This paper presents the fabrication of controlled release devices for anticancer drug paclitaxel using supercritical antisolvent method. The thermodynamic and hydrodynamic effects during supercritical antisolvent process on the particle properties obtained were investigated. Scanning electron microscopy was employed to study particle sizes and morphologies achieved. It was observed that increasing supercritical pressure improves the surface morphology of particles obtained, and increasing the flow rate of the organic solution jet reduces the particle sizes obtained. A modified Supercritical Antisolvent with Enhanced Mass transfer setup was developed to produce monodispersed nanoparticles with high recovery yield. High performance liquid chromatography was used to determine the encapsulation efficiency and in vitro release profiles of paclitaxel loaded particles obtained. The encapsulation efficiencies of particles obtained using the modified SASEM process were high and up to 83.5%, and sustained release of paclitaxel from the polymer matrix was observed over 36 days release. The thermogram properties of the particles were also analyzed using differential scanning calorimetry to determine the crystalline state of polymer and drug. / Singapore-MIT Alliance (SMA)

No / In this work, the possibility of bottom-up creation of a relatively stable aqueous hydrocortisone nanosuspension using microfluidic reactors was examined. The first part of the work involved a study of the parameters of the microfluidic precipitation process that affect the size of generated drug particles. These parameters included flow rates of drug solution and antisolvent, microfluidic channel diameters, microreactors inlet angles and drug concentrations. The experimental results revealed that hydrocortisone nano-sized dispersions in the range of 80¿450nm were obtained and the mean particle size could be changed by modifying the experimental parameters and design of microreactors. The second part of the work studied the possibility of preparing a hydrocortisone nanosuspension using microfluidic reactors. The nano-sized particles generated from a microreactor were rapidly introduced into an aqueous solution of stabilizers stirred at high speed with a propeller mixer. A tangential flow filtration system was then used to concentrate the prepared nanosuspension. The nanosuspension produced was then characterized using photon correlation spectroscopy (PCS), Zeta potential measurement, transmission electron microscopy (TEM), differential scanning calorimetry (DSC) and X-ray analysis. Results showed that a narrowsized nanosuspension composed of amorphous spherical particles with a mean particle size of 500±64 nm, a polydispersity index of 0.21±0.026 and a zeta potential of ¿18±2.84mVwas obtained. Physical stability studies showed that the hydrocortisone nanosuspension remained homogeneous with slight increase in mean particle size and polydispersity index over a 3-month period.

Yes / We report formation of polymorphs and new eutectics and cocrystals of curcumin, a sparingly water-soluble active component in turmeric, structurally similar to cinnamic acid. The curcumin polymorphs were formed using liquid antisolvent precipitation, where acetone acted as a solvent and water was used as the antisolvent. The metastable form 2 of curcumin was successfully prepared in varied morphology over a wide range of solvent-to-antisolvent ratio and under acidic pH conditions. We also report formation of new eutectics and cocrystals of curcumin with cinnamic acid acting as a coformer. The binary phase diagrams were studied using differential scanning calorimetry and predicted formation of the eutectics at the curcumin mole fraction of 0.15 and 0.33, whereas a cocrystal was formed at 0.3 mole fraction of curcumin in the curcumin–cinnamic acid mixture. The formation of the cocrystal was supported with X-ray powder diffraction, the enthalpy of fusion values, Fourier-transform infrared spectroscopy, and scanning electron microscopy. The hydrogen bond interaction between curcumin and cinnamic acid was predicted from Fourier-transform infrared spectra, individually optimized curcumin and cinnamic acid structures by quantum mechanical calculations using Gaussian-09 and their respective unit cell packing structures.

In this study, the supercritical antisolvent with enhanced mass transfer method (SASEM) is used to fabricate micro and nanoparticles of biocompatible and biodegradable polymer PLGA (poly DL lactide co glycolic acid). This process may be extended to the encapsulation of drugs in these micro and nanoparticles for controlled release purposes. Conventional supercritical antisolvent (SAS) process involves spraying a solution (organic solvent + dissolved polymer) into supercritical fluid (CO[subscript 2]), which acts as an antisolvent. The high rate of mass transfer between organic solvent and supercritical CO[subscript 2] results in supersaturation of the polymer in the spray droplet and precipitation of the polymer as micro or nanoparticles occurs. In the SASEM method, ultrasonic vibration is used to atomize the solution entering the high pressure with supercritical CO[subscript 2]. At the same time, the ultrasonic vibration generated turbulence in the high pressure vessel, leading to better mass transfer between the organic solvent and the supercritical CO₂. In this study, two organic solvents, acetone and dichloromethane (DCM) were used in the SASEM process. Phase Doppler Particle Analyzer (PDPA) was used to study the ultrasonic atomization of liquid using the ultrasonic probe for the SASEM process. Scanning Electron Microscopy (SEM) was used to study the size and morphology of the polymer particles collected at the end of the process. / Singapore-MIT Alliance (SMA)

