Sandrine Henry de Hassonville

Determination of the free/included piroxicam ratio in cyclodextrin complexes: comparison between UV spectrophotometry and differential scanning calorimetry

Few analytical techniques allow to evaluate the inclusion yield of cyclodextrin-drug complexes, because most manufacturing processes give amorphous products. In this study, we have developed an alternative method to differential scanning calorimetry, to accurately determine the free/complexed piroxicam ratio by UV spectroscopy. This method is based on the differential solubility of the piroxicam-beta-cyclodextrin 1:2.5 mol/mol complex in water-acetonitrile (1:1, v/v) (Solvent A) or in anhydrous acetonitrile (Solvent B), both containing 0.05 M HCl. In anhydrous acetonitrile, beta-cyclodextrin is insoluble and the included drug remains entrapped, allowing the free piroxicam determination, while with 50% of water, the complex is totally dissolved, allowing the determination of the total guest content. This method was validated for linearity, precision and accuracy. The presence of cyclodextrin does not influence the assays, but more than 0.5% of water in Solvent B significantly affects the determination of the free piroxicam content. In comparison with differential scanning calorimetry, both detectability and precision were improved. It is now possible to analyse complexes with an inclusion purity greater than 99%.

Application of Supercritical carbon dioxide for the preparation of drug-cyclodextrin inclusion compounds

Inclusion complexes of drugs into cyclodextrins (CDs) can be obtained at the solid state by means of supercritical dioxide (SCCO2). A successful inclusion with a yield >98.5% has been achieved with piroxicam and β-CD. The temperature and the time of exposure to SCCO2 have a significant effect on the inclusion yield while the pressure has a negative effect. However, there is a strong interaction between temperature and pressure and this interaction has a positive influence. The molar ratio piroxicam-β-CD and the addition of ternary alkaline agents were also found to be significant factors. The dissolution rate of the complexes formed using SCCO2 was found to be significantly higher than that of the physical mixture. Inclusion complexes have also been obtained with miconazole treating mixtures of miconazole, CDs and citric acid by SCCO2. This new technique of inclusion of poorly soluble drugs into CDs allows the preparation of solid complexes without using organic solvents and thus without residues.

Preparation of poly(D,L-lactide) nanoparticles assisted by amphiphilic poly(methyl methacrylate-co-methacrylic acid) copolymers.

When co-precipitated with amphiphilic copolymers from DMSO, poly(D,L-lactide)(PLA) can be readily converted into stable sub-200 nm nanoparticles by addition of an aqueous phase, free of any polymeric stabilizers such as poly(vinyl alcohol) or Poloxamer. In this work, the ability of random poly(methyl methacrylate-co-methacrylic acid) copolymers (PMMA-co-MA) to stabilize PLA nanoparticles was demonstrated, and the properties of PLA/PMMA-co-MA nanoparticles were investigated. When co-precipitated with PMMA-co-MA, PLA was totally converted into nanoparticles using a polymer concentration in DMSO (CP) below 17.6 mg ml-1, and a PMMA-co-MA proportion above a critical value depending on the content of MA repeating units (X). For instance, the lowest PMMA-co-MA proportion required was 0.9 mg mg-1 PLA for X = 12%, and 0.5 mg mg-1 PLA for X = 25% (for CPLA = 16 mg ml-1 DMSO). The nanoparticle diameter was essentially independent of X, the proportion of PMMA-co-MA, and the PLA molecular weight, except for oligomers for which the nanoparticle diameter was smaller. It decreased when the organic phase was diluted (126 ± 13 nm for CP = 17.6 mg ml-1, and 81 ± 5 nm for CP = 5.6 mg ml-1). The timedependence of the stability and the degradation of PLA/PMMA-co-MA nanoparticles was discussed. One of the main advantages of this technique is the ability to control surface properties and to bring functional groups to otherwise non-functionalized PLA nanoparticles. To illustrate this, a conjugate of PMMA-co-MA25 and biotin was synthesized, and used to prepare biotinylated nanoparticles that could be detected by fluorescence and transmission electron microscopy after infiltration into ligatured rat small intestine.

Inclusion Complexes of Cyproterone Acetate with Cyclodextrins in Aqueous Solution

Cyproterone acetate (CPA) is a steroidal antiandrogen with a progestogenic activity. Given that this molecule has a very poor water solubility (2.1 μg/mL), different cyclodextrins (CDs) were tested to form inclusion complexes and to increase solubility. Two different techniques were compared to study the affinity between CPA and CDs: phase-solubility studies and NMR spectroscopy. The stoichiometry and the stability constant could be determined for most complexes with the aid of phase-solubility studies. The greatest increase in solubility was achieved with the methylated β-CDs, but hydroxypropylated β- and γ-CDs also gave enhanced solubilities. 1H-NMR studies showed a solubility increase similar to that found with phase-solubility studies. The proof of inclusion in the2,6-dimethyl-β-CD (DIMEB) was shown by 1H-NMR and t-ROESY spectra.