CLIAMS:We claim:
1. Crystalline Form A of vardenafil base having an X-ray diffraction pattern with copper K aradiation, having significant peaks at about 8.58, 9.98, 13.97, 16.63, 20.05 and 21.31 ±0.2 degrees 2?.

2. Crystalline Form A of vardenafil base having an X-ray diffraction pattern with copper K aradiation as depicted in Figure- 1.

3. A process for the for preparation of a highly pure and stable crystalline form A of Vardenafil base, which comprises:
a) Providing a solution of Vilazodone hydrochloride in acetone and water;
b) Optionally, filtering the solvent solution to remove any extraneous matter; and
c) Substantially removing the solvent from the solution to afford Crystalline form A of Vardenafil base.

4. A compound of formula (III)

5. A compound of formula (I),

containing an amount of a compound of formula (III);

lower than 0.15%.

,TagSPECI:Field of the invention

The present invention relates to novel crystalline form A of Vardenafil base of formula (II) and the process for its preparation.

Formula (II)

Background of the invention

Chemically vardenafil hydrochloride is piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, mono -hydrochloride and can be structurally represented by Formula I.

Formula (I)
The monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guaosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). It is commercially available in products sold under the brand name LEVITRA formulated as 2.5 mg, 5 mg, 10 mg, 20 mg film-coated tablets.

U.S. Pat. No. 6,362,178 B1 discloses vardenafil, its related compounds and processes for their preparation. The patent describes a process in which vardenafil is obtained by recrystallization in ether in Example 19.The patent also describes processes for the preparation of its monohydrochloride and dihydrochloride salts, which are formed in a combination of ether and dichloromethane. The patent also describes a process for the preparation of vardenafil monohydrochloride trihydrate.
U.S. Patent Application Publication No. 2005/0203298 also describes a process for the preparation of vardenafil, and its monohydrochloride trihydrate.

Chemical synthesis of vardenafil has mostly been directed to the preparation of the trihydrate of monohydrochloride of vardenafil.

A considerable amount of work needs to be done on the polymorphic characterization of vardenafil to identify other forms that can be generated.

Regulatory authorities throughout the world require that all possible crystalline forms of the same active compound be synthesized and characterized as completely as possible. It is also required that the commercial product should not contain traces of any of the other forms or, if present, the percentages of each of the forms be well characterized to avoid changes in the dissolution and bioavailability characteristics of drug substance during storage.

There is thus a continuing need to prepare new polymorphic forms of pharmacologically active compounds of commercial interest such as vardenafil, which provide the pharmaceutical formulation scientist with a broader spectrum of polymorphic forms of an active ingredient to choose from, based on their differing physiochemical properties.

It is also important that the processes for the preparation of the polymorphic forms be robust and reproducible, so that the processes are easily scaled up in the plant.
The present invention relates to novel crystalline form A of Vardenafil base and the process for its preparation which are easily scalable and commercially viable.

It is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.

There is a need for pure Vardenafil base or a pharmaceutically acceptable salt thereof substantially free of impurities which has good flow properties, and better dissolution and solubility properties to obtain formulations with greater bioavailability.

Summary of the invention:

The present inventors have now surprisingly and unexpectedly discovered a novel pure Crystalline form A of Vardenafil base with high purity, adequate stability and good dissolution properties.

In one aspect, the present invention provides a novel, pure and stable crystalline form A of Vardenafil base.

In one aspect, the present invention provides a novel, pure and stable crystalline form A of Vardenafil base characterized by X-ray diffraction pattern as depicted in Figure- 1.

In another aspect of the present invention, a process is provided for preparation of a highly pure and stable crystalline form A of Vardenafil base, which comprises:
a) Providing a solution of Vilazodone hydrochloride in acetone and water;
b) Optionally, filtering the solvent solution to remove any extraneous matter; and
c) Substantially removing the solvent from the solution to afford crystalline form A of Vardenafil base.

In another aspect of the present invention, a compound formula (III)

Formula (III)

In another aspect of the present invention, compound of formula (I),

Formula(I)
containing an amount of a compound of formula (III)

Formula(III)
lower than 0.15%.

Brief description of Drawings:
Fig 1: X-ray powder diffraction (XRD) pattern of crystalline form A of Vardenafil base.
Fig 2: DSC thermogram pattern of Crystalline form A of Vardenafil base.

Detailed description of the invention:
In one embodiment present invention provides highly pure and stable crystalline form A of
Vardenafil base.

According to one embodiment of the present invention, there is provided a highly pure and stable crystalline form A of Vardenafil base in accordance with Figure 1.

In another embodiment, the present invention further encompasses a process for preparing the highly pure and stable crystalline form A of Vardenafil base.

In another embodiment of the present invention, a process is provided for preparation of a highly pure and stable crystalline form A of Vardenafil base, which comprises:
a) Providing a solution of Vilazodone hydrochloride in acetone and water;
b) Optionally, filtering the solvent solution to remove any extraneous matter; and
c) Substantially removing the solvent from the solution to afford crystalline form A of Vardenafil base.