Precipitation with a Compressed Fluid Antisolvent (PCA) and Rapid Expansion from Supercritical Solution (RESS) are two processes based on supercritical fluids that are capable of producing submicron particles. Novel variations of these basic processes have been examined to produce stable particles of various pharmaceutical compounds. PCA is an antisolvent precipitation technique where an organic solution of drug + polymer in solvent is atomized (sprayed) into supercritical (SC) CO₂. Upon liquid mixing, the solute materials precipitate to form microparticles. A Vapor-over-Liquid technique has been used to produce larger, uniform particle sizes of biodegradable polymers. By suspending a protein in the solvent phase, the protein can be encapsulated/coated by the precipitating polymer. RESS is a process by which a homogeneous solution at supercritical conditions is sprayed through an expansion nozzle to atmospheric conditions. The resultant change in phase leads to the precipitation of the solute materials. The production of extremely small particles (<50 nm) have been predicted but rarely demonstrated. Typically, particle growth occurs to form larger (~1 μm) particles. A novel adaptation was developed, dubbed RESAS (Rapid Expansion from Supercritical to Aqueous Solution), wherein the expansion is conducted within an aqueous environment. The aqueous phase can contain surfactant or lipid stabilizers to capture and preserve submicron particles of water-insoluble drug actives in the form of a suspension. / text

The applications of dense gas technology (DGT) in modern particle engineering have shown promising results in producing submicron particles with uniform particle morphology. In this study, two configurations of dense gas antisolvent processes were employed for the micronization, encapsulation and co-precipitation of pharmaceutical compounds. The encapsulation of superparamagnetic iron oxide nanoparticles (SPIONs) by a pH-responsive polymer (Eudragit?? S100) was successfully performed using the supercritical antisolvent (SAS) process. Nanocomposites of less than 200nm in diameter with encapsulated SPIONs content as high as 16 wt% were achieved. Magnetic characterization of the product was also performed and the data were fitted by the Langevin equation. The superparamagnetic properties of the composites were preserved and the effective magnetic size was about 10 nm. The magnetically and pH-responsive nanocomposites can be potentially utilized as magnetic resonance imaging contrast agents and drug carriers. Screening experiments of 8 active pharmaceutical ingredients and 5 pharmaceutical excipients were performed using the recently patented atomized rapid injection solvent extraction (ARISE) process. Candidates with promising product morphology and recovery were selected for co-precipitation studies. The co-precipitation of the anti-cancer drug 5-fluorouracil (5FU) and poly l-lactic acid (PLLA) was conducted to develop a controlled release system. Experiments were designed based on a two-level, three-factor factorial design, in order to investigate the effects of processing parameters on product characteristics. Submicron PLLA-5FU composites (diameter<0.8 ??m) with a drug loading of 7.4 wt% were produced.

No description available.

Yes / Itraconazole (ITR) is an antifungal drug with a limited bioavailability due to its poor aqueous solubility. In this study, ITR was used to investigate the impact of nanonisation and solid state change on drug’s apparent solubility and dissolution. A bottom up approach to the production of amorphous ITR nanoparticles (NPs), composed of 100% drug, with a particle diameter below 250 nm, using heat induced evaporative antisolvent nanoprecipitation (HIEAN) from acetone was developed. The NPs demonstrated improved solubility and dissolution in simulated gastrointestinal conditions when compared to amorphous ITR microparticles. NPs produced with polyethylene glycol (PEG) or its methoxylated derivative (MPEG) as a stabiliser enabled the production of smaller NPs with narrower particle size distribution and enhanced apparent solubility. MPEG stabilised NPs gave the greatest ITR supersaturation levels (up to 11.6 ± 0.5 μg/ml) in simulated gastric fluids. The stabilising polymer was in an amorphous state. Dynamic vapour sorption data indicated no solid state changes in NP samples with water vapour at 25 °C, while crystallisation was apparent at 50 °C. HIEAN proved to be an efficient method of production of amorphous ITR NPs, with or without addition of a polymeric stabiliser, with enhanced pharmaceutical properties. / Libyan Ministry of Higher Education and Scientific Research through the Libyan Embassy, London and supported by the Science Foundation Ireland under Grant No. 12/RC/2275 (Synthesis and Solid State Pharmaceuticals Centre).

