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Colli, Corrado. "Industrial crystallisation and polymorphism of active pharmaceutical ingredients." Thesis, Nottingham Trent University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442086.
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Smith, Kenneth Baird. "Crystallisation of active pharmaceutical ingredients using ionic liquids." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6039/.
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It is proposed that Ionic Liquids offer a new opportunity for exploration into a novel medium for processing Active Pharmaceutical Ingredients, particularly with respect to habit control and polymorphic form. A review of relevant literature relating to ionic liquids properties, commercial applications and current research has been summarised together with background into fundamental crystallisation theory. Crystallisations using thermal methods were employed at laboratory scale and the physical properties of the resultant powders were analysed and compared to commonly encountered crystal forms. For paracetamol it was found that the morphology of the crystals could be manipulated, producing in some cases, habits not reported for conventional organic solvent crystallisation. This was achieved through changing both the IL used and the saturation of the system whilst in all cases retaining the most stable polymorph. ILs ILs to be ‘designed’ for a given API but greater understanding of the interactions between IL and solute are required first. Properties such as increased solvation power, thermal stability, liquidus range and low vapour pressure bring a number of advantages when designing industrial crystallisations. However ILs also have a number of disadvantages including phase separation problems.
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Dogbe, Selasi Cudjoe. "Predictive milling of active pharmaceutical ingredients and excipients." Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/17937/.
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Spiral jet milling is a size reduction process used in various industries, ranging from paints to food and pharmaceuticals. It has great benefit in the pharmaceutical industry due to its ability to reduce particulate solids to micron sizes and narrow size distributions. Despite its heavy usage, the underlying size reduction mechanism of the mill is not well understood. However it is generally known that the milling behaviour is dependent on the grinding conditions of the mill, as well as the materials physical and mechanical properties. The system is also very energy inefficient. In this work the milling behaviour of active pharmaceutical ingredients and excipients in the spiral jet mill has been analysed based on their mechanical properties, as established from the Ghadiri and Zhang semi-brittle breakage model. Using the Single Particle Impact Test Rig, the breakability index (αH/KC2) of three pharmaceutical materials (paracetamol, aspirin, and α-lactose monohydrate) is determined. It is shown that the order of breakability is paracetamol > aspirin > α-lactose monohydrate. For milling studies the Hosokawa Alpine Aeroplex Spiral Jet Mill 50AS is used. The change in specific surface area (ΔSSA) due to milling is quantified by size analysis and related to the breakability indices. The order of ΔSSA is α-lactose monohydrate > paracetamol > aspirin at high grinding pressure conditions. The loading of particles in the grinding chamber of the mill is found to be an important characteristic for the classification of milled materials in addition to the effects of centrifugal and drag forces. Numerical simulations have been carried out and used to analyse the behaviour of the spiral jet mill. Using Computational Fluid Dynamics, the mechanics of internal particle classification by size of the 50AS has been analysed. Particles of 2 µm and less are shown to be classified. The Discrete Element Method is coupled with Computational Fluid Dynamics to investigate the effect of grinding conditions and particle properties on the particle motion and fluid-particle energy transfer, including gas pressure, the number of particles and the particle size distribution. A very small amount of energy is transferred to the particles from the fluid, highlighting the energy inefficiency of the system. Interparticle interactions are found to have a greater amount of dissipated energy compared to particle-wall interactions, which suggests interparticle collisions are the primary source of particle breakage. The majority of the stress exerted on the particles is close to the wall of the mill, with the normal stress being greater than the shear stress. A very low proportion of particles are found to be in contact at a given time, indicating particle breakage occurs from instantaneous collisions rather than particles shearing against each other. Finally the potential for scale-up of the spiral jet mill is investigated based on the fluid power input to the system. There is a good comparison of the ΔSSA of α-lactose monohydrate milled in four different mills at similar fluid power input conditions. Two of the mills are the 50AS and the Hosokawa Alpine Piconizer (33 AS), and the other two are of different design but with internal diameters of 2 inches and 4 inches, i.e. roughly similar size to the Hosokawa mills. The latter two mills had a greater fluid power as the grinding nozzle diameters are larger than the Hosokawa mills.
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Mazura, Sergiy. "Effect of active pharmaceutical ingredients on superoxide dismutase." Thesis, Київський національний університет технологій та дизайну, 2019. https://er.knutd.edu.ua/handle/123456789/13082.
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Tan, Li Ph D. Massachusetts Institute of Technology. "Heterogeneous nucleation of active pharmaceutical ingredients on polymers : applications in continuous pharmaceutical manufacturing." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/101511.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2015.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 92-105).
In this thesis work, we aimed to explore crystallization processes for small molecule API compounds based on engineered polymer surfaces that could be used in continuous manufacturing. First, we identified a library of polymers that can be used and selected PVA as the model polymer based on its solution and film properties. We also illustrated a rational approach for designing and fabricating PVA film surfaces for increasing heterogeneous nucleation rate of different compounds and enable polymorph selection. The design philosophy was to select prevalent angles between major faces of crystals according to a selection of compounds, and to create substrate surfaces with indentations that include these angles. Nucleation induction time trends showed that heterogeneous nucleation rates were accelerated by at least an order of magnitude in the presence of PVA due to the favorable interactions between the model compounds and the polymer. Nucleation rates were further increased for patterned substrates with matching geometries. Surface indentations with non-matching angles resulted in faster nucleation rates than flat films but slower than matching geometries because they only increased the effective area of the films and their roughness. X-ray diffraction was used to reveal faces that preferentially interacted with the PVA side chains and to deduce possible arrangement of solute molecules at the corners of the indentations. Combining X-ray data and morphology of the crystal product, we suggest that matching geometries on the substrate enhanced nucleation of compounds. In addition to enhancing nucleation rate, polymorph selection was possible in the presence of the polymer substrate to yield a higher percentage of thermodynamically stable gamma indomethacin. Offline Raman experiments and in-line morphology determination confirmed that polymorph control of the final crystal product via kinetic control of the nucleation process was viable. For the aspirin system, the 85 degree angle lead to the highest rate of nucleation; for the polymorphic indomethacin system, XRPD results showed that gamma form preferentially formed on the PVA films with 65 and 80 degree angles leading to the largest reduction in nucleation induction time. Kinetic Monte Carlo simulation showed that a crystallizer incorporating both nucleation and crystal growth in the absence of active mass transfer would have too small a throughput and too large a footprint to be useful. The main reasons were long average nucleation induction times and slow crystal growth in the absence of convection. A set of batch desupersaturation experiments showed that mass transfer limited growth dominate the crystal growth kinetics at low supersaturations when nucleation events were suppressed. An increase in the bulk fluid velocity increased the effective growth kinetics in the system when mass transfer kinetics dominated. Steady state modeling based on the first principle approach was performed using a combination of Navier Stokes Equations and diffusion-convection mass transport equations. The modeling result demonstrated that for mass transfer from a moving fluid to a stationary surface, a thin momentum and concentration boundary layer existed at the leading edge, which resulted in much higher local mass transfer rates. In the absence of momentum boundary layers, mass transfer could only occur via diffusion, which resulted in slow growth kinetics. The first principle model was used to derive dimensionless number correlations for the continuous crystallizer.
by Li Tan.
Ph. D.
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Almeida, Hugo F. D. "Treatment of aqueous effluents contaminated with active pharmaceutical ingredients." Doctoral thesis, Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica António Xavier, 2017. http://hdl.handle.net/10362/78785.
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"The need to significantly improve human living conditions led to a large
increase in the worldwide consumption of pharmaceutical drugs. Over the past
few years, the development of advanced analytical tools and investigations on
wastewater samples confirmed the presence of residual amounts of active
pharmaceutical ingredients (APIs) in wastewater treatment plants (WWTPs),
sewage treatment plants (STPs), groundwater and drinking water. Even at low
concentrations (ng.L-1 – μg.L-1), the regular contact and ingeston of APIs can lead
to deleterious effects towards living organisms. Numerous studies demonstrated
that APIs present in WWTPs are a matter of concern towards wildlife and public
health. Given the widespread occurance of these drugs in aquatic ecossystems
and their deleterious effects, the development of strategies able to mitigate their
introduction in the aquatic environment is of great importance.(...)"N/A
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Depasquale, Roberto. "Mechanical activation of secondary processed orally inhaled active pharmaceutical ingredients." Thesis, University of Bath, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665449.
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The physicochemical properties and surface chemistry of orally inhaled active pharmaceutical ingredients (API) are critical to the quality attributes of dry powder inhaler (DPI) formulations. The requirement to reduce the particle size distribution of the APIs to a respirable range, largely performed through air-jet micronisation, imparts large amounts of energy to the drug particles, which together with particle fracture and size reduction, it is accompanied by the generation of structural defects and, at the limit, the formation of amorphous regions. This is known as mechanical activation, which may cause instability in the physicochemical properties and interfacial chemistry at the particle surface as it undergoes structural relaxation. During the thermodynamically driven relaxation process, differing drug properties may lead to DPI formulations with unpredictable formulation structure and product functionality. A fundamental understanding of the structural relaxation dynamics is therefore essential in the development and commercialisation of a quality-by-design led inhalation product. This thesis investigated the structural relaxation dynamics of micronised fluticasone propionate (FP), salmeterol xinafoate (SX) and glycopyrrolate bromide (GLY). Physicochemical properties and surface interfacial chemistry, via cohesive-adhesive balance (CAB) measurements, of micronised drug are assessed as a function of environmental stressed laagering over well-defined periods of time and in situ conditioning in hydrofluoroalkane (HFA). The influence of these dynamics upon DPI performance was also examined in both binary (FP, SX, GLY) and tertiary formulations (FP-SX). The results indicated how structural relaxation of hydrophobic and hydrophilic APIs trigger off different stress relaxation pathways with different sensitivities to laagering conditions. These data suggested that the introduction of a post-micronisation conditioning step may expedite structural relaxation of hydrophobic APIs. Whilst the physical properties of hydrophobic APIs are largely unaffected by mechanical activation, surface interfacial chemistry governing inter-particulate forces between API and the lactose carrier is directly affected by environmental conditions of temperature and relative humidity during structural relaxation. The study also showed the potential use of post-micronisation conditioning to tailor the surface chemistry properties of APIs. For hydrophilic APIs, data suggested that post-micronisation conditioning is essential in enabling physical and chemical stability of inhaled formulations. Furthermore, in vitro aerosolisation studies suggested that the aerodynamic particle size distribution and fine particle mass were directly affected by post-micronisation laagering conditions. The importance of generating a well defined, understood and controlled design space throughout product development dictates the need for more robust API processing prior to DPI formulation. This work highlights how a tailored post-micronisation laagering strategy can have a significant effect on physicochemical and interfacial properties as well as product performance of binary and tertiary carrier based DPI formulations.
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Wang, Alan. "Quality Management System implementation for repackagers of active pharmaceutical ingredients." Thesis, California State University, Dominguez Hills, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10020158.
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Active Pharmaceutical Ingredient (API) repackagers play a niche, yet critical role in the expansive pharmaceuticals industry. Many repackagers have sub-optimally implemented quality management systems (QMS) leading to sub-optimal performance and elevated risks. This study sets out to demonstrate a strategy to strengthen the case for quality for this industry sector. Dr. Deming's Plan-Do-Study-Act cycle serves as the study's framework, while Phil Crosby's Quality Is Free philosophy forms the theoretical basis. An archival measure of FDA Warning Letters concerning APIs has been performed to bring a considerable failure cost factor to the forefront. A statistical analysis has been performed on data available from the study's pilot firm to demonstrate relationships between quality-related and revenue performance indicators in order to present a bottom-line approach preferred by management. Results from the study indicate a linkage between QMS factors and business outcomes and call for improved understanding, increased support, and a push towards QMS maturation.
