Crystals of laquinimod sodium and improved process for the manufacture thereof

Abstract

The subject invention provides a mixture of crystalline laquinimod sodium particles, wherein (i) 90% or more of the total amount by volume of the laquinimod sodium particles have a size of 40 microns or less or (ii) 50% or more of the total amount by volume of the laquinimod sodium particle have a size of 15 microns or less, and wherein: a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL; b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL; c) an amount of heavy metal in the mixture is no more than 0.002% of heavy metal relative to the amount by weight of laquinimod sodium; d) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC; e) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC; or f) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQME) in the mixture is no more than 0.12% relative to the amount of laquinimod sodium as measured by HPLC.

1 . A mixture of crystalline laquinimod sodium particles, wherein (i) 90% or more of the total amount by volume of the laquinimod sodium particles have a size of 40 microns or less and (ii) 50% or more of the total amount by volume of the laquinimod sodium particles have a size of 15 microns or less, and wherein:
 a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;   c) an amount of heavy metal in the mixture is no more than 0.002% of heavy metal relative to the amount by weight of laquinimod sodium;   d) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC;   e) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC; or   f) an amount of methyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQME) in the mixture is no more than 0.12% relative to the amount of laquinimod sodium as measured by HPLC.   
     
     
         2 . (canceled) 
     
     
         3 . The mixture of  claim 1 , wherein 10% or more of the total amount by volume of the laquinimod sodium particles have a size of 5 microns or less and wherein:
 a) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL; or   b) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC.   
     
     
         4 . The mixture of  claim 1 , wherein (i) 90% or more of the total amount by volume of the laquinimod sodium particles have a size of less than 40 microns, (ii) 50% or more of the total amount by volume of the laquinimod sodium particles have a size of less than 15 microns, and (iii) 10% or more of the total amount by volume of the laquinimod sodium particles have a size of less than 5 microns and wherein:
 a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;   c) an amount of heavy metal in the mixture is no more than 0.002% of heavy metal relative to the amount by weight of laquinimod sodium;   d) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC;   e) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC; or   f) an amount of methyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQME) in the mixture is no more than 0.12% relative to the amount of laquinimod sodium as measured by HPLC.   
     
     
         5 . The mixture of  claim 1  wherein:
 a) the mixture is prepared in a single batch comprising 2.5 kg or more of laquinimod sodium, 
 b) the size and amount by volume of laquinimod sodium particles are determined based on an unmilled sample of the mixture, 
 c) the size and amount by volume of laquinimod sodium particles are determined based on a milled sample of the mixture, 
 d) an amount of aluminum in the mixture is less than 5 ppm relative to the amount by weight of laquinimod sodium, 
 e) an amount of calcium in the mixture is less than 60 ppm relative to the amount by weight of laquinimod sodium, 
 f) an amount of copper in the mixture is less than 1 ppm relative to the amount by weight of laquinimod sodium, 
 g) an amount of iron in the mixture is less than 4 ppm relative to the amount by weight of laquinimod sodium, and/or 
 h) an amount of zinc in the mixture is less than 7 ppm relative to the amount by weight of laquinimod sodium. 
 
     
     
         6 - 21 . (canceled) 
     
     
         22 . The mixture of  claim 1 , wherein:
 a) a total amount of polar impurities in the mixture is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC,   b) an amount of ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQEE) in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,   c) a total amount of non-polar impurities in the mixture is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC,   d) an amount of N-ethyl aniline in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,   e) an amount of N-ethyl-4,5-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide (5-HLAQ) in the mixture is no more than 0.10% relative to the amount or laquinimod sodium as measured by HPLC,   f) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide (DELAQ) in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,   g) an amount of laquinimod acid in the mixture is no more than 1.00% relative to the amount oil laquinimod sodium as measured by HPLC,   h) an amount of dimethyl malonate in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,   i) an amount of diethyl malonate in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,   j) an amount of dimethyl sulfate in the mixture is no more than 1 ppm relative to the amount by weight of laquinimod sodium,   k) an amount of water in the mixture is no more than 1.5% by weight relative to the amount of laquinimod sodium as measured by K.F. coulometric titration,   l) an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium,   m) an amount of ethanol in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   n) an amount of n-heptane in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   o) an amount of n-octane in the mixture is no more than 2000 ppm relative to the amount by weight of laquinimod sodium,   p) an amount of methanol in the mixture is no more than 3000 ppm relative to the amount by weight of laquinimod sodium,   q) an amount of acetone in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   r) an amount of dioxane in the mixture is no more than 380 ppm relative to the amount by weight of laquinimod sodium, or   s) an amount of dimethyl formamide in the mixture is no more than 880 ppm relative to the amount by weight of laquinimod sodium.   
     
