The present invention relates to the process for preparation of Azilsartan or its esters or salts thereof with reduced particle size using cryogenic milling technology. Specifically, the present invention relates to milling of Azilsartan or Azilsartan medoxomil potassium to reduce the particle size using cryogenic milling technology.
BACKGROUND OF THE INVENTION
Azilsartan medoxomil potassium is chemically described as (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl-2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl -4-yl]methyl}-1H-benzimidazole-7-carboxylate monopotassium of Formula I.

Azilsartan medoxomil potassium is a prodrug of Azilsartan of Formula II.

Azilsartan medoxomil potassium is an angiotensin II receptor blocker sold under the trade name EDARBI in USA and is indicated for the treatment of hypertension to lower blood pressure in the recommended dose of 40 mg taken once daily and escalation to 80 mg per day as necessary.
Azilsartan medoxomil potassium was described for the first time in U.S. Patent No. 7,157,584, which discloses its preparation and crystallization from acetone.
WO2013/088384A2 discloses Azilsartan particles have d90 less than 200 µm, d50 less than 100 µm and d10 less than 50 µm and Azilsartan medoxomil potassium particles have d0.9 less than 200 µm, d0.5 less than 100 µm and d0.1 less than 50 µm.
US2014113942A1 discloses crystalline Azilsartan medoxomil potassium having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 100 µm, the 50th volume percentile particle size (D50) is less than about 200 µm, or the 90th volume percentile particle size (D90) is less than about 400 µm or any combination thereof.
The particle size reduction of the drugs (API’s) is an important matter in pharmaceutical industry. The way to increase the bioavailability of drugs is to reduce the particle size of drugs and thus improve the absorption of them. There are number of processes employed such as crushing, milling and spray drying to reduce the size of drug particles in the pharmaceutical industry. Such processes cause thermal and chemical decomposition from the high heat generated during the processes. In addition, these processes have disadvantage of requiring high amount of solvents and high level of energy.

Therefore, there is need to develop a process which overcome all these disadvantages of prior arts. The present invention involves the cryomilling or cryogenic milling to reduce the particle size at extremely low temperature. Cryomilling also known as freezer milling, freezer grinding and cryogenic grinding, is the act of cooling or chilling a material and then reducing it into smaller particle size.
Cryomilling is a variation of mechanical milling, in which samples (e.g. temperature sensitive samples and samples with volatile components) are milled in a cryogen (usually liquid nitrogen or liquid argon) slurry or at a cryogenic temperature under processing parameters, so that a nanostructured microstructure is attained. Cryomilling takes advantage of both cryogenic temperature and conventional mechanical milling. The extremely low milling temperature suppresses recovery and recrystallization and leads to finer grain structures and more rapid grain refinement.
There is a need to develop a simple, cost effective, high yielding and industrially feasible process for the milling of Azilsartan or its esters or salts thereof.
OBJECT OF THE INVENTION
The principle object of the present invention is to provide a process for the preparation of Azilsartan or its esters or salts thereof with reduced particle size using cryogenic milling technology.
The another object of the present invention is to provide a process for milling and reducing the particle size of Azilsartan using cryogenic milling technology.
The another object of the present invention is to provide a process for milling and reducing the particle size of Azilsartan medoxomil potassium using cryogenic milling technology.
In yet another object of present invention, cryogenic milling process to reduce the particle size at extremely low temperature to avoid undesirable thermal and chemical degradation of Azilsartan or its ester or salts thereof.

SUMMARY OF THE INVENTION

The present invention provides the process for milling and reducing the particle size of Azilsartan or its esters or salts thereof using suitable cryogenic milling technology.

