United States Patent:  6,017,921

Assignee:  U.S. Bioscience, Inc. (West Conshohocken, PA)

Filed:  February 4, 1998

The present invention provides for a crystalline form of trimetrexate either as a glucuronate, acetate, hydrochloride, methanosulfonate or lactate salt, which can be processed galenically as a stable, well-defined solid substance and processes for producing the crystalline forms. Such crystalline forms allow for prolonged stability in storage and for oral and intravenous administration of the drug.

SUMMARY OF THE INVENTION

The present invention provides for crystalline forms of trimetrexate, either as a glucuronate, acetate, hydrochloride, methanesulfonate or lactate salt, which can be processed galenically as stable, well-defined solid substances. Such crystalline forms allow for prolonged stability in storage and for oral and intravenous administration of the drug.

Trimetrexate base is treated with a soft carbon acid, i.e, gluconic acid, glucuronic acid, lactic acid, acetic acid etc., but preferably gluconic acid, in either an aqueous or hydro-alcoholic solution to solubilize the free base. The trimetrexate solution is heated to between 40 to 80^oC. and stirred until practically homogeneous, treated with charcoal and vacuum filtered. The filtrate is treated with an excess of either the desired acid or conjugate base of the acid to give the desired trimetrexate salt. The solution is cooled to 20^oC., filtered and the crystals washed with an appropriate solvent followed by drying under vacuum.

The present invention further provides for novel processes for producing crystalline trimetrexate salts of good quality. In one preferred embodiment, the present invention provides for a novel process for producing crystalline trimetrexate glucuronate salt of good quality.

The process is characterized as follows:

a. water is used as a solvent;

b. excess glucuronic acid is used to prevent the co-precipitation of the trimetrexate free base with the desired trimetrexate glucuronate salt;

c. n-heptane is used in the water solution as an antifoaming agent;

d. the crystalline trimetrexate glucuronate salt is filtered and washed with a 2% glucuronic acid solution;

e. the salt is dried at an elevated temperature in the range of 40 to 50 degrees under vacuum so as to avoid decomposition of the salt, and the formation of lumps and agglomerates.

In another preferred embodiment, the present invention provides for a novel process for producing crystalline trimetrexate acetate hydrate salt of good quality. The process is characterized as follows:

a. ethanol, 20 to 30 percent in aqueous medium is used as a solvent to dissolve trimetrexate free base;

b. excess gluconic acid is then added to form trimetrexate gluconate and to prevent the co-precipitation of the trimetrexate free base with the resulting trimetrexate gluconate salt;

c. excess acetic acid is then added to convert the trimetrexate gluconate to the acetate salt;

d. the crystalline trimetrexate acetate hydrate is filtered and washed with a 3 to 7 percent acetic acid solution;

e. the salt is dried at an elevated temperature in the range of 70 to 80 degrees under vacuum so as to avoid decomposition of the salt, and to avoid the formation of lumps and agglomerates.

In a further preferred embodiment, the present invention provides for a novel process for producing crystalline trimetrexate hydrochloride hydrate salt of good quality. The process is characterized as follows:

a. water is used as a solvent to dissolve the trimetrexate free base;

b. excess gluconic acid is then added to form trimetrexate gluconate and to prevent the co-precipitation of the trimetrexate free base with the resulting trimetrexate gluconate salt;

c. excess sodium chloride is then added to convert the trimetrexate gluconate to the hydrochloride salt;

d. the crystalline trimetrexate hydrochloride hydrate is filtered and washed with an aqueous ethanol solution of 75 to 85 percent;

e. the salt is dried at an elevated temperature in the range of 70 to 80 degrees under vacuum so as to avoid decomposition of the salt, and the formation of lumps and agglomerates.

In a further preferred embodiment, the present invention provides for a novel process for producing crystalline trimetrexate methanesulfonate salt of good quality. The process is characterized as follows:

a. water is used as a solvent to dissolve the trimetrexate free base;

b. excess gluconic acid is then added to form trimetrexate gluconate and to prevent the co-precipitation-of the trimetrexate free base with the resulting trimetrexate gluconate salt;

c. excess methanesulfonic acid is then added to convert the trimetrexate gluconate to the methanesulfonate salt;

d. the crystalline trimetrexate methanesulfonate is filtered and washed with a water solution;

e. the salt is dried at an elevated temperature in the range of 75 to 90 degrees under vacuum so as to avoid decomposition of the salt, and the formation of lumps and agglomerates.

In yet a further preferred embodiment, the present invention provides for a novel process for producing crystalline trimetrexate lactate hydrate salt of good quality. The process is characterized as follows:

a. water is used as a solvent to dissolve the trimetrexate free base;

b. excess L-(+)-lactic acid is then added to convert the trimetrexate base to the lactate salt;

c. the crystalline trimetrexate lactate hydrate is filtered and washed with a 50% aqueous ethanol solution to avoid yield losses due to the dissolution of the salt;

d. the salt is dried at an elevated temperature in the range of 70 to 80 degrees under vacuum so as to avoid decomposition of the salt, and the formation of lumps and agglomerates.

Claim 1 of 9 Claims

1. Crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline glucuronate.

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