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Nyamayaro, Kudzanai. "Dissolution control of highly soluble active pharmaceutical ingredients via cocrystallisation." Thesis, Cape Peninsula University of Technology, 2017. http://hdl.handle.net/20.500.11838/2673.
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Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2017.Crystal engineering involves the manipulation of intermolecular interactions to design functionalised crystalline materials and has proved to be an effective tool for the modification of physicochemical properties of active pharmaceutical ingredients (APIs). In the first section of this study, the aim was to systematically influence the rate of dissolution of a highly soluble active pharmaceutical ingredient using crystal engineering principles. Salicylic acid (SA) was employed as a model API to form multicomponent crystals with a series of selected cinchona alkaloids, namely quinine (QUIN), quinidine (QUID), cinchonine (CINC), cinchonidine (CIND), N-benzylquininium chloride (NBQUIN), N-benzylcinchonidinium chloride (NBCIND) and N-benzylcinchoninium chloride (NBCINC). The resulting novel crystalline forms were found to be salts, and were characterised using single crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. The dissolution profiles of the salicylate salts, measured from an aqueous media using high performance liquid chromatography-mass spectroscopy, show a significant decrease in the rate of dissolution of SA. Subsequently, Hirshfeld surface analysis was used as a tool for quantitative and qualitative comparison of the crystal structures. This study indicates that the rate of dissolution can be successfully influenced by methodically adding extra hydrophobic groups onto the coformer. In the second section, we applied the information obtained from the SA studies to acetylsalicylic acid (aspirin, ASA). We sought to improve its thermal stability and dissolution via the formation of new solid forms with the aforementioned cinchona alkaloids. We successfully synthesized a novel drug-drug salt of an analgesic, non-steroidal antiinflammatory and antipyretic drug (ASA), and an antimalarial and analgesic drug (QUIN). The salt was formed both by using solution methods and liquid assisted grinding - a green chemistry technique. The salt exhibited physicochemical properties different from the parent drugs, and a reduced rate of dissolution.
National Research Foundation(NRF)
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Weyna, David Rudy. "Crystal Engineering of Multiple Component Crystal Forms of Active Pharmaceutical Ingredients." Scholar Commons, 2011. http://scholarcommons.usf.edu/etd/3406.
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Enhancing the physicochemical properties of solid-state materials through crystal engineering enables optimization of these materials without covalent modification. Cocrystals have become a reliable means to generate novel crystalline forms with multiple components and they exhibit different physicochemical properties compared to the individual components. This dissertation exemplifies methodologies to generate cocrystals of active pharmaceutical ingredients (API's) based upon knowledge of supramolecular interactions (supramolecular synthons), while focusing on enhanced delivery through in vitro and in vivo processes with both salts and cocrystals respectively.
The utility of mechanochemistry involving small amounts of an appropriate solvent, or solvent drop grinding (SDG), has been shown to reliably reproduce cocrystals with the anti-convulsant carbamazepine that were originally obtained by solution crystallization. This technique has been confirmed as a reliable screening method using solvents in which both components exhibit some solubility. The benefits of this technique lie in the time and cost efficiency associated with it as well as its inherently small environmental impact making it a "Green" method. SDG was also used as an efficient way to discover cocrystals of the anti-inflammatory meloxicam with carboxylic acids after analysis of existing reports and the analysis of structural data from the Cambridge Structural Database (CSD) to guide the choice of coformer. It has been shown that SDG can be used to screen for cocrystalline forms that are also obtainable by solution crystallization which is important in later stage development and manufacturing including but not limited to large scale up processes. Single crystals suitable for single crystal X-ray diffraction were obtained with meloxicam and two of the coformers, fumaric and succinic acid. Some of the meloxicam cocrystals exhibited enhanced pharmacokinetic (PK) profiles in rats exemplifying significantly higher serum concentrations after only fifteen minutes and consistently higher exposure over the time studied while others maintained lower exposure. This reveals that cocrystals can fine tune the PK profile of meloxicam in order to reduce or enhance exposure.
Two different sulfonate salts, 4-hydroxybenzenesulfonate (p-phenolsulfonate) and 4-chlorobenzenesulfonate, of the anti-spastic agent (R,S) baclofen were developed by strategically interrupting the intramolecularly stabilized zwitterionic structure of baclofen. This zwitterionic structure results in low solubility associated with physiological pH required for intrathecal administration. Structural data for both salts in the form of single crystal X-ray diffraction data was successfully obtained. Solubility based on baclofen was assessed and shown to increase in pure water and at pH's 1 and 7. Only the 4-chlorobenzenesulonate salt maintained an increased solubility over two days at pH 7 making it a viable candidate for further study in terms of intrathecal administration. During crystallization experiments with (R,S) baclofen two polymorphic forms of the baclofen lactam were generated, Forms II and III. Both forms are conformational polymorphs confirmed by single crystal X-ray diffraction and Form II has a Z' of 4 with an unusual arrangement of enantiomers.
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Cox, Jason R. "Controlling the Polymorphism of Active Pharmaceutical Ingredients with Two-Dimensional Templates." Digital WPI, 2009. https://digitalcommons.wpi.edu/etd-theses/362.
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Self-assembled monolayers on gold and glass substrates are employed as templates to direct the crystal growth and polymorphism of active pharmaceutical ingredients. Orthogonal approaches are used to control polymorphism either through complementary hydrogen-bonding interactions or through repulsive interactions.
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Djerafi, Rania. "Particle design and coating of pharmaceutical ingredients using supercritical fluid techniques." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0141.
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Ce travail de thèse a été dédié à l'élaboration de formulations de médicaments par procédé Supercritique Anti-Solvant (SAS). L'étude a été divisée en deux sections : la production de co-précipités de médicament / polymère en utilisant le procédé SAS et l’enrobage de particules de taille micrométrique en utilisant un lit fluidisé couplé au procédé SAS. L'éthyl cellulose a été choisi comme polymère biocompatible pour la préparation des deux systèmes. La micronisation de l'éthyl cellulose par procédé SAS a été réalisée avec succès; des particules submicroniques ayant une taille moyenne de 300 nm ont été obtenues. Les formulations composites micronisées, la quercétine et la rifampicine avec de l'éthyl cellulose ont été élaborées par co-précipitation à pression et température modérées (10 MPa et 35 °C). L'étude de faisabilité d'une nouvelle méthode d’enrobage par lit fluidisé en milieu supercritique couplé à l'utilisation du procédé SAS a été réalisée. Ce procédé vert alternatif permet d’enrober des particules micrométriques avec peu d'agglomération et une bonne qualité du film d’enrobage. Des expériences d’enrobage de billes de verre ont été effectuées dans des conditions opératoires variées pour deux configurations d'injection différentes, pulvérisation par le haut ou par le bas de l’autoclave. De meilleurs résultats ont été obtenus dans les expériences de pulvérisation par le haut, notamment en termes de qualité de revêtement. Ce travail de thèse apporte des éléments nouveaux et pertinents pour un meilleur contrôle des procédés d’enrobage en milieu supercritiqueThe elaboration of drug formulations using supercritical anti-solvent process was the subject of this thesis. The study was divided in two sections: production of drug/polymer co-precipitates using SAS process and coating of micron-sized particles using a fluidized bed coupled with SAS process. Ethyl cellulose was chosen as biocompatible polymer for preparing the two systems. The micronization of ethyl cellulose using GRAS ethyl acetate solvent through a supercritical anti-solvent process was successfully performed; submicron particles with mean size of 300 nm were obtained. Micronized drug composites of quercetin or rifampicin with ethyl cellulose at moderate pressure and temperature (10 MPa and 35 °C) were produced by co-precipitation using supercritical anti-solvent process. Depending on the operating conditions, different particle size, particle size distribution and morphology of the product, but also crystallinity and drug loading were observed.The feasibility study of a novel coating method using fluidization in supercritical medium coupled with SAS process has been demonstrated to be a good alternative green process to elaborate micron-sized coated particles with few agglomeration and good coating quality. Coating experiments of glass beads were carried out at different conditions for two different injection configurations, top and bottom spray. Better results were achieved in the top spray experiments in term of coating quality. This Ph. D. work brings new and relevant elements for a better control of the coating processes in supercritical medium
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Lubbe, Elizabeth Cornelia. "Influence of particle size on solubility of active pharmaceutical ingredients / E.C. Lubbe." Thesis, North-West University, 2012. http://hdl.handle.net/10394/8763.
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The aqueous solubility of an active pharmaceutical ingredient (API) is an important property that requires evaluation during early development and prior to formulation of the final product. With general, experimental, solubility testing of different APIs, the question always arises as to whether particle size had been determined beforehand or not. All available literature suggests that particle size, for pharmaceutical powders, does not significantly affect equilibrium solubility. The dissolution rate will differ according to different particle sizes, but the overall results should be identical after equilibrium is established.
This study was therefore planned to investigate as to whether different particle size fractions of the same API, dissolving at different rates, would all reach solubility equilibrium within 24 hours. Also, APIs from different solubility classes were investigated, because poorly soluble substances would most likely require a longer period of time to equilibrate. The time period of 24 hours was selected, because many published solubility studies report using that interval and is it the standard for our research group also.
Available APIs were selected to determine the influence (if any) of particle size on their equilibrium solubilities and the time required for attaining that status. For the purpose of this investigation, five APIs were selected from compounds at our disposal in-house, ranging from freely soluble to poorly soluble in the order: chloroquine phosphate > pyrazinamide > mefloquine hydrochloride > closantel sodium > roxithromycin.
Solubility studies were successfully completed on four of the five APIs selected. For closantel sodium, pyrazinamide and roxithromycin it was demonstrated that the 24 hour test period was sufficient for the attainment of equilibrium solubility, regardless of the particle size fractions tested. Surprisingly, the only API in this study for which 24 hours was an insufficient test period was mefloquine HCl, which was not the least soluble compound tested. Further testing would be required to clarify this anomaly.
What was evident from the outcomes of this investigation was that although the ubiquitous 24 hour solubility test may work well in many cases, its suitability should be reviewed on a case-by-case basis and not just for the most poorly soluble compounds. Researchers testing solubility at temperatures lower than 37°C should be especially cautious of using a standardised test period, because equilibrium solubility would take longer to achieve with less energy available to the system.Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013
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Smith, Mark Richard. "Near-infrared spectroscopic assay transfer for active pharmaceutical ingredients in intact tablets." Thesis, University College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414758.
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Maddar, Faduma. "Innovative approaches towards understanding the dissolution and growth of active pharmaceutical ingredients." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/101295/.
