The present invention relates to novel hydrate of irbesartan, amorphous irbesartan hydrate and pharmaceutical compositions containing them. The present invention also relates to novel processes for preparing crystalline form-A, crystalline form-B and amorphous form of irbesartan.
BACKGROUND OF THE INVENTION
Irbesartan or 2-Butyl-3-[[2'-(1 H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-dia2aspiro[4.4]non-1-en-4-one, which has the formula (1):

is a non-peptide angiotensin II - receptor antagonist.
The therapeutic uses of irbesartan and related compounds and their preparations are disclosed in U.S. Patent No, 5,270,317. The processes for preparation of irbesartan are described in J. Med. Chem. 1993, 36, 3371-3380.
U.S, Patent No. 5,629,331 discloses two crystalline polymorphic forms, Form-A and Form-B of irbesartan, process for their preparation and the use of the crystalline form-B for the treatment of hypertension,
WO patent application publication No. 03/050110 discloses amorphous form of irbesartan.
WO patent application publication No. 99/67236 discloses a modified crystalline habit of the form-A of irbesartan, process for its preparation and a composition containing it.

Amorphous forms of pharmaceutical products are usually known to have better dissolution properties than their crystalline forms. It can be formulated to a pharmaceutical composition having good dissolution properties.
We have discovered hydrate of irbesartan and the irbesartan hydrate in sufficiently stable amorphous form suitable for pharmaceutical compositions. So, amorphous form of irbesartan hydrate can be utilized to prepare stable pharmaceutical dosage forms having good dissolution properties.
The present invention also provides novel processes for the preparations of crystalline form-A, crystalline form-B and amorphous form of irbesartan.
One object of the present invention is to provide irbesartan hydrate, amorphous irbesartan hydrate and pharmaceutical compositions comprising them. Another object of the present invention is to provide novel processes for the preparations of irbesartan form-A, irbesartan form-B and amorphous irbesartan.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided a novel hydrate of irbesartan. The water content of the hydrate of irbesartan is between about 2.0 and 5.0% by weight of hydrate of irbesartan, typically between about 3.0 and 4.5% by weight of hydrate of irbesartan.
According to another aspect of the present invention, there is provided amorphous form of irbesartan hydrate, which is characterized by having broad x-ray diffraction spectrum as in figure 1.
According to another aspect of the present invention, a process is provided for preparation of irbesartan hydrate. Irbesartan hydrate is prepared by a process, which comprises precipitating irbesartan from water in a pH range about 2.0 to 5.5 at below about 20°C.
In the process irbesartan used may be in amorphous form, crystalline form-A or crystalline form-B for obtaining irbesartan hydrate.
Preferably irbesartan hydrate is prepared by precipitating irbesartan from water in a pH range about 4.0 to 5.5 between about 15°C and 0°C, more preferably in a pH range about 4.5 to 5.5 between about 10°C and 0°C.
Precipitation may preferentially be carried out by adjusting pH of an alkaline aqueous solution of irbesartan with an acid to about 4.0 to 5.5 and

