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Production of functional pharmaceutical nano/micro-particles by solvent displacement method using advanced micro-engineered dispersion devicesOthman, Rahimah January 2016 (has links)
The rapid advancement of drug delivery systems (DDS) has raised the possibility of using functional engineered nano/micro-particles as drug carriers for the administration of active pharmaceutical ingredients (APIs) to the affected area. The major goals in designing these functional particles are to control the particle size, the surface properties and the pharmacologically active agents release in order to achieve the site-specification of the drug at the therapeutically optimal rate and dose regimen. Two different equipment (i.e. glass capillary microfluidic device and micro-engineered membrane dispersion cell) were utilised in this study for the formation of functional nano/micro-particles by antisolvent precipitation method. This method is based on micromixing/direct precipitation of two miscible liquids, which appear as a straightforward method, rapid and easy to perform, does not require high stirring rates, sonication, elevated temperatures, surfactants and Class 1 solvents can be avoided. Theoretical selection of a good solvent and physicochemical interaction between solvent-water-polymer with the aid of Bagley s two-dimensional graph were successfully elucidated the nature of anti-solvent precipitation method for the formation of desired properties of functional pharmaceutical nano/micro-engineered particles. For the glass capillary microfluidic experiment, the organic phase (a mixture of polymer and tetrahydrofuran/acetone) was injected through the inner glass capillary with a tapered cross section culminated in a narrow orifice. The size of nanoparticles was precisely controlled by controlling phase flow rates, orifice size and flow configuration (two- phase co-flow or counter-current flow focusing). The locations at which the nanoparticles would form were determined by using the solubility criteria of the polymer and the concentration profiles found by numerical modelling. This valuable results appeared as the first computational and experimental study dealing with the formation of polylactide (PLA) and poly(ε-caprolactone) (PCL) nanoparticles by nanoprecipitation in a co-flow glass capillary device. The optimum formulations and parameters interactions involved in the preparation of paracetamol encapsulated nanoparticles (PCM-PCL NPs) using a co-flow microfluidic device was successfully simulated using a 25-full factorial design for five different parameters (i.e. PCL concentration, orifice size, flow rate ratios, surfactant concentration and paracetamol amount) with encapsulation efficiency and drug loading percentage as the responses. PCM-loaded composite NPs composed of a biodegradable poly(D,L-lactide) (PLA) polymer matrix filled with organically modified montmorillonite (MMT) nanoparticles were also successfully formulated by antisolvent nanoprecipitation in a microfluidic co-flow glass capillary device. The incorporation of MMT in the polymer matrix improved the drug encapsulation efficiency and drug loading, and extended the rate of drug release in simulated intestinal fluid (pH 7.4). The encapsulation of MMT and PCM in the NPs were well verified using transmission electron microscopy (TEM), energy dispersive x-ray spectroscopy (EDS), x-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). PCL drug-carrier nanoparticles were also produced by rapid membrane micromixing combined with nanoprecipitation in a stirred cell employing novel membrane dispersion. The size of the NPs was precisely controlled by changing the aqueous-to-organic volumetric ratio, stirring rate, transmembrane flux, the polymer content in the organic phase, membrane type and pore morphologies. The particle size decreased by increasing the stirring rate and the aqueous-to-organic volumetric ratio, and by decreasing the polymer concentration in the aqueous phase and the transmembrane flux. The existence of the shear stress peak within a transitional radius and a rapid decline of the shear stress away from the membrane surface were revealed by numerical modelling. Further investigation on the PCL nanoparticles loaded immunosuppressive rapamycin (RAPA) drug were successfully synthesised by anti-solvent nanoprecipitation method using stainless steel (SS) ringed micro-engineered membrane. Less than 10 μm size of monohydrate piroxicam (PRX) micro-crystals also was successfully formed with the application of anti-solvent precipitation method combined with membrane dispersion cell that has been utilised in the formation of functional engineered nanoparticles. This study is believed to be a new insight into the development of integrated membrane crystallisation system.
