Solution polymerization of high molecular weight poly(phosphoesters) in toluene

• US 5,952,451 A
• Filed: 06/23/1998
• Issued: 09/14/1999
• Est. Priority Date: 06/27/1997
• Status: Expired due to Fees

• Current Assignee: Guilford Pharmaceuticals Inc. (M G I Pharma Incorporated)
• Original Assignee: Guilford Pharmaceuticals Inc. (M G I Pharma Incorporated)
• Inventors: Zhao, Zhong
• Primary Examiner(s): BOYKIN, TERRESSA M
• Application Number:
  US09/102,813
• Time in Patent Office: 448 Days
• Field of Search: 528/272
• US Class Current: 528/272
• CPC Class Codes: C08G 79/04 Phosphorus linked to oxygen or to oxygen and carbon

Abstract

A process for making a high molecular weight poly(phosphoester) composition comprising:

(i) a biologically active substance; and

(ii) a poly(phosphoester) with the recurring monomeric units: ##STR1## wherein X is --O-- or --NR"--, where R" is H or alkyl; L is a divalent organic moiety, with the proviso that L cannot have the formula ##STR2## R'"'"' is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic, or heterocycloxy; and n is from about 25 to 2000,

is described. The process comprises the steps of:

(a) substantially dissolving p moles of a di--XH compound in a solvent comprising more than 75% toluene at a first temperature between about -75° C. and +60° C. to form a reaction mixture;

(b) while maintaining the reaction mixture at the first temperature, adding q moles, where p≈q, of a phosphorodihalo compound;

(c) gradually increasing said first temperature at a rate of less than about 1.5° C. per minute as necessary to achieve a second temperature between about 0° C. and 150° C., and mixing the reaction mixture at the second temperature to form the polymer of formula I; and

(d) isolating the polymer of formula I.

(e) incorporating the biologically active substance into the polymer of formula I.

Claims

1. A process for preparing a high molecular weight poly(phosphoester) composition comprising.

(i) a biologically active substance;

and

(ii) a poly(phosphoester) with the recurring monomeric units of formula I;

##STR13## wherein;

X is --O-- or --NR"--, where R" is H or alkyl;

L is a divalent organic moiety, with the proviso that L cannot have the formula ##STR14## R'"'"' is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic, or heterocycloxy; and

n is from about 25 to 2000,

said process comprising the steps of;

(a) substantially dissolving p moles of a di--XH compound having formula II;

space="preserve" listing-type="equation">II H--X--L--X--H

in a solvent comprising at least 75% toluene by volume at a first temperature between about -75°

C. and +60°

C. to form a reaction mixture;

(b) while maintaining the reaction mixture at the first temperature, adding q moles, where p≈

q, of a phosphorodihalo compound of formula III;

##STR15## wherein R'"'"' is defined as above and "halo" is Br, Cl or I;

(c) gradually increasing said first temperature at a rate of less than about 1.5°

C. per minute as necessary to achieve a second temperature between about 0°

C. and 150°

C., and mixing the reaction mixture at the second temperature to form the polymer of formula I;

(d) isolating the polymer of formula I; and

(e) incorporating the biologically active substance into the polymer of formula I.

2. The process of claim 1 wherein X is --O--.

3. The process of claim 1 wherein L comprises an aliphatic ring, a straight-chain or branched aliphatic group, or a carbonyl group.

4. The process of claim 1 wherein L is not halogenated.

5. The process of claim 1 wherein L is selected from the group consisting of:

##STR16## wherein R is branched or straight-chain alkylene and R"'"'"' is H, alkyl, aryl or heterocyclyl.

6. The process of claim 1 wherein R'"'"' is an alkoxy group.

7. The process of claim 1 wherein the solvent comprises at least 99.9% by volume toluene.

8. The process of claim 1 wherein the amount of solvent in step (a) is about 5-15 ml per gram of compound of formula II.

9. The process of claim 1 wherein an acid acceptor is present in said reaction mixture.

10. The process of claim 9 wherein the acid acceptor is a tertiary amine.

11. The process of claim 1 wherein said first temperature in between about -70°

C. and room temperature.

12. The process of claim 1 wherein said first temperature is lower than said second temperature and is raised to said second temperature at a rate of not more than about 1.25°

C. per minute.

13. The process of claim 1 wherein said reaction mixture is mixed at said second temperature for a time between about 10 minutes and 18 hours.

14. The process of claim 1 wherein said first temperature changes to said second temperature at a pressure of about atmospheric pressure.

15. The process of claim 1 wherein said polymer of formula I is isolated by quenching a solution of the polymer with a non-solvent or a partial solvent.

