Ireneo Kikic

Processing of carbamazepine–PEG 4000 solid dispersions with supercritical carbon dioxide: preparation, characterisation, and in vitro dissolution

The purpose of this study was to apply the attractive technique of the supercritical fluid to the preparation of solvent-free solid dispersions. In particular, the gas antisolvent crystallisation technique (GAS), using supercritical carbon dioxide as processing medium, has been considered to prepare an enhanced release dosage form for of the poorly soluble carbamazepine, employing PEG 4000 as a hydrophilic carrier. The physical characterisation of the systems using laser granulometer, powder X-ray diffraction, thermal analyses, and scanning electron microscopy was carried out in order to understand the influence of this technological process on the physical status of the drug. The results of the physical characterisation attested a substantial correspondence of the solid state of the drug before and after treatment with GAS technique, whereas a pronounced change in size and morphology of the drug crystals was noticed. The dramatic reduction of the dimensions and the better crystal shape, together with the presence of the hydrophilic polymer determined a remarkable enhancement of the in vitro drug dissolution rate.

High pressure fluid phase equilibria : experimental methods and systems investigated (1978-1987)

Abstract The phase behaviour of fluid mixtures at high pressure has received great attention over the past decade. This upsurge of interest has been occasioned by the importance that high pressure fluid phase equilibria has now assumed in some industrial areas. This work reviews and classifies recently developed experimental methods for investigating high pressure fluid phase equilibria. A review of the systems studied in the last 10 years is also given.

Unifac prediction of vapor-liquid equilibria in mixed solvent-salt systems

Abstract The Sander model for correlation and prediction of salt effects on vapor—liquid equilibria (VLE) of mixed solvents combines a term of the Debye—Huckel type with a modified UNIQUAC equation with concentration dependent parameters. In this work the UNIQUAC equation has been substituted by the original UNIFAC group-contribution model with concentration independent group interaction para-meters. Group interaction parameters have been estimated between ions (Li+, Na+, K+, Ca2+, Ba2+, Sr2+, Cu2+, Ni2+, Hg2+, F−, Cl−, Br−, J−, NO3− and CH3COO−), and solvent groups (CH2, OH, CH3OH, H2O, CH3CO), while previously published group interaction parameters between solvent groups have been maintained. It is shwon that the proposed model represents VLE for solvent—water—salt mixtures with an expected average accuracy of the total pressure around 9% and of the vapor-phase mole fractions around 4%. Since it is a predictive group-contribution method it has a much broader range of applicability than the Sander model.

Modelling solubility of solids in supercritical fluids using fusion properties

Abstract The modelling of solid solubilities in supercritical fluids is usually performed by means of thermodynamic models based on cubic equations of state together with the use of correlations for estimating the solid properties. However, it was shown in the literature, that the error in sublimation pressure, which is very low for high molecular weight compounds, is in many cases responsible for large deviations between experimental and calculated solubilities. In this work, the sublimation pressure of solids is estimated by using experimental fusion data and liquid–vapour equilibrium properties obtained from an equation of state (EOS). The results provided by this method are compared with those obtained using sublimation pressures from literature. It is shown that this method allows satisfactory solubility predictions when using a reliable EOS.

An experimental study of supercritical adsorption equilibria of salicylic acid on activated carbon

The supercritical desorption of solutes from porous media is a technology with a range of applications such as the treatment of contaminated soil and the regeneration of spent activated carbon. Although data in this field are scarce, previous studies have shown that supercritical adsorption equilibria have a significant role in defining supercritical desorption behaviour. The existing supercritical adsorption database is described and trends in the data are discussed. Experimental data for the system CO2 - salicylic acid - activated carbon are presented. A new apparatus incorporating dual high pressure syringe pumps and a high pressure UV cell was constructed to measure these data. Adsorption isotherms were measured at pressures between 90 and 250 bar and 308.1 K and 328.1 K. The influence of CO2 density and temperature on the adsorption equilibria is also studied. The adsorption data have been correlated with existing isotherm models.