L’objectif de ce travail est d’étudier l’influence de jets d’impact libres utilisés comme mode de mise en contact des phases dans les procédés de recristallisation utilisant un fluide supercritique comme anti-solvant. L’influence des variations de plusieurs paramètres opératoires sur l’hydrodynamique des jets et sur les caractéristiques des poudres de Sulfathiazole a été étudiée. Les paramètres sont la vitesse des jets (de 0,25 m.s-1 à 25,92 m,s-1), le rapport molaire solvant/CO2 (de 2,5 % à 20 %), la température (de 313 K à 343 K), la pression (10 MPa à 20 MPa) et la concentration du soluté dans la solution (de 0,5 % à 1,8 %). Les conditions de mélange ont été caractérisées par l’estimation des puissances dissipées par les jets d’impact, variant de 0,1 à 158 W.kg-1 dans les conditions étudiées. Les résultats ont montré que la vitesse des jets et la sursaturation sont deux paramètres-clés contrôlant la cristallisation avec un effet prépondérant de la sursaturation. Les cristaux obtenus ont des tailles, distributions de taille, faciès et nature polymorphique différents selon les conditions. La forme polymorphique la plus stable a été obtenue pure ou en mélange. Une comparaison avec le procédé SAS classique a montré que les particules sont significativement plus petites lorsqu’elles sont cristallisées avec les jets d’impact, ce qui confirme que ce dispositif créant un mélange plus intense, permet d’accélérer la cinétique de nucléation.Ce travail devrait contribuer à une meilleure maîtrise des procédés de cristallisation en milieu supercritique. / The aim of this work is to study the influence of free impinging jets used for the fluids’introduction in supercritical anti-solvent (SAS) processes. The influence of the variations of several operating parameters upon jets’ hydrodynamics and upon the powder characteristics is studied. Parameters are jets velocity (0.25 m.s-1 to 25.92 m.s-1), molar ratio solvent / CO2 (2.5 % to 20 %), temperature (313 K to 343 K), pressure (10 MPa to 20 MPa) and solute concentration in the organic solution (0.5 % to 1.8 %). Mixing conditions have been characterized estimating the dissipated powers of the impinging jets, varying from 0,1 à 158 W.kg-1 in the studied conditions. The results showed that jets velocity and supersaturation are two key-parameters controlling the crystallization with a preponderant effect of supersaturation. The obtained crystals have different size, particle size distribution, habit and polymorphic nature depending on the conditions. The most stable polymorphic form has been obtained pure or in mixture.A comparison with the classical SAS process showed that mean particle sizes are significantly smaller with impinging jets device proving that this device, creating a more efficient mixing, enhances the nucleation kinetics.This work may contribute to a better control of processes of crystallization in supercritical media.

Made available in DSpace on 2016-06-02T19:56:51Z (GMT). No. of bitstreams: 1 5172.pdf: 4441518 bytes, checksum: 17886d05d502204a3da9edca7448c0e9 (MD5) Previous issue date: 2013-03-28 / Financiadora de Estudos e Projetos / In the study of the sucrose crystallization process, the nucleation phenomena and crystalline growth have been evaluated, when the systems were submitted to different solvent and operational conditions. The main objective of the present work was to study the sucrose crystallization process in solution through the partial change of the solvent. This change occurs through studied with the ethanol addition of a second solvent, a compound that reduces the solute solubility, but that is miscible in the first one. The addition of a second solvent generates a high degree of supersaturation, and promotes the formation of crystalline nuclei of smaller size to be used as seeds in industrial processes. Another objective was to study the flowability properties of particle size by determining the Hausner ratio and repose angle that allows relate some variable results obtained by the crystallization of sucrose. With the obtained results, it would be possible to improve the control of the finally properties of the crystalline product, such as crystal size distribution (CSD), crystalline habit, crystalline fluid inclusions and the formation of crystalline polymorphs. / No estudo do processo de cristalização da sacarose foram avaliados os fenômenos de nucleação e crescimento cristalino, quando o sistema foi submetido a um segundo solvente e a diferentes condições operacionais. O objetivo central do presente trabalho foi estudar o processo de cristalização da sacarose em solução, através da mudança parcial de solvente. Essa mudança foi estudada com a adição de etanol como segundo solvente, composto que reduz a solubilidade do soluto, sendo, no entanto, miscível no primeiro. A adição de um segundo solvente gera um alto grau de supersaturação, que diminui a solubilidade do soluto em solução e promove a formação de núcleos cristalinos de menor tamanho para serem utilizados como sementes em processos industriais. Outro objetivo deste trabalho foi estudar as propriedades de escoamento granulométrico mediante a determinação do índice de Hausner e ângulo de repouso que permita relacionar alguma variável obtida pelo resultado da cristalização de sacarose. Com a realização do estudo proposto, foram obtidas informações que possibilitaram melhorar o controle das propriedades finais do produto cristalino, tais como a distribuição de tamanho dos cristais (DTC), hábito cristalino, inclusões fluidas cristalinas entre outras.