DESC:FIELD OF THE INVENTION
The present disclosure relates to sonocrystallization process for the preparation of Azilsartan having a lower particle size value.

BACKGROUND OF THE INVENTION
Azilsartan is chemically known as 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl) methyl)-lH-benzimidazole-7-carboxylic acid represented by Formula I

Formula-I

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.

United States Patent No. US 5243054 discloses azilsartan and its process for preparation.

Indian Patent application IN 4795/DELNP/2014 discloses Azilsartan having particle size distribution wherein, d90 less than 200 pm, d50 less than 100 pm and d10 less than 50 pm.

The traditional methods of particle size reduction like milling may not be suitable for the production of lower particle size in plant scale since it requires repeating the milling cycle at least 3-4 times which is time consuming, causes loss in yield and not suitable environmentally.

Sonocrystallization is a relatively new technique for producing smaller particles of a substance directly from a solution. Hatkar et al., Chemical Engineering and Processing 57– 58, 2012, 16–24 disclose sonocrystallization of salicylic acid. Min-Woo Park et al., Separation Science and Technology, 45, 2010, 1402-1410 discloses reduction of particle size of roxithromycin using sonocrystallization technique. Dennehy, Organic Process Research & Development 2003, 7, 1002-1006 discloses sonocrystallization technique for particle size reduction of three drugs, although the names of those drugs have not been disclosed.

OBJECT AND SUMMARY OF THE INVENTION
One aspect of the present application relates to sonocrystallization process for the preparation of Azilsartan having lower particle size value.

Another aspect of the present application relates to a process for the preparation of crystalline Azilsartan having lower particle size value comprising the steps of:
a) dissolving Azilsartan in a polar solvent;
b) sonocrystallizing the solution of step (a) by adding antisolvent; and
c) isolating crystalline Azilsartan

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to sonocrystallization process for the preparation of Azilsartan having lower particle size value.

Another aspect of the present application relates to a process for the preparation of crystalline Azilsartan having lower particle size value comprising the steps of:
a) dissolving Azilsartan in a polar solvent;
b) sonocrystallizing the solution of step (a) by adding antisolvent; and
c) isolating crystalline Azilsartan

Any crystalline or amorphous or solvate form of Azilsartan may be used as input material for the present application to get the desired particle size of Azilsartan.
According to this embodiment, Azilsartan may be dissolved in polar solvents under the heating or at ambient temperature.
Specific examples of polar solvent include but not limited to Dimethyl sulphoxide, N,N-Dimethyl formamide, N-Methylpyrrolidone, alcohols or mixtures thereof. Alcohol solvent include but not limited to methanol, ethanol, propanol, isopropanol, butanol or a mixtures thereof.
Within the context of this embodiment, the heating may be carried out at a temperature of about 35 °C to about 45°C. In some embodiments of the present invention, a temperature of about 40°C was found to be particularly useful for dissolving Azilsartam in alcohol solvent. As used herein, the term “about” means 10% above or below the value recited.
Further, the above resulted clear solution may be filtered through hyflo to remove any undissolved particulates.
Next, according to this embodiment the above resulted solution may be used for sonocrystallization. The process of sonocrystallizing a solution of Azilsartan may be carried out in presence of antisolvent to get azilsartan having lower particle size.
Within the context of this embodiment, suitable antisolvent includes but not limited to water; aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and mixture thereof.
It has been observed that the process for the preparation of Azilsartan having a lower particle size, comprising sonocrystallizing a solution of Azilsartan depends on the frequency of ultrasound. The frequency of ultrasound is from about 30 KHz to about 80 KHz. Specifically, the frequency of ultrasound is about 50 kHz.
It has also been observed that the process for the preparation of Azilsartan having a lower particle size, comprising sonocrystallizing a solution of Azilsartan depends on the sonication time. The sonication time may be from about 15 minutes to about 5 hours. Specifically, the sonication time may be from about 30 minutes to about 3 hours.
It has been further observed that the process for the preparation of Azilsartan having a lower particle size comprising sonocrystallizing a solution of Azilsartan depends on the power of ultrasound. The power of the ultrasound may be from about 50 W to about 1000 W. Specifically, the power of ultrasound may be from about 100 W to about 500 W.
It has been observed that the process for the preparation of Azilsartan having a lower particle size comprising sonocrystallizing a solution of Azilsartan depends on the temperature. The temperature of sonocrystallization may be about of 10 °C to about boiling point of the solution.
The obtained Azilsartan may then be isolated. Isolation may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by drying.

