Anhydrous amorphous imatinib mesylate
View Patent ↗Described is a highly stable amorphous form of imatinib mesylate having a water content of less than 0.5 percent by weight, based on the total weight of the amorphous imatinib mesylate, (anhydrous amorphous imatinib mesylate), a process for preparation thereof, and pharmaceutical compositions.
1. An amorphous form of imatinib mesylate having a water content of less than 0.5 percent by weight, based on the total weight of the amorphous imatinib mesylate, characterized by a powder X-ray diffraction pattern in accordance with FIG. 1 .
2. The amorphous imatinib mesylate of claim 1 , having a water content of less than 0.4 percent by weight.
3. The amorphous imatinib mesylate of claim 1 , having a water content of less than 0.1 percent by weight.
4. A process for the preparation of amorphous imatinib mesylate having a water content less than 0.5 percent by weight of claim 1 , comprising:
a) forming a first solution of imatinib mesylate in an anhydrous solvent medium comprising a first organic solvent and a second organic solvent, wherein the first organic solvent is selected from the group consisting of C 1 to C 4 straight or branched chain alcohols, chlorinated hydrocarbons, and mixtures thereof, and wherein the second organic solvent is an aromatic hydrocarbon solvent;
b) heating the first solution obtained in step-(a) under azeotropic conditions at a temperature of about 35° C. to about 110° C. to form a heated first solution;
c) removing greater than 50% of the first organic solvent from the heated first solution azeotropically at a temperature of about 35° C. to about 110° C. to form a reaction mass;
d) heating the reaction mass obtained in step-(c) azeotropically at a temperature of about 110° C. to about 150° C. to form a heated reaction mass;
e) removing greater than 50% of the remaining organic solvent from the heated reaction mass at a temperature of about 110° C. to about 150° C., optionally under azeotropic conditions, to obtain a residue containing amorphous imatinib mesylate having a water content less than about 0.5 percent by weight, based on the total weight of the amorphous imatinib mesylate;
(f) dissolving the residue obtained in step-(e) in a third organic solvent selected from the group consisting of C 1 to C 4 straight or branched chain alcohols, chlorinated hydrocarbon solvents, and mixtures thereof to form a second solution; and
g) removing greater than 50% of the solvent from the second solution obtained in step-(f) to afford amorphous imatinib mesylate having a water content less than 0.5 percent by weight, based on the total weight of the amorphous imatinib mesylate.
5. The process of claim 4 , wherein the first organic solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, methylene chloride, chloroform, and mixtures thereof; and wherein the second organic solvent is selected from the group consisting of toluene, xylene, and mixtures thereof.
6. The process of claim 5 , wherein the first organic solvent is selected from the group consisting of methanol, chloroform, and mixtures thereof; and wherein the second organic solvent is toluene.
7. The process of claim 4 , wherein the solution obtained in step-(a) or step-(f) is further subjected to carbon treatment.
8. The process of claim 4 , wherein the heating in step-(b) is carried out at a temperature of about 100° C. to about 110° C., from about 15 minutes to about 2 hours.
9. The process of claim 4 , wherein the removal of solvent in step-(c) is accomplished by azeotropic distillation of the first organic solvent from the solution.
10. The process of claim 9 , wherein the distillation is carried out at a temperature of about 100° C. to about 110° C.
11. The process of claim 4 , wherein the heating in step-(d) is carried out at a temperature of about 110° C. to about 130° C., from about 30 minutes to about 5 hours.
12. The process of claim 4 , wherein the removal of solvent in step-(e) is accomplished by evaporation of the solvent, concentrating the solution or distillation of solvent at a temperature of about 110° C. to about 140° C.
13. The process of claim 4 , wherein the third organic solvent used in step-(f) is selected from the group consisting of methanol, ethanol, isopropanol, methylene chloride, chloroform, and mixtures thereof.
14. The process of claim 13 , wherein the third organic solvent is selected from the group consisting of methanol, chloroform, and mixtures thereof.
15. The process of claim 4 , wherein the removal of the solvent in step-(g) is accomplished by distillation or complete evaporation of the solvent, spray drying, vacuum drying, lyophilization or freeze drying, or a combination thereof.
16. The process of claim 4 , wherein the amorphous imatinib mesylate obtained has a purity of about 99% to about 99.99% as measured by high pressure liquid chromatography.
17. A pharmaceutical composition comprising amorphous imatinib mesylate having a water content less than 0.5 percent by weight, based on the total weight of the amorphous imatinib mesylate, and characterized by a powder X-ray diffraction pattern in accordance with FIG. 1 , and one or more pharmaceutically acceptable excipients.
18. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is a solid dosage form or an oral suspension.
19. The pharmaceutical composition of claim 17 , wherein the amorphous imatinib mesylate having water content less than 0.5 percent by weight has a D 90 particle size of less than or equal to 400 microns.
20. The pharmaceutical composition of claim 19 , wherein the D 90 particle size is less than or equal to 200 microns.