Biphasic polymerization process

• US 6,359,102 B1
• Filed: 06/29/1998
• Issued: 03/19/2002
• Est. Priority Date: 06/27/1997
• Status: Expired due to Fees

• Current Assignee: Integra Lifesciences Corporation (Integra LifeSciences Holdings Corporation)
• Original Assignee: Integra Lifesciences Corporation (Integra LifeSciences Holdings Corporation)
• Inventors: Kemnitzer, John E., Brode, George L., Kohn, Joachim B.
• Primary Examiner(s): Mullis, Jeffrey C.
• Application Number:
  US09/107,753
• Time in Patent Office: 1,359 Days
• Field of Search: 528/174, 528/176, 528/203, 528/204, 528/179, 528/183, 528/184, 528/196, 528/199, 528/210, 528/288, 528/332, 528/368, 528/371, 528/422
• US Class Current: 528/179
• CPC Class Codes: C08G 63/6856 Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 63/79 Interfacial processes, i.e. processes involving a reaction at the interface of two non-miscible liquids
• CPC Class Codes: C08G 63/87 Non-metals or inter-compounds thereof boron C08G63/84
• CPC Class Codes: C08G 64/12 containing nitrogen
• CPC Class Codes: C08G 64/24 and phenols

Abstract

Improvements are disclosed for biphasic polymerization processes in which an aqueous solution of a first monomer that is hydrolytically unstable below a pH of about six or above a pH of about eight is admixed with a water-immiscible organic solvent and there is added to the admixture a catalyst selected from tertiary amine, quaternary amine and phosphonium catalysts, an acid-forming co-monomer for the first monomer, an acid scavenger, after which the resulting polymer is recovered, wherein the improvement includes providing the aqueous solution at a pH between about si and about eight, and adding to the admixture the acid-forming co-monomer and the acid scavenger at relative rates effective to maintain the pH of the admixture between about six and about eight. The catalyst may be added in a molar ratio to the first monomer effective to provide a predetermined weight-average or number-average molecular weight for the resulting polymer. Biphasic polymerization processes for monomers that are not pH sensitive are also disclosed.

Claims

1. In a biphasic polymerization process for providing an amino acid derived polymer, comprising the steps of:

admixing an aqueous solution comprising a first monomer with a water-immiscible organic solvent;

adding to the admixture a catalyst selected from the group consisting of tertiary amine, quaternary amine and phosphonium catalysts, an acid-forming co-monomer for said first monomer and an acid scavenger; and

recovering the resulting amino acid derived polymer,

the improvement comprising;

providing said aqueous solution at a pH from about six to about eight, and

adding to said admixture said acid-forming co-monomer and said acid scavenger at relative rates effective to maintain said pH of said admixture in a range from about six to about eight, to thereby prevent said first monomer from hydrolyzing to form an acid prior to polymerization, wherein said resulting amino acid derived polymer is hydrolytically unstable at physiological conditions.

2. The process of claim 1, wherein said water-immiscible organic solvent is selected from the group consisting of methylene chloride, chloroform and 1,2-dichloroethane.

3. The process of claim 1, wherein said catalyst is a phase transfer catalyst.

4. The process of claim 1, wherein said catalyst is a tertiary or quaternary amine compound selected from the group consisting of triethylamine, benzyltriethylammonium chloride, methyl C₈-C₁₀ trialkyl ammonium chlorides and tetrabutyl ammonium iodide.

5. The process of claim 1, wherein said catalyst is present in a molar ratio to said first monomer effective to provide a predetermined weight-average or number-average molecular weight for said resulting polymer.

6. The process of claim 1, wherein said acid scavenger is selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates and alkaline earth metal bicarbonates.

7. The process of claim 6, wherein said acid scavenger is sodium hydroxide.

8. The process of claim 1, wherein said addition rate of said co-monomer and said addition rate of said acid scavenger are effective to maintain said pH of said admixture at about seven.

