DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR THE PREPARATION OF PURE AZILSARTAN WITH CONTROLLED PARTICLE SIZE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
KONDAPUR, HITECH CITY,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed.

FIELD OF INVENTION

The present invention relates to a process for the preparation of pure Azilsartan of Formula I.

BACKGROUND OF THE INVENTION
Azilsartan (I) is chemically known as 2-ethoxy-1-{2' (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzo[d]-imidazole-7-carboxylic acid. Azilsartan (I) is a highly selective blocker of angiotensin II ATI receptors and is used for the treatment of high blood pressure. Azilsartan (I) is marketed under brand name Azilva® as tablet.

Azilsartan is a colorless prism when crystallizes from ethyl acetate having melting point at 156º to 157ºC.

Azilsartan medoxomil chemically known as (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2-ethoxy-1-{[2’-(5-oxo-4,5-dihydro-1,2,4-oxodiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate represented by Formula II.

Azilsartan medoxomil is a white to off-white crystalline substance and is marketed under brand name Edarbi® as tablet.

Edarbi (Azilsartan medoxomil), a prodrug, is hydrolyzed to Azilsartan in the gastrointestinal tract during absorption. Azilsartan is a selective AT1 subtype angiotensin II receptor antagonist.

Azilsartan is disclosed in United States patent No. US 5,243,054.

Azilsartan medoxomil and its potassium salt were disclosed in U.S. Pat. No. 7,157,584 ('584 patent).

Solvent medium and mode of crystallization play very important role in pure form of the compound. There are prior-art procedures reported for the crystallization of Azilsartan.

US '054 discloses that Azilsartan is purified by recrystallization from ethyl acetate.

The prior-art process produces Azilsartan with the higher particle size and require size reduction equipment (micronizer, or pin mill or homogenizer or other size reduction technology) to get the fine/controlled particle size leads to higher cost and lower the yield. It can be considered as major disadvantage of the prior-art process as it required additional cost of the operating process during size reduction and leads to loss of yield of the required product.

Hence, there is a need for the preparation of pure Azilsartan with controlled particle size with high purity and yield.

The present invention is directed towards a process for the preparation of pure Azilsartan (I) by crystallization, wherein Azilsartan in a first solvent is optionally subjected partial distillation, followed by adding a second solvent and isolation.

The advantage of the current invention is to produce pure Azilsartan with controlled particle size and high yield without using size reduction equipment.
OBJECTIVE OF INVENTION

The main objective of the present invention is to provide simple and cost effective process for the preparation of pure Azilsartan (I) with controlled particle size, which is industrially viable.

SUMMARY OF THE INVENTION

The main embodiment of the present invention is to provide a process for the preparation of pure Azilsartan (I) with controlled particle size of D90 is less than 60µm, which comprises:
(i) dissolving Azilsartan (I) in a first solvent;
(ii) heating the reaction mass at a suitable temperature;
(iii) optionally, partial distillation of the solvent;
(iv) adding a second solvent; and
(v) isolating pure Azilsartan (I) with controlled particle size of D90 is less than 60µm.

Another embodiment of the present invention is to provide a process for the preparation of pure Azilsartan (I) with controlled particle size of D90 is less than 60µm, which comprises:
(i) dissolving Azilsartan (I) in water;
(ii) adding a base to the reaction mass at a suitable temperature;
(iii) adjusting pH by adding an acid; and
(iv) isolating pure Azilsartan (I).

Another embodiment of the present invention is to provide a process for the preparation of pure Azilsartan (I) with controlled particle size of D90 is less than 60µm, which comprises:
(i) dissolving Azilsartan (I) in a first solvent;
(ii) heating the reaction mass at a suitable temperature;
(iii) optionally, partial distillation of the solvent;
(iv) adding the reaction mass obtained in step-(iii) to a second solvent placed in another reactor in a Sonicator bath; and
(v) isolating pure Azilsartan (I) with controlled particle size of D90 is less than 60µm.

Another embodiment of the present invention is the use of pure Azilsartan (I) with controlled particle size of D90 is less than 60µm as a medicament.

