BioMatNet Item: FAIR-CT95-0300 - Development from cyclodextrin derivatives to polymeric materials for selective transport, separation and detection of active substances (utilisation of CDX)

FAIR-CT95-0300
Development from cyclodextrin derivatives to polymeric materials for selective transport, separation and detection of active substances (utilisation of CDX)

Contacts
Summary Information

	Contract No:	FAIR-CT95-0300
	Date Prepared:	July 2001
	Source:	Final Report Executive Summary

Final Report Executive Summary

Source: Final report of 31-12-1998

Consortium: The project was co-ordinated by the Polymer Institute of the University Karlsruhe (Germany), in partnership with the Laboratory of Organic Chemistry, University of Twente, Enschede (The Netherlands), Laboratoire de Chimie Macromoleculaire, University of Lille, Villeneuve d'Ascq (France), Drecam/SCM, Gif sur Yvette (France), Inst fur Organische Chimie, Universitat Hamburg (Germany), Nordlys, Bailleul (France), Polymer Standards Service, Mainz (Germany), Pharmaceutical R&D, Astra Hassle AB, Molndal (Sweden), Dept de Pharmacochimie Moleculaire, Lab de Chimie des Glucides, Grenoble (France) and Wacker Chimie GmbH, Munchen (Germany).

EXECUTIVE SUMMARY

Cyclodextrins are a unique group of cyclic oligomers of glucose, as they are able to incorporate and recognise other molecules in their molecular cavities. The main objective of this project was to initiate a break through for industrial applications of cyclodextrin derivatives and cyclodextrin polymers. Therefore, the interesting inclusive properties of cyclodextrins were used to retard, transport, separate and detect active substances. These functions will lead to a great variety of applications: improved drug delivery and slow release of active substances, refined pharmaceuticals, decontamination of waste waters and detection of poisons in the environment. The project was structured into six tasks (A - F). The major results were as follows:

Task A: Waste water decontaminating systems Cyclodextrin gels (cyclodextrin content 0.3 - 0.7 mmol/g) were synthesised by condensation of cyclodextrins and epichlorohydrin in aqueous NaOH. They were characterised by solid state CP-MAS-NMR. Gels of alpha, beta, gamma-cyclodextrin were already produced in a laboratory pilot plant in 1 kg quantities. Cyclodextrin resins (cyclodextrin content 0.3 - 0.7 mmol/g) were prepared by inverse suspension polymerisation of hydroxyethyl methacrylate (HEMA) and methacryloyl beta-cyclodextrin (beta-W7MAHP, Wacker-Chemie). Cyclodextrin was also attached to silica beads (cyclodextrin content 0.1 mmol/g) in a two step procedure. Polypropylene filters were irradiated with electron beams and grafted by methacryloyl beta-cyclodextrin. The cyclodextrin content was around 0.1 mmol/g. Solid state ¹³C-MAS NMR spectroscopy of the various filter materials revealed valuable information about the structure, the cyclodextrin content and the mobility of the cyclodextrin moieties. The adsorption capacities of the filter materials were measured by both batch tests and column tests. The uptake of several dyes present in industrial waste waters could be demonstrated. Cyclodextrin gels turned out to be most efficient.

Task B: Large state separations by two phase systems New cationic cyclodextrin polymers were synthesised on 10 g scale by reaction of cyclodextrin inclusion compounds with epichlorohydrin or bisepoxides and further reaction with dimethylamine. These polymers are highly water-soluble and able to complex various hydrophobic 'guest' molecules. Binding constants Ks of 'guests' in various cyclodextrins and derivatives were measured by titration microcalorimetry. These data enabled two-phase equilibrium to be predicted. A complete extraction of a 'guest compound' from an organic phase could be achieved using an aqueous solution of a cyclodextrin derivative. In addition, the transport of 'guest' compounds (such as, for example, ibuprofen), through an aqueous phase mediated by a hydrophilic cyclodextrin was demonstrated. The two enantiomers of naproxen show different transport rates. Therefore a preparative separation of these enantiomers might be possible in two phase systems.

Task C: Analytical and preparative chromatographic separation of enantiomers Lipophilic cyclodextrin derivatives were synthesised with one functional group e.g. epoxy-, amino- or aldehyde. The synthesised functional derivatives were immobilised on functionalised silica microparticles. The highest cyclodextrin content achieved was 0.1 mmol/g of silica The immobilised cyclodextrin derivatives were first tested as enantioselective stationary phases in micro-HPLC. A lot of chiral compounds, e.g. atrop isomers were investigated. The chiral drugs pemoline, phenylhydantoin and mofebutazone could be resolved into enantiomers.

Task D: Highly selective sensor devices Cyclodextrin was coupled with monofunctionalised calixarenes bearing a fluorophore. The resulting fluorescent cyclodextrin-calixarene-couples are interesting for the sensing of guests, as the fluorescence is lowered as soon as a guest is incorporated in the cavity. The anti-germination agents carvone and skatol could be detected above a limiting concentration of 10^-3 mol/l, and hormones e.g. the contraceptive drug ethinyl-nortesterone above a limiting concentration of even 10^-4 mol/l by fluorescence spectroscopy. Functionalised cyclodextrins were also attached to gold surfaces in the form of well defined monolayers. Analytes could be detected specifically by electochemical methods with very high sensitivity.

Task E: Solubilization and targeting of drugs New methods for the selective mono-functionalisation of cyclodextrins were developed which a low the preparation of 50g quantities. Signalling groups (e.g. peptides, sugars) were attached to these monofunctional cyclodextrins. The inclusion of the drugs Ibuprofen, Methadone, Alprenolole, Oxazepam, Methadone and Indomethacin within various cyclodextrins was proven by titration micro-calorimetry and NMR spectroscopy. The cyclodextrin-peptide conjugates are able to transport a ( rug to a certain destination in the body. The direct cellular reaction of the peptide-cyclodextrins was observed in vivo after injection to rats. Cytological and histological experiments were used to prove the targeting was taking place.

Task F Coating of solid surfaces Cyclodextrins mono layers were obtained by linkage of functionalised cyclodextrin to silicon wafers. Epoxy- and isothiocyanato-functionalized beta-cyclodextrin was linked to amino groups at the surface. The thickness of the cyclodextrin layer was 0.8 - 1 nm, equivalent to the height of one cyclodextrin molecule. Reactive cyclodextrin polymers with pending epoxides were synthesised. They are highly water soluble. Because of the epoxy functionalities they can be covalently fixed to reactive surfaces like cotton, paper or wool. Active substances, fragrances for examples, can be complexed this way at the surface of clothes from which they are slowly released.