Solid state forms of laquinimod and its sodium salt

1. Laquinimod sodium as being greater than 98% pure:

a) in a crystalline Form A1;

b) in a crystalline Form A3; or

c) in a crystalline Form A4;

wherein:

e) the crystalline Form A1 has one or more of the following properties:

i) a powder X-ray diffraction pattern substantially in accordance with FIG. 4 ;

ii) a powder X-ray diffraction pattern having peaks at about 9.1, 10.7 and 11.2±0.2 degrees 2-theta;

iii) a powder X-ray diffraction pattern having additional peaks at about 7.25, 9.72, 10.03, 13.08, 13.91, 14.57, 14.99, 15.69, 16.12, 16.75, 17.57, 18.15, 19.16, 19.87, 20.44, 21.24, 21.68, 21.88, 22.98, 23.79, 24.63 and 25.63±0.2 degrees 2-theta;

iv) an IR spectrum substantially in accordance with FIG. 5 ;

v) an IR spectrum having absorption bands at about 3377, 3062, 2972, 2933, 1611, 1585, 1528, 1495, 1414, 1377, 1347, 1325, 1255, 1220, 1178, 1098, 811 and 697±2 cm −1 ; and

vi) a DSC thermogram substantially in accordance with FIG. 6 ;

f) the crystalline Form A3 has one or more of the following properties:

i) a powder X-ray diffraction pattern substantially in accordance with FIG. 10 ;

ii) a powder X-ray diffraction pattern having peaks at about 6.44, 6.65, 7.72 and 8.77±0.2 degrees 2-theta;

iii) a powder X-ray diffraction pattern having additional peaks at about 9.31, 9.60, 10.71, 11.14, 11.66, 13.25, 14.61, 15.32, 17.62, 17.98, 18.54, 19.21, 21.38, 22.11, 22.59, 23.43, 23.99, 25.04, 25.44 and 27.86±0.2 degrees 2-theta;

iv) an IR spectrum substantially in accordance with FIG. 11 ;

v) an IR spectrum having absorption bands at about 3368, 2970, 2936, 1615, 1583, 1526, 1495, 1412, 1377, 1344, 1326, 1253, 1218, 1177, 1097, 813 and 699±2 cm −1 ; and

vi) a DSC thermogram substantially in accordance with FIG. 12 ;

g) the crystalline Form A4 has one or more of the following properties:

i) a powder X-ray diffraction pattern substantially in accordance with FIG. 13 ;

ii) a powder X-ray diffraction pattern having peaks at about 6.09, 7.46 and 10.42±0.2 degrees 2-theta;

iii) a powder X-ray diffraction pattern having additional peaks at about 7.82, 8.47, 10.12, 14.15, 16.10, 18.95, 22.66, 23.50, 25.84, 26.13, 28.24, 29.07, 29.81, 31.62 and 33.94±0.2 degrees 2-theta;

iv) an IR spectrum substantially in accordance with FIG. 14 ;

v) an IR spectrum having absorption bands at about 3413, 2974, 2935, 1612, 1584, 1524, 1495, 1413, 1377, 1346, 1327, 1253, 1219, 1177, 1097, 811 and 698±2 cm −1 ; and

vi) a DSC thermogram substantially in accordance with FIG. 15 .

2. A process for the preparation of laquinimod sodium crystalline Form A1 of claim 1 , comprising:

a) providing a solution of laquinimod sodium in an alcoholic solvent;

b) optionally, filtering the solvent solution to remove any extraneous matter;

c) optionally, seeding the solution;

d) stirring the solution at about 15-30° C. for at least 1 hour to form a first reaction mass;

e) cooling the first reaction mass at below about 10° C. to form a second reaction mass; and

f) recovering the crystalline Form A1 of laquinimod sodium from the second reaction mass.

3. The process of claim 2 , wherein the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, butanol, amyl alcohol, hexanol, and mixtures thereof; wherein the solution obtained in step-(a) is optionally subjected to carbon treatment or silica get treatment; wherein the solution in step-(d) is stirred for about 2 hours to about 6 hours at a temperature of about 20° C. to about 30° C.; wherein the solution in step-(e) is stirred at a temperature of about 0-5° C. for about 30 minutes to about 4 hours; and wherein recovering in step-(f) is carried out by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.

4. The process of claim 3 , wherein the alcohol solvent is ethanol.

5. A process for the preparation of laquinimod sodium crystalline Form A3 of claim 1 , comprising:

a) providing a solution of laquinimod sodium in an alcoholic solvent;

b) optionally, filtering the solvent solution to remove any extraneous matter;

c) optionally, seeding the solution;

d) admixing the solution with an anti-solvent, wherein the anti-solvent is selected from the group consisting of an ether, a hydrocarbon, and mixtures thereof; and

e) recovering the crystalline Form A3 of laquinimod sodium from the reaction mass obtained in step-(d).

6. The process of claim 5 , wherein the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, butanol, amyl alcohol, hexanol, and mixtures thereof; wherein the solution obtained in step-(a) is optionally subjected to carbon treatment or silica get treatment; wherein the anti-solvent used in step-(d) is selected from the group consisting of diisopropyl ether, diethyl ether, tetrahydrofuran, dioxane, n-pentane, n-hexane and n-heptane and their isomers, cyclohexane, toluene, xylene, and mixtures thereof; and wherein recovering in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.