9. The process of claim 1, wherein said catalyst and said acid scavenger are blended together and added to said admixture at an addition rate relative to said addition rate of said co-monomer effective to maintain said pH of said admixture from about six to about eight.

10. The process of claim 1, wherein said first monomer is a diphenol and said co-monomer is a dihalide selected from the group consisting of:

wherein X is a halogen, R is carbon or sulfur, and Z is an aryl, alkyl, alkylaryl, alkyl ether, aryl ether or alkylaryl ether group containing up to 18 carbon atoms.

11. The process of claim 10, wherein said dihalide is selected from the group consisting of phosgene, diphosgene, triphosgene, adipoyl chloride and sebacoyl chloride.

12. The process of claim 11, wherein said dihalide is phosgene.

13. The process of claim 10, wherein said diphenol has the structure:

wherein R₁ and R₂ are independently selected from the group consisting of —

CH═

CH— and

(—

CH₂—

)_n, wherein n is between 0 and 6, inclusive, and R₃ is selected from the group consisting of alkyl and allylaryl groups containing up to 18 carbon atoms and biologically and pharmacologically active agents.

14. The process of claim 13, wherein R₁ and R₂ are (—

CH₂—

)_n, wherein n is independently 1 or 2 and R₃ is an ethyl or beneyl group.

15. The process of claim 14, wherein R₁ is —

CH₂—

CH₂— and

R₂ is —

CH₂—

.

16. The process of claim 15, wherein R₃ is an ethyl group.

17. The process of claim 14, wherein said diphenol is a first diphenol and said aqueous solution further comprises a second diphenol having the structure:

wherein R₁ and R₂ are (—

CH₂—

)_n, wherein n is independently 1 or 2 and R₃ is an ethyl or benzyl group.

18. The process of claim 17, wherein R₁ for both said first and second diphenols is —

CH₂—

CH₂—

, R₂ for both said first and second diphenols is —

CH₂—

, R₃ for said first diphenol is an ethyl group and R₃ for said second diphenol is a benzyl group.

19. In a biphasic polymerization process for providing an amino acid derived polymer, comprising the steps of:

admixing an aqueous solution of a first monomer with a water immiscible organic solvent;

adding to the admixture a catalyst selected from the group consisting of tertiary amine, quaternary amine and phosphonium catalysts, an acid-forming co-monomer for said first monomer, and an acid scavenger; and

recovering the resulting amino acid derived polymer;

the improvement comprising;

providing said aqueous solution at a pH from about six to about eight,

adding said catalyst to said admixture at a molar ratio to said first monomer effective to provide a predetermined weight-average or number-average molecular weight for said resulting polymer, and

adding to said admixture said acid-forming co-monomer and said acid scavenger at relative rates effective to maintain the pH of said admixture in a range from about six to about eight, wherein said resulting amino acid derived polymer is hydrolytically unstable at physiological conditions.

20. The process of claim 19, wherein said water-immiscible organic solvent is selected from the group consisting of methylene chloride, chloroform and 1,2-dicholoroethane.

21. The process of claim 19, wherein said catalyst is a phase transfer catalyst.

22. The process of claim 21, wherein said catalyst is selected from the group consisting of triethylamine, benzyltriethylammonium chloride, methyl C₈-C₁₀ trialkyl amonium chlorides and tetrabutyl ammonium iodide.

23. The process of claim 19, wherein said acid scavenger is selected from the group consisting of alkali metal hydroxides, alkane earth metal hydroxides, alkali metal carbonates, alkle earth metal carbonates, alkali metal bicarbonates and alkaine earth metal bicarbonates.

24. The process of claim 23, wherein said acid scavenger is sodium hydroxide.

25. The process of claim 19, wherein said first monomer is a diphenol and said co-monomer is a dihalide selected from the group consisting of:

wherein X is a halogen, R is carbon or sulfur, and Z is an alkyl aryl, alkylaryl, alkyl ether, aryl ether or alkylaryl ether group containing up to 18 carbon atoms.

