scales. The first goal of this study was to develop and validate an artificial gut simulator apparatus (AGS) consisting of a hollow fiber-based absorption module suspended in the drug donor. The hollow fibers provide a large surface area for absorption, significantly improving mass transfer rate of drugs from the donor into the aqueous receiver media in the hollow fiber lumen. Continuous pumping of the drug-free receiver media into the lumen helps maintain an absorptive sink. A theory for mass transfer across the hollow fiber membrane was developed and validated using caffeine. Physiological rate of drug absorption was attained by tuning the AGS operating parameters per the theoretical model. This is an important step in developing a biorelevant test for BCS-II drugs. The next goal of this project was to understand how absorption impacts dissolution of ASDs and subsequent crystallization from supersaturated solutions of a model BCS-II compound, ketoconazole. Relative to a non-sink ‘control’, continuous drug removal by absorption enhanced ASD dissolution and significantly decreased both amorphous and crystalline precipitation. This can be attributed to both a decreased driving force for precipitation due to lower drug concentration in the AGS donor as well as to redissolution of any precipitate that is formed to replenish the drug in solution lost to absorption. On the other hand, polymer excipient added to the ASD to stabilize the drug against crystallization during storage and dissolution reduced the drug’s absorption rate by possibly interacting favorably with the free drug species and reducing the drug’s thermodynamic activity. Simple analytical techniques used in conjunction with the AGS helped decouple and understand the impact of dissolution, precipitation and speciation on absorption and vice-a-versa. The final goal of this project was to implement a scheme to establish in vitro/in vivo correlation with another BCS-II drug, dipyridamole, by inputting the drug concentration absorbed by the AGS receiver media into a compartment-based disposition model to ultimately predict the in vivo plasma concentration-time profile of the drug. The human intestinal absorption rate constant of dipyridamole, determined from Caco-2 cell monolayer permeability coefficient, was used to tune the AGS. Gastric emptying was simulated at a physiological rate to ensure a physiological rate of supersaturation generation as the weakly basic dipyridamole is solubilized and emptied from acidic gastric compartment into a neutral duodenum. This methodology of simulating gastric emptying and absorption enabled accurate prediction of drug in vivo intestinal and plasma concentration-time profiles. This approach and apparatus is anticipated to be of great utility during drug product development for screening and optimization of potential oral formulations.Item An Investigation of Nanoparticle Toxicity Mechanisms against Environmentally Relevant Bacteria and the Potential for Sustainable Agriculture Applications(2019-05) Buchman, JosephDue to the unique physicochemical properties of nanoparticles, largely due to their high surface area-to-volume ratio, they are being increasingly used in consumer products. At any time during the manufacture, use, and ultimately, disposal of these products, there is a reasonable likelihood of nanoparticle release into the environment. Once released, their impact on the environment are less well-understood. Therefore, there is a growing emphasis to understand the impacts of nanoparticles on the environment, by understanding how the nanoparticles interact with ubiquitous organisms that have important ecological roles. Beyond looking solely at whether nanoparticle introduction will kill these organisms, the molecular-level mechanisms of their toxicity have been studied. By understanding the mechanisms, the goal is to be able to predict the toxicity of nanoparticles prior to their mass production, and to inform a more sustainable design and use of nanomaterials. Chapter One of this work reviews the understanding of molecular-level toxicity mechanisms to organisms in the environment, with an emphasis on beneficial bacteria. It also describes different strategies that have been employed to redesign nanoparticles that reduce the impact of these toxicity mechanisms. Chapter Two illustrates the importance of using more than one organism when doing studies of nanoparticle toxicity. Not all organisms respond equally, and there are some that are not impacted by a given nanoparticle type, so use of multiple species that cover a range of complexities improves the chances that a nanoparticle will not be incorrectly labeled as “nontoxic”. By using multiple organisms, those that are most impacted can also be identified for follow-on research to investigate the mechanism of toxicity. Chapter Three assesses the toxicity mechanism of an important nanomaterial often used in energy storage applications that is made of the complex oxide, lithium nickel manganese cobalt oxide, across a range of industrially-relevant stoichiometries. While for equimolar stoichiometries of this material, the importance of nickel and cobalt release has been implicated as the main toxicity driver to Shewanella oneidensis MR-1, this work demonstrates that even at increased nickel concentrations in the material, the toxicity remained