Crystalline forms of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile and methods of preparing the same

1. An isolated crystalline form of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate having an x-ray diffraction pattern wherein at least one of the 2θ angles (°) of the significant peaks are at about: 9.19, 11.48, 14.32, 19.16, 19.45, 20.46, 21.29, 22.33, 23.96, 24.95, 25.29, 25.84, 26.55, 27.61, and 29.51.

2. The crystalline form of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate of claim 1 , having an x-ray diffraction pattern wherein 2θ angles (°) of significant peaks are at about: 9.19, 9.98, 11.48, 14.32, 14.85, 15.64, 19.16, 19.45, 19.71, 20.46, 21.29, 22.33, 22.58, 23.96, 24.95, 25.29, 25.84, 26.55, 27.61, 28.42, 29.51, 30.32, 31.40, and 32.39.

3. The crystalline form of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate of claim 2 , having the x-ray diffraction pattern substantially as shown in FIG. 1 as Pattern A.

4. An isolated crystalline form of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate having a transition temperature to a liquid of about 109° C. to about 115° C.

5. The crystalline form of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate of claim 4 , wherein the transition temperature to a liquid is about 112° C.

6. A method of preparing 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate (Form I) comprising the step of treating anhydrous 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile with heated water.

7. A method of preparing 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate (Form I) comprising the step of converting polymorphs of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile, which have a x-ray diffraction pattern substantially the same as one of Patterns B, C, and D, as shown in FIG. 1 and as Form VI pattern in FIG. 11 , by treatment with water.

8. The method of claim 6 , wherein the water is heated to at least about 90° C.

9. The method of claim 8 , wherein the water is heated to at least about 95° C.

10. The method of claim 7 , wherein the water is at a temperature where no heat source or cold source is applied.

11. The method of claim 10 , wherein the water is at room temperature.

12. A pharmaceutical composition comprising a therapeutically effective amount of crystalline 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile and a pharmaceutically acceptable carrier, wherein more than 50% by weight of said therapeutically effective amount consists of a crystalline form having an x-ray diffraction pattern substantially as shown in FIG. 1 as Pattern A and in FIG. 11 as Form I.

13. The composition of claim 12 , further comprising acetic acid.

14. The composition of claim 12 , further comprising a detergent.

15. The composition of claim 12 , further comprising about 0.5% to about 5.0% by weight of a detergent and about 0.01% to about 0.1% by weight acetic acid.

16. The composition of claim 12 , further comprising about 2.0% by weight detergent and about 0.06% by weight acetic acid.

17. The composition of claim 12 , wherein the pharmaceutically acceptable carrier is selected from a sugar, a polyol and cellulose, or a combination thereof.

18. The composition of claim 17 , wherein the pharmaceutically acceptable carrier is a polyol and cellulose.

19. The composition of claim 18 , wherein the polyol is selected from mannitol, sorbitol and xylitol.

20. The composition of claim 19 , wherein the polyol is mannitol.

21. The composition of claim 20 , wherein the crystalline form of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile, the mannitol and the cellulose are individually present in amounts of about 20 to about 50 percent by weight.