Process for the preparation of amphiphilic poly(N-vinyl-2-pyrrolidone) block copolymers
View Patent ↗The instant invention provides a two-step polymerization process for preparing amphiphilic poly(N-vinyl-2-pyrrolidone), (PVP)-block-polyester copolymers and other diblock and triblock copolymers consisting of PVP as one block. The block copolymers of the invention can be used as vehicles for drug delivery.
1. A process for preparing diblock and triblock copolymers comprising the steps of:
(a) performing radical polymerization of N-vinyl-2-pyrrolidone in the presence of a radical initiator, a chain transfer agent and an alcoholic solvent to form hydroxy-terminated poly (N-vinylpyrrolidone) wherein said hydroxy-terminated poly (N-vinylpyrrolidone) is isolated by dissolution and precipitation and
(b) performing ionic polymerization of monomers or comonomers selected from the group consisting of 3,6-dimethyl-1,4-dioxane-2,5-dione, ε-caprolactone and γ-caprolactone in the presence of a base and a macroinitiator wherein said macroinitiator is the hydroxy-terminated poly (N-vinylpyrrolidone) formed in step (a) thereby preparing said diblock and triblock copolymers, wherein said copolymers self-assemble in polymeric micelles or stabilized nanoparticles in aqueous solution.
2. The process in accordance with claim 1 wherein said alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol, tert-butanol, 1-pentanol and 2-pentanol.
3. The process in accordance with claim 1 wherein said chain transfer agent is a thiol derivative selected from the group consisting of 2-mercaptoethanol, 3-mercapto-1-propanol, 3-mercapto-2-propanol, 4-mercapto-1-butanol, 3-mercapto-2-butanol and 6-mercapto-1-hexanol.
4. The process in accordance with claim 1 wherein said radical initiator is an azo derivative selected from the group consisting of 2,2′-azobis (2-methyl-N-(2-hydroxyethyl)-propionamide), 2,2′-azobis [2-methyl-N-(2-(1-hydroxybutyl)]-propionamide and 1,1′-azobis(cyclohexane-carbonitrile).
5. The process in accordance with claim 1 wherein said base is potassium or sodium hydride.
6. The process in accordance with claim 1 wherein said poly (N-vinylpyrrolidone) formed in step (a) comprises a hydroxyl group on at least one chain end.
7. The process in accordance with claim 1 wherein the solvent for said dissolution is selected from the group consisting of methanol, ethanol, isopropanol, acetone, 2-butanone, 4-methyl-2-pentanone, dichloromethane and tetrahydrofuran.
8. The process in accordance with claim 7 wherein at least two solvents are combined for said dissolution.
9. The process in accordance with claim 1 wherein the solvent for said precipitation is selected from the group consisting of diethyl ether, tert-butyl methyl ether, hexane derivatives, heptane derivatives, ethyl acetate, isopropyl acetate, toluene and xylene derivatives.
10. The process in accordance with claim 9 wherein at least two solvents are combined for said precipitation.
11. The process in accordance with claim 1 wherein said poly (N-vinylpyrrolidone) formed in step (a) is dried under vacuum at a final temperature over 100° C.
12. The process in accordance with claim 1 wherein said poly (N-vinylpyrrolidone) formed in step (a) is dried by azeotropic distillation using an inert organic solvent.
13. The process in accordance with claim 12 wherein said inert organic solvent is selected from the group consisting of toluene, xylene derivatives and hepatane derivatives.
14. The process in accordance with claim 1 wherein said diblock and triblock copolymers are isolated by precipitation using an inert organic solvent.
15. The process in accordance with claim 14 wherein said inert organic solvent is selected from the group consisting of diethyl ether, tert-butyl methyl ether, hexane derivatives, heptane derivatives, ethyl acetate, isopropyl acetate, toluene and xylene derivatives.
16. The process in accordance with claim 15 wherein at least two inert organic solvents are combined for said precipitation.
17. The process in accordance with claim 1 wherein said diblock and triblock copolymers are purified by charcoal treatment.
18. The process in accordance with claim 1 wherein said poly (N-vinylpyrrolidone) formed in step (a) has a number average molecular weight between 1,000 D and 700 kD.
19. The process in accordance with claim 1 wherein said diblock and triblock copolymers have a number average molecular weight between 2,000 D and 700 kD.
20. The diblock copolymer prepared by the process of claim 1 .
21. The diblock copolymer of claim 20 wherein said diblock copolymer is poly (N-vinylpyrrolidone)-block-poly (D,L-lactide).
22. The triblock copolymer prepared by the process of claim 1 .
23. The triblock copolymer of claim 22 wherein said triblock copolymer is poly (D,L-lactide)-block-poly (N-vinylpyrrolidone)-block-poly(D,L-lactide).