Crystals of laquinimod sodium and improved process for the manufacture thereof

• US 9,233,927 B2
• Filed: 03/14/2014
• Issued: 01/12/2016
• Est. Priority Date: 03/14/2013
• Status: Expired due to Fees

• Current Assignee: Teva Pharmaceutical Industries Limited
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Frenkel, Anton, Laxer, Avital
• Primary Examiner(s): Seaman, D Margaret M.
• Application Number:
  US14/214,191
• Publication Number:
  US 20140271878A1
• Time in Patent Office: 669 Days
• Field of Search: 546/156
• US Class Current: 1/1
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4
• CPC Class Codes: G01N 30/06 Preparation
• CPC Class Codes: G01N 33/15 Medicinal preparations ; Physical properties thereof, e.g. dissolubility drug screening with animal cells G01N33/5008

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-dihydroqunoline-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.

Claims

1. A mixture of crystalline laquinimod sodium particles, wherein 1) (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, or 2) (i) 90% or more of the total amount by volume of the laquinimod sodium particles have a size of less than 40 microns and (ii) 50% or more of the total amount by volume of the laquinimod sodium particles have a size of less than 15 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.

2. The mixture of claim 1, wherein 10% or more of the total amount by volume of the laquinimod particles have a size of 5 microns or less and wherein:

a) the mixture has a tapped density of 0.40 q/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.

3. The mixture of crystalline laquinimod sodium particles 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 nave 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:

the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;

the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;

an amount of heavy metal in the re 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) en 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.

4. The mixture of claim 1, wherein,

a) it 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, or the size and amount by volume of laquinimod sodium particles are determined based on a milled sample of the mixture,

c) an amount of aluminum in the mixture is less than 5 ppm or less than 2 ppm relative to the amount by weight of laquinimod sodium,

d) an amount of calcium in the mixture is less than 60 ppm or less than 25 ppm relative to the amount by weight of laquinimod sodium,

e) an amount of copper in the mixture is less than 1 ppm or less than 0.6 ppm relative to the amount by weight of laquinimod sodium,

f) an amount of iron in the mixture is less than 4 ppm or less than 3.6 ppm relative to the amount by weight of laquinimod sodium,

g) an amount of zinc in the mixture is less than 7 ppm or less than 4 ppm relative to the amount by weight of laquinimod sodium,

h) an amount of heavy metal in the mixture is no more than 2 ppm relative to the amount by weight of laquinimod sodium,

i) 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,

j) a total amount of non-polar impurities in the mixture no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC,

k) 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,

l) 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,

m) 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,

n) 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,

o) 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,

p) 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,

q) or amount of dimethyl sulfate in the mixture is no more than 1 ppm relative to the amount by weight of laquinimod sodium,

r) 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. coulemetric titration,

s) an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium,

t) an amount of ethanol in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,

u) an amount of n-heptane in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,

v) an amount of n-octane in the mixture is no more than 2000 ppm relative to the amount by weight of laquinimod sodium,

w) an amount of methanol in the mixture is no more than 3000 ppm relative to the amount by weight of laquinimod sodium,

x) an amount of acetone in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,

y) an amount of dioxane in the mixture is no more than 380 ppm relative to the amount by weight of laquinimod sodium,

z) an amount of dimethyl formamide in the mixture is no more than 880 ppm relative to the amount by weight of laquinimod sodium, and/or

aa) 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.

5. A pharmaceutical composition comprising the mixture of claim 1 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition of claim 5, 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 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,

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 sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium,

j) an amount of ethanol in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,

k) an amount of n-heptane in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,

l) an amount of n-octane in the pharmaceutical composition is no more than 2000 ppm relative to the amount by weight of laquinimod sodium,

m) an amount of methanol in the pharmaceutical composition is no more than 3000 ppm relative to the amount by weight of laquinimod sodium,

n) an amount of acetone in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,

o) an amount of dioxane in the pharmaceutical composition is no more than 380 ppm relative to the amount by weight of laquinimod sodium,

p) an amount of dimethyl formamide in the pharmaceutical composition is no more than 880 ppm relative to the amount by weight laquinimod sodium, and/or

q) 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 pharmaceutical composition is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC.

7. 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 (CH1) mediated disorder, or an ocular inflammatory disorder comprising administering to the subject the mixture of claim 1 or a pharmaceutical composition comprising the mixture and a pharmaceutically acceptable carrier, so as to thereby treat or alleviate the symptom in the subject.

19. The mixture of claim 1, 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 0.4 g/mL to 0.7 g/mL;

c) an amount of ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (NCQEE) in the mixture is no more than 0.10% relative to the amount of laquinimod sodium as measured by HPLC,

d) 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,

e) 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,

f) 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,

g) 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,

h) 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,

i) 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,

j) 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,

k) 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,

l) an amount of dimethyl sulfate in the mixture is no more than 1 ppm relative to the amount by weight of laquinimod sodium,

m) 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,

n) an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium,

o) an amount of ethanol in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,

p) an amount of n-heptane in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,

q) an amount of n-octane in the mixture is no more than 2000 ppm relative to the amount by weight of laquinimod sodium,

r) an amount of methanol in the mixture is no more than 3000 ppm relative to the amount by weight of laquinimod sodium,

s) an amount of acetone in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium,

t) an amount of dioxane in the mixture is no more than 380 ppm relative to the amount by weight of laquinimod sodium, and

u) an amount of dimethyl formamide in the mixture is no more than 880 ppm relative to the amount by weight of laquinimod sodium.

