381 |
Approches thermodynamiques pour la prédiction de la solubilité de molécules d'intérêt pharmaceutique / Solubility prediction of products of pharmaceutical interest with thermodynamic modelsBouillot, Baptiste 09 December 2011 (has links)
La cristallisation est un procédé majeur de l’industrie pharmaceutique. Dans la mise au point d’un nouveau procédé de cristallisation, l’information essentielle est la solubilité de la molécule produite dans le solvant de cristallisation. Cette donnée n’est généralement pas connue lors de la phase de développement d’un nouveau principe actif. Elle doit donc être déterminée. L’objectif de cette thèse est d’étudier, et d’approfondir, l’utilisation de modèles thermodynamiques pour prédire la solubilité de molécules organiques complexes. Pour cela, six molécules sont prises pour référence : l’ibuprofène, le paracétamol, les acides salicylique, benzoïque et 4-aminobenzoïque et l’anthracène. Les modèles étudiés sont UNIFAC et ses modifications, COSMO-SAC, NRTL-SAC et PC-SAFT. Dans un premier temps, les potentialités de chaque modèle pour prédire la solubilité dans des solvants purs et des mélanges de solvants sont analysées. Dans un second temps, le modèle COSMO-SAC est approfondi et amélioré pour la prédiction des équilibres liquide-solide mettant en jeu des molécules complexes. Enfin, une nouvelle voie de mesure expérimentale de la solubilité dans de très faibles volumes est ouverte par l’intermédiaire de l’outil microfluidique. / Crystallization is a key process of the pharmaceutical industry. When developing a new crystallization process, the most important thing to discover is the final product solubility in a given solvent. However, it is generally unknown at this early step of drug development. The solubility has to be determined. The objective of this work is to study, and deepen, the use of thermodynamic models for solubility predictions of molecules of pharmaceutical interest. To do so, six complex organic molecules have been chosen : ibuprofen, paracetamol, salicylic acid, benzoic acid, 4-aminobenzoic acid and anthracene. The studied models are UNIFAC and its modifications, COSMO-SAC, NRTL-SAC and PC-SAFT. Initially, these models are analysed and used for predicting solubility in pure and mixed solvents. Subsequent work concerns the COSMO-SAC model in more details. It is more particularly improved for solubility predictions. Finally, a road is opened for solubility measurements in low volumes with the use of microfluidics.
|
382 |
Supramolecular reagents for the construction of predictable architecturesSmith, Michelle M. January 1900 (has links)
Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / Tailoring the properties of a bulk material such as a pharmaceutical compound, through non-covalent interactions, could lead to the enhancement of its physical properties without chemically modifying the individual molecules themselves. In order to obtain a
degree of control and reliability of these non-covalent interactions, we must develop a series of synthons - patterns of non-covalent interactions between molecules. A family a N-heterocyclic amides were synthesised and an assessment of their
binding selectivities was made, by evaluation of the supramolecular yield, (the frequency of occurrence of the desired connectivities). It was found that the supramolecular yield increased with increasing basicity of the heterocyclic nitrogen atom. However, there is a point where the heterocycle becomes basic enough to produce salts, which often leads to
unpredictable connectivity and stoichiometry.
Once the effectiveness of the N-heterocyclic amides as supramolecular reagents was
established, a series of more closely-related ditopic hydrogen-bond acceptor molecules were synthesized. The supramolecular reagents contained imidazole and pyridine binding sites, so that the two sites differ in terms of their basicity and geometry. An assessment of the ability
of these molecules to induce selectivity when a hydrogen bond donor such as a cyanoxime or a carboxylic acid is introduced was made. A total of nineteen crystal structures were obtained, of which one yielded a salt with unpredictable connectivity, and eighteen were cocrystals.
