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1
Roberts, R. J. "The elasticity, ductility and fracture toughness of pharmaceutical powders." Thesis, University of Bradford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320442.
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Watling, Christopher Peter. "The effects of humidity and lactose grade on pharmaceutical inhalation formulations." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611589.
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Mackin, L. A. "The effects of moisture on triboelectrification of selected pharmaceutical excipient powders." Thesis, University of Sunderland, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245985.
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The literature contains conflicting reports on the effect of moisture on triboelectrification, indeed experiments have shown moisture to increase, decrease or have no effect at all on the charging of solids. The research programme investigated the role of moisture in the triboelectrification of a range of pharmaceutical excipients. Selection of excipients was made on the basis of a) moisture sorption capacity (the starch group) and b) potential use in dry powder inhaler formulations (the sugar and sorbitol group). The following excipients were selected for preliminary investigations:- a-lactose monohydrate, dextrose monohydrate, sorbitol spray dried (SSD), sorbitol powder, sucrose, maize and potato starch and Primojel™.
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Es-Saheb, Mahir Hamdi Hamed. "An investigation into the mechanics of dynamic compaction of pharmaceutical powders." Thesis, University of Manchester, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385033.
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This thesis is 'concerned with aspects of dynamic compaction of pharmaceutical powders. The research is mainly aimed at the influence of compression rates on the residual resilience and strength of the tablet. A wide range of compression strain rates (103 - 10 per sec. ) is covered for di-pac-sugar, sodium chloride, potassium bromide, paracetamol, copper sulphate, avicel, lactose and calcium phosphate. The influence of compression rate on the form of the pressure-density relationship including the IHeckel and 1: awakita diagrams is investigated. Theoretical and experimental work are conducted on the relationship between radial and axial pressures during uniaxial straining. The general tendency for all the powders tested except for the paracetamol d. c., is to exhibit increased compaction pressure with strain rate up to 105 per sec. Due to morphological and compositional factors paracetamol d. c. softens with the rate of straining up to about 102 per sec. At higher rates it behaves like other powders. Generally, at high strain rates, the brittle behaviour dominates the process and tablet capping becomes more evident. The scope, origin and the main objectives of the present work are presented in Chapter 1. A brief historical account of the development of uniaxial compression techniques is given in'Chapter 2. Past work in the field of uniaxial compaction is reviewed and. classified. Various dynamic processes are classified according to the rates of compaction. Discussion of the various mechanisms responsible for, and governing, the way in which a powder consolidates when subjected to uniaxial compaction is presented together with a brief discussion of the capping phenomenon. Chapter 3 describes the construction and operation of a specially designed die incorporating a pressure pin for radial pressure measurement. The effect of compression rate on the form of the characteristic compaction curves, for all powders, is investigated using the above die on a servohydratlic variable speed machine (ICI simulator) at constant compression rate conditions (10-110 per sec). Investigations, using this apparatus indicate that all materials tested exhibit strain rate sensitivity to varying degrees (i. e. increased resistance to compaction as the speed is increased). In Chapter 4a brief review and discussion of viscoelastic aspects and theoretical modelling of the compaction process are presented. By plotting axial versus radial pressures during successive compression and decompression cycles at various speeds and by observing the decay of both pressures under constant volume conditions, it is possible toi draw certain conclusions about the relative elastic-plastic behaviour of each material. Investigations ' indicate that the use of linear viscoelastic theory could be useful in predicting the general trend of the process but insufficient to model the response of the various powders to the different loading conditions. Accurate modelling would require more experimental work and analysis of a high level. Also, the elastic recovery of all the compacts within the die is found to range from 8-120. Chapter 5 describes various aspects of forming and testing of tablets on an Instron machine at constant speed. Crack initiation, propagation and modes of failure during the Brazilian test are investigated by employing -high speed photography. An analysis of the effect of die and punch rigidity on the Kawakita relationship is attempted. An account of 'the variation of the. ejection pressure and the residual tensile strength with the maximum applied pressure is given. in this-chapter, the effect of ageing time and the effect of the ejection speed, for both straight and tapered dies, are also examined. Investigations indicate that, during the Brazilian test, in all compacts for all materials, the crack starts at the centre of the tablet and propogate up and down towards the plattens. Three main types (modes) of failure are observed: The 'traditional' mode of failure, in compacts of elastic-plastic deforming materials , (such like di-pac-sugar, paracetamol); The (random) mode of failure in plastically deforming compacts (such like sodium chloride potassium bromide), End capping which is observed in almost all materials compacted at high speeds. The values of the constant "b" (in the Kawakita Equation) is significantly influenced by the die and punch materials while the constant "a" remains unchanged. Also, the ejection pressure is increased with the increased axial maximum pressure and decreases with increasing speeds of compaction. All materials tested, show slight increase in the compact tensile strength as the. ageing time is increased - Also all compacts formed in the tapered die show higher tensile strength than those formed in the straight die over the range of ejection speed tested. Chapter 6 describes the construction and operation of an apparatus used for quasistatic"and medium rate (10 2_ 103 per sec) uniaxial compaction of powders. This apparatus allows the powder volume, 'axial and radial compaction pressures to be measured simultaneously. The investigations indicate that the properties of the resulting compacts are influenced by the compaction rate employed. Also, the compact tensile strength at this range is found to decrease together with the capping pressures. Chapter 7 describes the construction and operation of especially designed high pressure air projectile launcher compaction apparatus suitable for high rate uniaxial compaction of powders. Both, the axial pressure and powder volume can be measured on this apparatus. Problems of stress wave reflections in the system are overcome by using long load cells which enable accurate measurements to be obtained. Almost in all compacts, formed on this apparatus, ' end capping is observed. Chapter 8 gives a detailed description of the design, construction and operation of a high pressure triaxial cell working at pressures of up to 207 MPa, together with the associated equipment. Also, the sample preparation procedure is established. Preliminary, tests carried out on di-pac-sugar, lactose and paracetamol d. c. indicate that the powder characteristics can be designed by controlling the axial-and radial stresses. Chapter 9 describes the theory, equipment and the experimental results of a new technique based on the Split Hopkinson Bar principle to determine 'tension and compression Young's moduli of'a. tablet. The investigation indicates that the modulus in compression is higher than that in tension (in some cases by almost 20t). Finally, chapter 10 outlines general conclusions and suggestions for further work.