26. The process of claim 25, wherein said dihalide is selected from the group consisting of phosgene, diphosgene, triphosgene, adipoyl chloride and sebacoyl chloride.

27. The process of claim 26, wherein said dihalide is phosgene.

28. In a biphasic polymerization process for providing an amino acid derived polymer, comprising the steps of;

admixing an aqueous solution comprising a first monomer with a water-immiscible organic solvent;

adding to the admixture a catalyst selected from the group consisting of tertiary amine, quaternary amine and phosphonium catalysts, an acid-forming co-monomer for said first monomer and an acid scavenger; and

recovering the resulting amino acid derived polymer,

the improvement comprising;

providing said aqueous solution at a pH from about six to about eight, and

adding to said admixture said acid-forming co-monomer and said acid scavenger at relative rates effective to maintain said pH of said admixture from about six to about eight, to thereby prevent said first monomer from hydrolyzing prior to polymerization, the molar ratio of acid-forming co-monomer to first monomer being 1.4;

1 or greater,

wherein said resulting amino acid derived polymer is hydrolytically unstable at physiological conditions.

29. The process of claim 28, wherein said water-immiscible organic solvent is selected from the group consisting of methylene chloride, chloroform and 1,2-dichloroethane.

30. The process of claim 28, wherein said catalyst is a phase transfer catalyst.

31. The process of claim 28, wherein said catalyst is a tertiary or quaternary amine compound selected from the group consisting of triethylamine, benzyltriethylanuonium chloride, methyl C₈-C₁₀ trialkyl ammonium chlorides and tetrabutyl ammonium iodide.

32. The process of claim 28, wherein said acid scavenger is selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates and alkaline earth metal bicarbonates.

33. The process of claim 32, wherein said acid scavenger is sodium hydroxide.

34. The process of claim 28, wherein said addition rate of said co-monomer and said addition rate of said acid scavenger are effective to maintain said pH of said admixture at about seven.

35. The process of claim 28, wherein said catalyst and said acid scavenger are blended together and added to said admixture at an addition rate relative to said addition rate of said co-monomer effective to maintain said pH of said admixture from about six to about eight.

36. The process of claim 28, wherein said first monomer is a diphenol and said co-monomer is a dihalide selected from the group consisting of

wherein X is a halogen, R is carbon or sulfur, and Z is an aryl, alkyl, alkylaryl, alkyl ether, aryl ether or alkylaryl ether group containing up to 18 carbon atoms.

37. The process of claim 36, wherein said dihalide is selected from the group consisting of phosgene, diphosgene, triphosgene, adipoyl chloride and sebacoyl chloride.

38. The process of claim 37, wherein said dihalide is phosgene.

39. The process of claim 36, wherein said diphenol has the structure:

wherein R₂, and R₂ are independently selected from the group consisting of —

CH═

CH— and

(—

CH₂—

)_n, wherein n is between 0 and 6, inclusive, and R₃ is selected from the group consisting of alkyl and alkylaryl groups containing up to 18 carbon atoms and biologically and pharmacologically active agents.

40. The process of claim 39, wherein R₁ and R₂ are (—

CH₂—

)_n, wherein n is independently 1 or 2 and R₃ is an ethyl or benzyl group.

41. The process of claim 40, wherein R₁ is —

CH₂—

CH₂— and

R₂ is —

CH₂—

.

42. The process of claim 41, wherein R₃ is an ethyl group.

43. The process of claim 40, wherein said diphenol is a first diphenol and said aqueous solution further comprises a second diphenol having the structure:

wherein R₁ and R₂ are (—

CH₂—

)_n, wherein n is independently 1 or 2 and R₃ is an ethyl or benzyl group.

44. The process of claim 43, wherein R₁ for both said first and second diphenols is —

CH₂—

CH₂—

, R₂ for both said first and second diphenols is —

CH₂—

, R₃ for said first diphenol is an ethyl group and R₃ for said second diphenol is a benzyl group.

45. The process of claim 28 in which the molar ratio of acid-forming co-monomer to first monomer is less than about 3:

1.