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

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Abstract

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.

Introduction

In the 1970s and 1980s, supercritical fluid technology was mainly focused on extraction and separation. However in the last 10 years, interest in supercritical fluid processing has also arisen in other areas. In particular, supercritical carbon dioxide is known to be a quasi-ideal solvent medium for preparation of pharmaceutical formulations such as microparticle formation, impregnation with supercritical solutions and microencapsulation, with the additional advantage of being able to remove completely the residual solvent in the processed carrier/drug formulation.

The particle formation processes involving supercritical fluid are based on the rapid expansion of supercritical solution (RESS) and gas anti-solvent (GAS) crystallisation. The latter is mostly used for recrystallisation of powders, the most important limitation of RESS development being the excessively low solubility of substances in supercritical fluids. The GAS method originates from the knowledge that the absorption of a gas in a liquid causes the liquid to expand. In particular, when a solution is expanded sufficiently by a gas, the liquid phase is no longer a good solvent for the solute (drug, polymer or both) and nucleation takes place. Advantages include higher solute throughput and flexibility of solvent choice [1], [2], [3], [4], [5].

The objective of this study was to investigate the applicability of the GAS method to the formation of carbamazepine (CBZ) particles and to control their characteristics by determining the influence of the process and the solvents on solid-state properties of drug particles. CBZ, a well-known anticonvulsivant drug, characterised by a slow and irregular gastro-intestinal absorption due to its low water solubility [6], has been extensively investigated in terms of solid-state studies [7], [8], [9], [10], [11]. Previous data have shown that CBZ exists as several polymorphic and pseudo-polymorphic forms [12], [13], [14].

With regards to supercritical fluid processing, Bettini et al. [15] investigated whether mixtures of CBZ polymorphs could be processed in dynamic and static condition in supercritical CO2 to select the pure stable form III, and found that the conversion in the stable crystalline phase could be promoted by treating the mixture at 55°C and 350 bar. Edwards et al. [16] processed all anhydrous CBZ polymorphs by solution enhanced dispersion with supercritical fluids (SEDS), showing that polymorph generation is influenced by crystallisation kinetics, solvent effects and temperature. In our previous work, we improved the dissolution properties of carbamazepine, applying GAS technique for the preparation of solid dispersions with PEG 4000, maintaining the original polymorphic form of the drug unaltered [17]. More recently, Sethia and Squillante [18] compared the physico-chemical properties and dissolution performances of CBZ in solid dispersions, formulated by supercritical carbon dioxide and conventional solvent evaporation method, using PEG 8000, Gelucire 44/14 and vitamin E TPGS NF (d-α-tocopheryl PEG1000 Succinate) as carriers. The authors found that CBZ after CO2 treatment converted into form I, whilst the conventional solvent evaporation method gave a CBZ sample consisting of a mixture of form III (starting) and form I.

In this work, we investigated the influence of GAS method on the physico-chemical properties of pure CBZ, while considering the effects of using different solvents. After selection of the appropriate solvents on the basis of their CO2-volumetric expansions, the precipitation of the drug was carried out by GAS technique and conventional evaporation method (RV) from acetone, ethylacetate and dichloromethane. Then, the characterisation of drug solid state encompassed the use of X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), hot stage microscopy (HSM) and diffuse reflectance Fourier-transform infrared spectroscopy (DRIFT) analyses. The shape and size of drug were determined by scanning electron microscopy analysis (SEM) and image analyses. Finally, the in vitro dissolution tests were performed.

Section snippets

Materials

Carbamazepine USP-grade was provided by Sigma-Aldrich Chemicals (Steinheim, Germany, Germany) and was used as received. All the solvents (acetone, dichloromethane, ethylacetate) were of analytical grade and were provided by Carlo Erba (Milan, Italy). CO2 (purity 99.9%) was supplied by SIAD (Trieste, Italy).

Solubility studies

The solubility of carbamazepine in supercritical CO2 was determined using the dynamic method at the temperature of 40°C and at three different pressures: 100, 130 and 160 bar. The detailed

Results and discussion

The solubility results are the average of at least three separate measurements. The maximum deviation between the measurements was ±3% giving a good indication of the expected accuracy of the results. Since the overall error (i.e. pressure, temperature, mass and volume) related to the individual equipment errors is significantly lower, the deviation is due to random experimental errors associated with the difficulties of working with high-pressure supercritical fluids and with the problems

Conclusions

The above reported experimental evidence shows that treating with supercritical CO2 solution of commercial CBZ in acetone, ethylacetate or dichloromethane, at the performed operating conditions, yields to a sample mostly made up of form I. Since this transition into the trigonal form also occurred by simple recrystallisation in vacuum evaporator, it is reasonable to infer that this transformation is due to the solvents rather than to the treatment with supercritical CO2. The photomicrographs of

Acknowledgements

The authors wish to thank the Italian Ministry of University and Scientific Research (MIUR) and Regione Friuli Venezia Giulia for financial support and Dr Formichi and Tecno Galenica s.r.l. for laser diffractometer analyses.

References (27)

  • A. Kordikowski et al.

    Volume expansions and vapor-liquid equilibria of binary mixtures of a variety of polar solvents and certain near-critical solvents

    J. Supercrit. Fl.

    (1995)
  • R.J. Roberts et al.

    Mechanical properties for polymorphs of sulphathiazole and carbamazepine

    Eur. J. Pharm. Sci.

    (2000)
  • P.M. Gallagher et al.

    Gas antisolvent recrystallization: a new process to recrystallize compounds in supercritical fluids

    Am. Chem. Soc. Symp. Ser.

    (1989)
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