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 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.

What is claimed: 
     
         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 or (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 . 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 or (ii) 50% or more of the total amount by volume of the laquinimod sodium particles have a size of less than 15 microns. 
     
     
         3 . The mixture of  claim 1  or  2 , 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 . 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 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 any one of  claims 1 - 4  prepared in a single batch comprising 2.5 kg or more of laquinimod sodium. 
     
     
         6 . The mixture of any one of  claims 1 - 5 , wherein the laquinimod sodium particles are determined based on an unmilled sample of the mixture. 
     
     
         7 . The mixture of any one of  claims 1 - 5 , wherein the size and amount by volume of laquinimod sodium particles are determined based on a milled sample of the mixture. 
     
     
         8 . The mixture of any one of  claims 1 - 7 , having a bulk density of 0.2 g/mL to 0.4 g/mL. 
     
     
         9 . The mixture of any one of  claims 1 - 8 , having a tapped density of 0.40 g/mL to 0.7 g/mL. 
     
     
         10 . The mixture of any one of  claims 1 - 9 , wherein an amount of aluminium in the mixture is less than 5 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         11 . The mixture of any one of  claims 1 - 10 , wherein an amount of aluminium in the mixture is less than 2 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         12 . The mixture of any one of  claims 1 - 11 , wherein an amount of calcium in the mixture is less than 60 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         13 . The mixture of any one of  claims 1 - 12 , wherein an amount of calcium in the mixture is less than 25 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         14 . The mixture of any one of  claims 1 - 13 , wherein an amount of copper in the mixture is less than 1 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         15 . The mixture of any one of  claims 1 - 14 , wherein an amount of copper in the mixture is less than 0.6 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         16 . The mixture of any one of  claims 1 - 15 , wherein an amount of iron in the mixture is less than 4 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         17 . The mixture of any one of  claims 1 - 16 , wherein an amount of iron in the mixture is less than 3.6 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         18 . The mixture of any one of  claims 1 - 17 , wherein an amount of zinc in the mixture is less than 7 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         19 . The mixture of any one of  claims 1 - 18 , wherein an amount of zinc in the mixture is less than 4 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         20 . The mixture of any one of  claims 1 - 19 , wherein an amount of heavy metal in the mixture is no more than 20 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         21 . The mixture of  claim 20 , wherein an amount of heavy metal in the mixture is no more than 2 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         22 . The mixture of any one of  claims 1 - 21 , wherein 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. 
     
     
         23 . The mixture of any one of  claims 1 - 22 , wherein 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. 
     
     
         24 . The mixture of any one of  claims 1 - 23 , wherein 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. 
     
     
         25 . The mixture of any one of  claims 1 - 24 , wherein 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. 
     
     
         26 . The mixture of any one of  claims 1 - 25 , wherein 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. 
     
     
         27 . The mixture of any one of  claims 1 - 26 , wherein 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. 
     
     
         28 . The mixture of any one of  claims 1 - 27 , wherein 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. 
     
     
         29 . The mixture of any one of  claims 1 - 28 , wherein 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. 
     
     
         30 . The mixture of any one of  claims 1 - 29 , wherein 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. 
     
     
         31 . The mixture of any one of  claims 1 - 30 , wherein 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. 
     
     
         32 . The mixture of any one of  claims 1 - 31 , wherein 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. 
     
     
         33 . The mixture of any one of  claims 1 - 32 , wherein 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. 
     
     
         34 . The mixture of any one of  claims 1 - 33 , wherein an amount of dimethyl sulfate in the mixture is no more than 1 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         35 . The mixture of any one of  claims 1 - 34 , wherein 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. 
     
     
         36 . The mixture of any one of  claims 1 - 35 , comprising an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium. 
     
     
         37 . The mixture of any one of  claims 1 - 36 , wherein an amount of ethanol in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         38 . The mixture of any one of  claims 1 - 37 , wherein an amount of n-heptane in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         39 . The mixture of any one of  claims 1 - 38 , wherein 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. 
     