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Sanchez-Castillo, Francisco Xavier. "Compaction of powders by molecular dynamics simulation." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272141.
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Tan, Soo Bin. "Filling of hard gelatin capsules with powders of different flow properties." Thesis, University College London (University of London), 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252001.
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Macritchie, Helen Barbara. "The development of a laser diffraction technique for use in the physical characterisation of dry powders for inhalation." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300089.
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Laycock, Steven. "A study of interparticle adhesion in pharmaceutical powder mixtures." Thesis, University of Bath, 1987. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380414.
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Grosvenor, Martin Paul. "The physico-mechanical properties of electrostatically deposited polymers for use in pharmaceutical powder coating." Thesis, Online version, 1991. http://ethos.bl.uk/OrderDetails.do?did=1&uin=uk.bl.ethos.303452.
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Beard, Timothy. "The effect of powder properties on the filling of antibiotics into vials." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266431.
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Zeng, Xian Ming. "The influence of particle engineering on drug delivery by dry powder aerosols." Thesis, King's College London (University of London), 1997. https://kclpure.kcl.ac.uk/portal/en/theses/the-influence-of-particle-engineering-on-drug-delivery-by-dry-powder-aerosols(abf7b52d-6271-462c-96a7-e12b6acc7f32).html.
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Clarke, Martyn James. "An investigation into the factors governing the performance of nedocromil sodium as a dry powder inhalation system." Thesis, University of Bath, 1999. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299811.
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Tee, Seah Kee. "The influence of some formulation factors on drug delivery by dry powder aerosols : an in vitro/in vivo evaluation." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367513.
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Li, Xiaojian. "MULTI-COMPONENT MICROPARTICULATE/NANOPARTICULATE DRY POWDER INHALATION AEROSOLS FOR TARGETED PULMONARY DELIVERY." UKnowledge, 2014. http://uknowledge.uky.edu/pharmacy_etds/31.
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The aim of the work was to design, manufacture, and characterize targeted multi-component dry powder aerosols of (non-destructive) mucolytic agent (mannitol), antimicrobial drug (tobramycin or azithromycin), and lung surfactant mimic phospholipids (DPPC:DPPG=4:1 in molar ratio). The targeted dry powder for inhalation formulation for deep lung delivery with a built-in rationale of specifically interfering several disease factors of chronic infection diseases in deep lungs such as cystic fibrosis, pneumonia, chronic bronchitis, and etc. The dry powder aerosols consisting of selected chemical agents in one single formulation was generated by using spray drying from organic solution.
The physicochemical properties of multi-component dry powder inhaler (DPI) formulation were characterized by a number of techniques. In addition, the in vitro aerosol dispersion performance, storage stability test, and in vitro drug release of selected spray-dried (SD) multi-component systems were conducted.
The physicochemical study revealed that multi-component aerosol particles possessed essential particle properties suitable for deep lung delivery. In general, the multi-component particles (typically 0.5 to 2 µm) indicated that the designed SD aerosol particles could potentially penetrate deep lung regions (such as respiratory bronchiolar and alveolar regions) by sedimentation and diffusion, respectively. The essential particle properties including narrow size distribution, spherical particle and smooth surface morphologies, and low water content (or water vapor sorption) could potentially minimize interparticulate interactions. The study of in vitro aerosol dispersion performance showed that majority of SD multi-component aerosols exhibited low values (less than 5µm) of MMAD, high values (approximately above 30% up to 60.4%) of FPF, and high values (approximately above 90%) of ED, respectively. The storage stability study showed that azithromycin–incorporated multi-component aerosol particles stored at 11 and 40% RH with no partial crystallization were still suitable for deep lung delivery. Compared to SD pure azithromycin particles, the azithromycin-incorporated multi-component particles exhibited an enhanced initial release.
The targeted microparticulate and nanoparticulate multi-component dry powder aerosol formulations with essential particle properties for deep lung pulmonary delivery were successfully produced by using spray drying from organic solution. The promising experimental data suggest the multi-component formulations could be further investigated in in vivo studies for the purpose of commercialization.
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Doroudian, Ahmad. "Determination of compaction parameters of pharmaceutical powders with an instrumented hydraulic press." Thesis, University of British Columbia, 1991. http://hdl.handle.net/2429/29829.
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Prediction of the tabletting behavior of powdered drugs is of great importance in the pharmaceutical industry. An instrumented hydraulic press and punch and die assembly were used to study compaction behavior of 5 widely used pharmaceutical materials, Avicel, Emcompress, spray-dried lactose, crystalline acetaminophen USP and acetaminophen DC granules. The hydraulic press was able to compress the above materials at compaction speeds comparable to those of rotary tablet presses. The compression cycle of the Betapress could not be duplicated by the hydraulic press since, with the hydraulic press, the displacement was not constant at peak pressure.
The compaction parameters measured by the hydraulic press were elastic recovery (ER), punch travel distance beyond peak pressure (D), punch travel time beyond peak pressure (PTT) decrease in the force during punch travel beyond peak pressure (F). The strength of the tablets was measured with a CT40 tablet hardness tester. D and PTT appeared to be measures of flow and bonding and to be useful parameters for the tabletting behavior of the above materials. In general, materials that displayed relatively
long D and PTT values formed coherent tablets regardless of their elastic recovery. Avicel which displayed the longest D and PTT values (and the largest recovery) formed the strongest tablets while crystalline acetaminophen USP displayed the shortest D and PTT values and did not form coherent compacts. Thus for particulate materials that were able to flow and bond, elastic recovery did not appear to play an important role in the tabletting process.
Avicel and spray-dried lactose displayed similar D and PTT values (ie. similar extent of flow and deformation) and Avicel's elastic recovery was about 3 times as much as of that of spray-dried lactose, but Avicel formed tablets that were about 5 times stronger than those of spray-dried lactose. Therefore the nature and number of bonds that are formed between the particles (which are related to the inherent property of the materials) appeared to be the most important factor in tablet formation.