The present invention relates to a process for milling and reducing the particle size of Azilsartan or its esters or salts thereof comprising the steps of:
a) adding Azilsartan or its esters or salts thereof with balls into a container;
b) sealing the container; and
c) milling by cryogenic technology.
The present invention also relates to a process for milling and reducing the particle size of Azilsartan or its esters or salts thereof comprising the steps of:
a) adding Azilsartan or its esters or salts thereof with metal magnetic mandrels into a container;
b) sealing the container; and
c) milling by cryogenic technology.
DETAIL DESCRIPTION OF THE INVENTION
The present invention provides an efficient and advantageous process for milling and reducing the particle size of Azilsartan or its esters or salts thereof by any suitable cryogenic milling technology.
The present invention relates to a process for milling and reducing the particle size of Azilsartan or Azilsartan medoxomil potassium comprising the steps of:
a) adding Azilsartan or Azilsartan medoxomil potassium with balls into a container;
b) sealing the container; and
c) milling by cryogenic technology.
The weight ratio of balls to Azilsartan or its esters or salts thereof is selected from 100 to 1 or 1 to 100 or any combination thereof, preferably selected from 10:1. The rotation speed is 1 to 400 rpm (rotation per minute), preferably the rotation speed is 50 to 300 rpm and more preferably 100 to 200 rpm.

The ball for milling is selected from stainless steel balls, heavy tungsten carbide balls, Zr2O3 balls, zirconium silicate beads and the like thereof.
In yet another embodiment, the present invention also provides the process for milling and reducing the particle size of Azilsartan or its esters or salts thereof using cryogenic milling apparatus comprising the steps of adding compound together with metal magnetic mandrel into a suitable container. Further, sealing and placing it in a cryogenic milling apparatus and then milling is performed. The milling apparatus is supplied with a cryogenic milling fluid to maintain low temperature and ensuring continuous contact with the tube during milling.

The present invention also relates to a process for milling and reducing the particle size of Azilsartan or Azilsartan medoxomil potassium comprising the steps of:
a) adding Azilsartan or Azilsartan medoxomil potassium with metal magnetic mandrels into a container;
b) sealing the container; and
c) milling by cryogenic technology.
The weight ratio of metal magnetic mandrels to Azilsartan or its esters or salts thereof is selected from 100 to 1 or 1 to 100 or any combination thereof, preferably selected from 10:1. The rotation speed is 1 to 400 rpm (rotation per minute) preferably the rotation speed is 50 to 300 rpm and more preferably 100 to 200 rpm.
Cryogenic milling fluid is comprised of an inert substance or substance such as nitrogen, noble gases and combinations thereof. For instance, a cryogenic milling apparatus is supplied with at least one of nitrogen (N2), helium (He), argon (Ar), krypton (Kr), xenon (Xe) and the like thereof. Generally, the cryogenic milling fluid is a liquid used during operation of the cryogenic milling. Preferably, cryogenic milling fluid is liquid nitrogen.

Generally, the milling temperature is maintained at 0? to -180? or lower. Preferably milling temperature is maintained at -50? to -180? and more preferably milling temperature is maintained at -100? to -180?.

Preferably, the cryo-mill is equipped with a milling chamber comprising means for providing mechanical impact on the material to be milled, sometimes also referred to as “grinding jar”. Depending upon the type of the cryo-mill, said mechanical impact is provided in different forms that are known to the skilled person and that all have in common that the particle size of material is reduced through attrition and compressive forces at the grain size level. Suitable mills include but are not limited to ball mills, rod mills, autogenous mills, SAG mills, pebble mills, high pressure grinding rolls, buhrstone mills, vertical shaft impactor mills (VSI mills) and tower mills. Preferred mills are ball mills, colloid mills, conical mills, disintegrators, disk mills, edge mills, gristmills, hammer mills, jet mills, pellet mills, planetary mills, plate mills, stirred mills and vibratory mills.

Further, the cryo-mill is preferably equipped with a sieve that allows material of the desired particle size to exit the milling chamber but keeps the coarser material within the milling chamber so that it is subjected to additional mechanical impact.

Preferably, the cryo-milling according to the invention is performed until the desired particle size and particle size distribution of the pharmaceutical composition is achieved. The duration of cryomilling depends upon the equipment and the process parameters and determined by routine experimentation.