     
         40 . The mixture of any one of  claims 1 - 39 , wherein an amount of methanol in the mixture is no more than 3000 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         41 . The mixture of any one of  claims 1 - 40 , wherein an amount of acetone in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         42 . The mixture of any one of  claims 1 - 41 , wherein an amount of dioxane in the mixture is no more than 380 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         43 . The mixture of any one of  claims 1 - 42 , wherein an amount of dimethyl formamide in the mixture is no more than 880 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         44 . A pharmaceutical composition comprising the mixture of any one of  claims 1 - 43  and a pharmaceutically acceptable carrier. 
     
     
         45 . The pharmaceutical composition of  claim 44 , wherein 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. 
     
     
         46 . The pharmaceutical composition of  claim 44  or  45 , wherein 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. 
     
     
         47 . The pharmaceutical composition of any one of  claims 44 - 46 , wherein 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. 
     
     
         48 . The pharmaceutical composition of any one of  claims 44 - 47 , wherein an amount of 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. 
     
     
         49 . The pharmaceutical composition of any one of  claims 44 - 48 , wherein 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. 
     
     
         50 . The pharmaceutical composition of any one of  claims 44 - 49 , wherein 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. 
     
     
         51 . The pharmaceutical composition of any one of  claims 44 - 50 , wherein 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. 
     
     
         52 . The pharmaceutical composition of any one of  claims 44 - 51 , wherein 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. 
     
     
         53 . The pharmaceutical composition of  claim 44 - 52 , comprising an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium. 
     
     
         54 . The pharmaceutical composition of  claim 44 - 53 , wherein an amount of ethanol in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         55 . The pharmaceutical composition of  claim 44 - 54 , wherein an amount of n-heptane in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium; 
     
     
         56 . The pharmaceutical composition of  claim 44 - 55 , wherein an amount of n-octane in the pharmaceutical composition is no more than 2000 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         57 . The pharmaceutical composition of  claim 44 - 56 , wherein an amount of methanol in the pharmaceutical composition is no more than 380 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         58 . The pharmaceutical composition of  claim 44 - 57 , wherein an amount of acetone in the pharmaceutical composition is no more than 880 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         59 . The pharmaceutical composition of  claim 44 - 58 , wherein an amount of dioxane in the pharmaceutical composition is no more than 380 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         60 . The pharmaceutical composition of  claim 44 - 59 , wherein an amount of dimethyl formamide in the pharmaceutical composition is no more than 880 ppm relative to the amount by weight of laquinimod sodium. 
     
     
         61 . A method of treating a subject afflicted with 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 mixture of any one of  claims 1 - 33  or the pharmaceutical composition of any one of  claims 44 - 60  so as to thereby treat the subject. 
     
     
         62 . A method for alleviating a symptom 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 in a subject afflicted with a form of multiple sclerosis comprising administering to the subject the mixture of any one of  claims 1 - 43  or the pharmaceutical composition of any one of  claims 44 - 60  thereby alleviating the symptom of multiple sclerosis in the subject. 
     
     
         63 . The mixture of any one of  claims 1 - 43  or the pharmaceutical composition of any one of  claims 44 - 60  for use in the treatment of, or alleviation of symptoms 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. 
     
     
         64 . Use of the mixture of any one of  claims 1 - 43  or the pharmaceutical composition of any one of  claims 44 - 60  for the manufacture of a medicament for treating, or alleviating a symptom of, a form of multiple sclerosis, a GABA-related disorder, a cannabinoid receptor type 1 (CB1) mediated disorder, lupus nephritis, lupus arthritis, rheumatoid arthritis, a BDNF-related disorder, Crohn's disease, or an ocular inflammatory disorder. 
     
     
         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.   
     
     
         66 . The process of  claim 65 , wherein the amount of laquinimod sodium in step a) is 2.5 kg or greater. 
     
     
         67 . The process of  claim 65  or  66 , wherein step a) is performed with 10-12 mL of water per gram of laquinimod sodium. 
     
     
         68 . The process of  claim 67 , wherein step a) is performed with approximately 11 mL of water per gram of laquinimod sodium. 
     