precipitating the product from the solution at below about 20°C. The acid used for pH adjustment may be a mineral acid such as hydrochloric acid, sufuric acid, phosphoric acid or an organic acid such as trifluro acetic acid.
The alkaline aqueous solution of irbesartan may be prepared by dissolving an alkaline salt, preferably sodium or potassium salt, of irbesartan in water.
The alkaline aqueous solutions may be obtained as a reaction mixture in the synthesis of irbesartan as described in for example, U.S. Patent No. 5,270,317 or U.S. Patent No. 5.629,331. In such a case the isolation of irbesartan as hydrate provides a method of purification as the product obtained is in high chromatographic purity, having above about 93%, usually above about 95%.
The precipitation may be initiated by a method usually known in the art such as cooling, seeding, partial removal of the solvent from the solution or a combination thereof.
The precipitated product may be collected by filtration or centrifugation and dried to obtain hydrate of irbesartan.
The present invention also provides a pharmaceutical composition comprising the novel irbesartan hydrate and a pharmaceutically acceptable carrier, diluent, excipient, additive, filler, lubricant, binder, stabilizer or solvent.
Irbesartan in amorphous form may also be used in the composition.
The pharmaceutical composition may be in a form normally employed, such as tablets, capsules, lozenges, powders, syrups, solutions, suspensions, ointments, dragees and the like, may contain flavourants, sweetners, etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from about 1 to 25%, preferably about 1 to 15% by weight of active ingredient, the remainder of composition being one or more of a pharmaceutically acceptable carrier, diluent, excipient, additive, filler, lubricant, binder, stabilizer or solvent.
According to another aspect of the present invention, a process is provided for preparing amorphous irbesartan. Amorphous irbesartan is prepared by a process, which comprises slurrying amorphous irbesartan hydrate for sufficient time in a solvent; filtering or centrifuging; and drying to obtain amorphous irbesartan.

Preferable solvent is selected from alcohols such as ethanoi, methanol, isopropyl alcohol and tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone. More preferable alcohol is ethanoi and more preferable ketone is acetone.
Preferably, amorphous irbesartan is prepared by slurrying amophous irbesartan hydrate in a solvent such as ethanoi for about 30 minutes to 10 hours, preferably for about 30 minutes to 3 hours, at above about 10°C, preferably at about 20°C " 50°C; filtering or centrifuging; and drying to obtain amorphous irbesartan.
Irbesartan crystalline form-A is known and characterized by an x-ray powder diffraction spectrum having peaks expressed as 20 at about 4.7, 12.5, 13.3, 17.0, 19.4, 20.1, 20.6, 21.1, 21.7, 22.6, 23.2 and 23.7 degrees. Figure 2 shows typical form-A x-ray powder diffraction spectrum.
U.S. Patent No. 5,629,331 describes a process for preparing form-A, according to which form-A is prepared by crystallizing irbesartan from a siolvent containing less than 10% in volume of water.
According to another aspect of the present invention, a novel process is provided for preparation of irbesartan form-A. Irbesartan form-A is prepared by a process, which comprises crystallizing irbesartan from a solvent containing water under a condition that allows slow crystallization.
In the process irbesartan used may be in amorphous or crystalline form-B; or it can be irbesartan hydrate described above according to the present invention for obtaining c'7Stalline form-A.
Slow crystallization refers to crystallization in not less than about 1 hour, preferably in not less than about 2 hours.
Under these conditions quantity of water is not critical and form-A can be obtained by using a solvent containing even 10% or above by volume of water.
Preferable solvent is selected from alcohols such as ethanoi, methanol, isopropyl alcohol and tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone; ethers such as tert-butyl methyl ether, diethyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile; and a mixture thereof. More preferably, alcohol is ethanoi or methanol; ketone is acetone; ether is tetrahydrofuran or dioxane.

The condition required for slow crystallization depends among others on the solvent used, volunne of solvent and the volume of water and temperature at which crystallization occurs.
Thus, for example, crystallization of irbesartan from ethanol containing about 15 to 35% in volume of water requires about 2 to 20 hours at about 20°C -30°C.
Crystallization may be initiated by a method usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
Preferable anti-solvents are n-hexane, cyclohexane, toluene and xylene, more preferable anti-solvent is cyclohexane. The mixture of anti-solvents may also be used.
According to another aspect of the present invention, an another process is provided for preparation of irbesartan form-A. Irbesartan form-A is prepared by a process, which comprises crystallizing irbesartan from a solvent containing water in the presence of a carboxylic acid.
Preferably the water content in the solvent is about 1 - 50% by volume of the solvent, more preferably about 5 - 40% by volume of the solvent.
Preferable solvent is selected from alcohols such as ethanol, methanol, isopropyl alcohol and tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone; ethers such as tert-butyl methyl ether, diethyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile; and a mixture thereof. More preferably, alcohol is ethanol or methanol; ketone is acetone; ether is tetrahydrofuran or dioxane.
Preferable carboxylic acid is formic acid, acetic acid or propionic acid; or a mixture thereof. More preferable carboxylic acid is acetic acid.
The solution of irbesartan used in the process may be obtained by dissolving irbesartan in the solvent containing water and carboxylic acid.
Crystallization may be initiated by a method usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
Preferable anti-solvents are n-hexane, cyclohexane, toluene and xylene, more preferable anti-solvents is cyclohexane. The mixture of anti-solvents may also be used.