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Fabrication and Characterization of Organic and Inorganic Linear NanostructuresBoulet, Joel L Unknown Date
No description available.
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Evaluation of the Effect of Critical Process and Formulation Parameters on the Attributes of Nanoparticles Produced by Microfluidics. Design of Experiments Approach for Optimisation of Process and Formulation Parameters Affecting the Fabrication of Nanocrystals of Poorly Water-Soluble Drug Using Anti-solvent Precipitation in MicrofluidicObeed, Muthana M. January 2021 (has links)
Advanced drug delivery systems have shown immense success through
nanotechnology which overcomes the challenges posed by large sized particles
such as poor solubility, bioavailability, absorption, and target-specific delivery.
This study focuses on nano sizing by application of microreactor technology and
nanoparticles to obtain polymeric particulate with a selection of model drugs for
inhalation drug delivery routes. The development of nanoparticles of two
challenging compounds in terms of solubility and permeability, namely
Ibuprofen (IBU) and Salmeterol (SAL), was conducted using a continuous,
controlled, and scalable system offered by microfluidic reactor with the
incorporation of anti-solvent approach. The research explores the potential of
this technology to enhance absorption rate and hence bioavailability of IBU via
oral route, and SAL via inhalation.
IBU, an anti-inflammatory drug, is classified as BCS Class II drug with low
solubility and high permeability. SAL is a selective long acting β2-agonist which
is co-dispensed along with a short-acting β2-agonist for quick relief of acute
bronchoconstriction due to its long onset of action. This lack of the ‘kick’ effect
in SAL can be attributed to its relatively higher lipophilicity which causes a delay
in the diffusion to the β2 receptors on the smooth muscles. It is therefore
feasible to assume that increasing the dissolution and/or diffusion rate of SAL in the interstitial fluids would reduce the delay between administration and the
onset of action of this drug which would be beneficial to patients.
Process and formulation parameters were investigated to optimize the
production and stability of nano particles of both drugs using Y shaped microfluidic reactors.
IBU results show that the smaller the angle between the two inlets were the
smaller the particle size achieved. Moreover, the particle size increased with
increasing the concentration of IBU solution. The effect of the polymer mixture
ratio (PVP/HPMC) on the initial particle size was not clear though. The smallest
particle size (113 nm) was achieved using 10° Y shaped chip with IBU
concentration of 1 mg/mL and a polymer mixture of 0.3% w/v PVP and 0.5%
w/v HPMC. Using a polymer mixture of 0.5% w/v of each polymer though
yielded a better PDI (140nm and PDI of 0.5).
Same observations were noted when the syringe pumps were replaced with a
non-pulsatile pressure pump. Particle size though dropped significantly to
33nm. Stability data showed that all systems were practically stable regardless
of the process or formulation parameters.
In addition, a considerable 2.5 fold increase in dissolution rate was observed in
the first 20 minutes when compared to the raw material.
The optimized parameters were applied to SAL to produce nanocrystals with
best result (59 nm) were obtained using 50µg/mL Salmeterol with microfluidics
inlet angle 10° with non-pulse syringe pump. The stabilizing mixture was PVP
0.8% w/v and Tween 80 at a concentration of 0.02%. This approach offered a
basis for the generation of nano sized SAL particles with higher fine particle fraction and better deposition in NGI than currently marketed formulations, thus
providing a more efficient drug dose delivery and lung deposition.
