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1. WO2013155592 - CRYSTAL FORMS OF GOLOTIMOD AND PROCESS FOR ITS MANUFACTURING

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

What is claimed is:

1. A crystalline form of golotimod characterized by an X-ray powder diffraction pattern comprising peaks, in degrees 2-theta + 0.2, at: 10.59, 11.40, and 23.25.

2. The crystalline form of claim 1 wherein the X-ray powder diffraction pattern further comprises peaks, in degrees 2-theta + 2, at: 17.24, 18.04, 19.27, 19.49, 20.52, 21.36, 24.92, 25.33, 28.19, 29.74, and 32.68.

3. The crystalline form of claim 2 further characterized by a solid state 13C NMR spectrum comprising peaks, in ppm at 25.7, 35.2, 59.1 , 116.1 , and 179.3.

4. The crystalline form of claim 3 wherein the solid state 13 CNMR spectrum further comprises peaks, in ppm at: 24.7, 54.5, 114.0, 118.0, 120.9, 122.4, 125.9, 135.7, 173.7, and 176.8.

5. The crystalline form of claim 2 wherein the X-ray powder diffraction pattern is substantially the same as shown in FIG. 2.

6. The crystalline form of claim 5 further characterized by a solid state 13C NMR spectrum substantially the same as shown in FIG. 1.

7. The crystalline form of claim 6 further characterized by an IR spectra having absorption maxima, in cm-1, at 742, 1094, 1231 , 1455, 1536 1598, 1702, 3354, and 3405.

8. A pharmaceutical composition comprising the crystalline form of golotimod of any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

9. A crystalline form of golotimod characterized by an X-ray powder diffraction pattern comprising peaks, in degrees 2-theta + 0.2, at 10.30, 12.22, and 26.68.

10. The crystalline form of claim 9 wherein the X-ray powder diffraction pattern further comprises peaks, in degrees 2-theta + 2, at: 15.6, 17.53, 17.83, 18.10, 18.89, 19.68, 20.95, 22.17, 24.29, 24.88, 27.85 and 32.63.

11. The crystalline form of claim 10 further characterized by a solid state 13C NMR spectrum comprising peaks, in ppm, at 30.3, 112.6, and 129.3.

12. The crystalline form of claim 11 wherein the solid state 13CNMR spectrum further comprises peaks, in ppm, at: 24.0, 54.8, 111.4, 118.6, 120.8, 134.6, 172.3, 176.0, and 177.2.

13. The crystalline form of claim 10 wherein the X-ray powder diffraction pattern is substantially the same as shown in FIG. 8.

14. The crystalline form of claim 13 further characterized a solid state 13C NMR

spectrum substantially the same as shown in FIG. 7.

15. The crystalline form of claim 14 further characterized by an IR spectra having absorption maxima, in cm-1, at 744, 860, 1029, 1087, 1226, 1258, 1455, 1531 , 1609, 1655, 1700, 3374, 3401 , and 3418.

16. A pharmaceutical composition comprising the crystalline form of golotimod of any one of claims 9 to 15 and a pharmaceutically acceptable excipient.

17. A process for the preparation of golotimod comprising:

(a) reacting a solution of H-D-Glu(L-Trp-OMe)-O-Bzl.HCl salt in an alcohol with 3N NaOH at about 0°C, thereby forming a solution;

(b) removing insoluble particles from the solution by:

(b-i) (b-i-a) washing the solution with ethyl acetate, thereby forming an aqueous layer; and

(b-i-b) separating and filtering the aqueous layer, thereby forming an aqueous solution;

or (b-ii):

(b-ii-a)filtering the solution, thereby forming a filtrate;

(b-ii-b)adjusting a pH of the filtrate with 6N HCI to a pH of from about 10 to about 11, thereby forming a basic solution;

(b-ii-c) evaporating the basic solution to about 50% of the original volume of the basic solution, thereby forming an evaporated basic solution;

(b-ii-d) extracting the evaporated basic solution with ethyl acetate, thereby forming an aqueous layer; and

(b-ii-e) separating the aqueous layer, thereby forming an aqueous solution;

or (b-iii)

(b-iii-a) filtering the solution, thereby forming a filtrate;

(b-iii-b) adjusting a pH of the filtrate with 6N HCl to a pH of about 7.0, thereby forming a neutral solution,

(b-iii-c) evaporating the neutral solution to about 50% of the original volume of the neutral solution, thereby forming an aqueous solution;

(c) acidifying the aqueous solution to a pH of from about 2.6 to about 3.1 with 6N HCl solution at about 0°C with stirring, thereby forming an acidic solution;

(d) isolating a solid from the acidic solution; and

(e) drying the solid by drying the solid in air followed by drying in a vacuum oven at about a pressure of about 0.2 inch Hg and at a at temperature of about 42°C for a period of time of from about 10 hours to about 12 hours.