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Studies of the kinetics and mechanisms of the dissolution and growth of crystals and other solids are beneficial in many areas of science. In pharmaceutical science, dissolution testing is a key quality control procedure used to determine the rate at which an active pharmaceutical ingredient (API) is released and is thus available for absorption in the gastro-intestinal tract. However, the general processes governing the dissolution and growth of crystals are poorly understood despite many years of study. This thesis focuses on the implementation of various microscopy and electrochemical techniques as a novel approach to further understand the dissolution and growth of API crystals and amorphous solids. The motive of the first part of the thesis, was the use of atomic force microscopy (AFM) to obtain new insight into API dissolution and growth from both the crystalline form and amorphous solid state. Studies of the crystalline API, bicalutamide have focused on measuring the 3D morphological changes of individual microcrystals in aqueous solution, in real time, from which the intrinsic dissolution rates of each crystal surface exposed to solution have been extracted. In addition, with finite element method (FEM) modelling, interfacial concentrations around the dissolving crystal have been obtained, allowing the elucidation of the kinetic regime of the overall dissolution reaction. A major conclusion of this work is that the dissolution kinetics accelerate significantly during the process, due to changes in nanoscale features on the surface. AFM was then used to examine targeted regions of dissolving amorphous solid dispersions (ASDs), comprising of felodipine API and the water-soluble polymer copovidone, in aqueous solution, together with a localized electrochemical-droplet (flux measuring) technique and Raman spectroscopy. This multi-microscopy approach allowed real-time information about initial API release rates, and changes in solid-state composition and morphology during dissolution. This thesis then transitions to the study of nanocrystallization of APIs using nanopipettes under electrochemical control in a nanoscale anti-solvent configuration using bicalutamide, as an example system. A key feature of the technique is that a bias between an electrode in the nanopipette, and one in bulk solution, can be used to control the supersaturation level at the end of the nanopipette and the current-time response detects nucleation and growth events. Using Raman microscopy the formation of the least stable crystal polymorph of Form II was demonstrated. To highlight the generality of nanopipette-based electrochemical techniques, a final results chapter reports the use of scanning electrochemical cell microscopy (SECCM) to study the electro-oxidation of nicotinamide adenine dinucleotide (NADH), on various carbon electrodes, showing how active surface sites are readily identified and quantified.
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Setty, Prashant (Prashant Neelappanavara). "Optimal handling of Highly Active Pharmaceutical Ingredients during milling and blending operations." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/81020.
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Thesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering; in conjunction with the Leaders for Global Operations Program at MIT, 2013.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 32-33).
This thesis investigates best practices for Highly Active Pharmaceutical Ingredient (HAPI) milling and blending. We utilize a qualitative analysis centering on a benchmarking study and quantitative analyses using a probabilistic capacity simulation and tradeoff methodology. The analyses indicate that the growing number of HAPI products in a manufacturer's portfolio may result in capacity constraints. Therefore, we recommend that manufacturers pursue process improvement technologies. Suggested process improvements include implementing online particle size measurement and Wash in Place (WIP) and Clean in Place (CIP) cleaning systems. Online particle size measurement allows for better process control and eliminates the need for HAPI blending for homogenization. Automated WIP and CIP systems decrease changeover time and allow for higher equipment availability. Additionally, the results of the analyses suggest that manufacturers consider standardizing transportation containers with the upstream vendors and downstream consumers. Lastly, from an organizational standpoint, we recommend that manufacturers include both subject matter experts and operations personnel when developing and implementing internal guidelines so as to ensure the guidelines are practical and uniformly applied.
by Prashant Setty.
S.M.
M.B.A.
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Xia, Xin. "Dissolving the Rocks : Solubility Enhancement of Active Pharmaceutical Ingredients using Mesoporous Silica." Doctoral thesis, Stockholms universitet, Institutionen för material- och miljökemi (MMK), 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-103190.
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Poor aqueous solubility is one of the greatest barriers for new drug candidates to enter toxicology studies, let alone clinical trials. This thesis focuses on contributing to solving this problem, evaluating the oral toxicity of mesoporous silica particles, and enhancing the apparent solubility and bioavailability of active pharmaceutical ingredients in vitro and in vivo using mesoporous silica particles. Toxicological studies in rats showed that two types of mesoporous silica particles given by oral administration were well tolerated without showing clinical signs of toxicity. Solubility enhancement, including in vivo bioavailability and in vitro intracellular activity, has been evaluated for selected drug compounds. Mesoporous silica was shown to effectively increase drug solubility by stabilizing the amorphous state of APIs, such as itraconazole (anti-fungal), dasatinib (anti-cancer), atazanavir (anti-HIV) and PA-824 (anti-tuberculosis). Itraconazole was successfully loaded into a variety of porous silica materials showing a distinct improvement in the dissolution properties in comparison to non-porous silica materials (and the free drug). Microporosity in SBA-15 particles has advantages in stabilizing the supersaturation state of dasatinib. Small pore sizes show better confinement of atazanavir, contributing to a higher dissolution of the drug compound. In the in vivo animal studies, NFM-1 loaded with atazanavir shows a four-fold increase in bioavailability compared to free crystalline atazanavir. PA-824 has a higher dissolution rate and solubility after loading into AMS-6 mesoporous particles. The loaded particles show similar antibacterial activity as the free PA-824. This thesis aims at highlighting some of the important factors enabling the selection of adequate mesoporous structures to enhance the pharmacokinetic profile of poorly water-soluble compounds, and preparing the scientific framework for uncovering the effects of drug confinement within mesopores of varying structural properties.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Submitted. Paper 5: Submitted.
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Wales, Craig. "Multi-component crystallisation approaches to controlling crystalline forms of active pharmaceutical ingredients." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/3941/.
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Multi-component crystallisation is investigated as a route to controlling crystalline forms of selected materials that possess pharmaceutical properties. This includes investigating the use of co-crystallisation methodology to selectively crystallise metastable polymorphs and solvated forms of these materials. This differs from the conventional use of co-crystallisation, as the aim of this aspect of the investigation is not to obtain a molecular complex of the two components, but instead for them to crystallise independently, while one component perturbs the solution environment to direct the crystallisation of the second component towards a different, often metastable, polymorph (or solvate). This co-crystallisation methodology is used as a route to crystallising new or elusive polymorphs (or solvates) of the active pharmaceutical ingredients paracetamol, piroxicam, gallic acid monohydrate and piracetam. It is also demonstrated that the use of this method can lead to crystal forms with otherwise unobtainable structural features. Co-crystallisation is also investigated as a route to controlling the ionisation state of piroxicam in the formation of molecular complexes. Molecular complexes were formed with a number of mono-substituted benzoic acids as well as with nitrogen-heterocycles and strong acids. In the molecular complexes formed, piroxicam was found to adopt the non-ionised, zwitterionic, anionic or cationic form, depending on the co-former used. Attempts are made to rationalise the occurrence of each ionisation state by consideration of the relative pKa values of piroxicam and the co-formers. The hydrogen bonded supramolecular synthons in these molecular complexes are also investigated. Co-crystallisation is also used as a route to obtaining molecular complexes of paracetamol and its derivative, 4-acetamidobenzoic acid, with nitrogen-heterocycles as co-formers. Molecular complexes of the two, with similar co-formers, are compared in terms of their hydrogen bonded supramolecular synthons. Despite having otherwise similar structural features, the phenolic hydroxyl group in paracetamol and carboxylic acid group in 4-acetamidobenzoic acid result in the formation of very different synthons and in some cases different component ratios. The susceptibility of 4-acetamidobenzoic acid to deprotonation is found to play a major role in the differences observed. Molecular complexes of paracetamol with co-formers containing multiple carboxylic acid groups are also investigated, with a view towards further crystal engineering approaches for molecular complexes of paracetamol. Piracetam complexes with carboxylic acids are investigated in a similar manner. The potential for transfer of a range of these multi-component crystallisations into a non-evaporative environment, with a view to implementing continuous crystallisation approaches, is also investigated. This transfer is found to be challenging for the systems investigated.
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Santos, Ramos Javier. "Process development for the synthesis at industrial scale of active pharmaceutical ingredients." Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/671919.
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Aquesta Tesi és friut d’una col·laboració entre l’empresa Farmhispania S.A. i el grup de Recerca de Síntesi Orgànica Estereoselectiva del Departament de Química de la Universitat Autònoma de Barcelona que té com a principal finalitat el desenvolupament de processos químics per tal d’obtenir a escala industrial una sèrie de principis actius d’interès comercial.
En la Tesi s’estudia en profunditat diverses rutes sintètiques prèviament definides per tal d’optimitzar-les i portar a terme l’escalat passant de treballar d’escala de pocs grams fins a escala de kilograms mitjançant l’ús de reactors químics.
En aquesta Tesi s’ha desenvolupat i implementat una metodologia d’avaluació de risc per a la qualitat del procés (PQRA) que ha permès definir els punts crítics associats a cada paràmetre de procés i establir estratègies de control adequades.
L’eina metodològica desenvolupada s’utilitzarà en altres projectes de fabricació interna o contractual a Farmhispania. SA i ha de servir per facilitar l’obtenció de l’aprovació de les autoritats reguladores per a la comercialització dels seus productes.
Aquesta tesi també conté un apartat que està relacionat amb la utilització d’eines informàtiques in-silico com el programari Dynochem. La utilització d’aquest programari ha permès reduir el nombre d’experiments necessaris per optimitzar i comprendre els processos i va accelerar el desenvolupament dels processos. El seu ús serà avaluat durant els propers projectes executats a Farmhispania S.A per ajudar a desenvolupar i ampliar mètodes de fabricació futurs.Esta Tesis es fruto de una colaboración entre la empresa Farmhispania S.A. y el grupo de Investigación de Síntesis Orgánica Estereoselectiva del Departamento de Química de la Universidad Autónoma de Barcelona que tiene como principal finalidad el desarrollo de procesos químicos para obtener a escala industrial una serie de principios activos de interés comercial. En la Tesis se estudian en profundidad varias rutas sintéticas previamente definidas para optimizarlas y llevar a cabo el escalado del proceso pasando de trabajar de escala de pocos gramos hasta escala de kilogramos mediante el uso de reactores químicos. En esta Tesis se ha desarrollado e implementado una metodología de evaluación de riesgo para la calidad del proceso (PQRA) que ha permitido definir los puntos críticos asociados a cada parámetro de proceso y establecer estrategias de control adecuadas. La herramienta metodológica desarrollada se utilizará en otros proyectos de fabricación interna o contractual a Farmhispania S.A. y debe servir para facilitar la obtención de la aprobación de las autoridades reguladoras para la comercialización de sus productos. Esta tesis también contiene un apartado que está relacionado con la utilización de herramientas informáticas in-silico como el software Dynochem. La utilización de este software ha permitido reducir el número de experimentos necesarios para optimizar y comprender los procesos y aceleró el desarrollo de los procesos estudiados. Su uso será evaluado durante los próximos proyectos ejecutados en Farmhispania S.A. para ayudar a desarrollar métodos de fabricación futuros.
This Thesis is the result of a collaboration between the company Farmhispania S.A. and the Stereoselective Organic Synthesis Research group of the Department of Chemistry of the Universitat Autònoma de Barcelona whose main purpose is the development of chemical processes to obtain a series of active pharmaceutical ingredients of commercial interest on an industrial scale. In the Thesis, several previously defined synthetic routes are deeply studied to optimize them and to carry out its scale-up from a few grams to kilograms through the use of chemical reactors. In this Thesis, a process quality risk assessment methodology (PQRA) has been developed and implemented. This methodology, has allowed defining the critical points associated with each process parameter and establishing adequate control strategies. The methodological tool developed will be used in other internal or contractual manufacturing projects at Farmhispania S.A. and it should serve to facilitate obtaining the approval of the regulatory authorities for the commercialization of its products. This thesis also contains a section that is related with the use of in-silico tools such as the Dynochem software. The use of this software has made possible to reduce the number of experiments necessary to optimize and understand the processes and accelerated the development of the studied processes. Its use, will be evaluated during the next projects executed in Farmhispania S.A. to help develop future manufacturing methods.
Universitat Autònoma de Barcelona. Programa de Doctorat en Química
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Silva, Ana Maria Freitas da. "A simple closed-loop membrane process for the purification of active pharmaceutical ingredients." Master's thesis, Faculdade de Ciências e Tecnologia, 2012. http://hdl.handle.net/10362/10707.