the same due to increased material stability leading to a similar dissolution profile. For another important environmental organism, Daphnia magna, the toxicity did increase with increasing nickel content, indicating that a material redesign will not necessarily have the same impact on different organisms. Chapter Four investigates the impact of iron oxide nanoparticles to S. oneidensis, which showed that these nanoparticles improved bacterial survival, mostly due to the release of beneficial iron ions. Since changing bacterial populations can perturb an environment, a mesoporous silica coating was applied to the iron oxide nanoparticles to reduce their dissolution and their impact on the bacteria. While more understanding of the mechanisms by which nanoparticles can exhibit toxicity is being gained, there are many nanoparticles for which there is a low toxicity to organisms. In Chapter Five, we apply silica nanoparticles, which have been found to be largely nontoxic, to our plant model, Citrullus lanatus. Through dissolution, silica nanoparticles are capable of serving as a source of silicic acid, an important micronutrient, for plants. These nanoparticles benefit healthy plants by increasing their biomass and improving the overall fruit yield. This work demonstrates a way to apply nanoparticle toxicity knowledge to proactively utilize nanoparticles to improve sustainability in agriculture.Item Linking morphology and reactivity: growth and ligand-assisted dissolution of cobalt oxyhydroxide.(2010-08) Myers, Jason C.Reactions at the interface of solid materials have a significant role in many fields of study, ranging from environmental science to industrial manufacturing. Identifying and quantifying the reactive surface area of these materials is vital to understanding the reactions in which they participate. The most basic effect of reactive surface area is governing the reaction rate at the surface but, in some cases, it is necessary to have a far more detailed understanding of the surface structure. Many reactions occur most efficiently, or even exclusively, at specific types of surface site. The ability to identify and measure these sites could dramatically improve the design of many applications, such as heterogeneous catalysts or waste remediation systems. One proposed method of measuring reactive surface area is the use of carefully selected probe molecules that are specifically reactive with the surface sites of interest. This work focuses on the development of a method for analyzing the surface characteristics of heterogenite (β-CoOOH) using the ligand iminodiacetic acid (IDA) as a probe. To investigate this system, first a range of model materials were necessary. The method of heterogenite synthesis was explored, revealing that a surprising amount of control can be exerted over the final particle morphology by altering simple factors such as reaction temperature or choice of oxidizing agent. The ligand-assisted dissolution of heterogenite by IDA produces a mixture of sfac and u-fac isomers of Co(IDA)2 –, and the relative amount of each isomer depends upon the surface characteristics of the heterogenite. When heterogenite particles were aged in suspension at room temperature, a rapid evolution of the number and type of surface site present was observed. This change was tracked by reacting the particles with IDA then separating and quantifying the resulting Co(IDA)2 – isomers. Through this method, it was found that the surface evolution occurs more slowly when aged in lower pH buffer. The connection between particle morphology and reactivity was strengthened when a link was found between the height of cylindrical heterogenite plates and the ratio of isomers formed during the dissolution reaction. From this, an empirical relationship between particle height and the relative amount of s-fac isomer was derived. This relationship allowed the tracking of particle growth via dissolution reactions rather than direct measurements. The final connection between morphology and reactivity was discovered when kinetic and thermodynamic studies were undertaken. The rate of reaction when the reactant concentrations are altered suggests that both surface diffusion and product desorption processes are involved in determining the overall reaction rate. Finally, it was hypothesized that the reactivity of some sites varies with temperature. Thus, the ratio of products produced depends not only on the number and type of surface site present, but also on the temperature of the reaction. Additional work is necessary to quantify this temperature dependence.Item Lubrication In Pharmaceutical Tablet Manufacturing(2020-03) Dun, JiangnanAppropriate compaction properties are critical to ensure a successful and robust tablet manufacture. According to Materials Science Tetrahedron (MST) theory, the quality of the tablet product is determined by the properties of pharmaceutical materials and the process conditions during manufacture. Lubricant, as one of the most important tablet excipients, has great impacts on the flow and mechanical properties of formulation. This work is heavily focused on understanding of the effects of process parameters on the lubrication as well as development of new lubricants for tablet formulation. Magnesium stearate, the most commonly used tablet lubricant, though exhibits excellent lubrication