Claims for Patent: 9,604,990

Summary for Patent: 9,604,990

Title:	Crystalline forms of pemetrexed diacid and manufacturing processes therefor
Abstract:	Crystalline forms of pemetrexed diacid are provided (Forms 1 and 2) which are readily produced for either laboratory-scale or industrial scale. Processes for the preparation of Forms 1 and 2 are also provided.
Inventor(s):	Lin; Ying-Tzu (Tainan, TW), Wang; Kuan-Hsun (Tainan, TW), Lo; Wei-Shuo (Tainan, TW), Lin; Wen-Wei (Tainan, TW), Cheng; Wan-Yin (Tainan, TW)
Assignee:	SCINOPHARM TAIWAN, LTD. (Tainan, TW)
Application Number:	14/924,909
Patent Claims:	1. A crystalline Form 2 of pemetrexed diacid, characterized by a powder X-ray diffraction pattern with peaks at about 9.0, 12.7, 14.4, 16.3 and 25.3.+-.0.2 degrees two-theta, wherein the crystalline Form 2 is substantially free of other crystalline forms of pemetrexed diacid. 2. The crystalline Form 2 of pemetrexed diacid of claim 1, further characterized by a powder X-ray diffraction pattern with peaks at about 13.4, 13.8, 17.2, 25.9 and 27.3.+-.0.2 degrees two-theta. 3. The crystalline Form 2 of pemetrexed diacid of claim 2, further characterized by a powder X-ray diffraction pattern with peaks at about 15.5, 18.1, 18.4, 27.9 and 31.6.+-.0.2 degrees two-theta. 4. The crystalline Form 2 of pemetrexed diacid of claim 1, characterized by a powder X-ray diffraction pattern as substantially depicted in FIG. 2. 5. The crystalline Form 2 of pemetrexed diacid of claim 1, further characterized by a weight loss not more than 1.5% at a temperature up to 120.degree. C., as measured by thermal gravimetric analysis. 6. The crystalline Form 2 of pemetrexed diacid of claim 1, wherein the crystalline Form 2 of pemetrexed diacid is an anhydrous form. 7. A process for preparing the crystalline Form 2 of pemetrexed diacid of claim 1, wherein the process comprises: a) dissolving pemetrexed disodium in a mixture of water and methanol at a temperature of about 15-30.degree. C. to form a solution; b) adjusting the pH of the solution to a range of 2.5 to 3.5 with an acid to form a precipitate; c) isolating the precipitate; and d) drying the precipitate at 60-90.degree. C. to provide the crystalline Form 2 of pemetrexed diacid. 8. The process of claim 7, wherein the crystalline Form 2 of pemetrexed diacid is isolated substantially free of other crystalline forms of pemetrexed diacid. 9. The process of claim 7, wherein the mixture of water and methanol has a volume ratio of 3:1 to 1:1 (water:methanol). 10. The process of claim 7, wherein the acid is an inorganic acid selected from the group consisting of: HCl, HBr, H.sub.2 SO.sub.4, and mixtures thereof. 11. The process of claim 7, wherein the acid is an organic acid selected from the group consisting of: acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, and mixtures thereof. 12. The crystalline Form 2 of pemetrexed diacid of claim 1, wherein the crystalline Form 2 of pemetrexed diacid contains 10% or less of another form. 13. The crystalline Form 2 of pemetrexed diacid of claim 1, wherein the crystalline Form 2 of pemetrexed diacid contains 5% or less of another form. 14. The crystalline Form 2 of pemetrexed diacid of claim 1, wherein the crystalline Form 2 of pemetrexed diacid contains 3% or less of another form. 15. The crystalline Form 2 of pemetrexed diacid of claim 1, wherein the crystalline Form 2 of pemetrexed diacid contains 1% or less of another form.