7. The process of claim 6 , wherein the alcohol solvent used in step-(a) is ethanol; and wherein the anti-solvent is diisopropyl ether.

8. A process for the preparation of laquinimod sodium crystalline Form A4 of claim 1 , comprising:

a) providing a solution of laquinimod sodium in a ketone solvent;

b) optionally, filtering the solvent solution to remove any extraneous matter;

c) optionally, seeding the solution; and

d) isolating crystalline Form A4 of laquinimod sodium from the solution.

9. The process of claim 8 , wherein the ketone solvent used in step-(a) is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof; wherein the solution obtained in step-(a) is optionally subjected to carbon treatment or silica get treatment; wherein the isolation of laquinimod sodium crystalline Form A4 in step-(d) is carried out by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof; and wherein the solid obtained in step-(d) is recovered by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.

10. The process of claim 9 , wherein the ketone solvent is acetone and wherein the isolation in step-(d) is carried out at about 0° C. to about 25° C.

11. A process for the preparation of crystalline Form A2 of laquinimod sodium, comprising:

a) providing a solution of laquinimod sodium in an alcoholic solvent, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol and mixtures thereof;

b) optionally, filtering the solvent solution to remove any extraneous matter;

c) optionally, seeding the solution;

d) stirring the solution at a temperature of about 25° C. to about 30° C. for about 6 hours to about 30 hours to produce a reaction mass; and

e) recovering the crystalline Form A2 of laquinimod sodium from the reaction mass obtained in step-(d);

wherein the laquinimod sodium crystalline Form A2 is characterized by one or more of the following properties:

i) a powder X-ray diffraction pattern substantially in accordance with FIG. 7 ;

ii) a powder X-ray diffraction pattern having peaks at about 8.36, 25.10 and 29.35±0.2 degrees 2-theta;

iii) a powder X-ray diffraction pattern having additional peaks at about 7.22, 9.68, 10.00, 11.79, 13.37, 13.78, 14.08, 14.31, 14.62, 15.02, 15.73, 16.14, 16.74, 17.82, 18.20, 18.90, 20.07, 22.09, 23.17 and 24.08±0.2 degrees 2-theta;

iv) an IR spectrum substantially in accordance with FIG. 8 ;

v) an IR spectrum having absorption bands at about 3301, 2971, 2935, 1613, 1585, 1526, 1495, 1414, 1378, 1347, 1328, 1253, 1220, 1178, 1098, 811 and 700±2 cm −1 ; and

vi) a DSC thermogram substantially in accordance with FIG. 9 .

12. A crystalline Form A of laquinimod acid characterized by at least one, or more, of the following properties:

i) a powder X-ray diffraction pattern substantially in accordance with FIG. 1 ;

ii) a powder X-ray diffraction pattern having peaks at about 7.15, 12.58, 14.84, 25.09 and 26.38±0.2 degrees 2-theta;

iii) a powder X-ray diffraction pattern having additional peaks at about 6.19, 8.78, 14.04, 14.37, 15.36, 16.20, 18.48, 18.81, 20.44, 20.73, 21.71, 23.21, 23.50, 23.76, 28.96 and 31.08±0.2 degrees 2-theta;

iv) an IR spectrum substantially in accordance with FIG. 2 ;

v) an IR spectrum having absorption bands at about 3081, 2976, 1647, 1617, 1586, 1562, 1496, 1378, 1327, 1303, 1237, 1197, 812 and 701±2 cm −1 and

vi) a DSC thermogram having an endotherm peak at about 240° C. substantially as depicted in FIG. 3 .

13. A process for the preparation of laquinimod crystalline Form A of claim 12 , comprising:

a) providing a suspension of N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide (laquinimod or laquinimod acid) in a solvent medium comprising an ester solvent and a halogenated hydrocarbon solvent;

b) optionally, cooling the suspension obtained in step-(a); and

c) recovering crystalline Form A of laquinimod from the suspension;

wherein the halogenated hydrocarbon solvent is selected from the group consisting of methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof; and wherein the ester solvent is selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, and mixtures thereof.

14. A pharmaceutical composition comprising a therapeutically effective amount of laquinimod crystalline Form A of claim 12 , and one or more pharmaceutically acceptable excipients.

15. A pharmaceutical composition comprising a therapeutically effective amount of any one or a mixture of the laquinimod sodium solid state forms (Form A1, Form A3 and Form A4 and amorphous form) of claim 1 , and one or more pharmaceutically acceptable excipients.

16. The pharmaceutical composition of claim 15 , wherein the solid state form of laquinimod sodium has a D 90 particle size of less than or equal to about 500 microns.

17. The pharmaceutical composition of claim 16 , wherein the solid state form of laquinimod sodium has a D 90 particle size of less than or equal to about 300 microns; less than or equal to about 100 microns; less than or equal to about 60 microns; or less than or equal to about 15 microns.

18. A method for treating a patient suffering from diseases caused by multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis, asthma, atherosclerosis, stroke and Alzheimer's disease; comprising administering any one or a mixture of the solid state forms of laquinimod sodium (Form A1, Form A3 and Form A4 and amorphous form) of claim 1 , or a pharmaceutical composition that comprises any one or a mixture of the solid state forms of laquinimod sodium along with pharmaceutically acceptable excipients.