Ten of these were 2:1 co-crystals, which shows that the two sites are accessible for
binding. Eight were 1:1 stoichiometry, with five out of eight (63%) forming a hydrogen
bond to the best acceptor. In addition, a series of molecular electrostatic potential
calculations were employed to investigate the binding preferences and probe the best
donor/best acceptor hypothesis. A ternary supermolecule was also constructed from a
central, asymmetric hydrogen-bond acceptor and two different hydrogen-bond donor
molecules. It was found that the best donor, the cyanoxime, bound to the best acceptor, the imidazole nitrogen atom, while the second best donor, a carboxylic acid, bound to the second best acceptor. The calculated molecular electrostatic potential values were used to rationalize this event. A series of substituted cyanophenyloxime, hydrogen bond donor molecules were synthesized and their effectiveness at forming co-crystals was examined. It was found that simple R group substitution could have a significant effect upon the co-crystal forming ability of the hydrogen bond donors, having improved the yield from 4% and 7% in a series of co-crystallizations with closely-related oximes, to 96% with the cyanoximes. A series of di- and tritopic cyanoximes were synthesized and an assessment of their co-crystal-forming ability was made. They were found to be equally effective at producing co-crystals as the monotopic cyanoximes, having done so in 23 out of 24 cases. In contrast to their carboxylic acid counterparts, the polycyanoximes also exhibited excellent solubility. Finally, a series of ditopic ligands (N-heterocyclic amide and pyridyl cyanoximes) were employed in the synthesis of metal complexes. The amide-based ligands were found to be very effective at organizing the metal architectures with coordination through the heterocyclic nitrogen atom and propagation of one-dimensional chains through carboxamidecarboxamide interactions. These interactions prevailed even in the presence of potentially disruptive species such as solvent molecules, (in Ag(I) complexes) counterions, or other hydrogen bond acceptors. The self-complementarity of the oxime moiety was found not to prevail in any of the cases, but the pyridyl cyanoximes were consistent in their behaviour, forming an O-H…O (oxime-oxygen) hydrogen bond to a carboxylate or acac moiety.
|
383 |
The effect of co-crystallization and polymorphism on the physicochemical properties of amoxicillin tri-hydrateJaaida, Nesren Al-Hadi January 2013 (has links)
Magister Pharmaceuticae - MPharm / Many active pharmaceutical ingredients (APIs) have poor physicochemical properties such as solubility, dissolution and chemical stability. Several strategies are used to enhance and improve these properties of the API. Co-crystallization and polymorphism studies are possible strategy used in pre-formulation studies to optimize these properties of the drug without modifying its pharmacological effect. The purpose of this research was to investigate the polymorphism and co-crystallization effects of the penicillin-type antibiotic, amoxicillin tri-hydrate. Several techniques such as: slow evaporation, slow cooling, vapour diffusion, sublimation, grinding and solvent assisted grinding was employed. In producing co-crystals, the API was non-covalently bound to selected co-formers such as: saccharin, nicotinamide, salicylic acid, L-tartaric acid, D-tartaric acid, L-aspartic acid, stearic acid, benzoic anhydride, oxalic acid di-hydrate, cinnamic acid, succinic acid and citric acid monohydrate. Nine co-crystals of amoxicillin tri-hydrate had been formed. Differential scanning calorimetry (DSC), hot stage microscopy (HSM) and thermal gravimetric analysis (TGA) was conducted to analyse the thermal behaviour of the co-crystals. Powder X-ray diffraction (PXRD) and spectroscopic techniques [infra-red (FTIR) and H1-nuclear magnetic resonance (H1MNR)] were employed for screening of the co-crystal forms. Furthermore, dissolution testing was conducted to investigate the application of the newly derivatised forms.
|
384 |
Crystallization of chiral molecules from emulsions : DL-threonine, R,S-2-chloromandelic acid and R,S-clopidogrel hydrogen sulphateGilks, Sara January 2014 (has links)
The objective of this project is to explore the potential for enantiomer separation by preferential crystallization using tailor-made emulsions. Preferential crystallization is widely used as a means of separating pure enantiomers from racemic solutions. This is usually assisted by the addition of seed crystals of one enantiomer for which crystallization yields a conglomerate rather than a racemic compound. Three racemic materials, DL-threonine (stable conglomerate), R,S-2-chloromandelic acid (racemic compound with the occurrence of a metastable conglomerate) and R,S-clopidogrel hydrogen sulphate (stable racemic compound) were chosen based on their different racemic properties to both develop and test the limitations of an emulsion crystallization process. Since threonine is reported to form only a stable conglomerate it seemed an ideal material to use for the development of an emulsion crystallization process. Indeed this was successful with enantiomer enrichments of up to 88 % of the D-enantiomer being achievable. 