     
         69 . The process of any one of  claims 65 - 68 , wherein step a) is performed by heating the aqueous solution to a temperature of 58-75° C. 
     
     
         70 . The process of  claim 69 , wherein step a) is performed by heating the aqueous solution to a temperature of 60-73° C. 
     
     
         71 . The process of any one of  claims 65 - 70 , wherein crystallization occurs after step a) and before step c). 
     
     
         72 . The process of  claim 71 , wherein crystallization is induced by rapid stirring during or after the concentrating step b). 
     
     
         73 . The process of  claim 71 , wherein crystallization is induced by addition of a seed crystal during or after the concentrating step b). 
     
     
         74 . The process of  claim 71 , wherein crystallization occurs without addition of a seed crystal. 
     
     
         75 . The process of any one of  claims 65 - 74 , wherein 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. 
     
     
         76 . The process of any one of  claims 65 - 74 , wherein step b) is performed at 28-45° C. 
     
     
         77 . The process of  claim 76 , wherein step b) is performed at 30-40° C. 
     
     
         78 . The process of any one of  claims 65 - 77 , wherein step c) is performed with the concentrated solution at 40-55° C. 
     
     
         79 . The process of  claim 78 , wherein step c) is performed with the concentrated solution at 45-50° C. 
     
     
         80 . The process of any one of  claims 65 - 79 , wherein step c) is performed with 6-12 mL of acetone per gram of laquinimod sodium. 
     
     
         81 . The process of  claim 76 , wherein step c) is performed with approximately 10 mL of acetone per gram of laquinimod sodium. 
     
     
         82 . The process of any one of  claims 65 - 81 , wherein step c) is performed over a period of 1-4 hours. 
     
     
         83 . The process of  claim 82 , wherein step c) is performed over a period of 1.2-2.5 hours. 
     
     
         84 . The process of any one of  claims 65 - 83 , wherein step c) is followed by cooling the solution to a temperature no less than −14° C. and no more than 6° C. 
     
     
         85 . The process of  claim 84 , wherein step c) is followed by cooling the solution to a temperature no less than −4° C. and no more than 4° C. 
     
     
         86 . The process of any one of  claims 65 - 85 , wherein the solution is cooled over a period of 3-5 hours. 
     
     
         87 . The process of  claim 86 , wherein the solution is cooled over a period of 3.5-4.5 hours. 
     
     
         88 . The process of any one of  claims 65 - 86 , wherein 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). 
     
     
         89 . The process of  claim 88 , wherein step d) further comprises washing the recrystallized laquinimod sodium with approximately 3 mL of acetone per gram of crude laquinimod sodium used in step a). 
     
     
         90 . The process of any one of  claims 65 - 89 , wherein 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. 
     
     
         91 . The process of any one of  claims 65 - 90 , 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 any one of  claims 65 - 91 . 
     
     
         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  or  93 , 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  or  93 , 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. 
 
     
     
         96 . A pharmaceutical composition comprising the mixture of any one of  claims 92 - 95  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 380 ppm relative to the amount by weight of laquinimod sodium;   k) an amount of acetone in the pharmaceutical composition is no more than 880 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 380 ppm relative to the amount by weight of laquinimod sodium;   k) an amount of acetone in the pharmaceutical composition is no more than 880 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 . 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 particles have a size of 15 microns or less, and wherein
 a) an amount of aluminium in the mixture is less than 5 ppm relative to the amount by weight of laquinimod sodium;   b) an amount of calcium in the mixture is less than 60 ppm relative to the amount by weight of laquinimod sodium;   c) an amount of copper in the mixture is less than 1 ppm relative to the amount by weight of laquinimod sodium;   d) an amount of iron in the mixture is less than 4 ppm relative to the amount by weight of laquinimod sodium; or   e) an amount of zinc in the mixture is less than 7 ppm relative to the amount by weight of laquinimod sodium.   f) sodium.   
     
     
         100 . A pharmaceutical composition comprising the mixture of  claim 99  and a pharmaceutically acceptable carrier.