efficiency, leads to deterioration in tablet strength and dissolution. Sodium lauryl sulfate (SLS), Poloxamer 188 and Poloxamer 407 were selected as MgSt-alternative lubricants to be tested in tablet formulations. We found that the lubrication efficiency of these three materials are comparable with MgSt. More importantly, no significant tablet strength reduction was observed. Given to the higher hydrophilicity, tablets containing either of SLS, P188 or P407 showed enhanced dissolution profiles compared with MgSt containing tablets. Furthermore, robustness of formulation was remarkably improved when P188 or P407 was used as lubricant.Item Polyphosphate-accumulating Bacteria: Potential Contributors to Mineral Dissolution in the Oral cavity(2017-05) Breiland, AshleyThe role of oral bacteria in the dissolution of dental enamel and dentin that can result in carious lesions has long been solely ascribed to metabolic acid production. However, other microbial processes may also influence tooth dissolution. Recently, bacteria that accumulate polyphosphate in marine sediments have been shown to dynamically influence the solubility of phosphatic minerals. Here we show, using microscopy and genomic databases, that dental plaque and caries lesions, all contain abundant polyphosphate-accumulating bacteria. Using a culture of the model organism, Lactobacillus rhamnosus, a known polyphosphate-accumulating bacteria that is known to inhabit advanced caries lesions, we show that polyphosphate accumulation can lead to undersaturated conditions with respect to hydroxyapatite under some, but not all, oral cavity conditions. Samples of L. rhamnosus grown in various environmental conditions, including exposure to changing oxygenation conditions, input/removal of organics and trace nutrients, were collected over a course of 24 hours and stained with 4',6-diamidino-2-phenylindole (DAPI) to confirm/deny the presence of poly-p in the cells. A comparison of changes in extracellular inorganic phosphate between cultures grown under conditions that result in polyP accumulation vs conditions that did not, was used a a means of measuring the phosphate fluctuation that was likely contributed by intracellular phosphate accumulation. We suggest, through an extrapolation from our model organism results, that polyphosphate-accumulating bacteria, which we observed to be ubiquitous in oral fluids, have a similar influence on the solubility of minerals that comprise the tooth structure. These results suggest that the generation of undersaturated conditions by polyphosphate-accumulating bacteria constitutes a new potential mechanism of tooth dissolution that may augment the effects of metabolic acid production.Item Women's friendship dissolution: A qualitative study(2008-12) Jalma, Katie S.This study is the first of its kind to explore and describe female experiences of ending a friendship (non-romantic) with a female friend. The adult friendship did not end through death or moving away, and it ended within the last five years. The unique and specific characteristics of women's relationships with women may suggest that the maintenance of their relationships carry a particular importance that differs from social connections in the lives of men. Given the importance of relational connection in women's lives and the scarcity of literature regarding friendship dissolution, an investigation of the process of women's friendship dissolution was warranted. A survey of the literature provided direction for the exploratory research questions that guided the development of the interview protocol. Participants included in this study were 15 professional women (ages 25-72 years, median age = 32) self-selected from three different recruitment pools. The primary researcher conducted face-to-face interviews with all of the participants. The interviews were analyzed by a research team of three judges employing a qualitative research methodology guided by Consensual Qualitative Research (CQR; Hill, et al, 1997; Hill et al., 2005). The analysis was reviewed by an outside auditor for the study. Final data analysis revealed four domains (Friendship Characteristics, Components of Friendship Dissolution, Learning about Self and Friendship Dissolution, and Experience Related to Participation in Study and Interview), nine core ideas (Friendship Formation, Nature of Friendship, Reason for Dissolution, Process of Dissolution, Nature of Relationship Post-Dissolution, Outcome of Dissolution Experience, Increased Self-Awareness, Awareness Regarding Friendship and Dissolution, and Reaction to Interview), and thirty-two categories. Study strengths include exploratory investigation of an unexamined phenomenon, goodness of fit between research topic, data collection, and research methodology, and participant ability to describe complex facets of relationship dynamics due to their professions. Limitations of this study include the inability to generalize the findings outside of the participants of this study, self-select and self-report data collection methods, and possible interviewer and research team bias. Future research directions incorporate theoretical connections to female stress response (e.g. Taylor et al., 2000), relational aggression (Crick, 1995), and women's development (Josselson, 1996). Implications for the study for counseling women were discussed.