The effects of peak pressure (Pmax) and average compression rate (ACR) were examined on the above parameters. Generally peak pressure influenced the elastic recovery, D, PTT and hence the strength of the tablets more than the average compression rate.Pharmaceutical Sciences, Faculty of
Graduate
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Theuma, Anthony S. "The future of pharmacy : pharmacy leaders' perceptions and experiences on the pharmacy lifeworld." Thesis, University of Reading, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272705.
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Tharp, Brent W. "Elixirs, Drops, Powders, and Pills: The Origins and Foundation of the American Patent Medicine Industry." W&M ScholarWorks, 1988. https://scholarworks.wm.edu/etd/1539625478.
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Newall, Carol Anne. "Herbal medicines and pharmacy." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286407.
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O'Neill, Catherine A. "Formulation of pharmaceutical gels." Thesis, Queen's University Belfast, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317524.
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Warisnoicharoen, Warangkana. "Pharmaceutical nonionic oil-in-water microemulsions." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286790.
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Khalaf, Ahmed S. "Pharmaceutical characterisation of novel microcrystalline cellulose." Thesis, University of Bath, 2000. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288235.
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Sun, Hongzhe. "Biological chemistry of bismuth drugs." Thesis, Birkbeck (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244018.
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Varma, Sumanthra. "Pharmaceutical care of elderly congestive heart failure patients." Thesis, Queen's University Belfast, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388199.
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Sturgess, Ian K. "Pharmaceutical care provision to community dwelling elderly patients." Thesis, Queen's University Belfast, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268313.
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Mama, Joseph Etsu. "Pharmaceutical applications of porous graphitic carbon in HPLC." Thesis, University of Bradford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305781.
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Scanlan, Justine Claire. "Pharmaceutical care for cancer patients : a multidisciplinary approach." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289814.
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Miller, Mark Russell. "Preclinical evaluation of AG10 for therapeutic use against familial amyloid cardiomyopathy and its application in various other technologies." Scholarly Commons, 2017. https://scholarlycommons.pacific.edu/uop_etds/3556.
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Transthyretin (TTR) amyloidosis is a progressive, fatal disease in which deposition of amyloid derived from either mutant or wild-type TTR causes severe organ damage and dysfunction. TTR cardiomyopathy is an infiltrative, restrictive cardiomyopathy characterized by progressive left and right heart failure. Familial amyloid cardiomyopathy (FAC) is driven by pathogenic point mutations in the TTR gene that destabilize the TTR tetramer, prompting its dissociation into dimers and monomers, with subsequent misfolding, aggregation and deposition of toxic TTR amyloid aggregates in the myocardium. The most prevalent mutation that causes FAC is the V122I variant, carried by 3.4% of African Americans, that increases the risk of cardiomyopathic events several-fold in this population. AG10, a potent TTR kinetic stabilizer, prevents dissociation of V122I-TTR in serum samples obtained from patients with FAC. Further, we have described structural, biochemical, and animal studies of AG10 which reveal mechanistic and structural insights on the ability of AG10 to mimic the disease suppressing T119M variant in stabilizing TTR.
The second part of the thesis discusses harnessing TTR as a platform to enhance in vivo half-life (t1/2) of therapeutic peptides. Native peptides typically display short in vivo t1/2, however conjugation of peptides to macromolecules causes steric hindrance which often harms the binding of peptides to target receptors, compromising the in vivo efficacy. Utilizing Gonadotropin Releasing Hormone (GnRH) as a model peptide, we show that t1/2 may be extended without compromising potency. Our approach involves endowing peptides with a small molecule that binds reversibly to the serum protein transthyretin. Our strategy was effective in enhancing the t1/2 of an agonist for GnRH receptor while maintaining its binding affinity, which was translated into superior in vivo efficacy.
The third and final part of the thesis describes our effort on developing a fluorescent probe to quantify TTR in human serum using fluorescence polarization. TTR is used as a marker for nutritional and inflammatory status in critical patients. This assay development has the potential to minimize lab cost, effort, and time with regards to determination of TTR concentration in patients.
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Šupuk, Enes. "Tribo-electrification and associated segregation of formulated bulk powders." Thesis, University of Leeds, 2009. http://eprints.hud.ac.uk/12603/.
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Powder handling operations can give rise to the electrification of particles therein, causing particles to adhere to the walls of processing equipment. This can lead to a loss of powder through deposition; however the problem often extends further and affects the end products’ quality. Segregation can also occur when powders have been subjected to tribo-electrification. The existing literature reveals that the few methods that are available to predict the dynamic charging of bulk powders are unsuitable for testing/handling small quantities of powders, some of which are highly active. Furthermore, very little work has been reported on the effect of triboelectrification on the segregation of components of mixtures. The objective of this work is to develop a methodology for investigating the triboelectrification of small quantities of bulk powders through the adaptation of a Retsch® shaking device, with the aim of characterising two common pharmaceutical excipients; namely alpha-lactose monohydrate (a-LM) and hydroxypropyl cellulose (HPC). The electric charge transferred to the particles has been quantified as a function of shaking time, frequency and container material. The temporal trend follows a first order rate process. Using numerical simulation based on Distinct Element Modelling, the transient charge accumulation of an assemblage of alumina beads inside the shaking device was predicted based on the single particle contact charge obtained from the experiments. It is shown that the inclusion of electrostatic parameters into the DEM model leads to an acceptable prediction of the charge build-up. Binary mixtures comprising of a-LM and HPC were firstly tribo-charged and then the wall adhered particles were separated by a selective dissolution of one component and the filtration of the non-dissolving component, followed by a gravimetric analysis. The findings reveal that a considerable level of segregation can take place on the wall-adhered particles. The methodology developed in this work has the potential to be used to characterise small quantities of pharmaceutical powders including active pharmaceutical ingredients (API), which are sparse in the early development stages.
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Brown, Stacy D., Andy Coop, Paul Trippier, and Eric Walters. "Contemporary Approaches For Teaching Medicinal Chemistry." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/5251.