Another aspect of the present application relates to Azilsartan particles obtained by the sonocrystalliazation having a particle distribution of about D90 less than 100 urn, or 90 urn or 80 urn or 70 urn or 60 urn or 50 urn or 40 urn or 30 urn or 20 urn or 10 urn preferably D90 less than 50 urn; more preferably D90 less than 20 urn.

The PSD conditions for the measurement of PSD of Azilsartan of the present application are as follows:

Instrument : Master Sizer 3000
Make : Malvern
Accessory : Hydro MV
Lens : Auto
Tank fill Behavior : Manual
Tank medium : Water
Size range : 0.01-3500µm
Result : Volume distributed
Clean Type : Normal
Mode : Wet method
Dispersant : Water
Analysis model : General purpose

In one of the embodiment, the particle size of Azilsartan obtained in the present application by using the instrument, Malvern with the above described conditions is as follows: D90 :11.28µm, D50:6.02µm, D10: 2.85µm.

The inventors of the present application were surprisingly found that, the sonocrystallization method results crystalline Azilsartan having lower particle size value and sustained the undesired des-ethyl impurity compound of formula II at the level of 0.08 % to 0.01% before and after sonocrystallization respectively.

Des-ethyl impurity of Formula II

Whereas, the traditional methods like micronization results the azilsartan with increased des-ethyl impurity from 0.01% to 0.26%. i.e Before micronization the des-ethyl impurity level is 0.01 and after the micronization the des-ethyl impurity level is 0.26. The level of des-ethyl impurity has increased to 26 times after the micronization. Hence, the inventors of present application are particular about sonocrystallization rather than traditional methods like micronization.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES
Example 1: Preparation of Azilsartan
Azilsartan (5 g) was dissolved in Methanol (150 ml) at 43°C. The solution was filtered at 43°C to remove undissolved particulate. A sonotrod (50 Hz) was introduced into solution while water (225 ml) was being added to the solution at 25-35°C. Maintained Sonotrod condition for 15 minutes. The solid obtained was filtered, washed with water (5 ml) and dried at 42.0°C under vacuum for 3hours.

Yield= 3.2 g
PSD: D90 :13.8 µm, D50:5.5 µm, D10: 2.1µm
Sonotrod Condition: Sonotrod condition:50Htz for 15 min.
HPLC Before sonotrod: Purity: 99.84%, Des ethylsartan- 0.08%
HPLC After Sonotrod: Purity:99.94%, Des ethylsartan- 0.01%.

Example 2: Preparation of Azilsartan
Azilsartan (5 g) was dissolved in Methanol (150 ml) at 43°C. The solution was filtered at 43°C to remove undissolved particulate. A sonotrod (50 Hz) was introduced into solution while water (225 ml) was being added to the solution at 25-35°C. Maintained Sonotrod condition for 15 minutes. The solid obtained was filtered, washed with water (5 ml) and dried at 42.0°C under vacuum for 3hours.

Yield= 3.6 g
PSD: D90 :11.28µm, D50:6.02µm, D10: 2.85µm
Sonotrod Condition: Sonotrod condition:50Htz for 15 min.
HPLC Before sonotrod: Purity: 99.84%, Des ethylsartan- 0.08%
HPLC After Sonotrod: Purity:99.94, Des ethylsartan- 0.014
Example 3: Preparation of Azilsartan
Azilsartan (5 g) was micronized at Feed-4 and chamber-3at 25-35°C. Maintained. The solid obtained dried at 42.0°C under vacuum for 3hours.
Yield= 3.6 g
PSD: D90 :4.2µm, D50:2.2µm, D10: 1.1µm
HPLC Before micronization: Purity: 99.97%, Des ethylsartan- 0.01%
HPLC After micronization: Purity:99.58%, Des ethylsartan- 0.26

Example 4: Preparation of Azilsartan
Azilsartan (5 g) was dissolved in methanol (150 ml) at 43°C. The solution was filtered at 43°C to remove undissolved particulate and then cooled to 25-30°C. The clear solution of Azilsartan was slowly added into cold water (225ml) maintained at 5-10°C for 15-20 min and stirred at same temperature for 30-60min. The solid obtained was filtered, washed with water (5 ml) and dried at 42.0°C under vacuum for 3hours.