18. The process of claim 17 wherein the isolating the solid from the acidic solution comprises filtering the acidic solution.

19. The process of claim 18 wherein the isolating the solid from the acidic solution further comprises suspending the solid in water at a temperature of about 48°C by stirring for at least about 30 minutes followed by cooling to a temperature of from about 20°C to about 24°C, followed by filtering.

20. The process of claim 18 wherein the isolating the solid from the acidic solution further comprises washing the solid with de-ionized water followed by washing the solid with acetone.

21. The process of any one of claims 17 to 20 wherein the alcohol is methanol or isopropanol.

22. The process of any one of claims 17 to 21 wherein the acidifying the aqueous solution comprises stirring for a period of time of from about 8 hours to about 16 hours.

23. The process of any one of claims 17 to 22 wherein the drying the solid in air comprises drying for a period of time of from about 2 hours to about 2 days.

24. The process of any one of claims 17 to 23 wherein the drying the solid in air comprises drying for a period of time of from about 2 hours to about 4 hours.

25. A process for the preparation of golotimod from H-D-Glu(L-Trp-OMe)-OBzl.HCI salt comprising:

(a) reacting a solution of H-D-Glu(L-Trp-OMe)-0-Bzl.HCl salt in isopropanol with 3N NaOH at a temperature of about 0°C, thereby forming a solution;

(b) washing the solution with ethyl acetate, thereby forming an aqueous layer;

(c) separating and filtering the aqueous layer thereby forming a filtrate;

(d) acidifying, with HCOOH solution at a temperature of about 0°C, the filtrate to a pH of from about 2.6 to about 3.1 , thereby forming a material;

(e) stirring the material for a period of time of from about 8 hours to about 16 hours and filtering, thereby forming a solid;

(f) washing the solid with de-ionized water, thereby forming a washed solid;

(g) drying the washed solid in air for a period of time of about 4 hours, followed by drying the washed solid in a vacuum oven at a pressure of about 0.2 inch Hg and at a temperature of about 42°C for a period of time of from about lOhours to about 12 hours.

26. A process for the crystallization of golotimod comprising:

(a) dissolving H-D-Glu(L-Trp-OH)-OH in water by heating a suspension of golotimod in water, thereby forming a solution;

(b) filtering the solution, thereby forming a filtrate;

(c) adding isopropanol to the filtrate at a ratio of about 1 :2 to the volume of the filtrate, thereby forming a crystallization solution;

(d) leaving the crystallization solution to crystallize.

27. A process for the crystallization of golotimod comprising:

(a) dissolving H-D-Glu(L-Trp-OH)-OH in water by heating a mixture of H-D- Glu(L-Trp-OH)-OH in water to a temperature of about 80°C, thereby forming a material;

(b) filtering the material, thereby forming a solution;

(c) cooling the solution, thereby crystallizing the H-D-Glu(L-Trp-OH)-OH in a crystallized solution;

(d) filtering the crystalized solution, thereby forming a solid; and

(e) drying the solid in air for a period of time of from about 2 hours to about 4 hours followed by drying the solid under vacuum at a temperature of from about 40°C to about 45°C.

28. A process for the crystallization of golotimod comprising:

(a) adjusting, with sodium hydroxide solution, a pH of a solution of H-D-Glu(L-Trp-OH)-OH in water to a pH of from about 10 to about 11 , thereby forming a basic solution;

(b) extracting the basic solution with ethyl acetate thereby forming an aqueous solution;

(c) filtering the aqueous solution, thereby forming a filtrate;

(d) precipitating crystalline H-D-Glu(L-Trp-OH)-OH by adjusting a pH of the filtrate to pH of from about 2.6 to about 3.1 , thereby forming a precipitated solution;

(e) filtering the precipitated solution, thereby forming a solid;

(f) washing the solid thereby forming a washed solid; and

(g) drying the washed solid in air for a period of time of from about 2 hours to about 4 hours followed by drying the washed solid under vacuum at a temperature of about 40°C to about 45°C.