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Arora, Deepali. "High-Pressure Microfluidic Crystallization of Active Pharmaceutical Ingredients Using a Gas Antisolvent Process." Thesis, Curtin University, 2021. http://hdl.handle.net/20.500.11937/86251.
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The work focused on the development of a novel microfluidic platform that enables continuous pharmaceutical crystallization in an efficient and reproducible manner using pressurized carbon dioxide. Excellent control over the pharmaceutical crystal shape, size and structure was achieved. This is a step forward in the process intensification of existing crystallization methods. It combines greener processes and flexible microtechnology to improve the bioavailability and therapeutic efficiency of pharmaceutical products.
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Kubavat, Harshal A. "The influence of crystallization on the mechanical and interfacial properties of active pharmaceutical ingredients." Thesis, University of Bath, 2011. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.548090.
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Lucero, Borja Diego Sebastián. "Solubility and Dissolution Rate of Active Pharmaceutical Ingredients: Dissolution Media and Effect of Enhancers." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/671762.
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The present doctoral thesis is focused on the effect of pH, enhancers and biorelevant media in the Solubility and the Dissolution Rates of some selected acidic active pharmaceutical ingredients (API). Because of the effect of these physicochemical parameters in the bioavailability of drugs and their pharmacological action, deepen the knowledge on the factors affecting the dissolution properties is of paramount importance in the drug development process.
Solubility and dissolution rates are examined in different aqueous solutions and buffering systems, accounting for the pH values of main interest in the gastrointestinal tract (2.0, 5.8 and 6.5), together with dissolution media that simulate intestinal fluids in fasted (FaSSIF) and fed states (FeSSIF). It is also determined in these media and discussed the effect of some excipients intended as dissolution enhancers, such as cyclodextrins, polyvinylpyrrolidones and hydroxypropylcellulose. Finally, differential scanning calorimetry was used to identify solid-solid interactions between excipients and APIs. As a complementary investigation, this thesis also presents a comparative study of the reference shake-flask and potentiometric CheqSol methods for the determination of solubility, including APIs with different acid/base properties (acidic, amphoteric and basic).
The study confirms that solubility is pH dependent, and an accurate pKa determination of the drugs is needed to detect the presence of concurrent aggregation or complexation reactions affecting the amount of compound dissolved. As expected, the addition of excipients increases the solubility of APIs, but in different degrees depending on the drug, excipient, and pH conditions. Solubility in simulated intestinal fluids is generally improved, and the addition of excipients might increase, diminish or even cancel the enhancement, depending on the matrix formed. Interestingly, the factors improving the solubility of an API do not necessarily enhance its dissolution rate. The release of the drug from its compressed solid form (tablet) is a complex process, involving an aqueous boundary layer between the solid and the bulk solution.
The results of this thesis point out the need of systematic and detailed dissolution studies in the step of pharmaceutical formulation, as long as the enhancement produced by a particular excipient in a singular dissolution medium can be characteristic of an individual API, and these results cannot be uncritically extended to other drugs.La presente tesis doctoral se enfoca en el efecto del pH, excipientes y medios biorelevantes sobre la solubilidad y velocidad de disolución de algunos principios activos (PA). Dado el efecto de estos parámetros fisicoquímicos en la biodisponibilidad de los fármacos y su acción farmacológica, el profundizar en el conocimiento de los factores que afectan estas propiedades de disolución es de suma importancia en el desarrollo de medicamentos. La solubilidad y velocidad de disolución se examinan en diferentes soluciones y sistemas tamponadores, de acuerdo a valores de pH de interés del tracto gastrointestinal, junto a medios de disolución que simulan fluidos intestinales. También se determina el efecto que puedan tener en estos medios, sustancias como excipientes que aumenten la disolución, tales como ciclodextrinas, polivinilpirrolidonas e hidroxipropilcelulosa. Calorimetría diferencial de barrido fue utilizada para identificar interacciones sólido-sólido entre excipientes y PA. Complementariamente, en esta tesis también se presenta un estudio comparativo entre el método de referencia de equilibrio de fases y el método potenciométrico CheqSol para la determinación de solubilidad, incluyendo PA de diferentes propiedades fisicoquímicas. El estudio confirma la dependencia entre pH y solubilidad, una medición exacta del pKa de los fármacos es necesaria para detectar la presencia de agregados o complejos que afecten la cantidad de muestra disuelta. Como se esperaba, la adición de excipientes incrementa la solubilidad pero en diferente grado dependiendo del compuesto, el excipiente y las condiciones de pH. La solubilidad generalmente es mejorada cuando se usan medios biorelevantes, mientras que el uso de excipientes en estos medios podría incrementar, disminuir o cancelar el efecto de solubilización, dependiendo de la matriz formada. Sorpresivamente, los factores que incrementan la solubilidad no necesariamente lo hacen en la velocidad de disolución. La liberación del compuesto desde la superficie de la tableta es un proceso complejo, relacionado con la capa acuosa intermedia entre la tableta y la solución. Los resultados de esta tesis señalan la necesidad de estudios sistemáticos y detallados en el paso previo de formulación farmacéutica, pues la mejora producida por un excipiente en particular en condiciones singulares del medio, puede ser característica para un PA específico, y estos resultados no deben ser extrapolados sin criterio a otros fármacos.
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Chen, Xiaoyu. "Investigation of liposomes and liposomal gel for prolonging the therapeutic effects of pharmaceutical ingredients." HKBU Institutional Repository, 2013. http://repository.hkbu.edu.hk/etd_ra/1524.
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Wahl, Oliver [Verfasser], and Ulrike [Gutachter] Holzgrabe. "Impurity Profiling of Challenging Active Pharmaceutical Ingredients without Chromophore / Oliver Wahl. Gutachter: Ulrike Holzgrabe." Würzburg : Universität Würzburg, 2016. http://d-nb.info/1112466258/34.
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Piggott, Matthew John. "Characterising the force balance between active pharmaceutical ingredients for inhalation and its impact on deposition." Thesis, University of Nottingham, 2013. http://eprints.nottingham.ac.uk/28807/.
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Interparticulate interactions play a significant role in determining the downstream behaviours of all pharmaceutical formulations and are therefore essential considerations when approaching formulation design. Inhalation product formulation in particular is inherently bound to an understanding of these forces. Delivery of drugs to the lower airways to treat conditions like asthma and COPD requires a particle size of below 5 micron. This implicitly demands micronization of the active pharmaceutical ingredients (APls) and this process renders many particles of large surface area with high surface energies and an auto-adhesive tendency. There is therefore a concurrent reduction in the flowability and dispersion properties of these systems. The interactive character predisposes agglomeration, flocculation or device retention and will compromise manufacture, stability, device function, and the aerosolization behavior of a formulation. Ultimately the ability of any aerosolized API to reach the deep airways is dependent upon adhesion force dynamics. As such, an appreciation of the forces of attraction and scale of particulate interactions within inhaler technology is critical if a successful drug delivery device is to be realized. The advancement of the atomic force microscope (AFM) as a force probing apparatus, has meant that it is now possible to measure the force of adhesion between two particles of interest. However these measurements could not easily be compared, because there is no simple means to account for differences in the contact regime (geometrics) between measurements. However, the development of the cohesive adhesive balance (CAB) approach by Begat, Morton, Stainforth and Price in 2004 has offered a means to negate this limitation. Using a colloidal probe microscopy (CPM) derived technique a particle of a selected material of interest (API, carrier molecule etc.) is attached to an AFM cantilever and ramped onto and off the surface of another material of interest (adhesion measurement), and to a surface of the same material as the tip (cohesion measurement). By graphically plotting the adhesive force values of a series of tips, as a function of the cohesive force values of the same tips, a representation of the relative particle interaction can be obtained. Quantitative information regarding the adhesive/cohesive nature of the interaction can then be extracted from the graph and a description of the interaction formulated that can be compared to other material combinations. The CAB work carried out to date has used recrystallized model substrates. These molecularly flat surfaces ensured there would be no difference between the contact geometry of a functionalised AFM probe and the adhesive and cohesive surfaces of the study respectively. In this fashion the only variable between the two measurements would be the chemical interactivity, and not the interactive surface area. However while using such methodology guarantees the validity of the approach, it is not necessarily a true representation of the materials 'in-situ' and requires more complex sample preparation and complex experimental design. For a variety of reasons this can be misleading in its own right. This thesis details the .investigation into the application of an adapted CAB approach in characterizing the force balance between APls for inhalation in their real state. In so doing, the aim was to see whether such a CAB would offer a quicker and simpler, yet relevant and informative assessment of a drug system force balance. It was hoped that said force balance could in turn be associated with a measurable impact upon the formulation performance of the characterised ingredients as measured 'in-vitro'. This interest was particularly directed at the lesser characterized pressurized metered dose inhaler (pMOI) systems. While these formulations are solvent based, it was of interest to identify whether a simple API to API challenge could infer a descriptive balance that could link to 'in-vitro' performance. Furthermore there was interest in evaluating the use of a range of surface specific imaging techniques to analyse the deposition dynamics of the combination formulations. It was hoped that by doing so, the localisation of the individual components within the binary deposits could again be associated back to the force balance of that system, and that an appreciation of the capability of the techniques involved would be gained. The work that follows therefore commences with the evaluation and description of the capacity for the CAB approach to be adapted to measure force relationships between real beclomethasone dipropionate (BOP) particles and pMDI component surfaces. From this assessment it was found that even with relatively smooth substrates, the combination of bulky functional particles and the inherent substrate roughness caused a critical failure in the CAB model. The parity between cohesive and adhesive geometries of contact was excessively stretched, leading to a loss of force normalisation which was reflected in uncorrelated CAB plots. As a consequence little could be confidently gleaned from the force data acquired, although there was the suggestion that the use of a fluorinated ethylene proplylene (FEP) coating reduced the adhesive interaction between the APls and the pMDI canister wall. This was then followed by an attempt to find a compromise between the model crystal substrates of a pure CAB process and the real particle morphologies that had caused the CAB model to fail. Using a compression process to form API powder compacts, in conjunction with small and discreet functional particles, a confident CAB was achieved for two combinations of APls selected on the basis of surface energy and physical stability analysis. Salbutamol sulphate was characterised with beclomethasone dipropionate, and salmeterol xinafoate with fluticasone propionate. Both combinations showed CAB plots with a sufficiently strong linear regression analysis to suggest a broad accuracy of force balance assessment. Both beta2-agonists showed cohesively dominated relationships with respect to the paired glucocortiocoids, while in reverse both glucocorticoids showed adhesively dominated relationships with the beta2-agonists. There was concern raised over the compression process of the powder discs, and its impact on the physicochemical state of the APls, with some thermodynamic evidence of polymorphic changes that required further work. The next chapter looks at the 'in-vitro' deposition performance of the two API combinations from a HFA134a pMDI system by analysis in an Andersen Cascade Impactor (ACI). The coformulation of salmeterol with fluticasone induced an improvement in the fine particle performance of fluticasone, with a concurrent decrease in the fine particle performance of salmeterol. This impact was hypothesised to be related to alterations in the structure and strength of particle-particle agglomerates. The impact on deposition performance of coformulating beclomethasone and salbutamol was unclear, as a critical unexplained loss of beclomethasone by total recovered mass was seen from all beclomethasone containing formulations. This instability of beclomethasone within the HFA134a system, precluded an accurate assessment of a direct impact on salbutamol deposition. The final chapter, compared a range of surface specific imaging techniques, including scanning electron microscopy (SEM), desorption electrospray ionization mass spectrometry (DESI), Raman spectrometry and time-of-flight secondary ion mass spectrometry (ToF-SIMS) in assessing the extent and nature of 'in-vitro' co-deposition from the salmeterol and fluticasone pMDI formulations. It was apparent that the deposition of the two APls on ACI plates was not likely to be directly comparable assessment of the incidence of particle co-deposition 'in-vivo' due to the forced nature of nozzle directed impaction. However the combination of techniques employed produced a wealth of physical and chemical data that did suggest that the two APls showed extensive co-ordination 'in-vitro'. Raman spectroscopy was able to identify individual particle character and showed frequent salmeterol and fluticasone particle combinations, but suffered from exceptionally long run times and anomalies from photoreactive surface elements. The use of a multivariate approach to ToF-SIMs analysis defined the strong co-association of the two APls, although could not differentiate particle to particle deposition. Multivariate curve resolution (MeR) was used and produced distinct components that segregated ions from both APIS from the background plate but not from each other. SEM imaging was able to define the morphologies of the deposited particles, but was unable to differentiate the two. DES I imaging showed the presence of the two APls together within several drug spots, but could not be used to investigate individual drug spots, and the distribution within, due to inadequate spatial resolution and differences in desorption efficacy. While the co-association of the two APls was observed, the lack of a comparator in another combination of APls made the link between deposition performance and force balance purely descriptive. It was unclear as to whether the force balance of the system lends itself to a particular increase in co-deposition behaviour. However it was apparent that the analytical techniques employed all had respective strengths and weaknesses as mapping tools, and with further work with other formulations could be used to provide a tailored formulation screening process, if subsequent links to force balances could be made.