Example 5: Preparation of Azilsartan
Azilsartan (5 g) was dissolved in methanol (150 ml) at 43°C. The solution was filtered at 43°C to remove undissolved particulate and then cooled to 25-30°C. The clear solution of Azilsartan was slowly added into water (225ml) maintained at 25-30°C for 15-20 min and stirred at same temperature for 30-60min. The solid obtained was filtered, washed with water (5 ml) and dried at 42.0°C under vacuum for 3hours.

Example 6: Preparation of Azilsartan
Azilsartan (5 g) was dissolved in methanol (150 ml) at 43°C. The solution was filtered at 43°C to remove undissolved particulate and then cooled to 25-30°C. The clear solution of Azilsartan was slowly added water (75ml) to Azilsartan methanol solution at 40-43°C for 15-20 min and stirred at same temperature for 10-10min. Cooled the slurry mass to 25-30°C stirred at same temperature for 30-60min.The solid obtained was filtered, washed with water (5 ml) and dried at 42.0°C under vacuum for 3hours.

Example 7: Preparation of Azilsartan
Azilsartan (25 g) was dissolved in Dimethylsulphoxide (50 ml) at 30°C. The solution was filtered at 30°C to remove undissolved particulate. The clear solution of Azilsartan was slowly added to water (300 ml) to Azilsartan solution at 25-30°C for 15-20 min and stirred at same temperature for 30-60 min. The solid obtained was filtered, washed with water (100 ml) and dried at 40-45°C under vacuum for 12 hours.

Example 8: Preparation of Azilsartan
Azilsartan (5 g) was dissolved in Dimethylsulphoxide (10 ml) at 30°C. The solution was filtered at 30°C to remove undissolved particulate. Water (60 ml) was added to the clear solution of Azilsartan at 25-30°C for 15-20 min and stirred at same temperature for 30-60 min. The solid obtained was filtered, washed with water (10 ml) and dried at 40-45°C under vacuum for 12 hours.

Example 9: Preparation of Azilsartan
Azilsartan (10 g) was dissolved in Dimethylsulphoxide (20 ml) at 30°C. The solution was filtered at 30°C to remove undissolved particulate and then cooled to 5-10°C. The clear solution of Azilsartan was slowly added to chilled water (120 ml) at 5-10oC for 15-20 min and stirred at same temperature for 30-60min. The solid obtained was filtered, washed with water (50 ml) and dried at 45-50°C under vacuum for 3hours.

Example 10: Preparation of Azilsartan
Azilsartan (10 g) was dissolved in Dimethylformamide (25 ml) at 30°C. The solution was filtered at 30°C to remove undissolved particulate. The clear solution of Azilsartan was slowly added to water (150 ml) to Azilsartan solution at 25-30°C for 15-20 min and stirred at same temperature for 30-60 min. The solid obtained was filtered, washed with water (50 ml) and dried at 40-45°C under vacuum for 12 hours.

Example 11: Preparation of Azilsartan
Azilsartan (5 g) was dissolved in Dimethylformamide (12.5 ml) at 30°C. The solution was filtered at 30°C to remove undissolved particulate. Water (75 ml) was added slowly to Azilsartan solution at 25-30°C for 15-20 min and stirred at same temperature for 30-60 min. The solid obtained was filtered, washed with water (50 ml) and dried at 40-45°C under vacuum for 12 hours.
,CLAIMS:1. Process for the preparation of crystalline Azilsartan having lower particle size value comprising the steps of:
a) dissolving Azilsartan in a polar solvent;
b) sonocrystallizing the solution of step (a) by adding antisolvent; and
c) isolating crystalline Azilsartan