2-Chloromandelic acid is reported to crystallize as a stable racemic compound but with both metastable (polymorphic) compound and conglomerate known. An investigation into solution crystallization was performed as a means of preparing the metastable conglomerate and also to explore the possibility of developing an emulsion crystallization process in this system. Crystallization of 2-chloromandelic acid yielded both stable and metastable racemic compounds and the metastable conglomerate. Solubility data of the pure enantiomer, stable racemic compound and metastable conglomerate have been determined in acetonitrile and a robust drown-out method developed for consistent preparation of the conglomerate in diethyl ether. In situ UV-Vis spectroscopy studies revealed that in a stirred slurry, the metastable conglomerate converts to the stable racemic compound in approximately 10 minutes at 15 °C. This time scale defined the subsequent process of preferential crystallization from a seeded, tailor-made, non-aqueous emulsion which was successful in providing a route to a product with significant chiral enrichment of the R-enantiomer. R,S-Clopidogrel hydrogen sulphate is a stable compound forming system, which has been reported in patents to form six different polymorphs. The possibility of conglomerate formation is not known. During the course of this work, attempts were made to preferentially crystallize one enantiomer from an already enriched racemic solution. This was unsuccessful, largely due to the fact that the pure enantiomer was found to be more soluble that the enriched starting material. No evidence of a conglomerate was found, but an amorphous form and four crystalline forms of S-clopidogrel hydrogen sulphate (S-I, S-II, S-III and S-IV) have been crystallized from various solvents via different crystallization conditions. Forms III and IV are believed to be present as hydrates which are not currently reported in the literature. The amorphous form and crystalline polymorphs have been characterized using DSC, pXRD and FTIR, of which data for the latter technique is lacking in the literature. Overall this thesis demonstrates the development of both aqueous and non-aqueous emulsion crystallisation processes for enantiomer separations, highlighting the importance of the phase behaviour of the solute as a major determinant for success.
|
385 |
The effect of alumina pick-up on mould flux behaviour in continuous castingBezuidenhout, Gert Adrian 21 December 2006 (has links)
The aim of this study was to determine the influence of alumina increase on the functioning of casting powder during continuous casting. Two aspects of the powder's performance were experimentally measured, namely the influence of alumina on the viscosity and the crystallisation behaviour. These two aspects were then related to the in-mould functioning of the casting powder with the aid of literature references. Casting slag must provide lubrication between the mould surface and the thin steel shell. Alumina increase will cause viscosity increase in casting slags and will hinder lubrication when the inflow of casting slag into the mould/strand gap deteriorates. Heat transfer across the gap is determined by the amount of solid casting slag and the form (glass or crystalline) thereof. Heat transfer across a crystalline material may be up to seven times lower than that across a glass phase. The increased alumina will serve to increase the ratio of glassy phase to crystalline phase in the gap, so increasing the heat transfer. To determine the true extent of alumina increase with modern clean steel practice, samples were taken from the moulds of both the VI and V2 continuous casters at ISCOR Vanderbijlpark. The influence of this alumina increase on the viscosity and the crystallisation behaviour of the casting slag were experimentally measured. Viscosity measurements were done with a rotating bob viscometer (in a vertical tube furnace) on two commercial casting powders (with increasing AI2O3 content). Viscosity prediction models were evaluated with the data from the measured viscosity values. Crystallisation measurements were done by quench experiments with the aid of the hot thermocouple technique. Crystallisation behaviour after a specified heat cycle was presented as the percentage opaque material (crystalline) to vitreous material (glassy) measured with an optical microscope. For the seven sequence casts during which samples were collected from the mould, it was found that the alumina content of the casting slag reached a steady-state value within the first ladle (first 40 minutes) with an increase of 3 to 4 mass %. The influence of a 4 mass % alumina increase on the measured viscosity is small enough that proper lubrication function of the slag will not be negatively affected. Viscosity prediction models vary in their accuracy and are limited with respect to the composition range of the casting powder and the temperature range for which they are valid. The increased alumina content was found to have a strong influence on the percentage crystalline material present. After the sample was heated to 1300°C, kept there for 10s, and then quenched, the crystalline material will decrease from 60 % to 30 % for 5 mass % alumina added. This decreased crystalline material present may notably increase heat transfer. Full crystallisation does not occur at a single temperature, and crystallisation occurs over a temperature interval (of up to 200°C). This means that crystallisation temperature values quoted by casting powder manufacturers depend on the heat cycle and the technique used during crystallisation measurements. Several crystalline phases are usually present in solidified casting slag and these crystalline phases are strongly influenced by the alumina content: the stable crystalline phases may change as alumina content increases. For the current alumina increase in casting powders the effect on viscosity is small, while crystallisation behaviour may be influenced to a greater extent. / Dissertation (M Eng (Metallurgical Engineering))--University of Pretoria, 2006. / Materials Science and Metallurgical Engineering / unrestricted
|
386 |