     
         23 . The mixture of  claim 1 , wherein:
 a) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC,   b) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC; or   c) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQME) in the mixture is no more than 0.12% relative to the amount of laquinimod sodium as measured by HPLC,   d) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL,   e) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL,   f) an amount of heavy metal in the mixture is no more than 0.002% of heavy metal relative to the amount by weight of laquinimod sodium,   g) a total amount of polar impurities in the mixture is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC,   h) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQEE) in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,   i) a total amount of non-polar impurities in the mixture is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC,   j) an amount of N-ethyl aniline in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,   k) an amount of N-ethyl-4,5-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide (5-HLAQ) in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,   l) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide (DELAQ) in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,   m) an amount of laquinimod acid in the mixture is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC,   n) an amount of dimethyl malonate in the mixture is no more than 0-10% relative to the amount of laquinimod sodium as measured by HPLC,   o) an amount of diethyl malonate in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,   p) an amount of dimethyl sulfate in the mixture is no more than 1 ppm relative to the amount by weight of laquinimod sodium,   q) an amount of water in the mixture is no more than 1.5% by weight relative to the amount of laquinimod sodium as measured by K.F. coulometric titration,   r) an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium   s) an amount of ethanol in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   t) an amount of n-heptane in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   u) an amount of n-octane in the mixture is no more than 2000 ppm relative to the amount by weight of laquinimod sodium,   v) an amount of methanol in the mixture is no more than 3000 ppm relative to the amount by weight of laquinimod sodium,   w) an amount of acetone in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   x) an amount of dioxane in the mixture is no more than 380 ppm relative to the amount by weight of laquinimod sodium, and   y) an amount of dimethyl formamide in the mixture is no more than 880 ppm relative to the amount by weight of laquinimod sodium.   
     
     
         24 - 43 . (canceled) 
     
     
         44 . A pharmaceutical composition comprising the mixture of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         45 . The pharmaceutical composition of  claim 44 , wherein:
 a) a total amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC,   b) a total amount of polar impurities in the pharmaceutical composition is no more than 2.00% relative to the amount of laquinimod sodium as measured by HPLC,   c) an amount of N-ethyl aniline in the pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC,   d) an amount 5-chloro-N-ethyl-3-hydroxy-1-methyl-5-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide (3-HLAQ) in the pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC,   e) a total amount of non-polar impurities in the pharmaceutical composition is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC,   f) an amount of N-ethyl-4-hydroxy-1-methyl-5-(methyl(2,3,4,5,6-pentahydroxyhexyl)amino)-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide (MEG-LAQ) in the pharmaceutical composition is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC,   g) an amount of water in the pharmaceutical composition is no more than 1.50% relative to the amount of laquinimod sodium as measured by K.F. coulometric titration,   h) an amount of water in the pharmaceutical composition is no more than 0.80% relative to the amount of laquinimod sodium as measured by K.F. coulometric titration,   i) an amount of ethanol in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   j) an amount of n-heptane in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   k) an amount of n-octane in the pharmaceutical composition is no more than 2000 ppm relative to the amount by weight of laquinimod sodium,   l) an amount of methanol in the pharmaceutical composition is no more than 3000 ppm relative to the amount by weight of laquinimod sodium,   m) an amount of acetone in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   n) an amount of dioxane in the pharmaceutical composition is no more than 380 ppm relative to the amount by weight of laquinimod sodium,   o) an amount of dimethyl formamide in the pharmaceutical composition is no more than 880 ppm relative to the amount by weight of laquinimod sodium, or   p) an amount of sodium in the pharmaceutical composition is from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium.   
     
