WO2012090043A1

WO2012090043A1 - Novel solid state forms of azilsartan medoxomil and preparation thereof

Info

Publication number: WO2012090043A1
Application number: PCT/IB2011/003055
Authority: WO
Inventors: Himanchal MISHRA; Deepak Bansal; Muni Bhaskar PALLOORU; Alka Srivastava CHOUDHARY; Dharam Vir; Ashutosh Agarwal; Shailendr Kumar DUBEY
Original assignee: Jubilant Life Sciences Limited
Priority date: 2010-12-29
Filing date: 2011-12-16
Publication date: 2012-07-05
Also published as: WO2012090043A8

Abstract

The present invention provides novel solid state forms of azilsartan medoxomil and process for the preparation thereof. The solid state forms of the present invention includes crystalline forms viz. J₂, J₃, J₄, J₅, J₆, J₇, J₈, J₉ and amorphous forms of azilsartan medoxomil. Further, it relates to the pharmaceutical composition and use of the said formulation to treat the conditions in a subject in need thereof.

Description

NOVEL SOLID STATE FORMS OF AZILSARTAN MEDOXOMIL

AND PREPARATION THEREOF

Field of invention

The present invention provides novel solid state forms of azilsartan medoxomil and process for the preparation thereof. Further, it relates to the pharmaceutical composition and method of using the formulation to treat conditions in a subject in need thereof. The solid state forms of azilsartan medoxomil are useful for preparing azilsartan medoxomil in high purity of desired solid state form.

Background of the invention

Azilsartan medoxomil i.e. (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl-2-ethoxy-

1 - ([2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-lH- benzimidazole-7-carboxylate (I) has the uses 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 (US7, 157,584). Azilsartan medoxomil is the prodrug of

2- ethoxy-l-([2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-lH- benzimidazole-7-carboxylic acid.

(I) (IA)

It is disclosed in US7, 157,584 that azilsartan medoxomil and salt thereof such as monopotassium salt (IA) are benzimidazole derivative useful as an angiotensin II receptor antagonist.

Pharmaceutical Research, (2008) 25, 530, explains that the ability to deliver the drug to the patient in a safe, efficacious and cost effective way depends largely upon the physicochemical properties of the APIs in the solid state and accordingly one of the challenging tasks in the pharmaceutical industry is to design pharmaceutical materials with specific physiochemical properties. It is known that different solid forms of the same drug may exhibit different properties, including characteristics that have functional implications with respect to their use as drug may have substantial differences in such pharmaceutically important properties as dissolution rates and bioavailability. Likewise, different polymorphs may have different processing properties, such as hygroscopisity, flow ability and the like, which could affect their suitability as active pharmaceuticals for commercial production. Also, it is known in the art that the amorphous forms of APIs generally exhibit the better solubility profile over the corresponding crystalline forms. This is because the lattice energy does not have to be overcome in order to dissolve the solid state structure as in the case for crystalline forms.

Thus, there is a need to develop the novel solid state forms of pharmaceutically active compound, having better physicochemical properties. Especially, for the enhancement of the solubility. Also there is a constant need to have the cost effective and industrial friendly process for the preparation of the solid state form.

Description of the drawings

FIG. l depicts a powder X-ray diffractogram (PXRD) of crystalline Form J₂ of azilsartan medoxomil.

FIG.2 represents IR spectrum of crystalline Form J₂ of azilsartan medoxomil.

FIG.3 Differential scanning calorimetry (DSC) heating trace of crystalline Form J₂ of azilsartan medoxomil.

FIG.4 Thermo-gravimetric analysis (TGA) heating trace of crystalline Form J₂ of azilsartan medoxomil.

FIG.5 depicts a powder X-ray diffractogram (PXRD) of crystalline Form J₃ of azilsartan medoxomil.

FIG.6 represents IR spectrum of crystalline Form J₃ of azilsartan medoxomil.

FIG.7 Differential scanning calorimetry (DSC) heating trace of crystalline Form J₃ of azilsartan medoxomil.

FIG.8 Thermo-gravimetric analysis (TGA) heating trace of crystalline Form J₃ of azilsartan medoxomil. FIG.9 depicts a powder X-ray diffractogram (PXRD) of crystalline Form J₄ of azilsartan medoxomil.

FIG.10 represents IR spectrum of crystalline Form J₄ of azilsartan medoxomil.

FIG.1 1 Differential scanning calorimetry (DSC) heating trace of crystalline Form J₄ of azilsartan medoxomil.

FIG.12 Thermo-gravimetric analysis (TGA) heating trace of crystalline Form J₄ of azilsartan medoxomil.

FIG.13 depicts a powder X-ray diffractogram (PXRD) of crystalline Form J₅ of azilsartan medoxomil.

