POLYMORPHIC FORM OF VARDENAFIL
INTRODUCTION TO THE INVENTION
The present invention relates to crystalline Form II of vardenafil and a process for its preparation.
Chemically vardenafil hydrochloride is piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-T-propylimidazotSJ-fltl^^ltriazin^-ylH-ethoxyphenyllsulfonyll^-ethyl-, mono-hydrochloride and can be structurally represented by 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. Patent 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. Vardenafil produced as per Example 19 is hereinafter referred as "crystalline Form I" of vardenafil. 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.
Vardenafil is key intermediate in 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 provides polymorphic forms of vardenafil and processes for their preparation, which are easily scaleable and commercially viable.
SUMMARY OF THE INVENTION
The present invention relates to crystalline Form II of vardenafil and a process for its preparation.
One aspect of the invention provides crystalline Form II of vardenafil characterized by its X-ray powder diffraction (XRPD) pattern, infrared absorption

spectrum (IR), differential scanning calorimetry (DSC) curve, and thermogravimetric analysis (TGA) curve.
Another aspect of the invention provides a process for the preparation of the crystalline Form II of vardenafil free base comprising the steps of:
a) providing a solution of vardenafil in a suitable solvent;
b) crystallizing the solid from the solution; and
c) recovering crystalline Form II of vardenafil free base.
Still another aspect of the invention provides a pharmaceutical composition comprising vardenafil Form II prepared in accordance with this invention along with one or more pharmaceutical^ acceptable carriers, excipients or diluents.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an XRPD pattern of crystalline Form II of vardenafil prepared in Example 1.
Fig. 2 is an IR spectrum of crystalline Form II of vardenafil prepared in Example 1.
Fig. 3 is a DSC curve of crystalline Form II of vardenafil prepared in Example 1.
Fig. 4 is a TGA curve of crystalline Form II of vardenafil prepared in Example 1.
DETAILED DESCRIPTION OF THE INVENTION One aspect of the invention provides crystalline Form II of vardenafil characterized by its X-ray powder diffraction pattern (XRPD), infrared absorption spectrum (IR), differential scanning calorimetry (DSC) curve, and thermogravimetric analysis (TGA) curve.
Crystalline Form II of vardenafil is characterized by its XRPD pattern, which differs from crystalline Form I of vardenafil described in the prior art. The XRPD data reported herein were obtained using Cu Ka radiation, having the wavelength 1.541 A, and was measured on a Bruker Axe, D8 Advance Powder X-ray Diffractometer. The crystalline Form II of vardenafil is characterized by its XRPD pattern substantially in accordance with the pattern of Fig. 1. The crystalline Form II of vardenafil is also characterized by an XRPD pattern having significant peaks at about

16.4, 11.2, 15.8, 13.8, 7.8, 9.1, 17.3, 17.6, 18.3, 23.7, 24.2, 24.3, 24.6, 25.5, and 12.3, ± 0.2 degrees 20. It is also characterized by additional XRPD peaks at about 18.5, 19.9, 20.2, 21.1, 21.3, and 22.9, ± 0.2 degrees 20.
The comparison of 20 values (in degrees) and % intensity between crystalline Form I and Form II of vardenafil free base is given in the following table.

The infrared spectra of the crystalline Form II of vardenafil has been recorded on Perkin Elmer System 200 FT-IR spectrophotometers, between 400 cm*1 and 4000 cm'1, with a resolution of 4 cm*1, in a potassium bromide pellet, the test compound being at the concentration of 0.5% by mass.
The crystalline Form II of vardenafil is characterized by an infrared absorption spectrum comprising peaks at about 583, 737, 956, 1114, 1169, 1151, 1345, 1625, 1701, and 3274, ± 5 cm*1. The crystalline Form II of vardenafil is also characterized by an infrared absorption spectrum substantially in accordance with the spectrum of Fig. 2.
The crystalline Form II of vardenafil is still further characterized by a differential scanning calorimetry curve substantially in accordance with the curve of Fig. 3. The Crystalline Form II of vardenafil is also characterized by a DSC curve having an endotherm at about 193 °C.