16. The process of claim 1 wherein said process is conducted in a batchwise manner.

17. The process of claim 1 wherein said process is continuous.

18. The process of claim 1 wherein the weight average molecular weight of said polymer is at least 50% greater than when dichloromethane is used as the solvent.

19. The process of claim 1 wherein the weight average molecular weight of said polymer is at least 100% greater than when dichloromethane is used as the solvent.

39. The process of claim 1 wherein said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, hormones, antineoplastic agents, interferons or cytokines, and pro-drugs of these substances.

40. The process of claim 1 wherein said biologically active substance is a therapeutic drug or pro-drug.

41. The process of claim 40 wherein said drug is selected from the group consisting of antibiotics, anti-virals, antifungals, anti-inflammatories, anticoagulants and antineoplastic agents.

42. The method of claim 40 wherein said drug is paclitaxel.

20. A high molecular weight poly(phosphoester) composition comprising.

(i) a biologically active substance;

and

(ii) a poly(phosphoester) with the recurring monomeric units of formula I;

##STR17## wherein;

X is --O-- or --NR"--, where R" is H or alkyl;

L is a divalent organic moiety, with the proviso that L cannot have the formula;

##STR18## R'"'"' is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic, or heterocycloxy; and

n is from about 25 to 2000,

wherein said polymer is made by a process comprising the steps of;

(a) substantially dissolving p moles of a di--XH compound having formula II;

space="preserve" listing-type="equation">II H--X--L--X--H

in a solvent comprising at least 75% toluene by volume at a first temperature between about -75°

C. and +60°

C. to form a reaction mixture;

(b) adding to said reaction mixture at said first temperature q moles, where p≈

q, of a phosphorodihalo compound of formula III;

##STR19## wherein R'"'"' is defined as above and "halo" is Br, Cl or I;

(c) gradually increasing said first temperature at a rate of less than about 1.5°

C. per minute as necessary to achieve a second temperature between about 0°

C. and 150°

C., and mixing the reaction mixture at the second temperature to form the polymer of formula I;

(d) isolating the polymer of formula I; and

(e) incorporating the biologically active substance into the polymer of formula I.

21. The polymer of claim 20 wherein X is --O--.

22. The polymer of claim 20 wherein L comprises an aromatic ring, an aliphatic ring, a straight-chain or branched aliphatic group, or a carbonyl group.

23. The polymer of claim 20 wherein L is not halogenated.

24. The polymer of claim 20 wherein L is selected from the group consisting of:

##STR20## wherein R is branched or straight-chain alkylene and R"'"'"' is H, alkyl, aryl or heterocyclyl.

25. The polymer of claim 20 wherein R'"'"' is an alkoxy group.

26. The polymer of claim 20 wherein the solvent comprises at least 99.9% by volume toluene.

27. The polymer of claim 20 wherein the amount of solvent in step (a) is about 5-15 ml per gram of compound of formula II.

28. The polymer of claim 20 wherein an acid acceptor is present in said reaction mixture.

29. The polymer of claim 28 wherein the acid acceptor is a tertiary amine.

30. The polymer of claim 20 wherein said first temperature in between about -70°

C. and room temperature.

31. The polymer of claim 20 wherein said first temperature is lower than said second temperature and said first temperature is raised to said second temperature at a rate of not more than about 1.25°

C. per minute.

32. The polymer of claim 20 wherein said reaction mixture is mixed at said second temperature for a time between about 10 minutes and 18 hours.

33. The polymer of claim 20 wherein said first temperature changes to said second temperature at a pressure of about atmospheric pressure.

34. The polymer of claim 20 wherein said polymer of formula I is isolated by quenching a solution of the polymer with a nonsolvent or a partial solvent.

35. The polymer of claim 20 wherein said process is conducted in a batchwise manner.

36. The polymer of claim 20 wherein said process is continuous.

37. The polymer of claim 20 wherein the weight average molecular weight of said polymer is at least 50% greater than when dichloromethane is used as the solvent.

38. The polymer of claim 20 wherein the weight average molecular weight of said polymer is at least 100% greater than when dichloromethane is used as the solvent.

43. The polymer of claim 20 wherein said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, hormones, other antineoplastic agents, interferons or cytokines, and pro-drugs of these substances.

44. The polymer of claim 20 wherein said biologically active substance is a therapeutic drug or pro-drug.

45. The polymer of claim 44 wherein said drug is selected from the group consisting of antibiotics, anti-virals, antifungals, anti-inflammatories, anticoagulants and anti-neoplastic agents.

46. The process of claim 44 wherein said drug is paclitaxel.