Grinding is performed at a temperature below ambient temperature. Preferably, the temperature below ambient temperature is at most 0°C, or at most -5°C, or at most -10°C, or at most -15°C, or at most -20°C, or at most -25°C, or at most -30°C, or at most -35°C, or at most -40°C, or at most -45°C, or at most -50°C, or at most -55°C, or at most -60°C, or at most -65°C, or at most -70°C, or at most -75°C, or at most -80°C, or at most -85°C, or at most -90°C, or at most -95°C, or at most -100°C. Preferably, the temperature is that of liquid nitrogen (i.e. about -196°C).
Still further, the cryo-mill is preferably equipped with a feeding device supplying the cryo-mill with starting material to be milled. Both the feeding device and the milling chamber are preferably equipped with isolating protections and integrated cooling, e.g. suitable pipeline to allow refrigeration with liquid nitrogen. The grinding jar is preferably continuously cooled with liquid nitrogen from the integrated cooling system before and during the grinding process. The liquid nitrogen preferably circulates through the system and is continuously replenished from an autofill system in the exact amount which is required to maintain the temperature at about -196°C.
In a preferred embodiment, cryo-milling is performed by means of a plate mill. The mill preferably comprises a stainless steel milling chamber equipped with high speed rotating elements (plate beater) that apply a centrifugal force guiding the fed coarse material against a radial sieve of appropriate open sieve net. The milled material is then directly collected into a suitable container. Coarse material is preferably loaded by means of a feeding device directly in the centre of the milling chamber.
In another preferred embodiment, cryo-milling is performed by means of a hammer mill. The mill preferably comprises a stainless steel milling chamber equipped with a horizontal rotor shaft which carries grinding elements (hammers) rotating at variable speed depending on the mill size. Coarse material is grinded by impact and attrition and finally forced through a radial sieve of appropriate open sieve net. Preferably, the milled material is then directly collected into a suitable container. The mill is preferably loaded by the top by means of an appropriate feeding device.

The process of cryogenic milling is accomplished by using a suitable cryogenic milling instrument. For instance, a ball mill, impact mill, vibratory ball mill, attritor mill (e.g., stirred ball-type mill), rod mill, hammer mill, planetary mill and combinations thereof. Regardless of the milling apparatus used for the cryogenic milling, the milling apparatus is supplied with a cryogenic milling fluid. In some embodiments, the cryogenic milling fluid is generally non-reactive with the milling media (e.g., balls, arms, etc.). The milling fluid is comprised of an inert substance or substances such as nitrogen, noble gases and combinations thereof. For instance, a cryogenic milling apparatus is supplied with at least one of nitrogen (N2), helium (He), argon (Ar), krypton (Kr) and xenon (Xe). Generally, the cryogenic milling fluid is a liquid used during operation of the cryogenic milling. However, the cryogenic milling fluid is a gas-liquid mixture or gas. Thus, in some cases, the temperature of the milling fluid is less than the boiling point of the fluid. Low temperatures (e.g., less than 130K) utilized during the cryogenic milling facilitate fragmentation of the compound during milling, thereby producing compound with smaller particle size. Thus, cryogenically milling providing sufficient amount of energy to mechanically deform and fragmented the material into smaller pieces.

Freezer milling is also a type of cryogenic milling that uses a solenoid to mill samples. The solenoid moves the grinding media back and forth in the vial, grinding the sample down to analytical fitness. This type of milling is especially useful in milling temperature sensitive samples, as sample are milled at liquid nitrogen temperature.

Cryo-milling is a variation of mechanical milling, in which metallic powder or other samples such as temperature sensitive samples with volatile components are milled in cryogen slurry or at a cryogenic temperature under processing parameters so to attain microstructured particles. Grinding jar of cryo-mill performs radial oscillation in horizontal position. The inertia of grinding ball causes them to impact with high energy on samples material at the rounded ends of grinding.