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As the profession of pharmacy has transitioned from a chemistry-centered profession to a patient-centered profession, the role of medicinal chemistry in the curriculum has evolved. There is decreased emphasis on memorization of chemical structures, and priority placed on relating these structures to ADME, physical properties, and pharmacodynamics. Simultaneously, the delivery of this content has shifted from traditional lecture format to other styles. Here we discuss some new approaches to teaching medicinal chemistry.
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Doherty, C. "Microenvironmental role of pharmaceutical excipients in drug dissolution control." Thesis, University of Bradford, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374915.
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Douglas, Elizabeth Catherine. "The pharmaceutical care of patients with type 2 diabetes." Thesis, University of Strathclyde, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269997.
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Pearson, Alan. "Inhibition of crystal growth in a model pharmaceutical semisolid." Thesis, University of Strathclyde, 1988. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=26100.
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Crystal growth ofmiconazole andeconazole, two antimycoticimidazole derivatives, were studied with a view to preventing orlimiting crystal growth in atopical semisolid formulation. Crystal growth of the drugs from alcoholic solution was studied, and a ternary (water - cetostearyl alcohol - cetrimide) gel was prepared and considered as a model topical semisolid, principally using rheology and microscopy. The interaction of the drugs with gel components was studied, including interaction of crystalline drug material with aqueous surfactant solutions, and van't Hoff solubility profiles of drugs in nonaqueous components. The effect of gel quality (found to vary with manufacturing temperature) upon rate of crystal growth and crystalline habit was considered, and comparison was made between crystal growth in a ternary system, and in a similarly formulated semisolid emulsion. A range of molecules were screened as potential inhibitors of miconazole crystal growth in the ternary system, and β-cyclodextrin and Dextran-40 were studied in more detail. The additives reduced the rate of crystal growth and altered the proportion of the two habits, but did not prevent growth of crystals in the gels for any practical length of time. It was found that the appearance of a platy habit of miconazole was related to the development of a layered structure within the gel, and the effect of the additives, both in the bulk water phase, and within the layers of swollen gel phase, was considered.
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Lin, Yuh-Herng E. "Preparation and evaluation of poly (ortho esters) microspheres containing 5-fluorouracil." Scholarly Commons, 1998. https://scholarlycommons.pacific.edu/uop_etds/2331.
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Microencapsulation of 5-fluorouracil was successfully accomplished with poly(ortho esters) polymer by emulsification-solvent evaporation method. While actual drug loading increased with increasing drug load (5 to 15% w/w), the entrapment efficiency remained essentially unaffected under a given set of experimental conditions. Incorporation of sorbitan sesquioleate enhanced entrapment efficiency, decreased the volume-surface mean diameter of the poly(ortho esters) microspheres and provided controlled release of 5-fluorouracil. The volume of aqueous phase was more important than the concentration of polyvinyl alcohol in it. The entrapment efficiency improved from 13 to 33% (w/w) when the volume of the aqueous phase was increased from 20 to 80 ml. The volume of organic phase (methylene chloride) and the concentration of polymer in it played an important role. The use of smaller volumes of more concentrated polymer solution enhanced actual drug loading and entrapment efficiency, and produced larger microspheres. The release of 5-FU from the microspheres prepared with sorbitan sequioleate was found to be nearly independent of the initial drug load with a mean zero-order rate constant of 0.0063 % per hr. The data suggested that drug release was largely a diffusional process with contributions from dissolution and polymer degradation.
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Attardo, Giorgio G. (Giorgio Giovanni). "Drug design and synthesis of novel heteroanthracycline antitumor drugs." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74641.
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Novel heteroanthracycline antitumor drugs were designed based on structure activity relationship studies and known mechanisms of drug action. Their preparation required the development of a general synthetic approach.After extensive studies, three methodologies were developed for the general synthetic plan. The first method involved photoenolisation of 2,5-dimethoxybenzaldehyde and SO$ sb2$ entrapment of the o-quinodimethane to give 4,7-dimethoxy-1-hydroxy-1,3-dihydrobenzo(2,3-c) thiophene-2,2-dioxide. This compound served as a general intermediate towards the synthesis of several heteroanthracyclinones. It could be reduced to the oxathiin-2-oxide derivative which thermally extruded SO$ sb2$ to yield the o-quinodimethane. Reentrapment of this latter intermediate with various glyoxalates gave key isochroman derivatives. The second method is an improvement over the first. Isochromandiones with a C-1 hydroxyl functionality were prepared from oxidative demethylation of 1-hydroxyisochromans. These were obtained after acid hydrolysis of the coupling products between epoxides and the cuprate of 2,5-dimethoxy-6-methylbenzaldehydedioxane acetal. The third method involved a sequential cycloaddition routine with two o-quinodimethanes.
By combining newly developed techniques with known methods, a general synthetic plan was developed. Consequently, the total synthesis of six tetracyclic structural hybrids of the naphthoquinone(2,3-c) pyranyl class of antibiotics was accomplished; along with the total synthesis of (R) and (S) 1-(4$ sp prime$-O-p-nitrobenzoyl-N-trifluoroacetyldaunosamine)-$ 1,3$-dihydrothioxantho(2,3-c) thiophene-2,2-dioxide, p-nitrobenzyl(5,12-dihydroxy-3,4-dihydrothioxantho(2,3-c) and (3,2-c) pyran-3-yl)formate, and eight novel heteroanthracyclines with the 5,12-dioxo-2,3,5,12-tetrahydroanthraceno(2,3-c) pyranyl backbone. The diastereomeric mixture of (1$ sp prime$S, 1R, 3S) and (1$ sp prime$S, 1S, 3R) methyl(11-hydroxy-1-$(2 sp prime,3 sp prime,6 sp prime $-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-$5,12 $-dioxo-3,4,5,12-tetrahydroanthraceno(2,3-c) pyran-3-yl) formate was found to possess equipotent antileukemic activity to doxorubicin with no cross resistance.
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Ni, Na. "Preformulation and formulation of the anticancer drug, SarCNU." Diss., The University of Arizona, 2002. http://hdl.handle.net/10150/280237.
