Solid forms of pemetrexed

Abstract

There is provided polymorphs and amorphous form of pemetrexed or its pharmaceutical acceptable salts and process for making thereof.

1 .- 44 . (canceled) 
     
     
         45 . A compound, which is an amorphous form of disodium salt of pemetrexed. 
     
     
         46 . The compound of  claim 45 , wherein said amorphous form of disodium salt of pemetrexed has water content of less than about 15% w/w. 
     
     
         47 . The compound of  claim 45 , wherein said amorphous form of disodium salt of pemetrexed has water content between about 5% and about 10% w/w. 
     
     
         48 . A composition comprising a compound of  claim 45  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. 
     
     
         49 . The composition of  claim 48 , which is in the form of a powder suitable as active ingredient for pharmaceutical products. 
     
     
         50 . The composition of  claim 48 , wherein at least 95% by weight of said solid disodium salt of pemetrexed is in the amorphous form. 
     
     
         51 . The composition of  claim 50 , wherein at least 2% by weight of said solid disodium salt of pemetrexed is in the crystalline form. 
     
     
         52 . The composition of  claim 48 , wherein at least 5% w/w of said solid disodium salt of pemetrexed is a crystalline form of disodium salt of pemetrexed. 
     
     
         53 . The composition of  claim 52 , 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 K α-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. 
     
     
         54 . The composition of  claim 53 , which has X-ray powder diffraction pattern substantially in accordance with  FIG. 8 . 
     
     
         55 . A compound, which is a crystalline form of disodium salt of pemetrexed having an X-ray diffraction pattern, expressed in terms of 2.theta. angles and obtained with a diffractometer equipped with a copper K α-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. 
     
     
         56 . A solid dispersion of disodium salt of pemetrexed which comprises
 i) a compound of  claim 45 ; 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.   
     
     
         57 . The solid dispersion of  claim 56 , wherein the amorphous content is equal to or greater than about 95 wt %. 
     
     
         58 . The solid dispersion of  claim 56 , which is substantially free from crystalline forms of disodium pemetrexed. 
     
     
         59 . The solid dispersion of  claim 56 , wherein said pharmaceutically acceptable carrier is polyvinylpyrrolidone. 
     
     
         60 . The solid dispersion of  claim 56 , wherein said pharmaceutically acceptable carrier is hydroxypropylmethyl cellulose (HPMC). 
     
     
         61 . The solid dispersion of  claim 56 , which comprises from about 10% to about 90% of disodium salt of pemetrexed; and from about 90% to about 10% of the carrier. 
     
     
         62 . The solid dispersion of  claim 56 , which has solubility in water ranging from about 50 mg/ml to about 150 mg/ml. 
     
     
         63 . A process for preparing the compound of  claim 45  comprising:
 i) providing a solution of pemetrexed disodium in a solvent; and 
 ii) removing the solvent. 
 
     
     
         64 . The process of  claim 63 , further comprising drying the solid isolated after solvent removal. 
     
     
         65 . The process of  claim 63 , wherein said solvent is an organic solvent. 
     
     
         66 . The process of  claim 63 , wherein said solvent is water. 
     
     
         67 . The process of  claim 63 , wherein said solvent is removed by spray drying. 
     
     
         68 . The process of  claim 66 , wherein said removing step is carried out by using spray drier at an inlet temperature of about 100° C. or less. 
     
     
         69 . The process of  claim 63 , wherein said solvent is isopropyl alcohol, methanol, acetone, ethyl methyl ketone, methyl isobutyl ketone, water or mixtures thereof. 
     
     
         70 . The process of  claim 63 , wherein the providing step comprises dissolving disodium pemetrexed and a pharmaceutically acceptable carrier in the solvent. 
     
     
         71 . The process of  claim 70 , wherein said pharmaceutically acceptable carrier is polyvinylpyrrolidone. 
     
     
         72 . The process of  claim 70 , wherein said pharmaceutically acceptable carrier is hydroxypropylmethyl cellulose (HPMC). 
     
     
         73 . A process for making a solid containing a mixture of amorphous and crystalline forms of disodium salt of pemetrexed, said process comprising:
 i) providing a solution of disodium salt of pemetrexed in water;   ii) adding an organic hydrocarbon solvent which is capable of forming an azeotropic mixture with water; and   iii) carrying out an azeotropic distillation until a solid is obtained.   
     
     
         74 . The process of  claim 73 , wherein said organic hydrocarbon solvent is toluene or xylene. 
     
     
         75 . The process of  claim 73 , wherein said organic hydrocarbon solvent is toluene. 
     
     
         76 . A compound, which is Form A of pemetrexed diacid having X-ray powder diffraction pattern (XRPD) with peaks at about 5.8, 12.4, 18.3, 18.6, 19.6, 20.4, 24.5, 24.9, 25.8, 28.9, 29.2, 29.6, and 32.8, ±0.2 degrees 20. 
     
     
         77 . The compound of  claim 76  having X-ray powder diffraction pattern substantially in accordance with  FIG. 12 . 
     
     
         78 . A process for preparing a crystalline form A of pemetrexed diacid, comprising the steps of:
 a) providing a solution of pemetrexed diacid in ethanol;   b) cooling the mass to cause precipitation of a solid; and   c) isolating the precipitated solid, which is the crystalline form A of pemetrexed diacid.   
     
     
         79 . The process of  claim 78 , which further comprises drying the solid. 
     
     
         80 . The process of  claim 78 , wherein said providing a solution step comprises
 i) reacting dimethyl N-[4-(2-{4-hydroxy-6-aminopyrrolo-[2,3-d]pyrimidin-3-yl}ethyl)benzoyl]-L-glutamic acid PTSA salt with aqueous sodium hydroxide solution; and   ii) treating the reaction mass with an external acid until pH reaches about 3.   
     
     
         81 . The process of  claim 80 , wherein said external acid is hydrochloric acid. 
     
     
         82 . A compound which is Form B of pemetrexed diacid having X-ray powder diffraction pattern (XRPD) with peaks at about 5.7, 12.1, 12.3, 17.7, 18.4, 20.2, 22.2, 22.5, 22.7, 24.7, 25.6, 25.8, 26.6, 28.2, 30.3, 31.3, and 31.8, ±0.2 degrees 20. 
     
     
         83 . The compound of  claim 82  having X-ray powder diffraction pattern substantially in accordance with  FIG. 16 . 
     
     
         84 . A process for making a crystalline form B of pemetrexed diacid comprising:
 a) providing a solution of pemetrexed diacid in isopropyl alcohol;   b) cooling the mass to cause precipitation of a solid; and   c) isolating the precipitated solid, which is the crystalline form B of pemetrexed diacid.   
     
     
         85 . The process of  claim 84 , further comprising drying the solid. 
     
     
         86 . The process of  claim 84 , wherein said providing step comprises i) reacting Dimethyl N-[4-(2-{4-hydroxy-6-aminopyrrolo-[2,3-d]pyrimidin-3-yl}ethyl)benzoyl]-L-glutamic acid PTSA salt with aqueous sodium hydroxide solution; and ii) treating the reaction mass with an external acid until pH reaches about 3. 
     
     
         87 . The process of  claim 86 , wherein said external acid is hydrochloric acid.