Etude physico-chimique et structurale de pyrophosphates de calcium hydratés : application aux micro-calcifications associées à l’arthrose / Physico-chemical and structural study of hydrated calcium pyrophosphates : application to microcalcifications associated with arthritisGras, Pierre 14 October 2014 (has links)
Ce mémoire porte sur l’étude de pyrophosphates de calcium hydratés (CPP : Ca2P2O7•nH2O), composés rencontrés dans des micro-calcifications pathologiques associées à l’arthrose et, dans certains cas, responsables d’arthropathie destructive. Ces cristaux, présents dans les articulations de patients arthritiques, possèdent un fort potentiel inflammatoire susceptible d’engendrer une dégradation aigüe du cartilage. Cependant, les mécanismes de formation des phases de CPP et d’activation de leur potentiel inflammatoire n’ont pas encore été entièrement décrits. Nous nous sommes intéressés à l’étude des conditions de formation des différentes phases de pyrophosphates de calcium hydratés in vitro ainsi qu’à la caractérisation fine de chacune des phases d’intérêt biologique avec des outils de laboratoire et de grands instruments afin de mieux comprendre leurs propriétés physico-chimiques et d’améliorer leur identification in vitro et in vivo. Dans un premier temps, un protocole de synthèse a été établi permettant la synthèse de quantités importantes de chacune des phases pures de CPP (CPP amorphe, CPP dihydratés monoclinique et triclinique et CPP tétrahydraté). Les conditions de synthèse associées à la formation de chacune de ces phases, pH et température notamment, ont été explorées. Des échantillons purs ont été utilisés comme références pour les différentes études physico-chimiques et structurales qui ont ensuite été menées. Les échantillons de référence ont été caractérisés finement, d’un point de vue structural avec notamment la résolution de plusieurs structures cristallines (diffraction des rayons X et des neutrons, sur poudre et monocristal) mais aussi au travers de différentes analyses spectroscopiques (spectroscopies FTIR et Raman, RMN du solide) et d’analyses de la morphologie des cristaux (microscopies électroniques à balayage et en transmission, diffraction électronique). Chacune de ces analyses complémentaires, couplées à des modélisations ab initio, a permis de préciser les hypothèses suggérant un rôle de la surface des cristaux dans le potentiel inflammatoire de ces phases. Une troisième partie est consacrée à l’exploration de différentes techniques de synthèse mettant en œuvre différents milieux (cristallisation en solution et en gel). Ces expériences ont permis d’établir des comparaisons avec les processus de formation observés in vivo et d’évolution in vitro à haute température des phases de CPP. Finalement des études ex vivo de cartilages calcifiés seront présentées, mettant en évidence les avantages de ces techniques de caractérisation de laboratoire comme outils de diagnostic. Ce travail permet ainsi de préciser les mécanismes physico-chimiques liés aux différentes phases de CPP in vitro et in vivo afin de mieux comprendre la formation de ces phases et leur potentiel inflammatoire associé, tout en améliorant les possibilités de diagnostic des arthropathies microcristallines. / The present work concerns the study of hydrated calcium pyrophosphates (CPP: Ca2P2O7•nH2O), a group of phases detected in pathological microcalcifications and associated with arthritis. These crystals are frequently observed in the synovial fluid of arthritic patients and they were described as having a high inflammatory potential which could induce a severe degradation of cartilage. However, the mechanisms involved in the formation of the CPP crystals and the activation of their inflammatory potential are not fully understood. This work is focused on the study of the synthesis conditions of CPP in vitro and on the fine characterization of CPP phases of biological interest using laboratory equipments and large-scale facilities. The aim of this work was to describe the physico-chemical properties of these materials, including inflammatory potential, and to improve their identification in vivo and in vitro. First, a synthesis protocol was designed for the production of significant amounts of pure samples for each of the CPP phases (amorphous CPP, monoclinic and triclinic dihydrated CPP and tetrahydrated CPP). Different conditions, including pH and temperature, were studied to achieve the synthesis of reference materials. These samples were precisely characterized using complementary techniques to determine their crystalline structures (powder and single crystal X-ray diffraction and neutron diffraction) as well as using spectroscopic (FTIR and Raman spectroscopies, MAS-NMR) and morphologic analyses (SEM, TEM and electron diffraction). These analyses, combined with ab initio modeling, clarified the hypotheses concerning the role of the crystal surface on the adsorption properties of CPP crystals and their inflammatory potential. The third part of this thesis is focused on the study of CPP synthesis conditions, by using different experimental setups to study crystallization in solution and in gel. A comparison with in vivo formation processes and in vitro high temperature evolution phenomena of these phases was established based on the results of these experiments. Finally, ex vivo analyses of pathological cartilage are presented, highlighting the advantages of different laboratory characterizations as medical diagnostic tools. This work contributes to clarify the physico-chemical characteristics of CPP phases in vitro and in vivo, to improve the knowledge on the formation and the evolution of these phases, their properties including inflammatory potential, and to facilitate their identification in vivo.