FIG.14 represents IR spectrum of crystalline Form J₅ of azilsartan medoxomil.

FIG.15 Differential scanning calorimetry (DSC) heating trace of crystalline Form J₅ of azilsartan medoxomil.

FIG.16 Thermo-gravimetric analysis (TGA) heating trace of crystalline Form J₅ of azilsartan medoxomil.

FIG.17 depicts a powder X-ray diffractogram (PXRD) of crystalline Form J₆ of azilsartan medoxomil.

FIG.18 represents IR spectrum of crystalline Form J₆ of azilsartan medoxomil.

FIG.19 Differential scanning calorimetry (DSC) heating trace of crystalline Form J₆ of azilsartan medoxomil.

FIG.20 Thermo-gravimetric analysis (TGA) heating trace of crystalline Form J₆ of azilsartan medoxomil.

FIG.21 depicts a powder X-ray diffractogram (PXRD) of crystalline Form J₇ of azilsartan medoxomil.

FIG.22 represents IR spectrum of crystalline Form J₇ of azilsartan medoxomil.

FIG.23 Differential scanning calorimetry (DSC) heating trace of crystalline Form J₇ of azilsartan medoxomil.

FIG.24 Thermo-gravimetric analysis (TGA) heating trace of crystalline Form J₇ of azilsartan medoxomil.

FIG.25 depicts a powder X-ray diffractogram (PXRD) of crystalline Form J₈ of azilsartan medoxomil

FIG.26 represents IR spectrum of crystalline Form J₈ of azilsartan medoxomil. FIG.27 Differential scanning calorimetry (DSC) heating trace of crystalline Form J₈ of azilsartan medoxomil.

FIG.28 Thermo-gravimetric analysis (TGA) heating trace of crystalline Form J₈ of azilsartan medoxomil.

FIG.29 depicts a powder X-ray diffractogram (PXRD) of amorphous form of azilsartan medoxomil

FIG.30 represents IR spectrum of amorphous form of azilsartan medoxomil.

FIG.31 Thermo-gravimetric analysis (TGA) heating trace of amorphous form of azilsartan medoxomil.

FIG.32 depicts a powder X-ray diffractogram (PXRD) of amorphous form of azilsartan medoxomil.

FIG.33 represents IR spectrum of amorphous form of azilsartan medoxomil.

FIG.34 Differential scanning calorimetry (DSC) heating trace of amorphous form of azilsartan medoxomil.

FIG.35 depicts a powder X-ray diffractogram (PXRD) of crystalline form J₉ of azilsartan medoxomil.

FIG.36 represents IR spectrum of crystalline form J₉ of azilsartan medoxomil.

FIG.37 Differential scanning calorimetry (DSC) heating trace of crystalline form J₉ of azilsartan medoxomil.

Description of the invention

The principal embodiment of the present invention provides the details of azilsartan medoxomil (I) in the solid state viz. the novel solid state forms i.e. crystalline and amorphous forms of azilsartan medoxomil. Azilsartan medoxomil can be prepared by using any prior art processes such as known in US 7,157,584 that azilsartan medoxomil and salt thereof such as monopotassium salt (IA) or the improvements thereof.

(I) (IA) An embodiment of the present invention provides a process for the preparation of the novel solid state forms i.e. crystalline and amorphous form.s of azilsartan medoxomil.

The said process comprises of dissolving azilsartan medoxomil in one or more solvents; and recovering the azilsartan medoxomil in the novel solid state forms by the removal of solvent through convenient methods.

A "solvent" as defined herein is selected from the group comprising of alcohols, nitriles, ketones, esters, ethers, amides, dialkylsulfoxide, water or the mixtures thereof. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. The nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone etc. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Chlorinated solvents are selected from the group comprising of dichloromethane, chloroform, dichloroethane, chlorobenzene and the like. Ethers can be selected from the group comprising of diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like. Amides can be selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide and the like. Dialkyl sulfoxide can be selected from the group comprising of dimethyl sulfoxide, diethyl sulfoxide, dibutyl sulfoxide and the like.

"Antisolvent" is a non polar solvent, selected from the group comprising of hydrocarbons viz. aliphatic or aromatic hydrocarbons. Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected from the group comprising of toluene, xylene and the like.

A method for removal of the solvent can be selected from the methods mentioned below to obtain the crystalline and amorphous form of azilsartan medoxomil. The method can be selected from the processes comprising of distillation, precipitation, evaporation (evaporation under reduced pressure or evaporation under ambient pressure), spray drying, roller drying, freeze drying i.e. lyophilization, thin film drying and the like. An embodiment of the present invention provides novel crystalline form J₂ of azilsartan medoxomil.