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Noonan, Terence James. "Preformulation solid-state supramolecular beneficiation of selected active pharmaceutical ingredients and a novel drug candidate." Doctoral thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/29279.
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The aim from the outset of the project on which this thesis is based was to make use of contemporary methods in the field of supramolecular chemistry to improve the suboptimal physicochemical properties of selected compounds for use in the formulation of pharmaceutical products. The compounds selected were: Clevudine, an established drug that is currently in use for the treatment of chronic hepatitis B infections, 6-(3- (Methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-imidazo[1,2-b]pyridazine (MMV652103), a novel antimalarial drug candidate that displayed good in vitro potency against multidrug resistant and sensitive plasmodial strains and ()-α-lipoamide, a bioactive antioxidant that is currently in use for the clinical treatment of diabetic neuropathy and has other potential uses e.g. as an antiretroviral agent. The methods utilised in pursuit of novel solid-state forms of the compounds included a combination of crystal engineering and experimental screening for polymorphs, solvates/hydrates, cyclodextrin (CD) inclusion complexes, pharmaceutical salts and co-crystals. Screening involved grinding and co-precipitation methods. Characterisation of new forms involved thermal analytical methods including hot stage microscopy (HSM), differential thermal analysis (DTA), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and variable temperature powder X-ray diffraction (VTPXRD). In all cases where single-crystals of adequate quality and size were successfully prepared, the crystal structures were elucidated by single-crystal X-ray diffraction. Molecular conformations, inter- and intramolecular interactions and packing arrangements of crystals were characterised. Polymorphism of clevudine was addressed for the first time. Three polymorphs of clevudine were isolated and characterised in terms of crystal structures and thermal behaviour. The solubility and thermodynamic stability ranking of the three forms was established and schematic energy-temperature diagrams were constructed through the use of the thermal methods listed above, solvent-mediated transition experiments and by kinetic solubility experiments. Characterisation by infrared (IR) spectroscopy has made it possible to promptly and effortlessly identify each form. Multiple novel solid-state forms of the antimalarial drug candidate MMV652103 were produced including four polymorphs, a hydrate, five co-crystals and a salt. The solubility and thermodynamic stability ranking of the polymorphs was established through thermal analysis and kinetic solubility experiments. An amorphous form showed an improvement in dissolution rate, with a concentration 3-4 times that of the crystalline forms after one hour. The designation as co-crystals or salts was accomplished through the use of single crystal X-ray structural analysis and confirmed by IR spectroscopy. Stoichiometry was determined by 1 H - nuclear magnetic resonance (NMR) spectroscopy. A customised solubility experiment was carried out to compare the dissolution rates of the various multi-component forms of MMV652103 in an environment simulating the human duodenum. An enhancement of the dissolution rate was observed with a maximum concentration 4.7 times higher for the co-crystal than for the untreated active compound. Inclusion complexation of ()-α-lipoamide with native CDs (α-, β-, and γ-CD) was confirmed by comparison of putative PXRD traces with those of known isostructural series. Novel complexes were synthesised with the above mentioned native CDs as well as with three derivatised CDs (TRIMEA, DIMEB and TRIMEB). The crystal structures were characterised by single-crystal X-ray diffraction. Host-guest stoichiometries were determined by 1 H-NMR spectroscopy and validated by the ratio of mass loss through TGA. Water composition, melting points and thermal stability in terms of decomposition and guest loss temperatures of the complexes were determined by means of the appropriate thermal methods (DTA, TGA, DSC, HSM). Phase solubility experiments were carried out and showed solubility enhancements for the bioactive compound ranging from a 1.8 fold increase with α-CD to a 7.4 fold increase with randomly methylated β-CD.
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WILSON, HEATHER-ANNE MARIE. "OPTIMIZING THE RELEASE OF BOTANICAL INGREDIENTS FROM ANTIPERSPIRANTS/DEODORANTS." University of Cincinnati / OhioLINK, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1069796149.
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Bradley, Jonathan P. "Development and application of high-resolution solid-state NMR methods for probing polymorphism of active pharmaceutical ingredients." Thesis, University of Warwick, 2011. http://wrap.warwick.ac.uk/55436/.
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The objective of the work presented in this thesis is to apply advanced high-resolution solid-state NMR methods for the structural characterisation of organic crystalline systems, specifically active pharmaceutical ingredients (APIs). The determination of the crystal packing is an important stage in the development of new APIs, and solid-state magic angle spinning (MAS) NMR is well suited to complement existing techniques. Improvements in spectral resolution in recent years have led to the development of homonuclear correlation experiments capable of identifying intermolecular proximities between 1H nuclei. These experiments provide a powerful probe of the local environment of each 1H nucleus in the three-dimensional structure, and the majority of the research presented in this thesis is focussed on the development of detailed analysis methods that may be used to extract more detailed structural information from 2D solid-state NMR correlation spectra. Throughout this thesis, experimental solid-state NMR results are analysed alongside computational data, including density matrix simulations of experiments and first principles calculations of shielding tensors. The results of simulations of a 1H DQ (double-quantum) correlation experiment are compared to experiment, in order to investigate the dependence of the DQ build-up (change in peak intensity as a function of the recoupling pulse duration) on the precise nature of the dipolar coupled proton network. It is found (for a simple dipeptide) that quantitative information on the relative H{H distance may be obtained by comparison of the maximum intensity reached in the corresponding 1H DQ build-up curves. This method is then applied to pharmaceutically relevant systems. It is shown that differences between two polymorphs of an API may be identified in the 1H DQ build-up of particular peaks, and, following the analysis for the dipeptide, this difference may be ascribed to differences in specific intermolecular distances. In the study of a second API, -indomethacin, it is shown that the standard 1H DQ experiment provides insufficient resolution to identify specific DQ peaks. A recently developed 1H(DQ){13C correlation experiment is used to exploit the higher resolution in the 13C dimension, hence allowing the extraction of DQ build-up curves which may be used, in conjunction with simulations, to obtain structural data. Finally, a recently discovered polymorph of the API ibuprofen is studied using 13C CPMAS (cross polarisation) solid-state NMR. Through the use of first-principles calculations, the 13C spectra of both the well known and new polymorphs are assigned, and the conversion of an amorphous solid to the new polymorph is monitored through the use of temperature-controlled solid-state NMR experiments.
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Hutacharoen, Panatpong. "Prediction of partition coefficients and solubilities of active pharmaceutical ingredients with the SAFT-γ Mie group-contribution approach." Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/56214.
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Partition coefficient and solubility are very useful properties in a variety of product and process design problems. Especially in the octanol-water system, partition coefficients (Ki_OW) are used as indicators for a drug's lipophilicity which is a key physicochemical property in drug design. Solid phase solubility is a fundamental parameter in the design of crystallisation processes commonly used in the pharmaceutical and agrochemical industries. The ability to predict these properties from the molecular structure of compounds is therefore highly desirable. In this thesis, the recently developed SAFT-γ Mie group-contribution (GC) equation of state is used as a predictive framework to study the thermodynamic properties of multifunctional compounds. The SAFT-γ Mie approach allows one to determine the thermo-physical properties of molecules in terms of the constituent functional groups that represent their unique molecular identity. The parameters for each functional group are developed from fluid-phase equilibrium data for simple compounds and, once estimated, they are applied to the study of more complex molecules in a predictive manner. Novel SAFT-γ models are developed for fundamental systems such as alkane + water and alcohol + water mixtures, which are typically involved in various chemical and biological applications. These GC models are able to describe accurately mutual solubilities of water and hydrocarbons which span more than ten orders of magnitude, and are also transferable to the modelling of multifunctional compounds. As a result, a quantitative prediction of Ki_OW and solubility is achieved for several active pharmaceutical ingredients (API) including ibuprofen, ketoprofen, lovastatin, and simvastatin. We find that an important factor that needs to be taken into account in modelling these complex APIs is the formation of intramolecular hydrogen bonds (IMHB). IMHB have a pronounced effect on molecular structure and thermodynamic properties, but are often overlooked by other predictive approaches. Modelling complex organic molecules with the consideration of IMHB is challenging, especially for GC approaches which do not take into account details of molecular conformation. In this thesis, an effective treatment for IMHB is developed within the SAFT-γ Mie framework and proven to improve the property prediction of molecules with IMHB, especially in highly associated solvents. The findings in this thesis validate the applicability of the SAFT-γ Mie approach in modelling complex multifunctional molecules and demonstrate its broad relevance for the pharmaceutical industry.
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Lees, Katherine Edith. "The sorption fate of active pharmaceutical ingredients in soils receiving high wastewater inputs and implications for risk assessments." Thesis, University of Plymouth, 2018. http://hdl.handle.net/10026.1/11977.