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SarCNU (NSC364432, 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea), is a new antitumor agent of the nitrosourea family. Solubilization studies have shown that SarCNU is soluble in a variety of solvents including water. However, it is highly unstable in aqueous solutions with its t90 of 6 hrs in water. Therefore, the overall purpose of this project is to investigate the stabilization of this drug in various conditions. Two parental formulations are also proposed based on the result of stabilization study. The stability of SarCNU at different pH, temperature, and pharmaceutically acceptable solvents were investigated by HPLC. The influences of light, pH (2.0, 4.0, 6.0, and 8.5) at 0.01M and 0.1M phosphate buffer, antioxidants (ascorbic acid and sodium bisulfite), and a chelating agent (disodium EDTA) at pH 2.0 and pH 6.0 were studied at room temperature. The stability of the drug was also determined in water, pharmaceutically acceptable solvents, and in different combinations of these solvents at 4 different temperatures (25, 37, 50, and 60°C). The degradation of the drug, which was catalyzed not only by specific acid and base, but also by general acid and base, follows first order kinetics. Antioxidants, EDTA, and light have no effect on the degradation rate, suggesting oxidation is not the main degradation pathway. The t90 in pure cosolvent was twenty-five to fifty times higher than that in water or semi-aqueous vehicles. One major degradation product was confirmed by GC-MS and NMR. Two other possible degradation products were also suggested by GC-MS. The degradation products suggest that the degradation of SarCNU involves hydrolysis of its amide group. The stability profile suggests that we can increase the shelf life of the drug by the use of a pure cosolvent. This approach can be used to store drug so that it can be diluted with aqueous solvent prior to injection with the aid of a double syringe. A freeze-dried formulation is also studied. Neat tertiary butyl alcohol (TBA), a low toxicity, high vapor pressure and low melting solvent, was determined to be an excellent medium for SarCNU. Lyophilization of SarCNU from pure TBA produces a uniform cake composed of needle-shaped crystals. Thermal analysis and gas chromatography indicate that the cake contains less than 0.001% residual solvent. The SarCNU cake can be readily reconstituted with either water or an aqueous solution of 40% propylene glycol and 10% ethanol. These reconstituted solutions are stable for 4 and 13 hours, respectively.
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Pinsuwan, Sirirat 1961. "Stability kinetics of 4-dedimethylamino sancycline, a new anti-tumor drug, in aqueous solutions." Diss., The University of Arizona, 1998. http://hdl.handle.net/10150/282753.
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4-Dedimethylamino sancycline (col-3) is a new antitumor antibiotic of the tetracycline family. Preformulation studies have indicated that col-3 is not stable in aqueous solutions. The overall purpose of this research project is to investigate the stability kinetics of this drug in aqueous solutions. The physicochemical properties of col-3, including melting point, UV spectrum, mass spectrum, dissociation constants and solubility were determined. Col-3 is an acidic compound with two pKₐ values of 5.9 (pKₐ₁) and 8.1 (pKₐ₂). It is slightly soluble in water (0.01 mg/mL) and readily soluble in organic solvents such as polyethylene glycol and benzyl alcohol. Although the solubility of col-3 increases with increasing pH, its stability decreases with increasing pH. A HPLC assay was developed to quantitate col-3 and separate its degradation products. Four major degradation products of col-3 were detected under alkaline conditions. These degradates were identified by their elution times and their UV-absorption spectra. The kinetics of degradation of col-3 in aqueous solution at 25°C were investigated by HPLC over the pH-range of 2-10. The Influence of pH, buffer concentration, light, temperature and some additives on the degradation rate were studied. The degradation of col-3 was found to follow first-order kinetics at 25°C. A rate expression covering the degradation of the various ionic forms of the drug was derived and shown to account for the shape of the experimental pH-rate profile. Under basic conditions, the degradation of col-3 involves oxidation, which is catalyzed by metal ions. The separation of the four initial degradation products of col-3 was investigated. Partial separation of these compounds is achieved by liquid-liquid extraction. However, due to the instability of these compounds, their complete isolation cannot be successful. The UV spectroscopic analysis of these compounds shows that an absorbance at 360 nm is partially decreased in degradates I and II and totally absent in degradates III and IV. These results suggest that the phenolic diketone moiety, which produces this absorption band, has been altered upon degradation.
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Johnson, Jennifer Lynne Huff. "Principles of formulation physical stability in aqueous media." Diss., The University of Arizona, 2005. http://hdl.handle.net/10150/282897.
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Drugs often require formulation techniques to increase their solubility and/or increase their stability in aqueous media. In cases where solubility enhancement is necessary, ideally, the physical stability of the formulation should be maintained upon administration. Unfortunately, in some cases, drugs precipitate out of solution when the formulation is introduced into aqueous media. Intravenously, drug precipitation can cause phlebitis and orally, it can hinder absorption. In order to avoid phlebitis, new intravenous (IV) parenterals are commonly screened by injection into animals. An in vitro dynamic injection model is introduced and validated. Twenty-one currently marketed IV products were used to investigate the validity of the model. Logistic regression and a receiver operator curve (ROC) indicate a value of 0.003 to best delineate phlebitic and non-phlebitic products. Measures of sensitivity (0.83), specificity (0.93), positive predictive value (0.93) and negative predictive value (0.78) indicate the model's accuracy and reliability. The model was tested to screen different formulations of a new proprietary antibiotic, Van-An. The opacities obtained for the formulation with acetate addition were significantly smaller than for the phosphate buffered formulation at 4 injection rates. In general the results suggest acetate as a better buffer species than phosphate for the pH range defined. The solubilization and stabilization of an orally administered formulation of a new anti-hepatitis C drug, PG301029, is established through a novel method of complexation. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) and PG301029 are dissolved in glacial acetic acid. The acetic acid is removed by roto-evaporation such that the drug exists primarily in the complexed form. Formulated PG301029 is found to be stable upon storage and, once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours. Acetic acid and HPbetaCD provide several formulation advantages. PG301029 and HPbetaCD are both soluble in acetic acid. Once prepared, the formulation can be stored in solid form. Upon reconstitution, the cyclodextrin both protects the drug from water and enhances the solubility of PG301029. This unique method results in a solid dosage form of PG301029 which is soluble, stable and highly bioavailable in mice when given orally.
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Flagg, Melissa L. "Bioprospecting, chemical investigations and drug discovery from Chilean plants." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/284167.