|
387 |
Steric and electronic effects of phosphine and phosphite ligands in vaska-type complexes of rodiumMuller, Alfred Johannes 14 October 2008 (has links)
Ph.D. / In order for any new useful complexes to be developed, whether of catalytic, biological or of other importance, it is very important that sufficient knowledge exists regarding the fundamental principles applying to the chemistry involved. In all chemical processes involving metal complexes, the coordinated ligands govern the reactions to a great extent. It is thus very important that the properties (solubility, reactivity, steric bulk, etc.) of various ligands of these complexes is clearly understood in order to enable intelligent adjustments to be made, inducing the effects of choice. In most catalytic cycles, basic chemical reactions like substitution, addition, oxidative addition and reductive elimination are of importance. Some of the methods used to quantify ligand properties include single crystal X-ray studies as well as investigating various reactions on model square planar complexes. Several problems are normally associated with this type of investigation and are summarized below along with the aims of this study to improve upon this. (i) Very often the Vaska type compounds crystallise on an inversion centre as is shown in a generalized structure in Figure 1.1. This creates several problems ranging from less accurate bond distances/angles to problematic refinement of single crystal data. As the disorder is ruled by symmetry, the occupancies of the disordered atoms are 50%. The example shown in Figure 1.1 is also a fortunate case where the disordered atoms do not have the same positions, making refinement of the data easier, but there are examples27 such as [Pt(Me)Cl(PCy3)2] where the disordered moieties (Me- and Cl-) occupy virtually the same positions. In examples such as these restraints have to be applied, i.e. fixing bond distances to average distances from literature. The important parameter of the ligand trans effect is then meaningless and cannot be reliably compared to data from solution studies. / Prof. A. Roodt
|
388 |
Controlling Particle Structures in Polymers through Nanocomposite ProcessingJimenez, Andrew Matthew January 2020 (has links)
The use of polymer nanocomposites (PNCs) for their unique properties has been around for over a century, used in anything from airplanes to raincoats. In the past 30 years, the fabrication of advanced composite materials has expanded this field into a vast array of applications, tailoring the optical, mechanical, and electrical properties of the material for any specific use. As with any composite, the goal is to take advantage of the desirable properties in each individual component and form an overall superior material. In this body of work, we focus on mixing inorganic nanoparticles (NPs), which are strong and dense, with various polymers, typically used for being tough, light, and easy to work with. The reason for using nano-sized fillers is to maximize the inorganic surface area with which the polymer can interact with, allowing for a minimum amount of filler to be used with maximum benefit, though this is not always practically the case. The interaction between the NP and polymer is only optimized if the NP structure can be controlled. Each of the chapters in this thesis work toward finding new, and practical, methods for understanding and controlling NP dispersions in polymers.
In each of the chapters, we focus primarily on the use of silica NPs, ranging from 10-100 nm in diameter, studying methods for controlling their dispersion in polymers like polystyrene (PS), polyethylene (PE), polyisoprene (PI), poly(2-vinyl pyridine) (P2VP), poly(ethylene oxide) (PEO), poly(methyl acrylate) (PMA), and others. First, we take a closer look at how to control and quantify “well-dispersed” NPs in a polymer matrix, taking advantage of various techniques to stabilize the NPs in solution before casting them into the polymer. Once we understand how to reliably disperse the NPs, we can begin to find ways to reorganize them into structures that could provide further improvements in the mechanical properties of the composites, again focusing on methods that would be practically relevant in any polymer system. These techniques take advantage of thermodynamic and kinetic drivers to reorder the NPs in amorphous and semi-crystalline polymers. Forming bound layers of a polymer on a favorably interacting NP surface can stabilize the NPs in a variety of polymer systems, providing initially well-dispersed systems for further study. Alternatively, the grafting of chains onto the NP surface leads to various self-assemblies of the NPs in different matrices, depending on the interaction of the grafted and matrix chains.