20. The pharmaceutical composition of claim 5, 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 5-HLAQ is no more than 0.50% relative to the amount of laquinimod sodium as measured by HPLC,

c) 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,

d) 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,

e) 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,

f) 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,

g) 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,

h) 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, or 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, and

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.

8. 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 1.7-1.9 mL of water per gram of laquinimod sodium;

c) adding acetone to the concentrated solution of step b); and

d) isolating recrystallized laquinimod sodium.

9. The process of claim 8, 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 or approximately 11 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. or 60-73°

C.,

d) crystallization occurs after step a) and before step c),

a. wherein crystallization is induced by rapid stirring during or after the concentrating step b),

b. wherein crystallization is induced by addition of a seed crystal during or after the concentrating step b), or

c. wherein crystallization occurs without addition of a seed crystal,

e) 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,

f) step h) is performed at 28-45°

C. or 30-40°

C.,

g) step c) is performed with the concentrated solution at 40-55°

C. or 45-50°

C.,

h) step c) is performed with 6-12 mL or approximately 10 mL of acetone per gram of laquinimod sodium,

i) step c) is performed over a period of 1-4 hours or over a period of 1.2-2.5 hours,

j) step c) is followed by cooling the solution to a temperature no less than −

14°

C. and no more than 6°

C. or optionally no less than −

4°

C. and no more than 4°

C.,

k) the solution cooled over a period of 3-5 hours or over a period of 3.5-4.5 hours,

l) step d) further comprises washing the recrystallized laquinimod sodium with 1-4 mL or approximately 3 mL of acetone per gram of crude laquinimod sodium used in step a), and/or

m) 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.

10. The process of claim 8, 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 use than 5 microns, or 5 microns or less.

11. A mixture of crystalline laquinimod sodium particles prepared by the process of claim 8, 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.

12. A pharmaceutical composition comprising the mixture of claim 11 and a pharmaceutically acceptable carrier.

15. The mixture of claim 11, 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 aluminum 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 (MCQME) 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 o 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 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 6.44 relative to the amount weight of laquinimod sodium;

v) an amount of ethanol in the mixture is no more than 5000 ppm relatives 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-octane in the mixture is no more than 2000 ppm 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;

bb) an amount of dimethyl formamide in the mixture is no more than 880 ppm relative to the amount by weight of laquinimod sodium;

cc) 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; and

/or

dd) 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.

16. The mixture of claim 11, 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% relative to the amount by weight of laquinimod sodium;

d) 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;

e) 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;

f) 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;

g) 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;

h) an amount of ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQME) 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 s 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 laquinimod acid in the mixture is no more than 1.00% relative to the amount of laquinimod sodium as measured by HPLC;

l) 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;

m) 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;

n) an amount of dimethyl sulfate in the mixture is no more than 1 ppm relative to the amount by weight of laquinimod sodium;

o) 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;

p) the mixture comprises an amount of sodium from 5.8% to 6.4% relative to the amount by weight of laquinimod sodium;

q) an amount of ethanol in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;

r) an amount of n-heptane in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;

s) an amount of n-octane in the mixture is no more than 2000 ppm relative to the amount by weight of laquinimod sodium;

t) an amount of methanol in the mixture is no more than 3000 ppm relative to the amount by weight of laquinimod sodium;

u) an amount of acetone in the mixture is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;

v) an amount of dioxane in the mixture is no more than 380 ppm relative to the amount by weight of laquinimod sodium;

w) an amount of dimethyl formamide in the mixture is no more than 880 ppm relative to the amount by weight of laquinimod sodium;

x) 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; and

y) 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.

17. The pharmaceutical composition of claim 12, 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 5.3% 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;

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;

n) 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 0.50% relative to the amount of laquinimod sodium as measured by HPLC;

o) 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;

p) an amount or 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; and

/or

q) 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.

18. The pharmaceutical composition of claim 12, 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 or 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;

f) an amount of ethanol in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;

g) an amount of n-heptane in the pharmaceutical composition is no more than 5000 ppm relative to the amount by weight of laquinimod sodium;

h) an amount of n-octane in the pharmaceutical composition is no more than 2000 ppm relative to the amount by weight of laquinimod sodium;

i) an amount of methanol in the pharmaceutical composition is no more than 380 ppm relative to the amount by we of laquinimod sodium;

j) an amount of acetone in the pharmaceutical composition is no more than 880 ppm relative to the amount by weight of laquinimod sodium;

k) an amount of dioxane in the pharmaceutical composition is no more than 380 ppm relative to the amount by weight of laquinimod sodium;

l) an amount of dimethyl formamide in the pharmaceutical composition is no more than 880 ppm relative to the amount by weight of laquinimod sodium;

m) 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 0.50% relative to the amount of laquinimod sodium as measured by HPLC;

n) 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; and

o) 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.

21. The process of claim 8, 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, and (ii) 50% or more of the total amount by volume of the laquinimod sodium particles have a size of 15 microns or less.

22. The mixture of claim 11, 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 u size of 5 microns or less.

13. 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) an amount of aluminum 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.

14. A pharmaceutical composition comprising the mixture of claim 13 and a pharmaceutically acceptable carrier.