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This dissertation, completed as part of an International Cooperative Biodiversity Group (ICBG) Program, encompasses the field collection, taxonomic determination, bioassay-guided isolation, and chemical characterization of three plants native to Chile, each of which was collected using a distinct collection approach. Chuquiraga ulicina ssp. ulicina , collected by the ecological or environmental strategy, yielded ten compounds including four novel taraxastane-type triterpenoids, 3β-acetoxy-6β-hydroxytaraxasta-20-ene (1), 6β-hydroxytaraxast-20-en-3-one (2), 6β-hydroxytaraxasta-20-ene 3β-palmitate (3), and 3β, 6β-dihydroxytaraxasta-20-ene (4), together with the known triterpenoids lupeol (5), lupenyl acetate (6), lupenone (7), friedelinol ( 8), 3β-acetoxy-30-nor-lupan-20-one (9), and 30-norlupan-3β-ol-20-one (10). Lupeol (5) was the only compound to show antitubercular activity. Sphacele salviae, collected by the ethnobotanical or ethnomedical approach, allowed the isolation of three known compounds, including the two abietane diterpenoids carnosol ( 11) and rosmadial (12), as well as one pentacyclic triterpenoid, ursolic acid (13). Greigia sphacelata, collected according to the random approach, afforded nine compounds. These include the two novel flavanones 5,7,3'-trihydroxy-6,4' ,5'-trimethoxy flavanone (14) and 5,3'-dihydroxy-6,7,4',5 '-tetramethoxy flavanone (15), as well as four known phenylpropanoids, 1,3-O-di-trans-p-coumaroylglycerol (16), 1-O-trans-cournaroylglycerol (17 ), 1-(ω-feruloyldocosanoyl)glycerol and 1-(ω-feruloyltetracosanoyl)glycerol (18), and trans-ferulic acid 22-hydroxy docosanoic acid ester (19), and three known pentacyclic triterpenoids, arborinone (20), arborinol (21), and isoarborinol (22).
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Miketova, Petra 1967. "Mass spectrometry of compounds of biological interest." Diss., The University of Arizona, 1998. http://hdl.handle.net/10150/288810.
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Mass spectrometric methods, including EI, CI, FAB and ESI LC/MS have been surveyed as tools for identification and characterization of compounds of natural origin exhibiting biological activity. Bioactive catechins isolated from green tea were analyzed by mass spectral methods: EI spectra provided both molecular weight and structural information, including epimer differentiation. FAB mass spectrometry gave both molecular weight and structural information on all compounds. ESI LC/MS provided unambiguous MW information on all compounds and some additional structural data on compounds ECG and EGCG. ESI LC/MS provided a means for separation of all compounds in a mixture and is an appropriate method for analysis of a crude extract of this plant material. Based on the result from biological testing, showing that quinic acid derivatives possess considerable anti-HIV activity, four analogs of dicaffeoylquinic acid were characterized by mass spectral methods. An attempt was made to design a mass spectral method allowing the differentiation between the analogs. FAB mass spectral analysis provided good MW information for all compounds. In addition, ions representing the elimination of water from MH+ ion of the 3,5-DCQA-OAc clearly differentiated this isomer from the 3,4-DCQA-OAc. MIKES analysis of the MH+ ions of the acetate derivative confirmed the isomer specific water loss. ESI provided unambiguous MW information on all compounds, confirming that loss of water is specific for the 3,5-DCQA-OAc. The extract of the CSF in patients with ALL was surveyed for a suitable biomarker which would indicate brain tissue damage following therapy. Phospholipid levels in CSF in three groups of patients receiving different CNS propylaxis were monitored during the course of treatment and the elevated levels were correlated to the cognitive impairment evaluation results. As a result of the CNS propylaxis, the levels of phospholipids in CSF are significantly elevated, indicating disruption of brain cell membranes. Two major classes of phospholipid were identified by FAB mass spectral analysis, PC and SM. Their elevated levels were inversely correlated with the decreased scores from cognitive testing. A close correlation was found between the PC levels and some test scores.
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Kakkar, Tarundeep Singh. "Theoretical studies on enzyme inhibition kinetics." Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/289017.
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Enzyme inhibition studies are conducted to characterize enzymes and to examine drug-drug interactions. To characterize the inhibitory process (competitive, non-competitive and uncompetitive) and to determine the inhibitory constant (Kᵢ), data analysis techniques (e.g., Dixon, Lineweaver-Burk, etc.) are used to linearize the inherently non-linear rate of substrate metabolism vs. substrate concentration data. These techniques were developed before the general use of computers. However, many investigators still rely on these techniques in spite of the easy availability of non-linear regression fitting programs. In Chapter 2, three methods (simultaneous nonlinear regression fit (SNLR); Dixon; non-simultaneous, nonlinear fit [K(m,app)]) were compared for estimating Ki from simulated data sets generated from a competitive inhibition model equation with 10% CV added random error to the data values. Of the three methods, the SNLR method was found to be the most robust, the fastest and easiest to implement. The K(m,app) method also gave good estimates but was more time-consuming. The Dixon method failed to give accurate and precise estimates of Kᵢ. The purpose of the study in Chapter 3 was to examine the minimal experimental design needed to obtain reliable and robust estimates of Kᵢ (as well as V(max) and K(m)). Four cases were examined. In the experimental design that relied upon the least amount of data, a control data set was fit simultaneously with one of the substrate-inhibitor pairs (25-10 or 250-100 μM). A total of 4 rate values were analyzed per fit (i.e., 3 control + 1 inhibitor value). A total of 100 data sets were fit per substrate-inhibitor pair. The preceding was repeated for a random error of 20 %CV. Thus, the total number of experiments was reduced from 108 (in Chapter 2) to 12 (in Chapter 3) (Case IV). Good estimates of the enzyme kinetic parameters were obtained. In Chapter 4, the ability of the SNLR method to identify the correct mechanism of inhibition was evaluated; competitive or noncompetitive enzyme-inhibition. Two experimental designs were examined ("conventional, non-optimal" and "semi-minimal"). The semi-minimal design was successful in discriminating between the two enzyme-inhibition mechanisms even for data with 30 %CV added random error.
