Control of copolymer compositions

Abstract

Methods of making copolymers are described.

1 . (canceled) 
     
     
         2 . A method for preparing a composition comprising purified glatiramer acetate having a pyroglutamate concentration of 2000-7000 ppm and a Mp of 5000-9000 Da, comprising:
 polymerizing N-carboxy anhydrides of L-alanine, benzyl-protected L-glutamic acid, trifluoroacetic acid (TFA) protected L-lysine and L-tyrosine to generate a protected copolymer (Intermediate-1);   treating the Intermediate-1 with HBr and acetic acid to partially depolymerize the protected copolymer and deprotect benzyl-protected L-glutamic acid thereby generating a partially depolymerized product;   treating the partially depolymerized product with piperidine to deprotect TFA-protected lysines thereby generating glatiramer acetate; and   purifying the glatiramer acetate to create purified glatiramer acetate having a pyro-Glu concentration of 2000-7000 ppm and a Mp of 5000-9000 Da,   wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 5-25% weight/weight against intermediate-1 present at the beginning of the depolymerization reaction.   
     
     
         3 . The method of  claim 2  wherein the Intermediate-1 treated with HBr and acetic acid is not dry. 
     
     
         4 . The method of  claim 2  further comprising adding water at the start of the depolymerization reaction or during the depolymerization reaction. 
     
     
         5 . The method of  claim 2 , wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 8-14% w/w against Intermediate-1 present at the beginning of the depolymerization reaction. 
     
     
         6 . The method of  claim 2 , wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 10-20% w/w against Intermediate-1 present at the beginning of the depolymerization reaction. 
     
     
         7 . The method of  claim 2 , wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 7-15% w/w against Intermediate-1 present at the beginning of the depolymerization reaction. 
     
     
         8 . The method of  claim 2 , wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 9-13% w/w against Intermediate-1 present at the beginning of the depolymerization reaction. 
     
     
         9 . The method of  claim 2  wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 10-12% w/w against Intermediate-1 present at the beginning of the depolymerization reaction. 
     
     
         10 . The method of  claim 2 , wherein the depolymerization proceeds for at least 25 hrs. 
     
     
         11 . The method of  claim 2 , wherein the depolymerization proceeds for at least 30 hrs. 
     
     
         12 . The method of  claim 2 , wherein the depolymerization proceeds for at least 40 hrs. 
     
     
         13 . The method of  claim 2 , wherein the depolymerization reaction comprises contacting the protected copolymer with a solution comprising phenol, HBr and acetic acid. 
     
     
         14 . The method of  claim 2 , wherein the concentration of pyro-Glu in the purified glatiramer acetate is 2500-5500 ppm. 
     
     
         15 . The method of  claim 2 , wherein the concentration of pyro-Glu in the purified glatiramer acetate is 3000-5000 ppm. 
     
     
         16 . The method of  claim 2 , wherein the concentration of pyro-Glu in the purified glatiramer acetate is 3500-4500 ppm. 
     
     
         17 . The method of  claim 2 , wherein the Mp of the purified glatiramer acetate is 6,500-7,500 Da. 
     
     
         18 . The method of  claim 2 , wherein the protected copolymer is isolated and at least partially dried prior to treating the protected copolymer to partially depolymerize the protected copolymer and deprotect benzyl protected groups. 
     
     
         19 . The method of  claim 2 , further comprising measuring the amount of water in the depolymerization reaction at least once. 
     
     
         20 . The method of  claim 2 , further comprising:
 preparing a pharmaceutical composition comprising at least a portion of the purified glatiramer acetate.   
     
     
         21 . A method for preparing a drug product comprising glatiramer acetate having a pyroglutamate concentration of 2000-7000 ppm and a Mp of 5000-9000 Da, comprising:
 polymerizing N-carboxy anhydrides of L-alanine, benzyl-protected L-glutamic acid, trifluoroacetic acid (TFA) protected L-lysine and L-tyrosine to generate a protected copolymer (Intermediate-1);   treating the Intermediate-1 with HBr and acetic acid to partially depolymerize the protected copolymer and deprotect benzyl-protected L-glutamic acid thereby generating a partially depolymerized product;   treating the partially depolymerized product with piperidine to deprotect TFA-protected lysines thereby generating glatiramer acetate;   purifying the glatiramer acetate to create purified glatiramer acetate having a pyro-Glu concentration of 2000-7000 ppm and a Mp of 5000-9000 Da;   preparing a pharmaceutical composition comprising at least a portion of the purified glatiramer acetate;   processing at least a portion of the pharmaceutical composition as a drug product, thereby preparing a drug product,   wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 5-25% weight/weight against intermediate-1 present at the beginning of the depolymerization reaction.   
     
     
         22 . The method of  claim 21  wherein the Intermediate-1 treated with HBr and acetic acid is not dry. 
     
     
         23 . The method of  claim 21  further comprising adding water at the start of the depolymerization reaction or during the depolymerization reaction. 
     
     
         24 . The method of  claim 21 , wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 8-14% w/w against Intermediate-1 present at the beginning of the depolymerization reaction. 
     
     
         25 . The method of  claim 21 , wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 10-20% w/w against Intermediate-1 present at the beginning of the depolymerization reaction. 
     
     
         26 . The method of  claim 21 , wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 7-15% w/w against Intermediate-1 present at the beginning of the depolymerization reaction. 
     
     
         27 . The method of  claim 21 , wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 9-13% w/w against Intermediate-1 present at the beginning of the depolymerization reaction. 
     
     
         28 . The method of  claim 21 , wherein the amount of water present during the entirety of the depolymerization reaction is controlled to be within 10-12% w/w against Intermediate-1 present at the beginning of the depolymerization reaction. 
     
     
         29 . The method of  claim 21 , wherein the depolymerization proceeds for at least 25 hrs. 
     
     
         30 . The method of  claim 21 , wherein the depolymerization proceeds for at least 30 hrs. 
     
     
         31 . The method of  claim 21 , wherein the depolymerization proceeds for at least 40 hrs. 
     
     
         32 . The method of  claim 21 , wherein the depolymerization reaction comprises contacting the protected copolymer with a solution comprising phenol, HBr and acetic acid. 
     
     
         33 . The method of  claim 21 , wherein the concentration of pyro-Glu in the purified glatiramer acetate is 2500-5500 ppm. 
     
     
         34 . The method of  claim 21 , wherein the concentration of pyro-Glu in the purified glatiramer acetate is 3000-5000 ppm. 
     
     
         35 . The method of  claim 21 , wherein the concentration of pyro-Glu in the purified glatiramer acetate is 3500-4500 ppm. 
     
     
         36 . The method of  claim 21 , wherein the Mp of the purified glatiramer acetate is 6,500-7,500 Da. 
     
     
         37 . The method of  claim 21 , wherein the protected copolymer is isolated and at least partially dried prior to treating the protected copolymer to partially depolymerize the protected copolymer and deprotect benzyl protected groups. 
     
     
         38 . The method of  claim 21 , further comprising measuring the amount of water in the depolymerization reaction at least once. 
     
     
         39 . The method of  claim 21 , further comprising:
 preparing a pharmaceutical composition comprising at least a portion of the purified glatiramer acetate.