The Crystalline Form II of vardenafil is yet further characterized by a thermogravimetric analysis curve substantially in accordance with the "DTA" curve of Fig. 4.
Another aspect of the invention provides a process for the preparation of the crystalline Form II of vardenafil free base.
In an embodiment, the process for the preparation of crystalline Form II of vardenafil free base comprises;
a) providing a solution of vardenafil in a suitable solvent;
b) crystallizing the solid from the solution; and
c) recovering crystalline Form II of vardenafil free base. Step a) involves providing a solution of vardenafil.
Vardenafil for the purpose of dissolution can be obtained by any of the process described in the prior art.
The solution of vardenafil may be obtained by dissolving vardenafil in a suitable solvent, or such a solution may be obtained directly from a reaction in which vardenafil is formed.
When the solution is prepared by dissolving vardenafil in a suitable solvent, any form of vardenafil such as the crystalline or amorphous form, including any salts, solvates and hydrates may be utilized for preparing the solution.
Suitable solvents which can be used for dissolving vardenafil include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; or mixtures thereof or their combinations with water in various proportions.
The dissolution temperatures can range from about 20 to 120° C depending on the solvent used for dissolution. Any other temperature is also acceptable as long as a clear solution of vardenafil is provided.
The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted. The concentration of vardenafil in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.

Optionally, the solution obtained above can be filtered to remove any undissolved particles.
The undissolved particles can be removed suitably by filtration, centrifugation, decantation, and other techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step b) involves crystallizing the solid from the solution.
For crystallization to occur, the solution obtained in step a) may be maintained further at temperatures lower than the solution formation or concentration temperatures, such as for example below about 10° C to about 25° C, for a period of time as required for a more complete isolation of the product. The exact cooling temperature and time required for complete isolation can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
Optionally isolation may be enhanced by methods such as cooling, partial removal of the solvent from the mixture, by adding an anti-solvent to the reaction mixture or a combination thereof.
Optionally, small amounts of seeding crystals of vardenafil crystalline Form II may be added to the reaction mixture. Suitably, small amounts are about 1 to 20 weight %, more preferably about 5 weight %. Seeding crystals may be added before or, where appropriate, after the step initiating the precipitation.
Step c) involves recovering crystalline Form II of vardenafil free base.
The crystalline Form II of vardenafil can be recovered from the reaction mass using techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated can carry a small proportion of occluded mother liquor. If desired, the crystals can be washed on the filter with a solvent.
Optionally, the wet solid obtained can be dried. Drying can be carried out at reduced pressures, such as below 200 mm Hg or below 50 mm Hg, at temperatures of about 50° C to about 80° C. The drying can be carried out for any desired or required

time periods, such as for example about 1 to 20 hours being suitable for preparing some products.
Yet another aspect of the present invention provides an alternate process for the preparation of vardenafil, which is then converted insitu into crystalline Form II.
In an embodiment, the process for the preparation of vardenafil comprises the steps of:
a)reacting 2-(2-ethoxyphenyl)-5-methyl-7-propyI-3HHmidazot5,1 -f][1,2,4]-triazin-4-one of Formula II with an sulfonic acid optionally in the presence of a solvent to get 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3, 4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride of Formula III;

b) reacting 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3, 4-dihydroimidazo[5, 1 f][1,2,4]triazin-2-yl)benzenesulfonyl chloride of Formula III with N-ethylpiperazine in the presence of a suitable solvent to get vardenafil of Formula I; Suitably step a) is carried out insitu to avoid isolation of the chlorinated product.
Step a) involves reacting 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one of Formula II with an sulphonic acid in the presence or absence of any additional solvent to get 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3, 4-dihydroimidazo[5, 1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride of Formula III;
Suitable sulfonic acids which can be used for conducting the above reaction include, but are not limited to chlorsulfonic acid, sulphuric acid, and the like.
When the reaction is conducted in the presence of solvent, suitable solvents which can be used include, but are not limited to alcoholic solvents such as methanol, ethanol, propanol, butanol, and the like; ketonic solvents such as acetone, ethyl methyl ketone tert-butyl ketone and the like; nitrile solvents such as acetonitrile, dimethyl

formamide, triethylamine and the like; esters such as ethyl acetate, n-butyl acetate, t-butyl acetate, and the like; hydrocarbon solvents such as toluene, xylene, and the like.
Suitable temperatures for conducting the reaction range form about -10 °C to about 50 °C.
After the reaction completion, the reaction mass can directly be used for the next stage, or the product can suitably be extracted into a solvent in which the next stage reaction is to be conducted.
Suitable solvents which can be used for extracting the product include, but are not limited to chlorinated solvents like halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like.
Step b) involves reacting 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3, 4-dihydroimidazo[5, 1 f][1,2,4]triazin-2-yl)benzenesulfonyI chloride of Formula III with N-ethylpiperazine in the presence of a suitable solvent to get vardenafil of Formula I;
Suitable solvents which can be used for conducting the reaction include, but are not limited to halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like.
Suitable temperature for conducting the reaction range from about 20 °C to about 120 °C.
Vardenafil obtained from step b) is suitably dissolved in a solvent or a combination of solvents and isolated to get crystalline Form II of vardenafil.
Vardenafil Form II obtained above can be suitably converted to its pharmaceutical^ acceptable salts by processes known in the art.
Vardenafil is capable of forming a wide variety of mono or di-acid salts with various inorganic and organic acids. The acids that may be used include, but are not limited to those that form anions like acetate, benzoate, bicarbonate, bitartarate, citrate, iodide, chloride, bromide, mesylate, tartarate, inorganic acids like hydrochloric acid, hydrobromic acid, and the like.
Still another aspect of the invention provides a pharmaceutical composition comprising vardenafil Form II prepared in accordance with this invention along with one or more pharmaceutical^ acceptable carriers, excipients or diluents.