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Population growth, increasing affluence, and greater access to medicines have led to an increase in active pharmaceutical ingredients (APIs) entering sewerage networks. Wastewater in lower and lower middle-income countries use that use wastewater for irrigation may use untreated or poorly treated wastewater resulting in the potential for greater concentrations of APIs to enter soils in this way. Wastewater re-used for irrigation is currently not included in environmental risk assessments for APIs in soils. The addition of wastewater to soils changes the organic content and can increase the pH of soils, which will have an impact on the fate of any ionisable APIs introduced during the irrigation process. As the input of APIs to soil from wastewater irrigation is not currently included in the risk assessments, this is an area that requires increased attention. A study was undertaken using a modified sorption-desorption batch equilibrium method (OECD 106) to simulate the addition of synthetic wastewater (SWW) to soils compared to a normal OECD 106 study. The APIs studied were ofloxacin, propranolol, naproxen and nevirapine, and represent a range of API physico-chemical properties. These experiments showed that the changes to soil properties (pH and dissolved organic carbon (DOC)) caused by irrigation with SWW can change the fate of APIs in soils. The ionisation state of the API at the altered pH was more important for the positively charged propranolol than it was for the negatively charged naproxen and neutral nevirapine. The Kd and Log Koc increased during the sorption experiment in some cases with SWW. This has implications on the current terrestrial risk assessment where the trigger value for a more detailed soil risk assessment in at Log Koc >4. If the experiment is only performed in 10 mM CaCl2 as is currently required this may lead to unknown risks of APIs in wastewater irrigated soils not being taken into account. Three soil sterilisation or microbial enzyme suppression methods were investigated to identify how successful they were and if there was any impact on the soil physical chemical structure. Gamma irradiation, autoclaving and the addition of 0.2 g L-1 sodium azide were studied. None of the methods successfully sterilised the soils and some changes in soils were identified post-treatment. Autoclaving destroyed the soil structure, turning it into a fine powder and significantly increasing DOC. Sodium azide changed the pH of the loam soil but not the sandy loam soil. Literature suggested that gamma irradiation was the most likely to sterilise the soils with the least amount of disturbance to its physico-chemical properties but increases in DOC were identified in the current study. The changes to soils after sterilisation varied depending on the individual soil properties, indicating that soils should be studied on a case-by-case basis. Irrigation with wastewater provides continuous inputs of chemicals into soils throughout the growing season so it is vital that more work is done to understand the ultimate fate of pollutants in soil as a result. Wastewater has the potential to change the fate of chemicals in soils meaning that current risk assessments may not thoroughly assess all risks involved.
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Nguyen, Thi Trinh Lan. "Extrusion- spheronization of pharmaceutical products : system for the delivery of active ingredients which are poorly soluble by oral route." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF047/document.
Full textAbstract:
L'amélioration de la dissolution des médicaments peu solubles présente de nombreux défis.Dans cette thèse, un procédé d'extrusion-sphéronisation a été étudié en profondeur pour améliorer la dissolubilité du médicament avec une formulation de nano-émulsion. Le but du travail de thèse est de décrire les propriétés et les procédés de fabrication de minigranules permettant d'augmenter la solubilité des principes actifs peu solubles dans l'eau et donc d‘améliorer leur biodisponibilité lors de l'administration par voie orale, pour deux modèles de molécules différentes qui sont l‘acide folique (vitamine peu soluble dans l'eau) et le kétoprofène (anti-inflammatoire non stéroïdien qui présente une solubilité limitée dans les fluides gastriques à cause de son pKa (classe II dans le système de classification biopharmaceutique – BCS, ayant une action anti-inflammatoire, antalgique et antipyrétique). Cette étude décrit la préparation par extrusion-sphéronisation, caractérisation et étude de dissolution in vitro d'acide folique et de pastilles de kétoprofène revêtues de Acryl-EZE®, Advantia® Performance dans un minicoatère à lit fluidisé. Les résultats des essais ont montré la faisabilité de la préparation de pastilles enrobées entériques contenant un AINS et que, en revêtant le système multiparticulaire avec Acryl-EZE® 93A92545 et Advantia® Performance190024HA49 à un gain pondéral de 17,5%, 12,0%, respectivement, du médicament à partir des pastilles peuvent être obtenus. Les résultats des essais de dissolution ont indiqué que dans un milieu acide, le revêtement de film a entraîné un retard dans la libération du médicament, alors qu'aucun retard n'a été observé dans un milieu tampon à pH 6,8Improvement in dissolution of poorly soluble drugs has many challenges.In this thesis, an extrusion-spheronization process was thoroughly studied forimproving dissolubility of drug with nano-emulsion formulation.The aim of the thesis work is to describe the properties and manufacturing processes ofpellets to increase the solubility of poorly soluble active ingredients in water and thus improvetheir bioavailability when administered orally: folic acid (water-insoluble vitamin) andketoprofen (Non-steroidal anti-inflammatory, having anti-inflammatory, analgesic andantipyretic action, class II in the Biopharmaceutical Classification System).This study describes the preparation by extrusion-spheronization, characterisation andin vitro dissolution study of folic acid and ketoprofen pellets. Ketoprofen pellets coated withAcryl-EZE®, Advantia® Performance in a fluid-bed minicoater. The results of the tests showedthe feasibility of the preparation of enteric-coated pellets containing a NSAID and that bycoating the multiparticulate system with either 17.5% Acryl-EZE® 93A92545 or with 12%Advantia® Performance 190024HA49 weight gain, an enteric release of the drug from thepellets can be obtained. The results of dissolution testing indicated that in acidic media, entericfilm coating resulted in a delay in the release of the drug, while no delay was observed in pH6.8 buffer media
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Correll, Eric Owen. "Design of a rapid, continuous, small-scale device for creating dry powders from concentrated suspensions containing active pharmaceutical ingredients." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/68832.
Full textAbstract:
Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, June 2011."February 2011." Cataloged from PDF version of thesis.
Includes bibliographical references (p. 14).
Current methods of producing pharmaceutical compounds are large batch processes. The minimum time-to-patient for drug manufacturing is approximately 100 days. Using a continuous manufacturing process, the time-to-patient could be reduced to less than ten days. The scope of this paper encompasses the design of a machine for the desiccation of a mixture of solvent and pharmaceutical compound. The goal of this project was to provide a small-scale, high throughput method of continuous pharmaceutical drug drying for Novartis-MIT Center for Continuous Manufacturing. Specifications included a product flow rate of 100 grams per hour and a final product form of flowable powder. Several machines were built and tested, with the final design being comprised of a convective drum dryer and a modular continuous vacuum dryer.
by Eric Owen Correll.
S.B.
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Santos, Renato Brito Moreira dos. "Development of electrospun Ion jelly fibers® for drug delivery." Master's thesis, Faculdade de Ciências e Tecnologia, 2011. http://hdl.handle.net/10362/6593.
Full textAbstract:
Dissertação para obtenção do Grau de Mestre em
BiotecnologiaThe aim of this work was the development of a drug delivery system based on Ion Jelly fibers. Ion Jelly (IJ) is a highly versatile polymeric material and is the result from the combination of gelatin and an ionic liquid (IL). For that purpose, different IJs were created using ILs based on choline and active pharmaceutical ingredients. The ILs used were choline acetate ([Ch][Ac]), choline mandelate([Ch][Ma]), choline tiglate ([Ch][Ti]) and choline ibuprofenate([Ch][Ib]). IJ fibers for drug delivery systems were produced through electrospinning, owing to its ability of producing polymeric fibers with reduced diameters and high surface area. The aim of this approach was to overcome the low diffusion rate that the above ILs exhibit due to their high viscosity. The impacts of electrospinning parameters on fiber production were evaluated. We verified that the most important parameter to achieve defect-free and thin IJ fibers was IL concentration. Morphological studies of IJ electrospun fibers were performed through optical microscopy and scanning electron microscopy. It was observed that IJ - [Ch][Ib] yielded slightly thinner fibers when compared with IJ-[Ch][Ti] fibers. The results from antibacterial tests using mandelic acid, [Ch][Ma] and IJ-[Ch][Ma] fibers as antibacterial agents against Escherichia coli K-12 and Bacillus subtilis T-168 prove that[Ch][Ma] encapsulation in IJ electrospun fibers greatly increased the IL properties. In addition,toxicological data suggest that the ILs studied were not toxic with the exception of [Ch][Ib] which shows a similar toxicity to crystalline ibuprofene. In addition, tensile tests suggest that water content has an important impact on both IJ mechanic behavior and elasticity. Additionally, we also evaluated the fabrication of IJ fibers using other polymers beyond gelatin, namely DNA and N,N-Dimethylchitosan. Nevertheless, no fibers were obtained.
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Fritz, Emelie [Verfasser], Börje [Akademischer Betreuer] Sellergren, and Ralf [Gutachter] Weberskirch. "Molecularly imprinted polymer based scavengers for purifiying small and large active pharmaceutical ingredients / Emelie Fritz. Betreuer: Börje Sellergren. Gutachter: Ralf Weberskirch." Dortmund : Universitätsbibliothek Dortmund, 2014. http://d-nb.info/1108290167/34.
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Cheney, Miranda L. "The Role of Cocrystals in Solid-State Synthesis of Imides and the Development of Novel Crystalline Forms of Active Pharmaceutical Ingredients." Scholar Commons, 2009. http://scholarcommons.usf.edu/etd/3693.
Full textAbstract:
With a greater understanding of the fundamentals of crystal engineering lays the
potential for the development of a vast array of novel materials for a plethora of
applications. Addressed herein is the latent potential of the current knowledge base with
an emphasis upon cocrystallization and the desire for scientific exploration that will lead
to the development of a future generation of novel cocrystals. The focus of this
dissertation is to expand the cocrystallization knowledge base in two directions with the
utilization of cocrystals in the novel synthetic technique of cocrystal controlled solid-state
synthesis and in the development of active pharmaceutical ingredients.
Cocrystal controlled solid-state synthesis uses a cocrystal to align the reactive
moieties in such a way that the reaction occurs more quickly and in higher yield than the
typical solution methodology. The focus herein is upon cocrystal controlled solid-state
synthesis of imides where an anhydride and primary amine were the reactive moieties.
Forty-nine reactions were attempted and thirty-two resulted in successful imide
formation. In addition, the cocrystal was isolated as part of the reaction pathway in three
cases and is described in detail.
The impact of cocrystals upon active pharmaceutical ingredients is also addressed
with a focus upon generating novel crystal forms of lamotrigine and meloxicam.
Cocrystallization attempts of lamotrigine resulted in ten novel crystal forms including
three cocrystals, one cocrystal solvate, three salts, one solvated salt, a methanol solvate,
and an ethanol hydrate. Additionally, cocrystallization attempts of meloxicam afforded
seven novel cocrystals. Solubility and pharmacokinetic studies were conducted for a
selected set of lamotrigine and meloxicam crystal forms to determine the crystal form
with the most desirable properties. Properties between crystal form and cocrystal former
were also examined.
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Brits, Ilene. "International pharmacopoeia monographs for zinc acetate and zinc gluconate active pharmaceutical ingredients used in the treatment of paediatric diarrhoea / Brits I." Thesis, North-West University, 2012. http://hdl.handle.net/10394/8088.
Full textAbstract:
Acute diarrhoea is one of the largest health challenges globally, causing millions of child deaths every year.
A continued effort is made by the WHO, in collaboration with other institutions, to successfully combat diarrhoea. A new formulation for ORS (with a reduced osmolarity), in combination with zinc supplementation, was proposed to reduce the severity and duration of diarrhoea (WHO, 2006:1).
Appropriate zinc supplementation for the treatment of diarrhoea includes: zinc sulfate, zinc acetate dihydrate and zinc gluconate. With no monographs available in The Ph. Int. for zinc acetate dihydrate and zinc gluconate APIs, the development thereof has become a priority to the WHO.
During this study, suitable methods according to The Ph. Int. for the quality control testing of zinc acetate dihydrate and zinc gluconate APIs were investigated and proposed.
The following monograph requirements were proposed for zinc acetate dihydrate API:
* Identification of zinc by means of a precipitation reaction of zinc hydroxide and zinc sulfide,
* Identification of acetate by means of a precipitation reaction of ferric acetate,
* Clarity and colour of a 0.05 g/ml solution,
* pH value of a 0.05 g/ml solution,
* Assay by means of a complexometric titration with disodium EDTA,
* Impurities / Limit tests:
o reducing substances by means of a reduction reaction with potassium permanganate,
o chlorides by means of a precipitation reaction with silver nitrate,
o sulfates by means of a precipitation reaction of barium sulfate,
o arsenic by means of reaction between arsine and bromide,
o aluminium, cadmium, copper, iron and lead by means of atomic absorption spectrometry.