     
         46 . The pharmaceutical composition of  claim 44 , wherein:
 a) a total amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC,   b) a total amount of polar impurities in the pharmaceutical composition is no more than 2.00% relative to the amount of laquinimod sodium as measured by HPLC,   c) an amount of N-ethyl aniline in the pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC,   d) an amount 5-chloro-N-ethyl-3-hydroxy-1-methyl-5-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide (3-HLAQ) in the pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC,   e) a total amount of non-polar impurities in the pharmaceutical composition is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC,   f) an amount of N-ethyl-4-hydroxy-1-methyl-5-(methyl(2,3,4,5,6-pentahydroxyhexyl)amino)-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide (MEG-LAQ) in the pharmaceutical composition is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC,   g) an amount of water in the pharmaceutical composition is no more than 1.50% or no more than 0.80% relative to the amount of laquinimod sodium as measured by K.F. coulometric titration,   h ) an amount of ethanol in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   i) an amount of n-heptane in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   j) an amount of n-octane in the pharmaceutical composition is no more than 2000 ppm relative to the amount by weight of laquinimod sodium,   k) an amount of methanol in the pharmaceutical composition is no more than 3000 ppm relative to the amount by weight of laquinimod sodium,   l) an amount of acetone in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,   m) an amount of dioxane in the pharmaceutical composition is no more than 380 ppm relative to the amount by weight of laquinimod sodium, and   n) an amount of dimethyl formamide in the pharmaceutical composition is no more than 880 ppm relative to the amount by weight of laquinimod sodium.   
     
     
         47 - 60 . (canceled) 
     
     
         61 . A method of treating a subject afflicted with or for alleviating a symptom of a form of multiple sclerosis, lupus nephritis, lupus arthritis, rheumatoid arthritis, a BDNF-related disorder, Crohn's disease, a GABA-related disorder, a cannabinoid receptor type 1 (CB1) mediated disorder, or an ocular inflammatory disorder comprising administering to the subject the pharmaceutical composition of  claim 44  so as to thereby treat or alleviate the symptom of multiple sclerosis in the subject. 
     
     
         62 - 64 . (canceled) 
     
     
         65 . A process of recrystallization of laquinimod sodium comprising:
 a) dissolving an amount of laquinimod sodium in water to form an aqueous solution;   b) concentrating the aqueous solution to form a concentrated solution comprising approximately 1.7-1.8 mL of water per gram of laquinimod sodium;   c) adding acetone to the concentrated solution of step b); and   d) isolating recrystallized laquinimod sodium.   
     
     
         56 . The process of  claim 65 , wherein:
 a) the amount of laquinimod sodium in step a) is 2.5 kg or greater,   b) step a) is performed with 10-12 mL of water per gram of laquinimod sodium,   c) step a) is performed by heating the aqueous solution to a temperature of 58-75° C.,   d) crystallization occurs after step a) and before step c),   e) crystallization is induced by rapid stirring during or after the concentrating step b) or by addition of a seed crystal during or after the concentrating step b),   f) crystallization occurs without addition of a seed crystal,   g) step b) is performed under conditions appropriate to induce crystallization at the concentration of 1.7-1.8 mL of water per gram of laquinimod sodium,   h) step b) is performed at 28-45° C.,   i) step c) is performed with the concentrated solution at 40-55° C.,   j) step c) is performed with 6-12 mL of acetone per gram of laquinimod sodium,   k) step c) is performed over a period of 1-4 hours,   l) step c) is followed by cooling the solution to a temperature no less than −14° C. and no more than 6° C.,   m) step d) further comprises washing the recrystallized laquinimod sodium with 1-4 mL of acetone per gram of crude laquinimod sodium used in step a), and/or   n) step d) further comprises drying the recrystallized laquinimod sodium for no less than one hour at 30-40° C. under a vacuum of no more than 50 mmHg.   
     