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Investigation and Optimization of a Solvent / Anti-Solvent Crystallization Process for the Production of Inhalation ParticlesAgrawal, Swati 29 July 2010 (has links)
Dry powder inhalers (DPIs) are commonly used to deliver drugs to the lungs. The drug particles used in these DPIs should possess a number of key properties. These include an aerodynamic particle size < 5μm and particle crystallinity for long term formulation stability. The conventionally used micronization technique to produce inhalation particles offers limited opportunities to control and optimize the particle characteristics. It is also known to induce crystalline disorder in the particles leading to formulation instability. Hence, this research project investigates and optimizes a solvent/anti-solvent crystallization process capable of directly yielding inhalation particles using albuterol sulfate (AS) as a model drug. Further, the feasibility of the process to produce combination particles of AS and ipratropium bromide monohydrate (IB) in predictable proportions and in a size suitable for inhalation is also investigated. The solvent / anti-solvent systems employed were water / ethyl acetate (EA) and water / isopropanol (IPA). Investigation and optimization of the crystallization variables with the water / EA system revealed that particle crystallinity was significantly influenced by an interaction between the drug solution / anti-solvent ratio (Ra ratio), stirring speed and crystal maturation time. Inducing a temperature difference between the drug solution and anti-solvent (Tdrug solution > Tanti-solvent) resulted in smaller particles being formed at a positive temperature difference of 65°C. IPA was shown to be the optimum anti-solvent for producing AS particles (IPA-AS) in a size range suitable for inhalation. In vitro aerosol performance of these IPA-AS particles was found to be superior compared to the conventionally used micronized particles when aerosolized from the Novolizer®. The solvent / anti-solvent systems investigated and optimized for combination particles were water / EA, water / IPA, and water / IPA:EA 1:10 (w/w). IPA was found to be the optimum anti-solvent for producing combination particles of AS and IB with the smallest size. These combination particles showed uniform co-deposition during in vitro aerosol performance testing from the Novolizer®. Pilot molecular modeling studies in conjunction with the analysis of particle interactions using HINT provided an improved understanding of the possible interactions between AS and IB within a combination particle matrix.
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FABRICATION AND CHARACTERIZATION OF ORGANIC-INORGANIC HYBRID PEROVSKITE SOLAR CELLSSarvari, Hojjatollah 01 January 2018 (has links)
Solar energy as the most abundant source of energy is clean, non-pollutant, and completely renewable, which provides energy security, independence, and reliability. Organic-inorganic hybrid perovskite solar cells (PSCs) revolutionized the photovoltaics field not only by showing high efficiency of above 22% in just a few years but also by providing cheap and facile fabrication methods.
In this dissertation, fabrication of PSCs in both ambient air conditions and environmentally controlled N2-filled glove-box are studied. Several characterization methods such as SEM, XRD, EDS, Profilometry, four-point probe measurement, EQE, and current-voltage measurements were employed to examine the quality of thin films and the performance of the PSCs. A few issues with the use of equipment for the fabrication of thin films are addressed, and the solutions are provided.
It is suggested to fabricate PSCs in ambient air conditions entirely, to reduce the production cost. So, in this part, the preparation of the solutions, the fabrication of thin films, and the storage of materials were performed in ambient air conditions regardless of their humidity sensitivity. Thus, for the first part, the fabrication of PSCs in ambient air conditions with relative humidity above ~36% with and without moisture sensitive material, i.e., Li-TFSI are provided. Perovskite materials including MAPbI3 and mixed cation MAyFA(1-y)PbIxBr(1-x) compositions are investigated. Many solution-process parameters such as the spin-coating speed for deposition of the hole transporting layer (HTL), preparation of the HTL solution, impact of air and light on the HTL conductivity, and the effect of repetitive measurement of PSCs are investigated. The results show that the higher spin speed of PbI2 is critical for high-quality PbI2 film formation. The author also found that exposure of samples to air and light are both crucial for fabrication of solar cells with larger current density and better fill factor. The aging characteristics of the PSCs in air and vacuum environments are also investigated. Each performance parameter of air-stored samples shows a drastic change compared with that of the vacuum-stored samples, and both moisture and oxygen in air are found to influence the PSCs performances. These results are essential towards the fabrication of low-cost, high-efficiency PSCs in ambient air conditions.