Irbesartan crystalline form-B is known and characterized by an x-ray powder diffraction spectrum having peaks expressed as 2G at about 7.9, 11.9, 14.3, 16.0, 16.5, 17.7, 18.6, 19.4, 19.9, 21.3, 22.6, 23.8, 25.3 and 26.3 degrees. Figure 3 shows typical form-B x-ray powder diffraction spectrum.
U.S. Patent No, 5,629,331 describes a process for preparing form-B, according to which form-B is prepared by crystallizing irbesartan from a solvent containing more than 10% in volume of water. According to U.S. Patent No. 5,629,331, the presence of water is essential for obtaining form-B.
According to another aspect of the present invention, a novel process is provided for preparation of irbesartan form-B. Irbesartan form-B is prepared by a process, which comprises crystallizing irbesartan from dimethyl sulfoxide solvent.
We have discovered that when dimethyl sulfoxide is used as a solvent the presence of water is not essential for obtaining form-B.
Preferably irbesartan form-B is prepared by dissolving irbesartan in dimethyl sulfoxide and crystallizing from the solvent.
In the process irbesartan used may be in amorphous or crystalline form-A; or it may be irbesartan hydrate described above according to the present invention for obtaining crystalline form-B.
Crystallization may be initiated by a method usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
Preferable anti-solvents are cyclohexane, xylene, toluene and n-hexane, more preferable anti-solvents are cyclohexane and xylene. The mixture of anti-solvents may also be used.
According to preferred process, irbesartan is dissolved in dimethyl sulfoxide, crystallized by adding cyclohexane to the solution, collecting the solid precipitated to obtained irbesartan crystalline form-B.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction spectrum of amorphous form of irbesartan hydrate.
Figure 2 is a x-ray powder diffraction spectrum of irbesartan form-A. Figure 3 is a x-ray powder diffraction spectrum of irbesartan form-B.

Figure 4 is a x-ray powder diffraction spectrum of amorphous form of irbesartan.
x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-Ka radiation.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention.
Example 1
2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one hydrochloride (200 gm) is added to 10% sodium carbonate solution (150 ml) and methylene chloride (1000 ml) and stirred for 30 minutes. Layers are separated, the organic layer is washed with water and the solvent is distilled off to obtained a residue.
To the residue is added acetone (1000 ml), potassium carbonate (250 gm) and 4-bromomethyl-2-cyanobiphenyl (240 gm) and the contents are refluxed for 5 hours. The solvent is distilled off, water (1000 ml) is added, stirred for 4 hours and filtered to obtain 260 gm of 1-[(2-cyanobiphenyl-4-yl)methyl]-2-n-butyt-4-spirocyclopentane-2-imidazolin-5-one.
Sodium azide (135 gm), tributyltin chloride (650 gm) and 1-[(2-cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one obtained above are added to xylene (2000 ml), refluxed for 15 hours and filtered. The filtrate is distilled to obtain a residue. The residue is stirred with water (2 I) for 15 minutes and pH is adjusted with 10% sodium hydroxide solution to 10.5 to 11.2. The solution is washed with methylene chloride (1.5 I) and cooled to 5°C -10°C. The pH is adjusted to 4.8 with 10% hydrochloric acid solution. The separated solid is filtered, washed with chilled water (500 ml) and dried at 50°C to 55°C for 4 hours to give 230 gm of amorphous irbesartan hydrate (Moisture content: 3.8, HPLC purity: 98.2%)
Example 2 Irbesartan form-A (50 gm) and water (500 ml) are stirred for 15 minutes, cooled to 5°C and pH is adjusted to 10.5 to 11 with 10% sodium hydroxide solution for 45 minutes at 5°C to 10°C. The contents are stirred for 3 hours at