In accordance with one embodiment, the present invention provides a process for milling and reducing the particle size of Azilsartan or its esters or salts thereof using cryogenic milling apparatus comprising the steps of adding the compound with balls into a suitable container. Further, sealing and placing it into a cryogenic milling apparatus. The milling apparatus is supplied with a cryogenic milling fluid to maintain the low temperature. Then milling is performed to the particles of the compound with a stirrer.

The term particles mean a particle of relatively small discrete portion of the material of interest.

The term Azilsartan or its esters or salts includes Azilsartan or Azilsartan medoxomil potassium.

The milling process results increase in the surface area of Azilsartan or Azilsartan medoxomil potassium particles by reducing its particle size with the use of a cryogenic milling technology.

The particles of Azilsartan or its esters or salts thereof are obtained after cryogenic milling process is analyzed with XRD and a particle size analyzer.

The average size of particles of Azilsartan or its esters or salts thereof that are obtained after milling is depend on the time, type and speed of rotation per minute of the cryogenic milling apparatus.

In one aspect of the present invention provides crystalline Azilsartan or Azilsartan medoxomil potassium with smaller particle size after cryogenic milling.

The particles size of Azilsartan after milling have d90 less than 200µm, d50 less than 100 µm and d10 less than 50 µm. The particles size of Azilsartan medoxomil potassium particles have d90 less than 200µm, d50 less than 100 µm and d10 less than 50 µm.

In another aspect of the present invention provides an amorphous form of Azilsartan or Azilsartan medoxomil potassium after cryogenic milling.

In another aspect of the present invention provides crystalline form of Azilsartan or Azilsartan medoxomil potassium after cryogenic milling with reduced particle size.
The compounds Azilsartan or Azilsartan medoxomil potassium used for cryogenic milling process is prepared by any of the method known in the art.
In another aspect there is provided Azilsartan or Azilsartan medoxomil potassium according to the process of the present invention have HPLC purity above 99%.

The process of the present invention provides number of advantages over the conventional processes of reducing the particle size such as increase productivity through optimized particle size and increased throughput, elimination of caking product within the mill, decreased wear on grinding equipment, lower energy consumption, finer particle size, more uniform particle distribution, lower grinding cost, no heat generation which is good while grinding and provides an inert atmosphere thus eliminating the possibility of oxidation.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of amorphous form of Azilsartan or Azilsartan medoxomil potassium according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.

In yet another aspect there is provided a use of a pharmaceutical composition that includes a therapeutically effective amount of amorphous form of Azilsartan or Azilsartan medoxomil potassium according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of crystalline form of Azilsartan or Azilsartan medoxomil potassium according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.

In yet another aspect there is provided a use of a pharmaceutical composition that includes a therapeutically effective amount of crystalline form of Azilsartan or Azilsartan medoxomil potassium according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.

As used herein, the term “pharmaceutical compositions” includes pharmaceutical formulations like tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations or other pharmaceutical forms.

In yet another aspect there is provided a use of a pharmaceutical composition that includes a therapeutically effective amount of Azilsartan or Azilsartan medoxomil potassium thereof according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents to treat conditions in a subject, in need thereof such as a strong and long lasting angiotensin II antagonistic activity and hypotensive action, and an insulin sensitizing activity and which is useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension, cardiac diseases (cardiac hypertrophy, cardiac failure, cardiac infarction and the like), nephritis, stroke and the like and metabolic diseases such as diabetes and the like.

Although the following examples illustrate the present invention in more detail but the examples are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to the one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and variation of the concepts herein disclosed may be resorted to by those skilled in the art and that such modifications and variations are considered to be falling within the scope of the invention.

EXAMPLES
Example 1:
Azilsartan was added into a container together with balls, sealed and placed it in a cryogenic milling apparatus. Then milling was conducted to the particles with a stirrer for 5 hours. The weight ratio of balls to Azilsartan is 10:1 and the rotation speed was set to 100 rpm. Liquid nitrogen was flowed into the outer box to maintain the temperature at -70? to -100? or lower. The particle size of Azilsartan was reduced after milling.