     
         67 - 90 . (canceled) 
     
     
         91 . The process of  claim 65 , wherein the isolated recrystallized laquinimod sodium in step d) is a mixture of crystalline laquinimod sodium particles having a particle size distribution such that (i) 90% or more of the total amount by volume of the laquinimod sodium particles have a size of 40 microns or less, (ii) 50% or more of the total amount by volume of the laquinimod sodium particles have a size of 15 microns or less, and (iii) 10% or more of the total amount by volume of the laquinimod sodium particles have a size of less than 5 microns or less. 
     
     
         92 . A mixture of crystalline laquinimod sodium particles prepared by  claim 65 . 
     
     
         93 . The mixture of  claim 92 , wherein (i) 90% or more of the total amount by volume of the laquinimod sodium particles have a size of 40 microns or less, (ii) 50% or more of the total amount by volume of the laquinimod sodium particles have a size of 15 microns or less, and (iii) 10% or more of the total amount by volume of the laquinimod sodium particles have a size of 5 microns or less. 
     
     
         94 . The mixture of  claim 92 , wherein:
 a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;   c) an amount of aluminium in the mixture is less than 5 ppm relative to the amount by weight of laquinimod sodium;   d) an amount of calcium in the mixture is less than 60 ppm relative to the amount by weight of laquinimod sodium;   e) an amount of copper in the mixture is less than 1 ppm relative to the amount by weight of laquinimod sodium;   f) an amount of iron in the mixture is less than 4 ppm relative to the amount by weight of laquinimod sodium;   g) an amount of zinc in the mixture is less than 7 ppm relative to the amount by weight of laquinimod sodium;   h) an amount of heavy metal in the mixture is no more than 0.002% relative to the amount by weight of laquinimod sodium;   i) a total amount of polar impurities in the mixture is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC;   j) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC;   k) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC;   l) an amount of methyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQME) in the mixture is no more than 0.12% relative to the amount of laquinimod sodium as measured by HPLC;   m) an amount of ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQEE) in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC;   n) a total amount of non-polar impurities in the mixture is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC;   o) an amount of N-ethyl aniline in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC;   p) an amount of laquinimod acid in the mixture is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC;   q) an amount of dimethyl malonate in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC;   r) an amount of diethyl malonate in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC;   s) an amount of dimethyl sulfate in the mixture is no more than 1 ppm relative to the amount by weight of laquinimod sodium;   t) an amount of water in the mixture is no more than 1.5% by weight relative to the amount of laquinimod sodium as measured by K.F. coulometric titration;   u) the mixture comprises an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium;   v) an amount of ethanol in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   w) an amount of n-heptane in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   x) an amount of n-heptane in the mixture is no more than 2000 ppm n-octane relative to the amount by weight of laquinimod sodium;   y) an amount of methanol in the mixture is no more than 3000 ppm relative to the amount by weight of laquinimod sodium;   z) an amount of acetone in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   aa) an amount of dioxane in the mixture is no more than 380 ppm relative to the amount by weight of laquinimod sodium; or   bb) an amount of dimethyl formamide in the mixture is no more than 880 ppm relative to the amount by weight of laquinimod sodium.   
     
