Solid forms of pemetrexed
There is provided polymorphs and amorphous form of pemetrexed or its pharmaceutical acceptable salts and process for making thereof.
1. A compound, which is an amorphous form of disodium salt of pemetrexed, having an X-ray diffraction pattern in accordance with FIG. 1 .
2. The compound of claim 1 , wherein said amorphous form of disodium salt of pemetrexed has water content of less than about 15% w/w.
3. The compound of claim 1 , wherein said amorphous form of disodium salt of pemetrexed has water content between about 5% and about 10% w/w.
4. A composition comprising a compound of claim 1 as a solid, wherein at least 50% by weight of said solid disodium salt of pemetrexed is an amorphous form of disodium salt of pemetrexed.
5. The composition of claim 4 , which is in the form of a powder suitable as active ingredient for pharmaceutical products.
6. The composition of claim 4 , wherein at least 95% by weight of said solid disodium salt of pemetrexed is in the amorphous form.
7. The composition of claim 6 , wherein at least 2% by weight of said solid disodium salt of pemetrexed is in the crystalline form.
8. The composition of claim 4 , wherein at least 5% w/w of said solid disodium salt of pemetrexed is a crystalline form of disodium salt of pemetrexed.
9. The composition of claim 8 , wherein said crystalline disodium salt of pemetrexed has an X-ray diffraction pattern, expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper Kα-radiation source, wherein said X-ray powder diffraction pattern includes five or more peaks selected from the group consisting of peaks with 2 theta angles of 4.0±0.2, 17.3±0.2, 18.0±0.2, 19.5±0.2, 20.4±0.2, 21.0±0.2, 29.0±0.2 and 43.3±0.2 degrees.
10. The composition of claim 9 , which has X-ray powder diffraction pattern substantially in accordance with FIG. 8 .
11. A solid dispersion of disodium salt of pemetrexed which comprises
i) a compound of claim 1 ; and
ii) a pharmaceutically acceptable carrier, wherein the solid dispersion has a solubility in water ranging from about 50 mg/ml to about 150 mg/ml.
12. The solid dispersion of claim 11 , wherein the amorphous content is equal to or greater than about 95 wt %.
13. The solid dispersion of claim 11 , which is substantially free from crystalline forms of disodium pemetrexed.
14. The solid dispersion of claim 11 , wherein said pharmaceutically acceptable carrier is polyvinylpyrrolidone.
15. The solid dispersion of claim 11 , wherein said pharmaceutically acceptable carrier is hydroxypropylmethyl cellulose (HPMC).
16. The solid dispersion of claim 11 , which comprises from about 10% to about 90% of disodium salt of pemetrexed; and from about 90% to about 10% of the carrier.
17. The solid dispersion of claim 11 , which has solubility in water ranging from about 50 mg/ml to about 150 mg/ml.
18. A process for preparing the compound of claim 1 comprising:
i) providing a solution of pemetrexed disodium in a solvent; and
ii) removing the solvent.
19. The process of claim 18 , further comprising drying the solid isolated after solvent removal.
20. The process of claim 18 , wherein said solvent is an organic solvent.
21. The process of claim 18 , wherein said solvent is water.
22. The process of claim 18 , wherein said solvent is removed by spray drying.
23. The process of claim 22 , wherein said removing step is carried out by using spray drier at an inlet temperature of about 100° C. or less.
24. The process of claim 18 , wherein said solvent is isopropyl alcohol, methanol, acetone, ethyl methyl ketone, methyl isobutyl ketone, water or mixtures thereof.
25. The process of claim 18 , wherein the providing step comprises dissolving disodium pemetrexed and a pharmaceutically acceptable carrier in the solvent.
26. The process of claim 25 , wherein said pharmaceutically acceptable carrier is polyvinylpyrrolidone.
27. The process of claim 25 , wherein said pharmaceutically acceptable carrier is hydroxypropylmethyl cellulose (HPMC).