Edmundo Gomes de Azevedo

Formation of indomethacin–saccharin cocrystals using supercritical fluid technology

The main objective of the present work is to check the feasibility of supercritical fluid (SCF) technologies in the screening and design of cocrystals (novel crystalline solids). The cocrystal formation tendencies in three different SCF techniques, focusing on distinct supercritical fluid properties - solvent, anti-solvent and atomization enhancer - were investigated. The effect of processing parameters on the cocrystal formation behaviour and particle properties in these techniques was also studied. A recently reported indomethacin-saccharin (IND-SAC) cocrystalline system was our model system. A 1:1 molar ratio of indomethacin (gamma-form) and saccharin was used as a starting material. The SCF techniques employed in the study include the CSS technique (cocrystallization with supercritical solvent), the SAS technique (supercritical anti-solvent), and the AAS technique (atomization and anti-solvent). The resulting cocrystalline phase was identified using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform-Raman (FT-Raman). The particle morphologies and size distributions were determined using scanning electron microscopy (SEM) and aerosizer, respectively. The pure IND-SAC cocrystals were obtained from SAS and AAS processes, whilst partial to no cocrystal formation occurred in the CSS process. However, no remarkable differences were observed in terms of cocrystal formation at different processing conditions in SAS and AAS processes. Particles from CSS processes were agglomerated and large, whilst needle-to-block-shaped and spherical particles were obtained from SAS and AAS processes, respectively. The particle size distribution of these particles was 0.2-5microm. Particulate IND-SAC cocrystals with different morphologies and sizes (nano-to-micron) were produced using supercritical fluid techniques. This work demonstrates the potential of SCF technologies as screening methods for cocrystals with possibilities for particle engineering.

Phase equilibria of natural flavours and supercritical solvents

Abstract To study the possibility of separation of cineole from limonene (two of the main components of eucalyptus oil) we measured the vapour-liquid equilibrium of the systems containing either d-limonene or 1, 8-cineole in the supercritical solvents carbon dioxide (at 318.2 and 323.2 K) and an azeotropic mixture of ethane+carbon dioxide (at 303.2 K). The results obtained show that both solutes have similar solubilities in the supercritical solvents studied here.

The molecular basis for local compositions in liquid mixture models

Abstract The local-composition concept is examined critically. When a general local-composition model is subjected to different constraints, we obtain different forms, corresponding to those presented earlier in literature. For simple mixture, a physically meaningful constraint gives a one-parameter model whose properties are obtained from the Lennard-Jones potential. For this model, the calculated excess Helmholtz energy and calculated local compositions are in good agreement with results from Monte Carlo data and with results from perturbation theory, recently reported by Nakanishi et al.

Powder X-ray diffraction method for the quantification of cocrystals in the crystallization mixture.

Context: The solid state purity of cocrystals critically affects their performance. Thus, it is important to accurately quantify the purity of cocrystals in the final crystallization product. Objective: The aim of this study was to develop a powder X-ray diffraction (PXRD) quantification method for investigating the purity of cocrystals. The method developed was employed to study the formation of indomethacin-saccharin (IND-SAC) cocrystals by mechanochemical methods. Materials and methods: Pure IND-SAC cocrystals were geometrically mixed with 1:1 w/w mixture of indomethacin/saccharin in various proportions. An accurately measured amount (550 mg) of the mixture was used for the PXRD measurements. The most intense, non-overlapping, characteristic diffraction peak of IND-SAC was used to construct the calibration curve in the range 0–100% (w/w). This calibration model was validated and used to monitor the formation of IND-SAC cocrystals by liquid-assisted grinding (LAG). Results: The IND-SAC cocrystal calibration curve showed excellent linearity (R2 = 0.9996) over the entire concentration range, displaying limit of detection (LOD) and limit of quantification (LOQ) values of 1.23% (w/w) and 3.74% (w/w), respectively. Validation results showed excellent correlations between actual and predicted concentrations of IND-SAC cocrystals (R2 = 0.9981). Discussion: The accuracy and reliability of the PXRD quantification method depend on the methods of sample preparation and handling. The crystallinity of the IND-SAC cocrystals was higher when larger amounts of methanol were used in the LAG method. Conclusion: The PXRD quantification method is suitable and reliable for verifying the purity of cocrystals in the final crystallization product.