5°C to 10°C and the resulting solution is washed with methylene chloride (350 ml). The aqueous solution is cooled to 5°C and the pH is adjusted to 5.0 with 10% HCI solution for 20 minutes at 5°C to 10°C. Then the separated solid is filtered, washed with chilled water (800 ml) and dried at 50°C to 55°C for 3 hours to give 38 gm of amorphous irbesartan hydrate (Moisture content: 3.5%, HPLC purity: 99.3%).
Example 3 Irbesartan hydrate (100 gm) is stirred with water (500 ml) and ethanol (2000 ml) for 10 to 15 minutes at 25°C to 30°C, heated to 50°C to 55°C to form a clear solution and then stirred for 5 minutes at 50°C to 55°C. The reaction mass is slowly cooled to 25°C to 30°C and the solid separation is observed after 4 hours. The reaction mass is maintained for 12 hours more. The separated solid is filtered, washed with water (300 ml) and dried for 5 hours under vacuum at 60°C to 65°C to give 75 gm of irbesartan form-A (HPLC purity: 99.89%)
Example 4 The mixture of irbesartan form-B (10 gm), ethyl alcohol (200 ml) and water (50 ml) is stirred for 10 minutes at 25°C to 30°C, acetic acid (4 ml) is added drop wise for 10 minutes and stirred for 15 minutes at 25°C to 30°C. Then the reaction mass is heated to 90°C and stirred for 10 minutes at 85°C to 90°C to form a clear solution. The reaction mass is then cooled to 25°C to 30°C, stirred for 1 hour at the same temperature, then cooled to 5°C and stirred for 1 hour 30 minutes at 5°C to 10°C. Then the separated solid is filtered, washed with water (30 ml) and dried to give 9 gm of irbesartan form-A.
Example 5 Irbesartan form-A (10 gm) is dissolved in dimethyl sulfoxide (70 ml) at 25°C to 30°C and stirred for 2 hours 30 minutes at the same temperature. Then cyclohexane (20 ml) is added drop wise for 10 minutes to the reaction mass and stirred for 14 hours at 25°C to 30°C. The separated solid is filtered and dried at below 65°C under vacuum for 5 hours 30 minutes to give 8 gm of Irbesartan form-B (Moisture content: 0.49%).

Example 6 The mixture of amorphous irbesartan hydrate (10 gm, Moisture content: 3,5%) and ethanol (50 ml) is heated to 45°C - 50°C and stirred for 1 hour at 45°C - 50°C. Then, the contents are cooled to 10°C - 15°C, filtered and dried at 50°C -55°C for 4 hours to give 9.2 gm amorphous irbesartan.

