Crystalline form of pemetrexed disodium
The present invention relates to a new polymorphic or crystalline form of Pemetrexed Disodium, processes for its preparation and its use, in particular for the preparation of medicaments.
1. Crystalline form of Pemetrexed Disodium which has characteristic reflexes in an X-ray powder diffractogram using CuKα radiation with Cukβ filter at a 2θ angle: 7.7±0.2, 9.7±0.2, 18.6±0.2, 19.2±0.2, 20.4±0.2, 24.3±0.2, 26.6±0.2, 28.7±0.2, 28.9±0.2, and 30.0±0.2.
2. The crystalline form of Pemetrexed Disodium according to claim 1 , wherein the X-ray powder diffractogram also shows characteristic reflexes selected from the group consisting of 5.5±0.2, 10.9±0.2, 13.0±0.2, 13.6±0.2, and 21.8±0.2.
3. The crystalline form of Pemetrexed Disodium according to claim 1 , wherein the X-ray powder diffractogram also shows at least 20 of the characteristic reflexes selected from the group consisting of 5.5±0.2, 7.7±0.2, 9.2±0.2, 9.7±0.2, 10.9±0.2, 13.0±0.2, 13.6±0.2, 15.3±0.2, 16.0±0.2, 16.7±0.2, 17.0±0.2, 18.1±0.2, 18.6±0.2, 19.2±0.2, 20.0±0.2, 20.4±0.2, 21.8±0.2, 22.3±0.2, 22.7±0.2, 23.0±0.2, 24.3±0.2, 25.9±0.2, 26.6±0.2, 27.0±0.2, 27.2±0.2, 28.0±0.2, 28.7±0.2, 28.9±0.2, 30.0±0.2, 30.8±0.2, 31.5±0.2, 32.0±0.2, 33.6±0.2, 34.2±0.2, 34.6±0.2, 35.0±0.2, 36.2±0.2, 37.1±0.2, 37.9±0.2, 38.2±0.2, 38.9±0.2, and 39.4±0.2.
4. The crystalline form of Pemetrexed Disodium according to claim 1 , wherein the X-ray powder diffractogram corresponds to the X-ray powder diffractogram shown in FIG. 1 a and/or FIG. 1 b.
5. The crystalline form of Pemetrexed Disodium according to claim 1 , wherein said crystalline form has a Differential Scanning Calorimetry (DSC) corresponds to the DSC spectra shown in FIG. 3 .
6. Pharmaceutical composition comprising Pemetrexed Disodium according to claim 1 together with a pharmaceutical acceptable carrier, diluent and/or excipient.
7. A method for the inhibition of the folate metabolic Pathway, thymidylate synthase, dihydrofolate reductase and/or glycinamide ribonucleotide formyl transferase, comprising administering the pharmaceutical composition according to claim 6 to a patient in need of such treatment.
8. The method according to claim 7 wherein said patient is suffering from cancer.
9. The pharmaceutical composition according to claim 6 comprising a further active agent.
10. A method for inhibiting, the folate metabolic pathway, thymidylate synthase, dihydrofolate reductase and/or glycinamide ribonucleotide formyl transferase, comprising administering to a patient in need of such treatment, a crystalline form of Pemetrexed Disodium which has a property of characteristic reflexes in an X-ray powder diffractogram using CuKα radiation with Cukβ filter at a 2θ angle: 7.7±0.2, 9.7±0.2, 18.6±0.2, 19.2±0.2, 20.4±0.2, 24.3±0.2, 26.6±0.2, 28.7±0.2, 28.9±0.2, and 30.0±0.2.
11. The method of claim 10 wherein said patient is suffering from cancer.
12. Process for the preparation of Pemetrexed Disodium according to claim 1 comprising the steps
(a) providing a mixture of Pemetrexed Disodium in a solvent comprising 0% to 5% H 2 O (v/v),
(b) addition of seeding crystals,
(c) heating under reflux until transformation to Pemetrexed Disodium according to claim 1 is complete, and
(d) isolation of the product,
or
(a′) providing Pemetrexed Monosodium in a solvent,
comprising 0% to 5% H 2 O (v/v),
(b′) slow or portionwise addition of about 0.5 to 1.5 mole equivalents of NaOH,
(c′) heating under reflux until transformation to Pemetrexed Disodium according to claim 1 is complete, and
(d′) isolation of the product,
or
(a″) providing Pemetrexed in a solvent, comprising 0% to 5% H 2 O (v/v),
(b″) slow or portionwise addition of about 1.0 to 3.0 mole equivalents of NaOH,
(c″) heating under reflux transformation to Pemetrexed Disodium according to claim 1 is complete, and
(d″) isolation of the product.
13. The process according claim 12 ,
wherein the seed crystals of step (b) are of Pemetrexed Monosodium.
14. A method of inhibiting the folate metabolic pathway of a patient in need of such inhibition, comprising administering an effective amount of Pemetrexed Disodium of claim 1 to said patient.