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Ran, Yingqing. "Applications of liposomes on anti-cancer agents." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/290047.
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Toxicity is a major limitation in clinical use of most anticancer drugs. Liposomes, especially targeted long-circulating liposomes, provide the possibility of delivering drugs specifically to targeted cancer tissues, thus increasing anticancer activity and minimizing toxicity. 2-4'-Amino-3'-methylphenylbenzothiazole (AMPB), a potent anticancer drug, is inappropriate for traditional oral or parenteral formulations because of its severe dose-limiting hepatotoxicity. Several PEG-coated liposomal formulations were developed by using different drug/lipid ratios. Particle size and encapsulation efficiency of each formulation were investigated; the most stable liposomal formulation was selected for animal testing. The formulation with AMPB/egg phosphatidyl choline/cholesterol/1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-polyethylene glycol 2000, PEG2000-DSPE in a 1/5/5/1 molar ratio is the best formulation. This formulation contains 2 mg/ml AMPB with encapsulation efficiency above 95%, average particle size 120-150 nm. Daunorubicin is a well known anti cancer agent. To minimize its cardiotoxicity, targeted folate-PEG-liposomes were developed in this study. The pH-gradient loading method was used to increase the drug loading efficiency. Above 97% loading efficiency was reached by creating a 3 to 4 unit pH difference across the liposome membrane. The final folate-PEG-liposomml formulation contained 2.5 mg/ml daunorubicin HCI, with average particle size of 110∼120 nm, pH of ∼7.4, and a drug/lipid ratio 1/20 (w/w). The solvent, chloroform, commonly used for liposome preparation, is harmful to humans. Therefore, halothane, a commonly used inhalation anesthetic, was used in this study in place of chloroform to prepare liposomes. AMPB and several other proprietary anticancer agents were formulated in liposomes by using halothane and chloroform. No obvious differences in physicochemical properties were observed between halothane and chloroform mediated liposomes.
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Miller, Allan Harvey 1968. "Predicting the solubility of hydrogen bonding aromatics." Thesis, The University of Arizona, 1993. http://hdl.handle.net/10150/291667.
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The AQUAFAC (Aqueous Functional Group Activity Coefficients) method for predicting aqueous activity coefficients proposed by Myrdal et al. (1992) is expanded to include for hydrogen bonding groups: hydroxy, carboxy, nitro and amino. Activity coefficients can be used to estimate aqueous solubility. Using aqueous solubility data, from a number of sources, for a set of subsituted aromatic compounds, group or q values are derived. Group values have been generated for a number of substituents, none have included hydrogen bonding groups (Myrdal et al., 1992,1993). Q values are related to activity coefficients through the following relationship: log gammaw = Sigmaniqi where log gammaw is the log of the activity coefficient, qi is the group value subtituent i and ni is the group frequency. Ortho effects between hydrogen bonding groups is also examined. Intramoleculat hydrogen bonding involving carboxy substituted compounds, in this research, does appear to affect aqueous solubility.
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Yang, Gang. "Aqueous solubility prediction of organic compounds." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/298795.
Full textAbstract:
Aqueous solubility is one of the most important physical properties to consider in drug discovery and development. Drug candidates with poor solubility often have poor bioavailability, which leads to increased developmental cost and efforts. Therefore, there is a strong trend to perform solubility screening of drug candidates as early as possible in the drug discovery and development process. While experimental methods are being developed to increase the throughput of solubility measurement, the development of aqueous solubility prediction methods can be a powerful complementary tool. This dissertation starts by compiling a large collection of aqueous solubility data for organic compounds covering diverse classes of structures. The data set is first used to critically evaluate the General Solubility Equation (Yalkowsky et al., 1980, 1999), one of the most widely used methods for aqueous solubility prediction. The General Solubility Equation performs very well overall as measured by the average absolute error (AAE) of 0.56 log unit. Detailed analyses indicate that it gives better predictions for non-electrolytes than some classes of weak electrolytes. This method is then compared with a method based on an amended solvation energy relationship, which considers the hydrogen bonding potentials of functional groups. It is shown that averaging the prediction results from the two methods gives better prediction than either method alone. Following the concept of the AQUAFAC model developed by Myrdal et al. (1992, 1993, 1995), an extended version of the original structural fragmentation scheme is developed. The model is trained on the data set and has an R2 value of 0.881 and a standard error of estimation of 0.819 log unit. Group contribution parameters for a set of 104 fragments are obtained. A new group contribution model is developed to suit the needs in the early drug discovery stage, when melting information is generally not available. Calculated octanol-water partition coefficient is included in the model. The model has a standard error of estimation of 0.814 log unit. When evaluated on independent test sets, the new model provides comparable prediction results with the other two models. The independence of the new model of experimental melting information makes it a suitable tool for aqueous solubility screening in early drug discovery.
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Alvarez-Nunez, Fernando Antonio. "Solubilization of drugs. Formulation development perspective." Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/289009.
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This dissertation discusses some aspects of the solubilization of drugs from the perspective of the formulator. Chapter I emphasizes the importance of this research as well as the study of the practical aspects of aqueous solubilization of drugs. The most important solubilization techniques such as pH control, cosolvency, micellization, and complexation are introduced in Chapter II. Chapter III evaluates specifically the cosolvency technique by means of a discussion of the effect of pharmaceutically acceptable cosolvents upon the solubilization of several drugs. Chapter IV discusses the micellization technique in detail. In this chapter, the effect of Tween 80 on the solubilization of several drugs is evaluated. Finally, in Chapter V, the consequences of the dilution of a pH solubilized formulation are evaluated by means of two in vitro formulation dilution methods.
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Amerasinghe, Nirosha Devika. "The action of drugs on potassium-evoked release of acetylcholine from rat hippocampal prisms with special reference to tacrine and classical cholinesterase inhibitors." Thesis, King's College London (University of London), 1995. https://kclpure.kcl.ac.uk/portal/en/theses/the-action-of-drugs-on-potassiumevoked-release-of-acetylcholine-from-rat-hippocampal-prisms-with-special-reference-to-tacrine-and-classical-cholinesterase-inhibitors(1cb08fc7-c7f5-4b1c-8a7c-7a03038e0990).html.