We claim:
1. Irbesartan hydrate.
2. Irbesartan hydrate of claim 1, wherein water content of the hydrate of irbesartan is between about 2.0 and 5.0% by weight of hydrate of irbesartan.
3. Irbesartan hydrate of claim 2, wherein water content of the hydrate of irbesartan is between about 3.0 and 4.5% by weight of hydrate of irbesartan.
4. A process for preparation of irbesartan hydrate of claim 1, which comprises precipitating irbesartan from water in a pH range about 2.0 to 5.5 below about 20°C.
Z. The process according to claim 4, wherein the irbesartan hydrate is prepared by precipitating irbesartan from water in a pH range about 4.0 to 5.5 between about 15°C and O°C.
6. The process according to claim 5, wherein the irbesartan hydrate is prepared by precipitating irbesartan from water between about 10°C and O°C.
7. The process according to claim 4, which further comprises adjusting pH of an alkaline aqueous solution of irbesartan with an acid to about 4.0 to 5.5 before precipitation in claim 4.
8. The process according to claim 7, which further comprises the alkaline aqueous solution of irbesartan is prepared by dissolving an alkaline salt of irbesartan in water.
9. The process according to claim 8, wherein the alkaline salt of irbesartan is sodium or potassium salt of irbesartan.
10. The process according to claim 4, wherein the precipitation is initiated by cooling, seeding, partial removal of the solvent from the solution or a combination thereof.
11. The process according to claim 4, which further comprises collecting the precipitated product by filtration or centrifugation; and drying to obtain hydrate of irbesartan.
12. Amorphous irbesartan hydrate.
13. Amorphous irbesartan hydrate of claim 12 characterized by a x-ray powder diffraction spectrum as in figure 1.
14. A process according to claim 4, wherein the product obtained is amorphous irbesartan hydrate of claim 12.

15. A pharmaceutical composition comprising an irbesartan hydrate of claim 1 and a pharmaceutically acceptable carrier, diluent, excipient, additive, filler, lubricant, binder, stabilizer or solvent.
10. A pharmaceutical composition comprising an amorphous form of irbesartan hydrate of claim 12 and a pharmaceutically acceptable carrier, diluent, excipient, additive, filler, lubricant, binder, stabilizer or solvent.
17. A process for the preparation of irbesartan form-A, characterized by an x-ray powder diffraction spectrum having peaks expressed as 26 at about 4.7, 12.5, 13.3. 17.0, 19.4. 20.1, 20.6, 21.1, 21.7, 22.6, 23.2 and 23.7 degrees, which comprises crystallizing irbesartan from a solvent containing water under a condition that allows slow crystallization.
18. The process according to claim 17, wherein the crystallization occurs in not less than about 2 hours.
19. The process according to claim 17, wherein the solvent is selected from alcohols, ketones, ethers and nitriles; and a mixture thereof.
20. The process according to claim 19, wherein the alcohols are selected from ethanol, methanol, isopropyl alcohol and tert-butyl alcohol; ketones are selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone; ethers are selected from tert-butyl methyl ether, diethyl ether, tetrahydrofuran and dioxane; nitrile is acetonitrile.
21. The process according to claim 20, wherein alcohol is ethanol or methanol, ketone is acetone and ether is tetrahydrofuran or dioxane.
22. The process according to claim 17, wherein the crystallization is carried out in ethanol containing about 15 to 35% in volume of water at about 20°C to 30°C.
23. The process according to claims 17 and 22, wherein the crystallization is initiated by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
24. The process according to claim 23, wherein the anti-solvent is selected from n-hexane, cyclohexane, toluene and xylene; and a mixture thereof.
25. A process for preparation of form-A, characterized by an x-ray powder diffraction spectrum having peaks expressed as 29 at about 4.7, 12.5, 13.3, 17.0, 19.4, 20.1, 20.6, 21.1, 21.7, 22.6, 23.2 and 23.7 degrees, which