15. The method of claim 11 , wherein said cancer is a solid tumor.
16. The crystalline form of Pemetrexed Disodium according to claim 3 , wherein the X-ray powder diffractogram shows all of the characteristic reflexes selected from the group consisting of 5.5±0.2, 7.7±0.2, 9.2±0.2, 9.7±0.2, 10.9±0.2, 13.0±0.2, 13.6±0.2, 15.3±0.2, 16.0±0.2, 16.7±0.2, 17.0±0.2, 18.1±0.2, 18.6±0.2, 19.2±0.2, 20.0±0.2, 20.4±0.2, 21.8±0.2, 22.3±0.2, 22.7±0.2, 23.0±0.2, 24.3±0.2, 25.9±0.2, 26.6±0.2, 27.0±0.2, 27.2±0.2, 28.0±0.2, 28.7 ±0.2, 28.9±0.2, 30.0±0.2, 30.8±0.2, 31.5±0.2, 32.0±0.2, 33.6±0.2, 34.2±0.2, 34.6±0.2, 35.0±0.2, 36.2±0.2, 37.1±0.2, 37.9±0.2, 38.2±0.2, 38.9±0.2, and 39.4±0.2.
17. The process according claim 13 , wherein the seed crystals of step (b) are Pemetrexed Monosodium in an amount of about 5 to 30 mol %.
18. The process according to claim 17 , wherein the seed crystals of step (b) are Pemetrexed Monosodium in an amount of about 10 to 20 mol %.
19. The process according to claim 18 , wherein the seed crystals of step (b) are Pemetrexed Monosodium in an amount of about 15 mol %.
20. The method according to claim 8 , wherein said cancer is a solid tumor selected from the group consisting of malignant pleural mesothelioma and metastatic non-small cell lung cancer.
21. The process for the preparation of Pemetrexed Disodium according to claim 12 , wherein the solvent is a C 1 -C 4 alcohol comprising 1% to 4% H 2 O (v/v).
22. The process according to claim 21 , wherein the solvent is EtOH comprising 1% to 3% H 2 O (v/v).
23. The process according to claim 12 , wherein 0.7 to 1.3 mole equivalents of NaOH are added in step (b′).
24. The process according to claim 23 , wherein 0.8 to 1.1 mole equivalents of NaOH are added in step (b′).
25. The process according to claim 24 , wherein 1 mole equivalent of NaOH is added in step (b′).
26. The process according to claim 12 , wherein 1.7 to 2.3 mole equivalents of NaOH are added in step (b″).
27. The process according to claim 26 , wherein 1.8 to 2.1 mole equivalents of NaOH are added in step (b″).
28. The process according to claim 27 , wherein 2.0 mole equivalents of NaOH are added in step (b″).
29. The crystalline form of Pemetrexed Disodium according to claim 1 which additionally has the property of characteristic signals in FT (Fourier-Transformation) Infrared spectra at 3469±2 cm −1 , 1691±2 cm −1 , 1640±2 cm −1 , 1576±2 cm −1 , 1490±2 cm −1 , 1454±2 cm −1 , 1409±2 cm −1 , 1393±2 orn −1 , 1287±2 cm −1 , and 676±2 cm −1 .
30. The method according to claim 10 , wherein said crystalline form of Pemetrexed Disodium additionally has the property of characteristic signals in FT (Fourier-Transformation) Infrared spectra at 3469±2 cm−1, 1691±2 cm−1, 1640±2 cm−1, 1576±2 cm−1, 1490±2 cm−1, 1454±2 cm−1, 1409±2 cm−1, 1393±2 cm−1, 1287±2 cm−1, and 676±2 cm−1.
31. The crystalline form of Pemetrexed Disodium according to claim 29 , wherein the FT-Infrared spectra also shows characteristic signals selected from the group consisting of 3306±2 cm−1, 1610±2 cm−1, 1228±2 cm−1, 903±2 cm−1, and 778±2 cm−1.
32. The crystalline form of Pemetrexed Disodium according to claim 29 , wherein the FT-Infrared spectra shows the following characteristic signals at 3469±2 cm −1 , 3420±2 ce, 3407±2 cm −1 , 3388±2 cm −1 , 3306±2 cm −1 , 3206±2 cm −1 , 3098±2 cm −1 , 2925±2 cm −1 , 2901±2 cm −1 , 2867±2 cm −1 , 2752±2 cm −1 , 2364±2 cm −1 , 2355±2 cm −1 , 2323±2 cm −1 , 2292±2 cm −1 , 2165±2 cm −1 , 1984±2 cm −1 , 1691±2 cm −1 , 1640±2 cm −1 , 1610±2 cm −1 , 1576±2 cm −1 , 1530±2 cm −1 , 1520±2 cm −1 , 1490±2 cm −1 , 1454±2 cm −1 , 1409±2 cm −1 , 1393±2 cm −1 , 1349±2 cm −1 , 1287±2 cm −1 , 1249±2 cm −1 , 1227±2 cm −1 , 1212±2 cm −1 , 1181±2 cm −1 , 1161±2 cm −1 , 1149±2 cm −1 , 1140±2 cm −1 , 1105±2 cm −1 , 1092±2 cm −1 , 1081±2 cm −1 , 1040±2 cm −1 , 1018±2 cm −1 , 1000±2 ce, 950±2 cm −1 , 903±2 cm −1 , 876±2 cm −1 , 859±2 cm −1 , 846±2 cm −1 , 820 t 2 cm −1 , 778±2 cm −1 , 761±2 cm −1 , 741±2 cm −1 , 715±2 cm −1 , 706±2 cm −1 , 689±2 cm −1 , and 676±2 cm −1 .
33. The crystalline form of Pemetrexed Disodium according to claim 29 , wherein the FT-Infrared spectra corresponds to the FT-Infrared spectra shown in FIG. 2 a and/or FIG 2 b.