     
         95 . The mixture of  claim 92 , wherein:
 a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;   c) an amount of aluminium in the mixture is less than 5 ppm relative to the amount by weight of laquinimod sodium;   d) an amount of calcium in the mixture is less than 60 ppm relative to the amount by weight of laquinimod sodium;   e) an amount of copper in the mixture is less than 1 ppm relative to the amount by weight of laquinimod sodium;   f) an amount of iron in the mixture is less than 4 ppm relative to the amount by weight of laquinimod sodium;   g) an amount of zinc in the mixture is less than 7 ppm relative to the amount by weight of laquinimod sodium;   h) an amount of heavy metal in the mixture is no more than 0.002% relative to the amount by weight of laquinimod sodium;   i) a total amount of polar impurities in the mixture is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC;   j) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC;   k) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC;   l) an amount of methyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQME) in the mixture is no more than 0.12% relative to the amount of laquinimod sodium as measured by HPLC;   m) an amount of ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQEE) in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC;   n) a total amount of non-polar impurities in the mixture is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC;   o) an amount of N-ethyl aniline in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC;   p) an amount of laquinimod acid in the mixture is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC;   q) an amount of dimethyl malonate in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC;   r) an amount of diethyl malonate in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC;   s) an amount of dimethyl sulfate in the mixture is no more than 1 ppm relative to the amount by weight of laquinimod sodium;   t) an amount of water in the mixture is no more than 1.5% by weight relative to the amount of laquinimod sodium as measured by K.F. coulometric titration;   u) the mixture comprises an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium;   v) an amount of ethanol in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   w) an amount of n-heptane in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   x) an amount of n-heptane in the mixture is no more than 2000 ppm n-octane relative to the amount by weight of laquinimod sodium;   y) an amount of methanol in the mixture is no more than 3000 ppm relative to the amount by weight of laquinimod sodium;   z) an amount of acetone in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   aa) an amount of dioxane in the mixture is no more than 380 ppm relative to the amount by weight of laquinimod sodium; and   bb) an amount of dimethyl formamide in the mixture is no more than 880 ppm relative to the amount by weight of laquinimod sodium.   
     
     
         95 . A pharmaceutical composition comprising the mixture of  claim 92  and a pharmaceutically acceptable carrier. 
     
     
         97 . The pharmaceutical composition of claim  96 , wherein:
 a) a total amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC;   b) a total amount of polar impurities in the pharmaceutical composition is no more than 2.00% relative to the amount of laquinimod sodium as measured by HPLC;   c) an amount of N-ethyl aniline in the pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC;   d) a total amount of non-polar impurities in the pharmaceutical composition is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC;   e) an amount of water in the pharmaceutical composition is no more than 0.80% relative to the amount of laquinimod sodium as measured by K.F. coulometric titration;   f) the pharmaceutical composition comprises an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium;   g) an amount of ethanol in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   h) an amount of n-heptane in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   i) an amount of n-octane in the pharmaceutical composition is no more than 2000 ppm relative to the amount by weight of laquinimod sodium;   j ) an amount of methanol in the pharmaceutical composition is no more than 3000 ppm relative to the amount by weight of laquinimod sodium;   k) an amount of acetone in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   l) an amount of dioxane in the pharmaceutical composition is no more than 380 ppm relative to the amount by weight of laquinimod sodium; or   m) an amount of dimethyl formamide in the pharmaceutical composition is no more than 880 ppm relative to the amount by weight of laquinimod sodium.   
     
     
         98 . The pharmaceutical composition of claim  96 , comprising:
 a) a total amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC;   b) a total amount of polar impurities in the pharmaceutical composition is no more than 2.00% relative to the amount of laquinimod sodium as measured by HPLC;   c) an amount of N-ethyl aniline in the pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC;   d) a total amount of non-polar impurities in the pharmaceutical composition is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC;   e) an amount of water in the pharmaceutical composition is no more than 0.80% relative to the amount of laquinimod sodium as measured by K.F. coulometric titration;   f) the pharmaceutical composition comprises an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium;   g) an amount of ethanol in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   h) an amount of n-heptane in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   i) an amount of n-octane in the pharmaceutical composition is no more than 2000 ppm relative to the amount by weight of laquinimod sodium;   j) an amount of methanol in the pharmaceutical composition is no more than 3000 ppm relative to the amount by weight of laquinimod sodium;   k) an amount of acetone in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;   l) an amount of dioxane in the pharmaceutical composition is no more than 380 ppm relative to the amount by weight of laquinimod sodium; and   m) an amount of dimethyl formamide in the pharmaceutical composition is no more than 880 ppm relative to the amount by weight of laquinimod sodium.   
     
     
         99 . (canceled) 
     
     
         100 . (canceled)