Development of a novel mucosal vaccine against strangles by supercritical enhanced atomization spray-drying of Streptococcus equi extracts and evaluation in a mouse model

Strangles is an extremely contagious and sometimes deadly disease of the Equidae. The development of an effective vaccine should constitute an important asset to eradicate this worldwide infectious disease. In this work, we address the development of a mucosal vaccine by using a Supercritical Enhanced Atomization (SEA) spray-drying technique. Aqueous solutions containing the Streptococcus equi extracts and chitosan were converted into nanospheres with no use of organic solvents. The immune response in a mouse model showed that the nanospheres induced a well-balanced Th1 and Th2 response characterized by a unitary ratio between the concentrations of IgG2a and IgG1, together with IgA production. This strategy revealed to be an effective alternative for immunization against S. equi, and therefore, it may constitute a feasible option for production of a strangles vaccine.

High-pressure delignification of Eucalyptus Wood by 1,4-Dioxane-CO2 Mixtures☆

Abstract High-pressure reactive extraction of Eucalyptus globulus wood was undertaken. Extractions were carried out with CO 2 + 1,4-dioxane mixtures at 170 bar pressure at temperatures of 160–180 °C. The influence of temperature, extraction time, composition of the fluid mixture, and flow rate on the extraction were investigated. In the range of temperatures studied, only a small increase in lignin and hemicellulose extraction is observed when temperature is increased. At 180 °C, the degradative extraction of cellulose starts, but at lower temperatures, cellulose losses are small. The selectivity of the extraction depends upon the composition of the extracting mixture. CO 2 -rich fluid mixtures extract hemicellulose preferentially and total hemicellulose removal can be achieved. Maximum delignification was obtained by extraction with pure dioxane with 75% of the lignin initially present in wood being removed. Selectivity towards lignin vs. hemicellulose extraction increases with increasing flow rate until a plateau is reached.

Thermodynamics of the xenon+methyl chloride system

Abstract The total vapour pressure of the xenon + methyl chloride system has been measured as a function of composition at 175.44 and 182.32 K. The resulting data have been used to evaluate the excess Gibbs functions GE at the same temperatures. The excess enthalpy and excess molar volume have also been measured at 182.32 K. The system shows large positive deviations from Raoults law but negative volumes on mixing. These results are compared with theoretical predictions of a recent molecular theory and of standard engineering methods. The calculations show the superiority of the molecular theory over more empirical procedures such as those based on the Redlich-Kwong equation of state or the regular-solution model.

High Pressure Carbon Dioxide Extraction from Coriander Plants. Headspace Analysis

ABSTRACT Dried coriander plants were examined by headspace gas chromatographic analysis. Volatile concentrates of the same plants were obtained by three different methods: steam distillation, extraction with liquid CO2 (at 20°C, 5.7 MPa) and extraction with supercritical CO2 (at 34.5°C, 16 MPa). Yields between 0.6–1.0% were obtained in the extraction by liquid CO2 and yields of 0.3% were obtained by steam distillation. Headspace GC analysis of the volatile concentrates was also performed and the results were compared to those obtained directly from the plants. The difference in aroma of the CO2 extracts and of the steam distillate is quite noticeable, and can be attributed to quantitative differences in the proportions of the components. Within experimental error, CO2 extracts reproduce the natural headspace of the plants.

High Pressure CO2 Extraction from Geranium Plants

ABSTRACT The headspace of fresh and dried geranium plants were compared with those of extracts obtained by three different methods: liquid extraction (21°C, 56.5 bar), supercritical (34.5°C, 160 bar) CO2 extraction, and steam distillation. The difference in aroma of the CO2 extracts and of the steam distillate is due to quantitative differences in the composition of these two. A trend of increasing capability to extract the less volatiles is observed from the steam distillate to liquid to supercritical CO2, the first being richer in rose oxides, the second in isomenthone and the third extract in citronellyl formate and citronellol.

Phase equilibria of ethene + limonene and ethene + cineole from 285 k to 308 k and pressures to 8 mpa

Abstract Using a variable-volume high pressure equilibrium cell, phase behaviour was obtained for the binaries supercritical ethene with limonene and supercritical ethene with cineole. VLE, including the mixture critical points, was obtained at 288 K, 298 K and 308 K and for pressures to 8 MPa. Liquid-liquid-vapour (LLV) equilibrium was found for both binaries above the critical temperature of ethene, in the range 285–301 K. The results indicate that at these experimental conditions both terpenes have similar phase behaviour with ethene. The measured VLE data were correlated using the Peng-Robinson equation of state using the two parameter unsymmetric mixing rules of Panagiotopoulos and Reid.