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Stable pemetrexed arginine salt and compositions comprising it

a technology of pemetrexed arginine salt and pemetrexed salt, which is applied in the direction of biocide, drug composition, organic chemistry, etc., can solve the problems of unstable final product stability, problems such as problems, and formulating water soluble pemetrexed salts has not proved to be an easy task

Inactive Publication Date: 2016-05-26
SYNTHON BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text is discussing the need for stable alternatives to pemetrexed, a drug used in cancer treatment. It suggests that finding unstable amorphous forms of pemetrexed could be beneficial as they would break a prejudice against using them in crystal form. The technical effect of this would be to provide a more stable alternative to pemetrexed for cancer treatment.

Problems solved by technology

The above patent shows that problems may arise because of conversions between different crystalline forms (actually the above mentioned forms are different hydrates, not polymorphic forms) of pemetrexed when exposed to elevated temperatures, low humidity, etc.
Formulation processes may involve a variety of the above mentioned adverse conditions, resulting in a possibility that the stability of the final product may be affected.
Formulating water soluble pemetrexed salts, however, has not proven to be an easy task, due to its stability issues.
It is known that amorphous forms of active ingredients can be relatively more unstable, when compared with crystalline forms.

Method used

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  • Stable pemetrexed arginine salt and compositions comprising it
  • Stable pemetrexed arginine salt and compositions comprising it
  • Stable pemetrexed arginine salt and compositions comprising it

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0047]To 500 mg of pemetrexed diacid and 407 mg of arginine, 6 ml of water was added. The mixture was stirred until a clear solution was formed. This took approximately 5 minutes. The solvent was evaporated and the residue was dried over night at 40° C. under vacuum.

[0048]XRPD test confirmed amorphous character of the product.

[0049]TGA curve exhibits gradual mass loss of 4.738% of water between 25 and 220° C.

[0050]NMR confirmed the structure of bis-arginine salt (formula (2))

example 2

[0051]1000 mg of pemetrexed (diacid) and 815 mg of arginine was added to 6 ml of water. The mixture was stirred at ambient temperature until a clear solution was formed.

[0052]The solution was divided into 6 fractions and the following cosolvents were added to the respective fractions:

[0053].01 3 ml of methanol

[0054].02 3 ml of ethanol

[0055].03 2 ml of isopropanol

[0056].04 2 ml of acetonitrile

[0057].05 2 ml of tetrahydrofuran

[0058].06 2 ml of acetone

[0059]The solutions were evaporated on a rotary vacuum evaporator. The solid residues were dried at 40° C. under vacuum over night.

[0060]Analysis of the material by XRPD has proven an amorphous material.

example 3

[0061]Process for making unit dose lyophilized composition (50 mg pemetrexed per vial):

[0062]Under inert atmosphere of nitrogen, 875.0 mg of pemetrexed (diacid) was dissolved in a solution of 731.0 mg arginine (2.1 molar equivalents related to pemetrexed) in 30 ml of Water for injections under stirring. After that, 875 mg of mannitol was added and dissolved. The pH was adjusted to about 7.5 by 1 M hydrochloric acid and the weight of the solution was adjusted to 35 gram amount by Water for injections. The solution was filtered through PVDF filter 0.2 microns, filled in clear 10 R vials per 2 grams and freeze dried according to the program presented in the table.

DurationTemperatureVacuumSafety PressureProcess Phase(hh:mm)(° C.)(mbar)(mbar)Loading00:00+5Fast freezing01:00−45Freezing01:30−45Freezing00:45−15Annealing01:00−15Freezing01:30−45Freezing02:00−45Evacuation 100:10−450.370.63Sublimation05:00+50.370.63Sublimation06:15+50.370.63Evacuation 200:10+50.060.63Second drying05:35+300.060....

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Abstract

The present invention relates to arginine salt of pemetrexed of formula (1), particularly to a stable solid form thereof, and to pharmaceutical compositions comprising such salt.

Description

[0001]Pemetrexed is a common name for compound N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid of formula (1)[0002]The compound has been first disclosed in EP 432677.[0003]Pemetrexed is a pharmaceutically active compound, which is used, i.e., in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.[0004]As pemetrexed of the above formula (1) is a bivalent acid (a diacid) comprising two carboxylic groups, it may form various types of salts with bases. On the other hand, pemetrexed has basic nitrogens and, accordingly, it may form acid addition salts with various acids. The commercially available product, sold, e.g., under the brand name ALIMTA by Eli Lilly, comprises hydrated disodium salt of pemetrexed as the active substance and is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The preparation of lyophilized pemetrexed disodium composition is disclosed in ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D487/04C07C277/00C07C279/14
CPCC07D487/04C07C277/00C07C279/14A61P35/00
Inventor EUPEN VAN, JACOBUS, THEODORUS, HENRICUSZALUDEK, BOREK
Owner SYNTHON BV
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