Example 2:
Azilsartan medoxomil potassium was added into a container together with balls, sealed and placed it in a cryogenic milling apparatus. Then milling was conducted to the particles with a stirrer for 4 to 5 hours. The weight ratio of balls to Azilsartan medoxomil potassium is 10:1 and the rotation speed is set to 100 rpm. Liquid nitrogen was flowed into the outer box to maintain the temperature at -70? to -100? or lower. The particle size of Azilsartan medoxomil potassium was reduced after the milling.

Example 3:
Azilsartan together with metal magnetic mandrel was added into a container, sealed it and placed in a cryogenic milling apparatus ensuring continuous contact of the tube with liquid nitrogen. Liquid nitrogen was flowed into the outer box to maintain the temperature at -80? to -100? or lower. Then milling was conducted to the particles. The particle size of Azilsartan was reduced after milling.

Example 4:
Azilsartan medoxomil potassium together with metal magnetic mandrel was added in a container, sealed and placed it in a cryogenic milling apparatus ensuring the continuous contact of the tube with liquid nitrogen. Liquid nitrogen was flowed into the outer box to maintain the temperature at -80? to -100? or lower. Then milling was conducted to the particles. The particle size of Azilsartan medoxomil potassium was reduced after milling.

Example 5:
Azilsartan medoxomil potassium was added into a container together with balls, sealed and placed it in a cryogenic milling apparatus. Then milling was conducted to the particles with a stirrer for 4 to 5 hours. The weight ratio of balls to Azilsartan medoxomil potassium is 10:1 and the rotation speed is set to 200 rpm. Liquid nitrogen was flowed into the outer box to maintain the temperature at -70? to -100? or lower. The particle size of Azilsartan medoxomil potassium was reduced after the milling.

Example 6:
Azilsartan medoxomil potassium was added into a container together with balls, sealed and placed it in a cryogenic milling apparatus. Then milling was conducted to the particles with a stirrer for 4 to 5 hours. The weight ratio of balls to Azilsartan medoxomil potassium is 10:1 and the rotation speed is set to 150 rpm. Liquid nitrogen was flowed into the outer box to maintain the temperature at -70? to -100? or lower. The particle size of Azilsartan medoxomil potassium was reduced after the milling.

We Claim:

1.A process for reducing the particle size of the Azilsartan or its esters or salts thereof, comprising the milling of Azilsartan or its esters or salts thereof using cryogenic milling process.

2. The process as claimed in claim 1, comprising the steps of:
a) adding Azilsartan or its esters or salts thereof with balls into a container;
b) sealing the container; and
c) milling by cryogenic milling process.

3. The process as claimed in claim 1, comprising the steps of:
a) adding Azilsartan or its esters or salts thereof with metal magnetic mandrel into a container;
b) sealing the container; and
c) milling by cryogenic process.

4. The process as claimed in claim 1 to 3, wherein Azilsartan or its esters or salts thereof is selected from Azilsartan or Azilsartan medoxomil potassium.

5. The process as claimed in claim 1 to 3, wherein cryogenic milling comprises using ball mill, impact mill, vibratory ball mill, attritor mill, rod mill, hammer mill, planetary mill and combinations thereof.

6. The process as claimed in claim 1 to 3, wherein cryogenic milling comprises cryogenic milling fluid.

7. The process as claimed in claim 6, wherein cryogenic milling fluid comprises nitrogen (N2), helium (He), argon (Ar), krypton (Kr), xenon (Xe) and combination thereof.

8. The process as claimed in claim 1 to 3, wherein Azilsartan or Azilsartan medoxomil potassium after milling is in crystalline form or amorphous Form.

9. The process as claimed in claim 1 to 3, wherein particle size of Azilsartan after milling has d90 less than 200 µm, d50 less than 100µm and d10 less than 50 µm.

10. The process as claimed in claim 1 to 3, wherein particle size of Azilsartan medoxomil potassium after milling has d90 less than 200 µm, d50 less than 100µm and d10 less than 50 µm.