The pharmaceutical composition comprising vardenafil or its pharmaceutical^ acceptable salts of the invention along with one or more pharmaceutical^ acceptable carriers may further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that

are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
In the compositions of the present invention crystalline Form II of vardenafil is a useful active ingredient when present in the range of 0.5 mg to 50 mg, or 1 mg to 25 mg.
Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which examples are not intended to limit the scope of the appended claims in any manner.
EXAMPLE 1
PREPARATION OF CRYSTALLINE FORM II OF VARDENAFIL FREE BASE
14.0 g of vardenafil was charged into a four neck round bottom flask containing 70 ml of isopropyl alcohol and heated to about 82 °C. An additional 70 ml of isopropyl alcohol was added slowly to get complete dissolution. The undissolved solid particles were filtered through a perlite bed to get a particle free solution. The filtrate was charged into a clean round bottom flask and was allowed to cool to 20 °C for crystallization. The solid was filtered and washed with 10 ml of isopropyl alcohol. The material was dried at 44°C under vacuum for 2 hours to give 12.6 g (90% yield) of crystalline Form II of vardenafil free base.
EXAMPLE 2 PREPARATION OF THE CRYSTALLINE FORM II OF VARDENAFIL FREE BASE
28 ml of chloro sulphonic acid was charged into a round bottom flask and cooled to about 0-5° C. 14 g of 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5l1-f][1,2,4]-triazin-4-one was added to it at about 2 °C. The temperature was raised to about 22 °C and maintained for about 45 minutes. The reaction mixture was slowly quenched into ice. 350 ml of dichloromethane was added and stirred for 25 minutes and then 150 ml of water was added and stirred for 10 minutes and the organic and aqueous layers were separated. The organic layer was charged into a round bottom flask and cooled to -3 °C. 10.4 ml of N-Ethyl piperazine diluted with 15 ml of dichloromethane was added at about -3 °C. The temperature was raised to about 25 °C and maintained for 45 minutes.

The reaction mixture was washed with 140 ml of water in two equal lots. The organic layer was completely distilled off at 41 °C and a vacuum of 300 mm Hg and then 98 ml of 4% aqueous acetone was added to it. The suspension was heated to 55 °C for dissolution. The solution was then cooled to about 2 °C and maintained for about 60 minutes for crystallization. The solid was filtered under vacuum and washed with 14 ml of pre-cooled 4% aqueous acetone solution. The solid was dried at 48 °C for about 3 hours to afford 11.8 g of the desired crystalline Form II of vardenafil free base.

We Claim:
1. A compound that is crystalline Form II of vardenafil.
2. The compound of claim 1, which is characterized by its X-ray powder diffraction pattern using Cu Ka radiation comprising peaks at about 16.4, 15.8,11.2, 9.1, 18.5, 21.1 and 17.6 ± 0.2 degrees 20; an infrared absorption spectrum comprising peaks at about 583, 737, 956, 1114, 1169, 1151, 1345, 1625, 1701, and 3274, ± 5 cm"1; and DSC curve having an endotherm at about 193 °C.
3. A process for preparing crystalline Form II of vardenafil comprising crystallizing vardenafil from a solvent.

4. The process of claim 3, wherein the solvent is an organic solvent or its aqueous mixture.
5. The process of claim 4, wherein the organic solvent is isopropanol.

6. The process of claim 4, wherein the organic solvent is aqueous acetone.
7. A process for preparing vardenafil, comprising reacting 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one with chlorosulfonic acid, extracting an intermediate with dichloromethane, and reacting the intermediate with N-ethylpiperazine.
8. A pharmaceutical composition comprising crystalline Form II of vardenafil along
with one or more pharmaceutical^ acceptable carriers, excipients or diluents.
9. A process for the preparation of pharmaceutical^ acceptable salt of vardenafil
comprising reaction of vardenafil crystalline form II with a suitable acid.
10. The process of claim 9 wherein the acid is hydrochloric acid.