2-N-{5-[ [4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]methyl]-2,4-thiazolidinedione) butanedioic acid, methods of preparation and compositions with rosiglitazone maleate

Abstract

Disclosed is an isolated compound of the formula: along with methods of detecting it and of minimizing it in improved pharmaceutical compositions of rosiglitazone maleate.

1 - 51 . (canceled) 
   
   
       52 . A process for making a pharmaceutical composition comprising a compound having the formula (I): 
     
       
         
         
             
             
         
       
       in an amount of at least 0.2% based on the weight of the composition, and a carrier, or 
       a pharmaceutical composition comprising a granulate of a mixture of: 
       a) rosiglitazone maleate; 
       b) at least one pharmaceutically acceptable carrier; and 
       c) the compound of the formula (I) present in an amount of less than 0.1%, based on the combined weight of the compound of the formula (I) and rosiglitazone maleate, 
       wherein the pharmaceutical composition is in the form of a tablet comprising a tablet core, the tablet core comprising, by weight, between 1% and 4% rosiglitazone maleate, 6% croscarmellose sodium, 2% povidone, between 0.5% and 1% magnesium stearate and between 87% and 90% filler, the filler consisting of lactose and microcrystalline cellulose, 
       the process comprising 
       a) granulating in the presence of water a mixture of rosiglitazone maleate, croscarmellose sodium, povidone and a filler to obtain a granulate; 
       b) drying the granulate; 
       c) milling the granulate to obtain a milled granulate; 
       d) mixing the milled granulate with magnesium stearate to obtain a final blend; and 
       e) compressing the final blend into a tablet core. 
     
   
   
       53 . The process of  claim 52 , wherein steps c)-e) are performed in an atmosphere having a relative humidity of 30% or less. 
   
   
       54 . A process for making a pharmaceutical composition comprising a compound having the formula (I): 
     
       
         
         
             
             
         
       
       in an amount of at least 0.2% based on the weight of the composition, and a carrier, 
       or 
       a pharmaceutical composition comprising a granulate of a mixture of: 
       a) rosiglitazone maleate; 
       b) at least one pharmaceutically acceptable carrier; and 
       c) the compound of the formula (I) present in an amount of less than 0.1%, based on the combined weight of the compound of the formula (I) and rosiglitazone maleate, 
       wherein the pharmaceutical composition is in the form of a tablet comprising a tablet core, the tablet core comprising, by weight, between 75% and 76% metformin HCl, between 0.2% and 1% rosiglitazone maleate, between 5% and 6% povidone, between 1% and 2% croscarmellose sodium, between 4% and 5% starch, and between 0.5% and 1% magnesium stearate, 
       the process comprising 
       a) granulating in the presence of an aqueous povidone solution a mixture comprising rosiglitazone maleate and metformin to obtain a granulate; 
       b) drying the granulate; 
       c) milling the granulate to obtain a milled granulate; 
       d) mixing the milled granulate with croscarmellose sodium and starch to obtain an first blend; 
       mixing the first blend with magnesium stearate to obtain a final blend; and 
       f) compressing the final blend into a tablet core. 
     
   
   
       55 . The process of  claim 54 , wherein steps c)-f) are performed in an atmosphere having a relative humidity of 30% or less. 
   
   
       56 . The process of any of  claims 52 - 55 , further comprising coating the tablet core with a film coating. 
   
   
       57 . A process for preparing pharmaceutical composition comprising
 a granulate of a mixture of:   a) rosiglitazone maleate;   b) at least one pharmaceutically acceptable carrier; and   c) a compound of the formula (I):   
     
       
         
         
             
             
         
       
       which is present in an amount of less than 0.1%, based on the combined weight of the compound of the formula (I) and rosiglitazone maleate, or 
       a sealed package comprising a pharmaceutical composition comprising a compound having the formula (I) which is present in an amount of at least 0.2% based on the weight of the composition, and a carrier, 
       the process comprising: 
       a) obtaining rosiglitazone maleate drug substance; 
       b) determining the total amount of 2-N-{5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione}-butanedioic acid present in the rosiglitazone maleate drug substance; and 
       c) including the rosiglitazone maleate drug substance in the preparation of the pharmaceutical composition only if the drug substance is determined to have less than 0.10% by weight of 2-N-{5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione}-butanedioic acid. 
     
   
   
       58 . The process of  claim 57 , wherein the pharmaceutical composition is prepared by wet granulation in an aqueous solution. 
   
   
       59 . (canceled) 
   
   
       60 . (canceled) 
   
   
       61 . A process for producing a validated batch of a pharmaceutical composition containing rosiglitazone maleate and at least one pharmaceutically acceptable carrier for distribution comprising:
 a) producing a batch of the pharmaceutical product;   b) determining the total amount of 2-N-{5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione}-butanedioic acid in a sample of the batch after stability testing; and   c) validating the batch for distribution only if the sample of the batch is determined in step a) to contain less than 1.2% by weight of 2-N-{5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione}-butanedioic acid.   
   
   
       62 . The process of  claim 61 , wherein the batch is validated for distribution only if the sample of the batch is determined in step b) to contain less than 1.0% by weight of 2-N-{5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione}-butanedioic acid. 
   
   
       63 . The process of  claim 62 , wherein the batch is validated for distribution only if the sample of the batch is determined in step b) to contain less than 0.5% by weight of 2-N-{5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione}-butanedioic acid. 
   
   
       64 . A process for making an isolated compound of the formula: 
     
       
         
         
             
             
         
       
       comprising: 
       a) contacting rosiglitazone maleate with water at a temperature of 40-100° C., and 
       b) isolating the compound from the reaction mixture of step a). 
     
   
   
       65 . The process of  claim 64 , wherein the compound is isolated from the mixture via chromatography. 
   
   
       66 . The process of  claim 64 , wherein the compound is isolated from the mixture via recrystallization. 
   
   
       67 - 69 . (canceled) 
   
   
       70 . The process of  claim 52 , wherein the pharmaceutical composition comprising a compound having the formula (I) present in an amount of at least 1.5% based on the weight of the composition, and a carrier. 
   
   
       71 . The process of  claim 52 , wherein the pharmaceutical composition comprising a compound having the formula (I) present in an amount of at least 50% based on the weight of the composition, and a carrier. 
   
   
       72 . The process of  claim 54 , wherein the pharmaceutical composition comprising a compound having the formula (I) present in an amount of at least 1.5% based on the weight of the composition, and a carrier. 
   
   
       73 . The process of  claim 54 , wherein the pharmaceutical composition comprising a compound having the formula (I) present in an amount of at least 50% based on the weight of the composition, and a carrier. 
   
   
       74 . The process of  claim 57 , wherein the sealed package further comprising a desiccant. 
   
   
       75 . The process of  claim 74 , wherein the desiccant is silica gel. 
   
   
       76 . The process of  claim 57 , wherein the sealed package is a HDPE bottle.