In the second part, the research is focused on the fabrication of high-efficiency PSCs using the glove-box. Both single-step and two-step spin-coating methods with perovskite precursors such as MAyFA(1-y)PbIxBr(1-x) and Cesium-doped mixed cation perovskite with a final formula of Cs0.07MA0.1581FA0.7719Pb1I2.49Br0.51 were considered. The effect of several materials and process parameters on the performance of PSCs are investigated. A new solution which consists of titanium dioxide (TiO2), hydrochloric acid (HCl), and anhydrous ethanol is introduced and optimized for fabrication of quick, pinhole-free, and efficient hole-blocking layer using the spin-coating method. Highly reproducible PSCs with an average power conversion efficiency (PCE) of 15.4% are fabricated using this solution by spin-coating method compared to the conventional solution utilizing both spin-coating with an average PCE of 10.6% and spray pyrolysis with an average PCE of 13.78%. Moreover, a thin layer of silver is introduced as an interlayer between the HTL and the back contact. Interestingly, it improved the current density and, finally the PCEs of devices by improving the adhesion of the back electrode onto the organic HTL and increasing the light reflection in the PSC. Finally, a highly reproducible fabrication procedure for cesium-doped PSCs using the anti-solvent method with an average PCE of 16.5%, and a maximum PCE of ~17.5% is provided.
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Desenvolvimento de nanocristais de efavirenz para incremento do perfil de dissolução / Development of efavirenz nanocrystals for increasing the dissolution profileSartori, Gabriela Julianelly January 2016 (has links)
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Previous issue date: 2016 / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos/Farmanguinhos. Rio de Janeiro, RJ, Brasil. / O efavirenz é um antirretroviral amplamente utilizado no tratamento de HIV, porém este fármaco encontra problemas de biodisponibilidade devido à sua baixa dissolução em meio aquoso. Nanocristais de fármaco são uma forma considerada segura de aumentar a dissolução sem promover uma alteração na molécula. Seu preparo pode ser feito por diferentes técnicas, uma delas é a nanocristalização por antissolvente. Que consiste na precipitação de fármaco a partir de uma fase orgânica, inserindo-a em uma fase aquosa, na qual o fármaco é pouco solúvel. Esta técnica é considerada promissora pois frente a outros tipos de método de preparo tem menor demanda energética, de tempo e custo. O uso de nanocristais preparados por esta técnica é uma alternativa promissora para alcançar o incremento da dissolução. No presente trabalho foram preparados nanocristais de efavirenz testando-se diferentes condições experimentais. Como resultado foram obtidas suspensões que foram levadas então a secagem. O pó obtido foi caracterizado por técnicas de espectroscopia de IV, para identificação da estrutura química; DRX para verificação da cristalinidade e MEV a fim de observar a morfologia das partículas formadas. Também foi realizado ensaio de dissolução por dispersão. Uma vez obtidos os perfis das amostras, foi possível comparar os resultados e realizar alterações necessárias a fim de otimizar uma formulação como alterações nas concentrações de estabilizantes, no grau de saturação do sistema, no método de agitação, dentre outras. Também foi realizado um estudo inicial acerca da estabilidade física das suspensões formadas utilizando técnicas de espalhamento de luz. Por fim, foram encontradas algumas formulações que promoveram grande incremento na dissolução, a que teve melhor desempenho combinava uso de precipitação seguida por moagem em moinho coloidal.A análise da suspensão mostrou controle eficaz do tamanho de partícula, no que diz respeito tanto ao tamanho em escala nanométrica quanto redução na polidispersão das partículas; foi visto por DRX que esta amostra manteve a mesma estrutura cristalina da matériaprima, no IV não foi revelada qualquer reação química entre EFV e estabilizantes. O ensaio de dissolução apresentou incremento significativo do perfil, atingindo 98% de eficiência de dissolução. / Efavirenz is an antiretroviral widely used in the treatment of HIV, but this drug has
bioavailability problems due to their low dissolution in an aqueous medium. Drug
nanocrystals are considered a safe way to enhance dissolution without causing a change in the molecule. They can be prepared by different techniques, one of which is nanocrystallization by antisolvent. It constitutes in drug precipitation from an organic phase by adding it in an aqueous phase, in which the drug is poorly soluble. This technique is considered promising when compared to other preparation methods due to low energy, time and cost required. The use of nanocrystals prepared by this technique is a promising alternative to achieve a dissolution enhancement. In the present work, we prepared efavirenz nanocrystals by testing different experimental conditions. The obtained suspensions were dried. The powder was characterized by IR spectroscopy techniques for identification of chemical structure, XRD for verifying the
crystallinity and SEM in order to observe the morphology of the particles. The dissolution test by dispersion was also conducted. Once obtained the profiles of the samples, it was possible to compare the results and make necessary changes to optimize the formulations such as, changes in stabilizers concentrations, the degree of system saturation and the agitation method, among others. An initial
study on the physical stability of the suspensions formed, using light scattering
techniques was also carried out. Finally, we found some formulations that promoted large increase in dissolution profile. The one with the best performance combined precipitation followed by grinding in colloid mill. The suspension analysis exhibited effective control of particle size, as regards both the size at the nanometer scale as the reduction in the polydispersity of the particles; XRD showed that the sample maintained the same crystal structure of the raw material; the IV did not revealed any chemical reaction between EFV and stabilizers. The dissolution test presented large enhancement of the profile, reaching 98%
dissolution efficiency.