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Tan, Soo Choon. "Bioanalysis of ibuprofen enantiomers : application to pharmacokinetic studies in young and elderly volunteers." Thesis, King's College London (University of London), 1996. https://kclpure.kcl.ac.uk/portal/en/theses/bioanalysis-of-ibuprofen-enantiomers--application-to-pharmacokinetic-studies-in-young-and-elderly-volunteers(53fca9ed-c40d-49d6-afdb-9060fc8f1d15).html.
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Williams, Brett H. "Design and synthesis of 3-[N-(cyclopropylmethyl) amino]-7-(methoxy or hydroxy)-2, 2-dimethyl-1-tetralone analogs as potential opioid receptor antagonists." Scholarly Commons, 2004. https://scholarlycommons.pacific.edu/uop_etds/591.
Full textAbstract:
A series of 3-aminotetralins were synthesized as potential opioid antagonists. Each proposed target compound was based on a 3-(mono- or dialkylamino )-7 -(hydroxy or methoxy)-2, 2-dimethyl-1-tetralone parent structure. Three synthetic schemes were developed utilizing the common intermediate, ethyl3-benzylamino-2, 2-dimethyl-4-(4- methoxyphenyl)butyrate 3. In Scheme I, compound 3 was modified through a series of six steps to obtain 3-(N-methyl-N-cyclopropanecarboxamido )-7 -methoxy-2, 2-dimethyl- 1-hydroxy-1-phenyltetralin (9). To carry out further synthetic steps on the intermediate 9 required the reduction of the amide function, which proved to be problematic in terms of product isolation.
Scheme II was a four-step procedure, which utilized the intermediate ethyl 3- amino-2, 2 dimethyl-4-(4-methoxyphenyl)butyrate (4), also utilized in Scheme I. Ester hydrolysis of the amino ester 4 produced the amino acid 12. Internal cyclization of 12 yielded the key intermediate, 3-amino-7 -methoxy-2, 2-dimethyl-1-tetralone (13). TheNalkylation step was carried out on 13 and this yielded the target compounds, 3-[N- ( cyclopropylmethyl)amino ]- and 3-[N, N-( dicyclopropylmethyl)amino ]-7 -methoxy-2, 2- dimethyl-1-tetralone (14, 15). Subsequently, compounds 14 and 15 were 0-demethylated to obtain the respective target compounds, 3-[N-(cyclopropylmethyl)amino]- and 3-[N, N-(dicyclopropylmethyl)amino ]-7-hydroxy-2, 2-dimethyl-1-tetralone (16, 17).
Scheme III was an alternate synthetic route to obtain the target compounds 3-[Nmethyl- N-( cyclopropylmethyl)amino ]-2, 2-dimethyl-7-(hydroxy or methoxy)-1-hydroxy- 1-phenyltetralin (10, 11) without the amide reduction step required in Scheme I. The intermediate 3 was N-methylated to form the 3-N-methyl-N-benzylamino ester 18 by the Eschweiler-Clarke procedure. Compound 18 was converted through a series of four steps to obtain 3-[ N-methyl-N-( cyclopropylmethyl)amino ]-7 -methoxy-2, 2-dimethyl-1- tetralone (22), a target compound which was 0-demethylated to obtain compound 23, the 7-0H analog.
The mono- and dialkylated 3-aminotetralins were synthesized and confirmed for purity and correct molecular formula by utilizing 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The target compounds 14, 15, 16, 17,22 and 23 were converted to their salts and are being analyzed for opioid-related activity in receptor binding assays.
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Chopra, Ranjana. "The influence of shape on the properties of pharmaceutical pellets." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245138.
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Allen, Christine Jane. "Polycaprolactone-♭-poly(ethylene oxide) copolymer micelles : physico-chemical characterization and application in drug delivery." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35557.
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This thesis describes the preparation, characterization and biological study of block copolymer aggregates as drug delivery vehicles. A novel method is described for the synthesis of biodegradable and biocompatible copolymers of polycaprolactone-b-poly(ethylene oxide). The copolymers and their aggregates are then characterized with special attention given to properties which are of most interest to applications in drug delivery such as copolymer composition, thermal behavior, critical water content, critical micelle concentration, partition coefficient of hydrophobic solubilizates, morphology of the aggregates and in vitro biocompatibility. The polycaprolactone-b-poly(ethylene oxide) copolymer micelles are first explored as a delivery vehicle for the neurotrophic agents FK506 and L-658,818. The in vitro delivery and biological activity of the micelle-incorporated drugs are confirmed in PC12 cell cultures. The in vivo biological distribution of the micelle-incorporated FK506 was assessed in Sprague Dawley rats both 6 and 24 hours following intravenous administration. Also, the biological activity of the micelle-incorporated FK506 was shown to be retained in vivo using the sciatic nerve crush model of peripheral neuropathy in Hanover Wistar rats. The question of whether or not the cellular internalization of the polycaprolactone- b-poly(ethylene oxide) micelles proceeds by an endocytotic mechanism is addressed in PC12 cell cultures. Finally, the polycaprolactone- b-poly(ethylene oxide) micelles are explored as a delivery vehicle for dihydrotestosterone. We report on several of the physico-chemical characteristics of the micelle-incorporated dihydrotestosterone as well as in vitro delivery in HeLa cells which have been cotransfected with the MMTV-LUC reporter gene and the androgen receptor.
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Millard, Jeffrey W. "Synergistic solubilization." Diss., The University of Arizona, 2002. http://hdl.handle.net/10150/289853.
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This Dissertation presents a number of projects and novel ideas related to pharmaceutical solution chemistry, including: combination solubilization and formulation techniques, predictive modeling methods, and experimentally demonstrated complexation theory. Chapter 1 presents both the underlying theory and experimental results of a formulation project for a novel anticancer drug which resulted in an 8,000-fold increase in solubility. Chapter 2 presents an extensive computer and literature-based predictive model for the estimation of cosolvent solubilization. Finally, Chapter 3 presents an exhaustive theoretical derivation with experimental validation of a novel method to determine complexation stability constants in mixed stoichiometric systems of cyclodextrin complexes.