Another embodiment of the present invention is to provide a process for the preparation of pure Azilsartan (I) with average particle size of (D50) above 10 microns, which comprises:
(i) dissolving Azilsartan (I) in a first solvent;
(ii) heating the reaction mass to 40-50?C;
(iii) cooling the reaction mass to 30-40?C;
(iv) distilling the solvent up to 4-6 volumes;
(v) filtering the reaction mass obtained in step-(iv) and washing with second solvent;
(vi) isolating pure Azilsartan (I) with average particle size of above 10 microns.

Other embodiment of the present invention is the use of pure Azilsartan (I) in the process for the preparation of Azilsartan medoxomil or salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to a process for the preparation of pure Azilsartan (I) with controlled particle size.

The process comprises, Azilsartan (I) dissolved in a first solvent is subjected to heating at a suitable temperature. The reaction mass is optionally subjected to partial distillation. A second solvent is added to the reaction mass and pure Azilsartan (I) is isolated.

The above reaction is carried out at a temperature ranges from 10-60ºC, preferably the temperature ranges from 20-35ºC.

The isolation of pure Azilsartan (I) is carried out by partial distillation of solvent with vigorous mixing, continuous crystallization and/or Ultrasonic crystallization

Another embodiment of the present invention is to provide a process for the preparation of pure Azilsartan (I) with controlled particle size. The process comprises, a base is added to Azilsartan (I) dissolved in a first solvent at a suitable temperature, followed by pH is adjusted by adding an acid to the reaction mass. Pure Azilsartan (I) is isolated.

The suitable temperature ranges from 10-60ºC, preferably the temperature ranges from 20-35ºC.

The base comprises lithium hydroxide, sodium hydroxide, ammonia hydroxide, barium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tertiary butoxide, potassium tertiary butoxide methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine, ammonia or mixture thereof.

The acid comprises an organic acid selected from acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, methane sulfonic acid and p-toluene sulfonic acid or a inorganic acid selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid or mixtures thereof.

Another embodiment of the present invention is to provide a process for the preparation of pure Azilsartan (I) with controlled particle size. The process comprises, Azilsartan (I) dissolved in a first solvent is subjected to heating at a suitable temperature. The reaction mass is optionally subjected to partial distillation of the solvent. The reaction mass obtained is added to a second solvent placed in another reactor in sonicator bath. Pure Azilsartan (I) is isolated.

Another embodiment of the present invention is to provide a process for the preparation of pure Azilsartan (I) with average particle size of (D50) is above 10 microns. The process comprises, Azilsartan (I) dissolved in a first solvent at a suitable temperature and cooled. Solvent is distilled up to ~4-6 volumes and cooled to 0-5ºC, then filtered the mass followed by washed with a second solvent and pure Azilsartan (I) is isolated.

The first solvent and/or the second solvent used in the above embodiments is selected from the group comprising methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; hydrocarbon solvent selected from the group comprising toluene, benzene, o-xylene, m-xylene, p-xylene; acetone; acetonitrile; ethyl acetate; methylene chloride; DMF; dioxane, THF, water or mixture thereof.

Yet another embodiment, the present invention provides Azilsartan (I) having a D90 particle size of less than about 60 microns, preferably less than 30 microns and D10 particle size of less than about 15 microns.

Another embodiment of the present invention is the use of pure Azilsartan (I) with controlled particle size obtained by above process, in the preparation of pharmaceutical composition.

Another embodiment of the present invention is the use of pure Azilsartan (I) with controlled particle size obtained by above process as a medicament.

Other embodiment of the present invention is the use of pure Azilsartan (I) with controlled particle size obtained by above process, in the preparation of Azilsartan medoxomil or salt thereof.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE-1:

A process for the preparation of pure Azilsartan (I) with controlled particle size by partial distillation of the solvent:
Azilsartan (5g) dissolved in methanol 55 vol (275 ml) was taken into a reactor at 25-30°C. The reaction mixture was heated to 40-42 °C to get a clear solution and filtered the reaction mass to remove undissolved foreign particle and distilled out 18 vol (90 ml) methanol under vacuum at 40-45°C. DM water 35 vol (175 ml) was charged in another reactor at 20-25°C and the above product solution in methanol was added into the DM water within 15-20 min at 20-25 °C. The reaction mass was stirred for 2-3 hrs at 25-30°C under vigorous mixing (RPM 400, PBT) and filtered the reaction mass through Bunker funnel and washed with DM water 1 vol, (5 ml). Dried the product at 40-45°C under reduced pressure (20 mmHg) till water content is <0.5% w/w it takes 6 hr to achieve this result.