comprises crystallizing irbesartan from a solvent containing water in the presence of a carboxylic acid.
26. The process according to claim 25, wherein the water content in the solvent is about 1 to 50% by volume of the solvent.
27. The process according to claim 26, wherein the water content in the solvent is about 5 to 40% by volume of the solvent.
28. The process according to claim 25, wherein the solvent is selected from alcohols, ketones, ethers and nitriles; and a mixture thereof.
29. The process according to claim 28, wherein the alcohols are selected from ethanol, methanol, isopropyl alcohol and tert-butyl alcohol; ketones are selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone; ethers are selected from tert-butyl methyl ether, diethyl ether, tetrahydrofuran and dioxane; nitrile is acetonitrile.
30. The process according to claim 29, wherein alcohol is ethanol or methanol, ketone is acetone and ether is tetrahydrofuran or dioxane.
31. The process according to claim 25, wherein the carboxylic acid is selected from formic acid, acetic acid and propionic acid; and a mixture thereof.
32. The process according to claim 31, wherein the carboxylic acid is acetic acid.
33. The process according to claim 26, wherein the crystallization is initiated by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
34. The process according to claim 33, wherein the anti-solvent is selected from n-hexane, cyclohexane, toluene and xylene; and a mixture thereof.
35. A process for the preparation of irbesartan form-B, characterized by an x-ray powder diffraction spectrum having peaks expressed as 20 at about 7.9, 11.9, 14.3, 16.0, 16.5, 17.7, 18.6. 19.4, 19.9,21.3,22.6, 23.8, 25.3 and 26.3 degrees, which comprises crystallizing irbesartan from dimethyl sulfoxide solvent.
36. The process according to claim 35, wherein the crystallization is initiated by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
37. The process according to claim 36, wherein the anti-solvent is selected from n-hexane, cyclohexane, toluene and xylene; and a mixture thereof.

38. The process according to claim 37, wherein the anti-solvents are cyclohexane and xylene,
39. The process according to claim 14, which further comprises slurrying the product obtained in claim 14 in a solvent; filtering or centrifuging; and drying to obtain amorphous irbesartan.
40. The process according to claim 39, wherein the solvent is selected from alcohols and ketones.
41. The process according to claim 40, wherein the alcohols are selected from ethanol, methanol, isopropyl alcohol and tert-butyl alcohol; ketones are selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone.
42. The process according to claim 41, wherein the alcohol is ethanol.
43. The process according to claim 39, wherein amorphous irbesartan is prepared by slurrying amophous irbesartan hydrate in a solvent for about 30 minutes to 10 hours, at above about 10°C; filtering or centrifuging; and drying to obtain amorphous irbesartan.
44. The process according to claim 43, wherein amorphous irbesartan is prepared by slurrying amophous irbesartan hydrate in a solvent for about 30 minutes to 3 hours, at about 20°C - 50°C; filtering or centrifuging; and drying to obtain amorphous irbesartan.
45. The process according to claim 44, wherein the solvent is ethanol.
46. The process according to claim 4, wherein irbesartan used is in form-A, characterized by an x-ray powder diffraction spectrum having peaks expressed as 20 at about 4.7, 12.5, 13.3, 17.0. 19.4, 20.1, 20.6, 21.1, 21.7. 22.6, 23.2 and 23.7 degrees; form-B, characterized by an x-ray powder diffraction spectrum having peaks expressed as 20 at about 7.9, 11.9, 14.3, 16.0, 16.5, 17.7. 18.6, 19.4, 19.9, 21.3, 22.6, 23.8, 25.3 and 26.3 degrees; or amorphous form.
47. The process according to claim 17, wherein irbesartan used is in form-B. characterized by an x-ray powder diffraction spectrum having peaks expressed as 20 at about 7.9. 11.9, 14.3, 16.0, 16.5, 17.7, 18.6, 19.4, 19.9, 21.3, 22.6, 23.8, 25.3 and 26.3 degrees; hydrate of claiml or amorphous form.

48, The process according to claim 25, wherein irbesartan used is in form-B,
characterized by an x-ray powder diffraction spectrum having peaks
expressed as 26 at about 7.9, 11.9, 14.3, 16.0. 16.5, 17.7, 18.6, 19.4, 19.9,
21.3, 22,6, 23.8, 25.3 and 26.3 degrees; hydrate of claim 1 or amorphous
form.
49. The process according to claim 35, wherein irbesartan used is in form-A,
characterized by an x-ray powder diffraction spectrum having peaks
expressed as 29 at about 47, 12.5, 13.3, 17.0, 19.4, 20.1, 20,6, 21.1, 21.7,
22.6, 23.2 and 23.7 degrees; hydrate of claim 1 or amorphous form.