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Improvement of dissolution rate of a new antiretroviral drug using an anti-solvent crystallization technology / Amélioration de la cinétique de dissolution nouvelle molécule antirétrovirale en utilisant la cristallisation par effet antisolvantPaiva Lacerda, Suênia de 01 February 2013 (has links)
Cette étude concerne une nouvelle molécule antirétrovirale nommée CRS 74. Cette molécule présente une biodisponibilité limitée à cause de sa faible solubilité en phase aqueuse, sa mauvaise mouillabilité et sa faible vitesse de dissolution. Afin d'améliorer sa biodisponibilité, la molécule CRS 74 a été recristallisée par effet anti-solvant. Le solvant choisi est l'éthanol et l'anti-solvant l'eau. L'équilibre solide-liquide dans des mélanges binaires éthanol/eau a été mesuré à 30°C. Les solubilités obtenues ont été représentées en utilisant le modèle UNIQUAC pour le calcul des coefficients d'activité. Les solubilités expérimentales et calculées ont permis d'évaluer le ratio éthanol/eau optimum (25/75 % m/m) pour maximiser le rendement théorique en solide. Un mélange double jet avec pré-mélangeur type mélangeur en T a été choisi pour réaliser la cristallisation. Le solide cristallisé dans ces conditions semble plus aggloméré et son profil de dissolution comparé à celui du solide initial est inchangé. De plus, l'étude des cristaux obtenus en sortie de pré-mélangeur a montré que les vitesses de croissance et d'agglomération des cristaux sont élevées. Des additifs ont donc été utilisés en vue de modifier les propriétés de dissolution des cristaux, et d'optimiser les paramètres de formulation et de cristallisation. Les microcristaux produits en présence d'additifs présentent des profils de dissolution significativement plus rapides que les cristaux de la molécule initiale. Cette modification est attribuable à la modification de taille des cristaux et l'amélioration du mouillage en raison des interactions spécifiques entre la surface des cristaux et les additifs. / This study concerns a new antiretroviral drug named CRS 74. This molecule has a limited bioavailability because of its low aqueous solubility, poor water wettability and low dissolution rate. In an attempt to improve these properties, CRS 74 was recrystallized by using a Liquid Anti-Solvent (LAS) crystallization process. The chosen solvent is the ethanol and the anti-solvent the water. So solid-liquid equilibria in binary mixtures ethanol/water were measured at 30°C. The obtained solubility data were represented using UNIQUACbased model. The experimental and calculated solubilities permitted to estimate the optimal ethanol/water mass ratios (25/75 % w/w) in order to maximize the theoretical yield of solid. A double-jet with premixing (T-mixer) has been used to mix the two solutions. Particles of recrystallized CRS 74 seemed more agglomerated and the dissolution profile was not modified compared to the original drug. Furthermore, the study of crystals obtained at the exit of the mixer showed that the growth and agglomeration rates of crystals are high.In an attempt to improve its dissolution properties, CRS 74 has been recrystallized using different additives to optimize process and formulation parameters. Conclusively, produced microcrystals exhibited significantly faster dissolution rates than the original CRS 74 crystals. The improved dissolution is attributable to the modification of the particle size of drug crystals and enhancement of wetting properties due to specific interactions between the drug and the additives.