Starting with well-dispersed NPs in a semi-crystalline polymer allows us to take advantage of the crystallization process to kinetically force NPs into hierarchical structures throughout the composite. This concept alone encompasses a bulk of this thesis – a technique that simply requires the isothermal crystallization of the polymer at different temperatures to achieve vastly different NP structures. Understanding the interaction of the NPs and the crystal is studying using extensive calorimetry and microscopy experiments, specifically determining how to define the confinement of the system due to the presence of NPs and their effect on growth and nucleation. The resulting alignment of NPs into the interlamellar region of the crystal is then analyzed in detail using a correlation function, commonly applied to neat semi-crystalline structures, but applied here for the first time to a PNC. This analysis provides new insights into the alignment process and ways for quantifying the degree of NP alignment. The alignment technique is then applied to several other systems for the specific focus of improving the mechanical properties of unique and industrially relevant PNCs, specifically using polymer grafted NPs. Finally, we briefly discuss the effect of annealing time and temperature on NP dispersion, dynamics, and resulting in unprecedented changes in the macroscopic properties of the material, uncovering new insights in the aging of PNCs. Each of these techniques provides details around controlling the organization and structure of NPs in polymers for the purpose of improving their mechanical properties, all while simply changing the way in which the material is processed.
|
389 |
Process Intensification Enabling Direct Compression for Pharmaceutical Manufacturing: From Spherical Agglomeration to Precise Control of Co-AgglomerationKanjakha Pal (8065976) 03 December 2019 (has links)
Spherical agglomeration (SA) is a novel process intensification strategy for particulate manufacturing. In the context of pharmaceutical manufacturing, it has the potential to reduce the number of unit operations in downstream processing from seven to three, which significantly reduces the manufacturing cost. However, SA process development for a new API in the drug pipeline is still a challenging exercise, which has impeded its practical implementation. The major bottleneck lies in the lack of fundamental understanding of the mechanistic principles underlying agglomeration of primary crystals, which can enable rational process design. In addition, most SA processes reported in literature focus on only the API, which does not eliminate the blending and wet granulation unit operations. The major purposes of this thesis are to (i) develop a first principle mathematical framework which can identify the fundamental agglomeration mechanism (ii) develop a model based online optimization framework, which can control the process, even in the presence of model parametric uncertainties (iii) develop a rational framework for co-agglomerating APIs and excipients, guided by process analytical technology tools. It is believed that the novel technology developed in this thesis will lay the groundwork for fast and robust process development of co-agglomerating APIs and excipients in the future, thereby enabling one-step direct compression. The large-scale development and deployment of this technology will significantly reduce the time to market and the manufacturing costs for new APIs, thereby ensuring higher accessibility of life-saving drugs.
|
390 |
Characterization of the Phase Behavior of Supersaturated Solutions in Simulated and Aspirated Human FluidsAhmed H. a. a. Elkhabaz (8071994) 04 December 2019 (has links)
Supersaturating formulations
have become a popular approach for enhancing the oral bioavailability of poorly
water-soluble drugs. These formulation strategies can increase the intraluminal
concentration by generating and maintaining supersaturation, which provides an
enhanced driving force for <i>in vivo</i> absorption. Due to their inherent metastability however,
crystallization in these systems can occur, negatively impacting their
bioperformance. Therefore, it is critical to characterize the phase behavior
and crystallization tendency of supersaturated solutions under biorelevant
conditions in order to assess their potential for maximized oral absorption. Biorelevant
media are commonly employed to simulate the presence of bile salts and
phospholipids found in the human intestinal fluids. Currently, there is little knowledge of how simulated and aspirated intestinal
media can impact the complex phase behavior of supersaturated solutions. More
importantly, commonly-used simulated media rely on oversimplified recipes in
terms of bile salt composition. As a result, comprehensive understanding of how
well simulated media correlate with aspirated media with respect to supersaturation
stability and phase transition outcomes, is still lacking. The work presented
within this thesis aims to address the knowledge gap by assessing the phase
behavior of supersaturated solutions using complementary analytical approaches.
Depending on the type of medium used to evaluate supersaturation, variations in solubility, supersaturation
thermodynamics and crystallization kinetics can be observed. This understanding can aid future efforts to optimize
simulated media, design supersaturating formulations and predict their <i>in
vivo</i> performance.
|
Page generated in 0.0549 seconds