PSD results: D90 is 27.3 µm.

Yield: 8.5g [0.85 w/w, based on Azilsartan Final API)

EXAMPLE-2:
A process for the preparation of pure Azilsartan (I) with controlled particle size by Ultrasonic Crystallization:

Azilsartan (5 g) dissolved in methanol 55 vol (275 ml) was taken into a reactor at 25-30°C. The reaction mixture was heated to 40-42 °C to get the clear solution and distilled out 18 vol (90 ml) methanol under vacuum at 40-45°C. DM water 35 vol (175 ml) was charged in another reactor in sonicator setup (Batch or continuous) at 20-25°C and the above product solution in methanol was added into the DM water within 20 min at 20-25 °C. The reaction mass was stirred for 2-3 hrs at 25-30°C under vigorous mixing (RPM 400, PBT) and filtered the reaction mass through Bunker funnel then washed with DM water 1 vol, (5 ml). The product was dried at 40-45°C under reduced pressure (20 mmHg) till water content is <0.5% w/w.

PSD results: D90 is 6.6 µm.

Yield: 8.5g [0.85 w/w, based on Azilsartan Final API)

EXAMPLE-3:
A process for the preparation of pure Azilsartan (I) with controlled particle size by base/ acid treatment:

Azilsartan solid (25 g) suspended in DM water 6 vol (150 ml) was taken into the cylindrical vessel (1L.Agitator: PBT, RPM: 350) at 25-30°C. 2.6 g of NaOH in water (2.4 vol,60 ml) was taken in another reactor and stirred for 30 min to get clear solution. The NaOH solution was added to the above Azilsartan suspension at 25-30°C to get clear solution. The reaction mass was filtered through the Buckner funnel to remove the unwanted foreign particle and the clear filtrated was charged into the reactor with PBT as agitator with RPM 350. The pH was adjusted to 5.2-5.6 by adding 50% Aq. acetic acetic acid (1:1 ratio of acetic acid and water) slowly in 1-1.5 hr at 28-30°C under vigorous mixing till product precipitates and stirred the reaction mass for 30 min at 25-30°C (reaction mass becomes thick after pH adjustment). DM water (9.0 vol225 ml) was added to the thick reaction mass, stirred for 1-2 hrs at 25-30 °C, filtered the product and washed with DM water (1.0 vol, 50 ml) at 25-30 °C). The product was dried at 45-50°C under reduced pressure (20 mmHg) till water content is <0.5% w/w and De lumped the material by hand with glass stopper and shift with 50 mesh.

PSD results: D90 is 11.5 µm.

Yield: 20.0g [0.80 w/w, based on Azilsartan Final API)

EXAMPLE-4:
A process for the preparation of pure Azilsartan (I) with controlled particle size by Reverse addition Technique:

Azilsartan (10 g) suspended in methanol 32 vol (320 ml) was taken into a reactor at 25-30°C. The reaction mixture was heated to 60-62 °C to get a clear solution and filtered the reaction mass to remove undissolved foreign particle and kept the methanol filtrate at 55-60°C (if solution temperature comes down to below 50°C material precipitates out). DM water was charged at 10-15 °C for 45-60 min in another reactor and cooled to 10-15°C under nitrogen. The above methanol solution was added to the DM water in 45-60 min at 10-15°C, stirred the reaction mass for 1-2 hrs at 10-15 °C under vigorous mixing (RPM 400), filtered the reaction mass through Buckner funnel and washed with DM water 1 vol,(10 ml). The product was dried at 45-50°C under reduced pressure (20 mmHg) till water content is <0.5% w/w.

PSD results: D90 is 37.4 µm.

Yield: 8.5g [0.80 w/w, based on Azilsartan Final API)

EXAMPLE-5:
A process for the preparation of pure Azilsartan (I) with controlled particle size by continuous mode of crystallization:
SOLUTION-A PREPERATION: 5g of Azilsartan was suspended in 275ml methanol at 20-25°C. The reaction mass temperature was raised to 40-45°C till get clear solution. ~90ml methanol was distilled out from reaction mass at 40-45°C under vacuum. If required the remaining reaction mass was filtered after distillation to remove the junk particles.