The following monograph requirements were proposed for zinc gluconate API:
* Identification of zinc by means of a precipitation reaction of zinc ferrocyanide,
* Identification of gluconate by means of a thin layer chromatographic separation method,
* Clarity and colour of a 0.01 g/ml solution,
* pH value of a 0.01 g/ml solution,
* Water by means of the Karl Fischer method,
* Assay by means of a complexometric titration with disodium EDTA,
* Impurities / Limit tests:
o reducing sugars by means of a reduction reaction with cupri–tartaric test solution,
o chlorides by means of a precipitation reaction with silver nitrate,
o sulfates by means of a precipitation reaction of barium sulfate,
o heavy metals by means of a precipitation reaction of sulfides in acidic solutions,
o cadmium by means of atomic absorption spectrometry, and
o microbial testing if required by The Ph. Int.
The proposed methods were then validated or verified according to international standards. Once the methods were proven to be fit for purpose, they were assembled into the respective monographs for inclusion in The Ph. Int.
The newly developed monographs were then evaluated by determining the compliance of commercially available zinc acetate dihydrate and zinc gluconate to the proposed specifications.
The study contributes to the WHO, pharmaceutical industry and medicines regulatory authorities by making these two monographs globally available, thus providing a quality gauge to ensure the availability of zinc acetate dihydrate and zinc gluconate APIs of pharmaceutical acceptable quality.Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012.
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Caetano, Márcia de Windson Costa. "Polimorfismo da Clorpropamida investigado através de Espectroscopia Vibracional." reponame:Repositório Institucional da UFC, 2006. http://www.repositorio.ufc.br/handle/riufc/12371.
Full textAbstract:
CAETANO, Márcia de Windson Costa. Polimorfismo da Clorpropamida investigado através de Espectroscopia Vibracional. 2006. 141 f. Dissertação (Mestrado em Física) - Programa de Pós-Graduação em Física, Departamento de Física, Centro de Ciências, Universidade Federal do Ceará, Fortaleza, 2006.Submitted by Edvander Pires (edvanderpires@gmail.com) on 2015-05-21T22:22:40Z No. of bitstreams: 1 2006_dis_mwccaetano.pdf: 3508898 bytes, checksum: d30348bd90f71bc8902edd696cad9095 (MD5)
Approved for entry into archive by Edvander Pires(edvanderpires@gmail.com) on 2015-05-22T19:39:13Z (GMT) No. of bitstreams: 1 2006_dis_mwccaetano.pdf: 3508898 bytes, checksum: d30348bd90f71bc8902edd696cad9095 (MD5)
Made available in DSpace on 2015-05-22T19:39:13Z (GMT). No. of bitstreams: 1 2006_dis_mwccaetano.pdf: 3508898 bytes, checksum: d30348bd90f71bc8902edd696cad9095 (MD5) Previous issue date: 2006
Chlorpropamide (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) is a drug used to treat type II diabetes (non-dependent of insulin), especially when the diabetes can not be controlled by alimentary regimes. The polymorphism of this drug is widely documented exhibiting at least five crystalline forms. In this work, we present a vibrational study of four of these polymorphs by using Raman, infrared and near-infrared spectroscopies. The objective of this vibrational investigation is to correlate the vibrational modes with the possible crystalline structures, as well as, to evaluate these methods as a tool for identification and quality control of raw materials and formulated products. In order to provide a detailed characterization we also applied thermal analyses and x-ray powder diffraction techniques to identify the crystalline forms. Finally, the assignment of the bands observed in the vibrational spectra in terms of the normal vibrational modes was performed with the help the quantum mechanical calculations based on the density functional theory. These results allow us to investigate the conformational stability of chlorpropamide establishing correlations with the polymorphism of this drug.
A clorpropamida (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) é uma droga usada para tratar o diabetes tipo II (não dependente da insulina), em particular em pessoas cujo diabetes não pode ser controlada só pelo regime alimentício. O polimorfismo desta droga se encontra amplamente documentado exibindo, pelo menos, cinco diferentes formas cristalinas. Neste trabalho apresentamos um estudo de quatro destes polimorfos através das espectroscopias Raman, infravermelho e infravermelho próximo. O objetivo desta investigação vibracional é estabelecer correlações entre os modos vibracionais e as possíveis estruturas cristalinas, além de avaliar estes métodos como ferramentas para a identificação e controle de qualidade das matérias primas e produtos formulados. No intuito de prover uma caracterização detalhada também empregamos análises térmicas e difração de raios- X para a identificação prévia das formas cristalinas. Finalmente, a classificação das bandas observadas nos espectros vibracionais em termos dos modos normais de vibração da molécula foi realizada com a ajuda de cálculos computacionais baseados na teoria do funcional de densidade. Estes resultados também nos permitiram investigar a estabilidade conformacional da clorpropamida e estabelecer correlações com o polimorfismo da mesma.
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Ferreira, Susana Cristina Dias Ramos. "Application of OSN in membrane cascade for purification of the API Amoxicillin." Master's thesis, Faculdade de Ciências e Tecnologia, 2013. http://hdl.handle.net/10362/10710.
Full textAbstract:
Dissertação para obtenção do Grau de Mestre em
Engenharia Química e BioquímicaThe present work developed at Imperial College London (ICL) in collaboration with the Massachusetts Institute of Technology (MIT) had the objective of purifying the API amoxicillin containing an initial concentration of 30ppm of the compound 4-hydroxy-l-phenylglycine (impurity) using an OSN membrane cascade. Project proposal: Solubility and stability studies of the API in different solvents. Solvent choice for the separation process. Dissociation study of the API and impurity to exploit a promising optimization of the process. Membrane screening using dead-end and m-CSTR upside-down measurements. Process modeling and simulation of different configurations Amoxicillin showed to be a sensitive compound to work with having a low solubility and a fast decomposition in the studied solvents. The solvents tested in detail were water, acetone, ethanol and methanol, being water the one choose to performed the purification. From the dissociation study it was possible to understand the possible exploitation of the pH parameter in the optimization of the separation process. In the membrane screening the effect of pressure and pH were studied in six types of membranes. It could be conclude that the main obstacle for the purification process was the membrane performance itself, with insufficient separation between the compounds (difference of 10 p.p. in rejection). The most promising results were obtained using the TFNF-DL membrane, with an API rejection of 99.12% and an impurity rejection of 87.80%. The process modelling was performed in a semi-batch mode with one and two stages, respectively, and in continuous mode with two-stages and two different configurations. An increase from two to three stages was also analyzed for the continuous configuration II. A maximum purity of 99.65% with a yield of 97.86% was obtained with the semi-batch two-stage cascade system. From the continuous three stage cascade system, a purity of 98.65% and a yield of 98.54% were achieved.
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Greiner, Maximilian Martin [Verfasser], Heiko [Akademischer Betreuer] [Gutachter] Briesen, and Hans [Gutachter] Hasse. "Molecular and multiscale modeling of the dissolution of active pharmaceutical ingredients / Maximilian Martin Greiner. Betreuer: Heiko Briesen. Gutachter: Hans Hasse ; Heiko Briesen." München : Universitätsbibliothek der TU München, 2016. http://d-nb.info/111177627X/34.
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Balk, Anja [Verfasser], and Lorenz [Gutachter] Meinel. "Ionic liquids of active pharmaceutical ingredients: A novel platform addressing solubility challenges of poorly water soluble drugs / Anja Balk ; Gutachter: Lorenz Meinel." Würzburg : Universität Würzburg, 2016. http://d-nb.info/1119077036/34.
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Ilko, David [Verfasser], Ulrike [Gutachter] Holzgrabe, and Petra [Gutachter] Högger. "The use of charged aerosol detection for the analysis of excipients and active pharmaceutical ingredients / David Ilko. Gutachter: Ulrike Holzgrabe ; Petra Högger." Würzburg : Universität Würzburg, 2015. http://d-nb.info/1112943218/34.
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Santos, Joana Rita Afonso. "Caracterização do estado sólido e sua influência na qualidade dos medicamentos." Master's thesis, [s.n.], 2013. http://hdl.handle.net/10284/4404.
Full textAbstract:
Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências FarmacêuticasNa última década, a caracterização física de ingredientes ativos e excipientes tem crescido exponencialmente, uma vez que as propriedades físicas são determinantes em termos de biodisponibilidade e eficácia. A natureza física dos sólidos depende de fatores vários como os diferentes estados cristalinos em que um sólido se pode apresentar, o que implica um estudo do estado cristalino vs amorfo, o polimorfismo, que obriga à determinação do tipo de cristal, a granulometria e a área de superfície. A correta caracterização dos ingredientes farmacêuticos sólidos pode influenciar o processo de fabrico, as características finais do medicamento e, consequentemente, a biodisponibilidade e farmacocinética. Este trabalho tem como objetivo contribuir para divulgar a importância da caraterização do estado sólido, numa abordagem das suas principais implicações na qualidade e eficácia dos medicamentos. In the last decade, the physical characterization of active ingredients and excipients has grown exponentially, since the physical properties are decisive in terms of bioavailability and efficiency. The solids’ physical nature depend on several factors such as the different crystalline states in which a solid may present, which implies the study of its crystalline state vs. amorphous, the polymorphism, which implies the determination of the crystal’s type, its particle size and the surface area. The proper characterization of the solid pharmaceutial ingredients may influence the manufacturing process, the final characteristics of the product and hence the bioavailability and pharmacokinetics. This paper aims to contribute to the spreading of the solid state characterization’s importance, in addressing its major implications for the quality and efficacy of medicines.
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Barclay, Victoria K. H. "Development of LC-MS/MS Methods for the Analysis of Chiral and Achiral Pharmaceuticals and Metabolites in Aqueous Environmental Matrices." Doctoral thesis, Uppsala universitet, Avdelningen för analytisk farmaceutisk kemi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-171550.
Full textAbstract:
This thesis describes the development of liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the trace analysis of active pharmaceutical ingredients (APIs) and their metabolites in aqueous environmental matrices. The research was focused on the development of chiral LC-MS/MS methods for the analysis of fluoxetine and metoprolol, as well as their chiral metabolites in environmental water samples. A method was also developed for the achiral compounds, diazepam and nordiazepam. The LC-MS/MS methods were validated by the use of the isotope-labeled compounds. As these isotope-labeled compounds were not found in the wastewater samples, the validation could be assessed at trace level concentrations in the actual matrices in which the analytes were detected. The analytes were extracted from the water samples using solid phase extraction methods. Different types of solid phase extraction sorbents were evaluated. Fluoxetine and norfluoxetine were extracted through the use of a mixed mode polymeric based extraction sorbent. A hydrophilic and lipophilic balanced sorbent was employed for the simultaneous extraction of metoprolol and its metabolites, the base α-hydroxymetoprolol and the acidic metabolite deaminated metoprolol. Moreover, silica based C18 extraction discs were applied for the sample preparation of diazepam and nordiazepam. The chromatographic separations were conducted in reversed phase LC with MS compatible mobile phases. The enantiomers of fluoxetine and norfluoxetine were simultaneously separated using the chiral stationary phase (CSP), α1-acid glycoprotein (AGP). The Chiral AGP column was also applied for the separation of the enantiomers of deaminated metoprolol. For the simultaneous separation of the metoprolol enantiomers and the four stereoisomers of α-hydroxymetoprolol, the cellobiohydrolase (CBH) protein based CSP was used. An octadecyl silica based LC column was applied for the separation of diazepam and nordiazepam. The analytes were detected by the use of tandem quadrupole mass spectrometry operating in selective reactive monitoring mode. High resolution MS, employing a quadrupole time-of-flight (QqTOF) mass analyzer, was utilized for the identification of an unknown compound in wastewater samples. The APIs and their metabolites, as well as their respective enantiomers, were quantified in raw and treated wastewater from Uppsala, Sweden along with surface water from the River Fyris in Uppsala.
