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Publication Date: 2014-May-07
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The present application is directed to pemetrexed tromethamine salts, process for its preparation and its solid state forms thereof

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The present application is directed to pemetrexed tromethamine salts, process for its preparation and its solid state forms thereof.


Pemetrexed, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1Hpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-Glutamic acid (also known            as pemetrexed diacid), having the following formula:

Formula I

is a potent inhibitor of several folate-requiring enzymes and is useful for the treatment of non-small cell lung cancer and mesothelioma. Pemetrexed is available in the market under the brand name ALIMTA® with the active ingredient chemically described as L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]- disodium salt heptahydrate (“Pemetrexed disodium heptahydrate”).

            U.S. Patent. No. 5,344,932 (“the


‘932 patent”), which is incorporated herein by reference in its entirety, refers to pemetrexed diacid or a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of pemetrexed diacid described in the US ‘932 patent include those formed from the alkali metals, alkaline earth metals, non-toxic metals, ammonium, and mono-, di- and trisubstituted amines, such as for example the sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethanolammonium, pyridinium, and substituted pyridinium salts. Further, according to the


‘932 patent, the mono and disodium salts, particularly the disodium salt, are advantageous.

            International application publication No. WO 01/14379 A2 (“the WO ‘379 publication”) describes novel crystalline form of Pemetrexed disodium designated as “Hydrate Form I”. According to WO ‘379 publication, the term “hydrate” describes the crystalline lattice of pemetrexed disodium salt, which can contain variable amounts of water, from about 0.01 to about 3 equivalents of water, depending upon relative humidity in the storage conditions and preferably hydrate Form I contains from about 2 to about 3 equivalents of water, most preferred is 2.4-2.9 equivalents of water. Therefore, the “Hydrate form I” may not be suitable for making the finished dosage form of pemetrexed disodium because of the difficulties encountered due to its disadvantageous properties such as hygroscopic nature, and retaining variable amounts of water based on relative humidity.

            U.S. Patent. No. 7,138,521 (“the


‘521 patent”) describes that the pemetrexed disodium can exist in another crystalline form i.e., a heptahydrate form which is more stable than the previously known 2.5 hydrate and the primary advantages of the heptahydrate crystalline form is stability with respect to the solvent content and stability with respect to growth of related substances. However, according to the US ‘521 patent, the heptahydrate crystalline form when subjected to elevated temperatures, low humidity an...