SOLUTION-B PREPERATION: Charge 210 ml DM water at 15-20°C.
PROCESS DESCRIPTION: The solution-A (15 ml/min) and solution-B (15 ml/min) were fed through the tubular coil with residence time 36 sec at temperature of 15-20°C and kept in a sonicator. The mass was collected in a Beaker. The reaction mass was filtered and washed with DM water (10ml). The wet cake was dried at 45-50°C under reduced pressure till water content <0.5%.

PSD results: D90 is 58.5 µm.
Yield: 0.85 (w/w).

EXAMPLE-6:
A process for the preparation of pure Azilsartan (I) having average particle size (D50) above 10 microns.
Azilsartan (10 g) suspended in methanol (500 ml) was taken into a reactor at 20-30°C under nitrogen atmosphere. The reaction mixture was heated to 40-50°C and continued the stirring at this temperature under nitrogen atmosphere till get clear solution. The reaction mass was cooled to 30-40°C, add Azilsartan seed (0.1g). The reaction mass was stirred for 60 mins at 35-40°C. ~4 to 6 volumes of methanol was distilled under vaccume at 35-40°C. The reaction mass was cooled to 0-5°C and stirred at 0-5°C for 120±15mins. The reaction mass was filtered at 0-5°C, washed with ethanol (20ml) at 0-5°C and dried the product at 40-45°C under reduced pressure (~20 mm Hg) till water content is = 0.4% w/w.

PSD results: D50 is 130 µm.
Yield: 0.85 (w/w). ,CLAIMS:WE CLAIM:

1. A process for the preparation of pure Azilsartan (I) with controlled particle size of D90 is less than 60µm, which comprises:
(i) dissolving Azilsartan (I) in a first solvent;
(ii) heating the reaction mass at a suitable temperature;
(iii) optionally, partial distillation of the solvent;
(iv) adding a second solvent; and
(v) isolating pure Azilsartan (I) with controlled particle size of D90 is less than 60µm.

2. A process for the preparation of pure Azilsartan (I) with controlled particle size of D90 is less than 60µm, which comprises:
(i) dissolving Azilsartan (I) in water;
(ii) adding a base to the reaction mass at a suitable temperature;
(iii) adjusting pH by adding an acid; and
(iv) isolating pure Azilsartan (I).

3. The process as claimed in claim 2, the base comprises lithium hydroxide, sodium hydroxide, ammonia hydroxide, barium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tertiary butoxide, potassium tertiary butoxide methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine, ammonia and the like.

4. The process as claimed in claim 2, the acid comprises an organic acid selected from acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, methane sulfonic acid and p-toluene sulfonic acid or a inorganic acid selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid or mixtures thereof.

5. A process for the preparation of pure Azilsartan (I) with controlled particle size of D90 is less than 60µm, which comprises:
(i) dissolving Azilsartan (I) in a first solvent;
(ii) heating the reaction mass at a suitable temperature;
(iii) optionally, partial distillation of the solvent;
(iv) adding the reaction mass obtained in step-(iii) to a second solvent placed in another reactor in a Sonicator bath; and
(v) isolating pure Azilsartan (I) with controlled particle size of D90 is less than 60µm.

6. A process for the preparation of pure Azilsartan (I) with average particle size of (D50) above 10 microns, which comprises:
(i) dissolving Azilsartan (I) in a first solvent;
(ii) heating the reaction mass to 40-50? C;
(iii) cooling the reaction mass to 30-40? C
(iv) distilling the solvent up to 4-6 volumes;
(v) filtering the reaction mass obtained in step-(iv) and washing with a second solvent;
(vi) isolating pure Azilsartan (I) with average particle size of above 10 microns.

7. The process as claimed in claims 1, 2, 5 and 6, wherein the first solvent and/or the second solvent used in the above reaction comprises methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; a hydrocarbon solvent selected from the group comprising toluene, benzene, o-xylene, m-xylene, p-xylene; acetone; acetonitrile; ethyl acetate; methylene chloride; DMF; dioxane, THF, water or mixture thereof.

8. The process as claimed in claims 1, 2, 5 and 6, the isolation of pure Azilsartan (I) is carried out by partial distillation of solvent with vigorous mixing, continuous crystallization and/or Ultrasonic crystallization

9. The process as claimed in claims 1, 2, 5 and 6, the use of pure Azilsartan (I) in the process for the preparation of Azilsartan medoxomil or salt thereof.