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Formation de liposomes par un procédé innovant utilisant les fluides supercritiques / Liposome formation using supercritical fluid processesLesoin, Laurène 20 May 2011 (has links)
Cette thèse est une étude théorique et expérimentale sur la formation de liposomes par des procédés utilisant le dioxyde de carbone (CO2) supercritique. Les liposomes sont des vésicules sphériques nano- ou micrométriques dont la paroi est composée d’une ou plusieurs bicouches concentriques de phospholipides séparant un milieu aqueux d’un autre. L’efficacité des procédés supercritiques, comme alternative aux méthodes conventionnelles pour former des liposomes, a déjà été démontrée. Une synthèse critique des résultats de la littérature a été réalisée au cours de ce travail. Parallèlement, une étude fondamentale sur le comportement des systèmes ternaires CO2/eau/surfactant sous pression a été menée et il a été démontré qu’en fonction du type d’émulsions formées au cours du procédé sous pression, les caractéristiques des liposomes produits lors de la dépressurisation sont différentes. Le procédé Supercritical Anti-Solvent a été utilisé pour microniser des phospholipides. Des liposomes sphériques, multilamellaires et de tailles comprises entre 0,1 et 1µm ont ensuite été formés de manière reproductible par hydratation des phospholipides micronisés. Dans les mêmes conditions (même solvant), la méthode conventionnelle de Bangham n’a pas donné des résultats reproductibles et les liposomes formés n’étaient pas tous sphériques. Le résultat majeur de ce travail est la mise au point d’un procédé supercritique innovant. Innovant car continu et en une seule étape, le procédé Continuous Anti-Solvent permet de former de manière reproductible des liposomes sphériques, multilamellaires et de tailles comprises entre 10 et 100µm. / The present thesis is dedicated to liposome formation using supercritical carbon dioxide (CO2). Liposomes are spherical vesicles composed of one or more concentric phospholipid bilayers surrounding an aqueous core. Dense gas processes offer reliable alternatives to conventional methods in liposome formation. We present a review of the literature and we summarized all of the results in a discussion section, with particular attention to emulsion formation under pressure. As it has been shown, the phase behaviour of the ternary CO2/water/surfactant system under pressure greatly influences liposome formation during depressurization. The Supercritical Anti-Solvent process has been used to micronized phospholipids. Then, the micronized particles were hydrated to form spherical and multilamellar liposomes with diameters between 0.1 and 1µm in a reproducible way. Using the same conditions (the same solvent), the conventional Bangham method did not provide reproducible assay results and formed liposomes were not all spherical. The main result of this work is the design of a new supercritical process dedicated to liposome formation. Unlike the current dense gas technologies, the Continuous Anti-Solvent method breaks new ground because it is a single step and continuous process. Liposomes prepared with the Continuous Anti-Solvent method are spherical and multilamellar with diameters between 10 and 100µm.
