Pure polyanhydride from dicarboxylic acid and coupling agent

• US 4,916,204 A
• Filed: 07/31/1987
• Issued: 04/10/1990
• Est. Priority Date: 07/31/1987
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Ron, Eyal, Mathiowitz, Edith, Kothari, Rohit, Giannos, Steven, Langer, Robert S., Domb, Abraham J.
• Primary Examiner(s): Anderson, Harold D.
• Application Number:
  US07/080,332
• Time in Patent Office: 984 Days
• Field of Search: 528/271, 528/371, 528/370
• US Class Current: 528/271
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/39 having oxygen in the same ring
• CPC Class Codes: C08G 67/04 Polyanhydrides
• CPC Class Codes: C08G 69/08 derived from amino-carboxylic acids
• CPC Class Codes: C08G 69/10 Alpha-amino-carboxylic acids polysuccinimides C08G73/1092

Abstract

A method for synthesizing polyanhydrides in solution using coupling agents and a removable acid acceptor to effect a one-step polymerization of dicarboxylic acids. As used in the method, these coupling agents include phosgene, diphosgene, and acid chlorides. Insoluble acid acceptors include insoluble polyamines and crosslinked polyamines such as polyethyleneimine and polyvinylpyridine and inorganic bases such as K₂ CO₃, Na₂ CO₃, NaHCO₃, and CaCO₃. The only byproduct formed is a removable hydrochloric acid-acid acceptor.

Examples are provided of the polymerization of highly pure polyanhydrides using phosgene, diphosgene or an acid chloride as the coupling agent, in combination with either an insoluble acid acceptor or a soluble acid acceptor in a solvent wherein the polymerization byproduct or polymer is insoluble.

A particularly important application of these polyanhydrides is in the formation of drug delivery devices containing bioactive compounds. The method is also useful in the polymerization of dicarboxylic acids including heat liable dipeptides of glutamic or aspartic acid.

Claims

1. A highly pure polyanhydride produced by reacting a dicarboxylic acid with phosgene or diphosgene in the presence of an acid acceptor and in a solvent to produce a polyanhydride soluble in said solvent and byproduct acid acceptor insoluble in said solvent, and removing insoluble byproduct acid acceptor and any unreacted phosgene or diphosgene, said polyanhydride consisting essentially of polyanhydride.

2. The highly pure polyanhydride of claim 1 wherein the insoluble acid acceptor is selected from the group consisting of insoluble polyamines, crosslinked polyamines, and inorganic bases.

3. The highly pure polyanhydride of claim 2 wherein the acid acceptor is selected from the group consisting of K₂ CO₃, Na₂ CO₃, NAHCO₃, CaCO₃, poly(4-vinylpyridine) and polyethyleneimine.

4. A method for preparing highly pure polyanhydride comprising reacting a dicarboxylic acid with phosgene or diphosgene in the presence of an acid acceptor and in a solvent to produce a polyanhydride and byproduct acid acceptor insoluble in said solvent, and removing insoluble byproduct acid acceptor and any unreacted phosgene or diphosgene from said polyanhydride.

5. The method of claim 4 wherein the insoluble acid acceptor is selected from the group consisting of insoluble polyamines, crosslinked polyamines, and inorganic bases.

6. The method of claim 5 wherein the insoluble acid acceptor is selected from the group consisting of polyethyleneimine, poly(4-vinylpyridine), K₂ CO₃, Na₂ CO₃, NaHCO₃, and CaCO₃.