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Dogan, Berna [Verfasser], Karsten [Akademischer Betreuer] [Gutachter] Reuter, and Carlo [Gutachter] Camilloni. "In Silico Prediction of Dissolution Rates of Pharmaceutical Ingredients: Micro-Kinetic Model Based on Spiral Dissolution / Berna Dogan. Betreuer: Karsten Reuter. Gutachter: Karsten Reuter ; Carlo Camilloni." München : Universitätsbibliothek der TU München, 2016. http://d-nb.info/1106382234/34.
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Urlaub, Jonas [Verfasser], Ulrike [Gutachter] Holzgrabe, and Ann-Christin [Gutachter] Pöppler. "Development of analytical methods for the quality assessment of mineral oil based excipients and mechanochemically stressed active pharmaceutical ingredients / Jonas Urlaub ; Gutachter: Ulrike Holzgrabe, Ann-Christin Pöppler." Würzburg : Universität Würzburg, 2021. http://d-nb.info/1240148011/34.
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Caetano, MÃrcia de Windson Costa. "Polimorfismo da Clorpropamida investigado atravÃs de Espectroscopia Vibracional." Universidade Federal do CearÃ, 2006. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=1710.
Full textAbstract:
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicoA clorpropamida (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) à uma droga usada para tratar o diabetes tipo II (nÃo dependente da insulina), em particular em pessoas cujo diabetes nÃo pode ser controlada sà pelo regime alimentÃcio. O polimorfismo desta droga se encontra amplamente documentado exibindo, pelo menos, cinco diferentes formas cristalinas. Neste trabalho apresentamos um estudo de quatro destes polimorfos atravÃs das espectroscopias Raman, infravermelho e infravermelho prÃximo. O objetivo desta investigaÃÃo vibracional à estabelecer correlaÃÃes entre os modos vibracionais e as possÃveis estruturas cristalinas, alÃm de avaliar estes mÃtodos como ferramentas para a identificaÃÃo e controle de qualidade das matÃrias primas e produtos formulados. No intuito de prover uma caracterizaÃÃo detalhada tambÃm empregamos anÃlises tÃrmicas e difraÃÃo de raios- X para a identificaÃÃo prÃvia das formas cristalinas. Finalmente, a classificaÃÃo das bandas observadas nos espectros vibracionais em termos dos modos normais de vibraÃÃo da molÃcula foi realizada com a ajuda de cÃlculos computacionais baseados na teoria do funcional de densidade. Estes resultados tambÃm nos permitiram investigar a estabilidade conformacional da clorpropamida e estabelecer correlaÃÃes com o polimorfismo da mesma.
Chlorpropamide (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) is a drug used to treat type II diabetes (non-dependent of insulin), especially when the diabetes can not be controlled by alimentary regimes. The polymorphism of this drug is widely documented exhibiting at least five crystalline forms. In this work, we present a vibrational study of four of these polymorphs by using Raman, infrared and near-infrared spectroscopies. The objective of this vibrational investigation is to correlate the vibrational modes with the possible crystalline structures, as well as, to evaluate these methods as a tool for identification and quality control of raw materials and formulated products. In order to provide a detailed characterization we also applied thermal analyses and x-ray powder diffraction techniques to identify the crystalline forms. Finally, the assignment of the bands observed in the vibrational spectra in terms of the normal vibrational modes was performed with the help the quantum mechanical calculations based on the density functional theory. These results allow us to investigate the conformational stability of chlorpropamide establishing correlations with the polymorphism of this drug.
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Chan, Hin Chung Stephen. "Co-crystal screening of poorly water-soluble active pharmaceutical ingredients. Application of hot stage microscopy on curcumin-nicotinamide system and construction of ternary phase diagram of fenbufen-nicotinamide-water co-crystal system." Thesis, University of Bradford, 2009. http://hdl.handle.net/10454/4253.
Full textAbstract:
Curcumin is the major phenolic diarylheptane derivative in Curcuma longa and has been reported to possess pharmacological activities. Unfortunately this compound suffers from poor bioavailability and rapid neutral-alkaline degradation. Co-crystal of curcumin is one option under exploration, motivated by the fact that a number of active pharmaceutical ingredient (API) co-crystals with improved dissolution have recently been synthesized. Hence, co-crystallization technique highlights an alternative means to improve the performance of curcumin.
Within our work evidences for a co-crystal was ascertained from DSC, Kofler hot stage screening and PXRD, and all confirmed a new crystal phase could have been formed between curcumin and a co-crystallizing agent, nicotinamide. We report that re-crystallization step essentially aids the purification of commercial curcumin, a herbal based actives. Otherwise the prevalence of a new crystal phase in solvent-mediated co-crystallization will be significantly reduced.
Besides, phase diagram is an effective tool for the study of solubility behaviours in co-crystal system. In order to acquire related techniques, fenbufen, a poorly water soluble drug, was selected. The result showed the huge difference in solubility between fenbufen and nicotinamide lead to difficulty in the construction of phase diagram.
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Telford, Richard. "The Physical Chemistry of pMDI Formulations Derived from Hydrofluoroalkane Propellants. A Study of the Physical Behaviour of Poorly Soluble Active Pharmaceutical Ingredients; Bespoke Analytical Method Development Leading to Novel Formulation Approaches for Product Development." Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/10098.
Full textAbstract:
Active Pharmaceutical Ingredients (APIs) are frequently prepared for delivery to the lung for local topical treatment of diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma, or for systemic delivery. One of the most commonly used devices for this purpose is the pressurised metered dose inhaler (pMDI) whereby drugs are formulated in a volatile propellant held under pressure. The compound is aerosolised to a respirably sized dose on actuation, subsequently breathed in by the user. The use of hydrofluoroalkanes (HFAs) in pMDIs since the Montreal Protocol initiated a move away from chlorofluorocarbon (CFC) based devices has resulted in better performing products, with increased lung deposition and a concomitant reduction in oropharyngeal deposition. The physical properties of HFA propellants are however poorly understood and their capacity for solubilising inhaled pharmaceutical products (IPPs) and excipients used historically in CFCs differ significantly. There is therefore a drive to establish methodologies to study these systems in-situ and post actuation to adequately direct formulation strategies for the production of stable and efficacious suspension and solution based products. Characterisation methods have been applied to pMDI dosage systems to gain insight into solubility in HFAs and to determine forms of solid deposits after actuation. A novel quantitative nuclear magnetic resonance method to investigate the physical chemistry of IPPs in these preparations has formed the centrepiece to these studies, accessing solubility data in-situ and at pressure for the first time in HFA propellants. Variable temperature NMR has provided thermodynamic data through van’t Hoff approaches. The methods have been developed and validated using budesonide to provide limits of determination as low as 1 μg/mL and extended to 11 IPPs chosen to represent currently prescribed inhaled corticosteroids (ICS), β2-adrenoagonists and antimuscarinic bronchodilators, and have highlighted solubility variations between the classes of compounds with lipophilic ICSs showing the highest, and hydrophilic β2- agonist/antimuscarinics showing the lowest solubilities from the compounds under study. To determine solid forms on deposition, a series of methods are also described using modified impaction methods in combination with analytical approaches including spectroscopy (μ-Raman), X-ray diffraction, SEM, chromatography and thermal analysis. Their application has ascertained (i) physical form/morphology data on commercial pMDI formulations of the ICS beclomethasone dipropionate (QVAR®/Sanasthmax®, Chiesi) and (ii) distribution assessment in-vitro of ICS/β2-agonist compounds from combination pMDIs confirming co-deposition (Seretide®/Symbicort®, GlaxoSmithKline/AstraZeneca). In combination, these methods provide a platform for development of new formulations based on HFA propellants. The methods have been applied to a number of ‘real’ systems incorporating derivatised cyclodextrins and the co-solvent ethanol, and provide a basis for a comprehensive study of solubilisation of the ICS budesonide in HFA134a using two approaches: mixed solvents and complexation. These new systems provide a novel approach to deliver to the lung, with reduced aerodynamic particle size distribution (APSD) potentially accessing areas suitable for delivery to peripheral areas of the lung (ICS) or to promote systemic delivery.
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Silva, Milene Alexandra Cirne da. "Detection of non-steroidal anti-inflammatory drugs in aqueous effluents using ionic liquids." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/15495.
Full textAbstract:
Mestrado em Biotecnologia - Biotecnologia Industrial e AmbientalSignificant improvements in human health have been achieved through the increased consumption of pharmaceutical drugs. However, most of these active pharmaceutical ingredients (APIs) are excreted by mammals (in a metabolized or unchanged form) into the environment. The presence of residual amounts of these contaminants was already confirmed in aqueous streams since treatment processes either wastewater treatment plants (WWTPs) or sewage treatment plants (STPs) are not specifically designed for this type of pollutants. Although they are present in aqueous effluents, they are usually at very low concentrations, most of the times below the detection limits of analytical equipment used for their quantification, hindering their accurate monitoring. Therefore, the development of a pre-concentration technique in order to accurately quantify and monitor these components in aqueous streams is of major relevance. This work addresses the use of liquid-liquid equilibria, applying ionic liquids (ILs), for the extraction and concentration of non-steroidal anti-inflammatory drugs (NSAIDs) from aqueous effluents. Particularly, aqueous biphasic systems (ABSs) composed of ILs and potassium citrate were investigated in the extraction and concentration of naproxen, diclofenac and ketoprofen from aqueous media. Both the extraction efficiency and concentration factor achievable by these systems was determined and evaluated. Within the best conditions, extraction efficiencies of 99.4% and concentration factors up to 13 times were obtained.
As melhorias significativas alcançadas nas condições de vida dos seres humanos têm sido acompanhadas por um aumento no consumo de compostos farmacêuticos. No entanto, a maioria destes ingredientes farmacêuticos ativos (IFA) acabam por ser excretados pelos mamíferos (numa forma inalterada ou metabolizados) para o ambiente. A presença de quantidades residuais destes contaminantes já foi confirmada em correntes aquosas de abastecimento, uma vez que os processos de tratamento em estações de tratamento de águas residuais (ETARs) e estações de tratamento de esgoto (ETEs) não são projetados especificamente para este tipo de poluentes. Estes poluentes estão presentes em baixas concentrações nos efluentes aquosos (entre μg.L-1 e ng.L-1) e, por vezes, próximo dos limites de deteção do equipamento analítico utilizado dificultando a sua monitorização. Consequentemente, o desenvolvimento de uma técnica de pré-concentração assume uma enorme relevância a fim de quantificar com precisão e exatidão estes poluentes em correntes aquosas. Este trabalho aborda a utilização de equilibrio líquidolíquido, utilizando líquidos iónicos (LIs) como solventes, para a extração e concentração de fármacos anti-inflamatórios não esteroides (AINEs) a partir de correntes aquosas. Particularmente, foram estudados sistemas aquosos bifásicos (SAB) compostos por LIs e citrato de potássio na extração e concentração de naproxeno, diclofenaco e cetoprofeno. Avaliou-se quer a eficiência de extração quer o fator de concentração alcançado com este tipo de sistemas. Nas melhores condições estudadas, a eficiência de extração e o fator de concentração alcançados são de 99,4% e 13 vezes, respetivamente.