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Preparation of Pharmaceutical Powders using Supercritical Fluid Technology : Pharmaceutical Applications and Physicochemical Characterisation of PowdersVelaga, Sitaram P. January 2004 (has links)
<p>The main aim of the thesis was to explore the potential of supercritical fluid (SF) techniques in the field of drug delivery. In particular, the relatively recently developed solution-enhanced dispersion by supercritical fluids (SEDS) technology has been employed in the preparation of particles/powders. </p><p>The manufacturing, stability and bioavailability of a dosage form strongly depend on the physicochemical properties of the formulation particles. For example, dry powder inhalation (DPI) for administering drugs to the respiratory tract require particles in a narrow size range (1-5 μm) to be effective. The identification of polymorphs and control of purity are also important issues since the physicochemical properties and therapeutic effects of the alternative forms of a drug may differ substantially. Solvent-based traditional crystallisation processes provide the product that may require further down-stream processing to obtain particles for advanced drug delivery applications. This can result in unwanted changes in the physicochemical properties of the particles and thus affect the performance of the dosage form. SF processing has addressed many of the challenges in particle formation research. Among several SF technologies developed for particle processing over the last decade, the SEDS process with its specially designed co-axial nozzle with mixing chamber has resulted in improved control over the particle formation process. Carbon dioxide (CO<sub>2</sub>) was used as the SF, because it has low critical points and is non-toxic, non-flammable and relatively inexpensive. </p><p>The initial part of the thesis concerns the formation of particles of model drugs such as hydrocortisone, budesonide and flunisolide using SEDS technology and the determination of the influence of processing conditions and solvents on particle characteristics such as size, shape and crystal structure. Particles of model drugs of differing shapes in a size range suitable for inhalation delivery were prepared. In the process, two new polymorphic forms of flunisolide were identified. This was the first report of SEDS technology being shown as a polymorph-screening tool. The remainder of the thesis deals with the development of SEDS technology for precipitating therapeutic proteins such as recombinant human growth hormone (hGH) from aqueous solutions. Powders of hGH were precipitated using SEDS without significant changes in the chemical or physical stability of the protein. The addition of sucrose to hGH in the feed solution promoted precipitation and minimised the detrimental effects of the solvent and/or the process on the physical aggregation of the protein. </p><p>In conclusion, this thesis highlights the applicability of the SEDS process in drug delivery research and advances general understanding of the particle formation phenomenon. The SEDS process may also prove to be a potential alternative technology for the precipitation of stable powders of therapeutic proteins.</p>
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Preparation of Pharmaceutical Powders using Supercritical Fluid Technology : Pharmaceutical Applications and Physicochemical Characterisation of PowdersVelaga, Sitaram P. January 2004 (has links)
The main aim of the thesis was to explore the potential of supercritical fluid (SF) techniques in the field of drug delivery. In particular, the relatively recently developed solution-enhanced dispersion by supercritical fluids (SEDS) technology has been employed in the preparation of particles/powders. The manufacturing, stability and bioavailability of a dosage form strongly depend on the physicochemical properties of the formulation particles. For example, dry powder inhalation (DPI) for administering drugs to the respiratory tract require particles in a narrow size range (1-5 μm) to be effective. The identification of polymorphs and control of purity are also important issues since the physicochemical properties and therapeutic effects of the alternative forms of a drug may differ substantially. Solvent-based traditional crystallisation processes provide the product that may require further down-stream processing to obtain particles for advanced drug delivery applications. This can result in unwanted changes in the physicochemical properties of the particles and thus affect the performance of the dosage form. SF processing has addressed many of the challenges in particle formation research. Among several SF technologies developed for particle processing over the last decade, the SEDS process with its specially designed co-axial nozzle with mixing chamber has resulted in improved control over the particle formation process. Carbon dioxide (CO2) was used as the SF, because it has low critical points and is non-toxic, non-flammable and relatively inexpensive. The initial part of the thesis concerns the formation of particles of model drugs such as hydrocortisone, budesonide and flunisolide using SEDS technology and the determination of the influence of processing conditions and solvents on particle characteristics such as size, shape and crystal structure. Particles of model drugs of differing shapes in a size range suitable for inhalation delivery were prepared. In the process, two new polymorphic forms of flunisolide were identified. This was the first report of SEDS technology being shown as a polymorph-screening tool. The remainder of the thesis deals with the development of SEDS technology for precipitating therapeutic proteins such as recombinant human growth hormone (hGH) from aqueous solutions. Powders of hGH were precipitated using SEDS without significant changes in the chemical or physical stability of the protein. The addition of sucrose to hGH in the feed solution promoted precipitation and minimised the detrimental effects of the solvent and/or the process on the physical aggregation of the protein. In conclusion, this thesis highlights the applicability of the SEDS process in drug delivery research and advances general understanding of the particle formation phenomenon. The SEDS process may also prove to be a potential alternative technology for the precipitation of stable powders of therapeutic proteins.
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