Study of the solid state of carbamazepine after processing with gas anti-solvent technique

The purpose of this study was to investigate the influence of supercritical CO2 processing on the physico-chemical properties of carbamazepine, a poorly soluble drug. The gas anti-solvent (GAS) technique was used to precipitate the drug from three different solvents (acetone, ethylacetate and dichloromethane) to study how they would affect the final product. The samples were analysed before and after treatment by scanning electron microscopy analysis and laser granulometry for possible changes in the habitus of the crystals. In addition, the solid state of the samples was studied by means of X-ray powder diffraction, differential scanning calorimetry, diffuse reflectance Fourier-transform infrared spectroscopy and hot stage microscopy. Finally, the in vitro dissolution tests were carried out. The solid state analysis of both samples untreated and treated with CO2, showed that the applied method caused a transition from the starting form III to the form I as well as determined a dramatic change of crystal morphology, resulting in needle-shaped crystals, regardless of the chosen solvent. In order to identify which process was responsible for the above results, carbamazepine was further precipitated from the same three solvents by traditional evaporation method (RV-samples). On the basis of this cross-testing, the solvents were found to be responsible for the reorganisation into a different polymorphic form, and the potential of the GAS process to produce micronic needle shaped particles, with an enhanced dissolution rate compared to the RV-carbamazepine, was ascertained.

Liquid membrane permeation for the separation of C8 hydrocarbons

Abstract The parameters influencing the separation of C 8 hydrocarbons by permeation through a liquid membrane were examined. The methodology of operation was observed to influence the separation results. Single-drop experiments gave diffeent results from those obtained by emulsion techniques. The effect of the solvent on the separation factor was also investigated. The importance of the use of either a pure gas or a gas saturated with organic vapours as a solvent was also shown.

Determination of organic acids in urine by solid‐phase microextraction and gas chromatography–ion trap tandem mass spectrometry previous ‘in sample’ derivatization with trimethyloxonium tetrafluoroborate

A method for the determination of the organic acids directly in the urine employing derivatization with trimethyloxonium tetrafluoroborate as a methylating agent and sequential extraction by head space and direct immersion/solid phase microextraction is reported. Furoic acid, hippuric acid, methylhippuric acid, mandelic acid, phenylglyoxylic acid and trans, trans muconic acid contained in urine and proposed by the American Conference of Governmental Industrial Hygienists as biological exposure indices were determined after a fast and economically convenient preparation step and sensitive gas chromatography-ion trap-mass spectrometry/tandem mass spectrometry analysis. Urine is rather a complex sample and hence the acquisition method required specific GC-MS instrumentation capable of supporting the changeover, fully automated during a single chromatographic separation, from mass to tandem mass spectrometry and both chemical and electron ionization modes. The automation of the analytical method provides a number of advantages, including reduced analysis time for both routine analysis and method development, and greater reproducibility. The equilibrium and kinetics of this substances vs head space/direct immersion-solid phase microextraction were investigated and evaluated theoretically.

Supercritical fluids chromatography for impregnation optimization

Abstract Supercritical impregnation technique of polymeric matrix is going to have a very high interest in the pharmaceutical field. The possibility to obtain a final drug release product totally uncontaminated by organic solvents is a noticeable progress for the pharmaceutical factories. Two main steps are involved in the impregnation studies, the knowledge of the behavior of the drug/supercritical medium system, and the tedious and time consuming impregnation experiments for the choice of the conditions and for the choice of the proper matrix to be impregnated. In this work, an example of solubility study on anti inflammatory drug in supercritical carbon dioxide and in CO2/cosolvent mixtures, by a dynamic method is reported, moreover supercritical fluid (SF) chromatography technique is proposed as a tool which can give useful information on impregnation experiments in very short times.

Activity coefficients of hydrocarbons in phthalates

Abstract Activity coefficients at infinite dilution of hydrocarbons in eight phthalates at 25, 50, 75, 100 and 125 °C were determined by gas chromatography. The effects of the nature of the esterifying alcohols and of the solute and that of temperature are discussed. A non-linear behaviour of 1n γ1∞ versus 1/T was found; hence the excess partial molar heat capacities at infinite dilution of the solutes in the phthalates studied (CpE,∞) were evaluated over the temperature range 25–125 °C and a relationship between 1n γ1∞ and T (°K) was obtained.