In another embodiment of the present invention, a compound formula (III)

Formula (III)

In another embodiment of the present invention, compound of formula (I),

containing an amount of a compound of formula (III)

lower than 0.15%.
The invention will be further described with reference to the following non limiting examples.

EXAMPLE-1: Preparation of 2-Butyrylaminopropionic acid
Charged process water (500 ml), Sodium hydroxide (89.6 gm), DL-Alanine (100 gm) and Acetone (250 ml) into round bottom flask and cooled the reaction mass to 3 ± 3°C. Added slowly Butyryl chloride (131.26 gm) into reaction mass and stirred reaction mass for 3-4 hrs at 3 ± 3°C.After completion of the reaction distilled out Acetone and charged Process water (200 ml) and conc. Hydrochloric acid (~ 80 ml). Extracted product in Ethyl acetate and then removed solvent. Crystallized product in cyclohexane and then again recrystallised in ethyl acetate.

EXAMPLE-2: Preparation of 2-(2-Ethoxy-phenyl)-5-methyl-7-propyl-3H- imidazo [5, 1-f] [1, 2, 4] triazin-4-one
Charged Toluene (400 ml), 2-Butyrylaminopropionic acid (100 g), pyridine (150 ml) and Dimethyl amino pyridine (2.5 g) in the round bottom flask. Slowly charged Ethyl oxalyl chloride (171.5 g) into the reaction mass and stirred it for 3-4 hr at 67 ± 3°C. After completion of the reaction cooled the reaction mass to room temperature and filtered the solid. Filterate was washed with water and then solvent was removed. Charged methanol (400 ml) into the residue and Sodium bicarbonate (39.58 gm). Heated reaction mass to 67 ± 3°C for 2-3 hrs. Filtered the solid and removed the solvent from the filterate. Charged IPA (300 ml) into residue and stirred below 45 °C give solution 1.
In another flask charged Methanol (400 ml), 2-Ethoxybenzamidine Hydrochloride (100.84 gm) and cooled the reaction mass to 3 ± 3°C. Added Hydrazine hydrate (37.70 gm) slowly in 20-30 min at 3 ± 3°C and stirred the reaction mass for 3-4 hrs at 20 ± 3°C. Charged Sodium bicarbonate (29.55 gm) into the reaction mass at 20 ± 3°C and then distilled out the solvent completely. Charged IPA (300 ml) into the residue and filtered the solid. Filterate was heated to 77 ± 3°C and then slowly charged previously prepared solution 1. Stirred reaction mass for 4-5 hrs at 77 ± 3°C. After completion of the reaction filtered the solid and then removed solvent from the filterate. Charged Dichloromethane (300 ml) in to residue and washed organic layer with water. Removed solvent and then charged Acetic acid (400 ml) and phosphorous oxychloride (192.64 gm) in the residue and heated to 82 ± 3°C for 5-6 hr. After completion of the reaction added chilled water (500 ml). Product was extracted in Toluene and then removed solvent. Product was crystallized in Ethyl acetate. Product was recrystalised in acetonitrile and water.

EXAMPLE-3: Preparation of crystalline form A of Vardenafil base
Charged Chloro sulphonic acid (200 ml), Thionyl chloride (50 ml) and 2-(2-Ethoxy-phenyl)-5 methyl-7-propyl-3H- imidazo [5, 1-f] [1, 2, 4] triazin-4-one in MDC (100 gm in 500 ml) in round bottom flask. Heated it to 45 ± 3°C for 1 hr. After completion of the reaction charged process water (300 ml) and extracted product in organic layer. Separated organic layer and added Sodium bi carbonate (120 gm) and then added N-Ethyl piperazine (43.84 gm) into the reaction mass during 30-40 min at 17 ± 3°C. Heated reaction mass to 42 ± 3°C for 1 hr. After completion of the reaction filtered the solid. Filterate was washed with water and then distilled out solvent completely.
Charged Acetone (700 ml) and water (210 ml) into residual mass water below 40° C. The reaction mixture was heated to 55-60° C. The reaction mass was cooled to 4-10° C. The solid was filtered and washed with 100 ml of acetone. The material was dried at 40° C under vacuum for 2 hours to give crystalline Form II of vardenafil free base.

EXAMPLE-4: Preparation of Vardenafil Hydrochloride Trihydrate
Charged Acetone (277 ml), D.M.Water (23 ml) and vardenafil base(100 gm) in round bottom flask. Heated reaction mass to 52 ± 3°C and added Con.HCl (20.3 ml) during 10-15 min at 52 ± 3°C. Stirred reaction mass for 50-60 minutes at 52 ± 3°C. Cooled reaction mass to 7 ± 3°C for 30 min. Filtered the solid and washed wet cake with Chilled Acetone (50 ml) which is again recrystalised with acetone-water to get pure Vardenafil Hydrochloride Trihydrate.