Another embodiment of the present invention provides crystalline Form J₂ of azilsartan medoxomil, which is characterized by PXRD pattern, as depicted in FIG. 1.

Yet another embodiment of the present invention provides crystalline Form J₂ of azilsartan medoxomil, which is characterized by infrared absorption spectrum, as depicted in FIG. 2.

Further embodiment of the present invention provides crystalline Form J₂ of azilsartan medoxomil, which is characterized by DSC thermogram, as depicted in FIG. 3.

Yet further another embodiment of the present invention provides crystalline Form J₂ of azilsartan medoxomil, which is characterized by TGA analysis, as depicted in FIG. 4.

An embodiment of the present invention provides a process for preparing crystalline Form J₂ of azilsartan medoxomil comprising dissolving azilsartan medoxomil in a solvent or mixture of solvents and removal of solvent(s) to obtain crystalline Form J₂ of azilsartan medoxomil.

According to this embodiment the present invention provides a process for preparing crystalline Form J₂ of azilsartan medoxomil comprising dissolving azilsartan medoxomil in alcohol such as methanol and evaporating the solvent to obtain crystalline Form J₂ of azilsartan medoxomil. .

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of novel crystalline Form J₂ of azilsartan medoxomil 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 novel crystalline Form J₂ of azilsartan medoxomil 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.

An embodiment of the present invention provides novel crystalline form J₃ of azilsartan medoxomil.

Another embodiment of the present invention provides crystalline Form J₃ of azilsartan medoxomil, which is characterized by PXRD pattern, as depicted in FIG. 5.

Yet another embodiment of the present invention provides crystalline Form J₃ of azilsartan medoxomil, which is characterized by infrared absorption spectrum, as depicted in FIG. 6.

Further embodiment of the present invention provides crystalline Form J₃ of azilsartan medoxomil, which is characterized by DSC thermogram, as depicted in FIG. 7.

Yet further embodiment of the present invention provides crystalline Form J₃ of azilsartan medoxomil, which is characterized by TGA analysis, as depicted in FIG. 8.

An embodiment of the present invention provides a process for preparing crystalline Form J₃ of azilsartan medoxomil comprising dissolving azilsartan medoxomil in a solvent or mixture of solvents and removal of solvent(s) to obtain crystalline Form J₃ of azilsartan medoxomil.

An another embodiment of the present invention provides a process for preparing crystalline Form J₃ of azilsartan medoxomil comprising dissolving azilsartan medoxomil in nitriles such as acetonitrile and evaporating the solvent to obtain crystalline Form J₃ of azilsartan medoxomil.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of novel crystalline Form J₃ of azilsartan medoxomil 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 novel crystalline Form J₃ of azilsartan medoxomil 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.

An embodiment of the present invention provides novel crystalline form J₄ of azilsartan medoxomil.

Another embodiment of the present invention provides crystalline Form J₄ of azilsartan medoxomil, which is characterized by PXRD pattern, as depicted in FIG. 9.

Yet another embodiment of the present invention provides crystalline Form J₄ of azilsartan medoxomil, which is characterized by infrared absorption spectrum, as depicted in FIG. 10.

Further embodiment of the present invention provides crystalline Form J₄ of azilsartan medoxomil, which is characterized by DSC thermogram, as depicted in FIG. 1 1.

Yet further embodiment of the present invention provides crystalline Form J₄ of azilsartan medoxomil, which is characterized by TGA analysis, as depicted in FIG. 12.

An embodiment of the invention provides the crystalline Form J₄ of azilsartan medoxomil, which is obtained through solvent precipitation by using polar-nonpolar solvent systems i.e. by solvent - anti solvent method. The polar solvent is the "solvent" which can be selected from the group comprising of ketones, esters, alcohols, mixture of alcohols and chlorinated solvents, or the mixtures thereof. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone etc. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Chlorinated solvents are selected from the group comprising of dichloromethane, chloroform, dichloroethane, chlorobenzene and the like. The non polar solvent (antisolvent) can be selected from the group comprising of hydrocarbons viz. aliphatic or aromatic hydrocarbons. Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected from the group comprising of toluene, xylene and the like.

An another embodiment of the present invention provides a process for preparing crystalline Form J₄ of azilsartan medoxomil comprising dissolving azilsartan medoxomil in ketone(s) such as acetone. To the resulting solution, the antisolvent such as hydrocarbon like cyclohexane was added to obtain crystalline Form J₄ of azilsartan medoxomil.

Yet another embodiment of the present invention provides a process for preparing crystalline Form J₄ of azilsartan medoxomil comprising dissolving azilsartan medoxomil in mixture of ketones and esters such as acetone and ethyl acetate and allowed to cool to obtain crystalline Form J₄ of azilsartan medoxomil.

An another embodiment of the present invention provides a process for preparing crystalline Form J₄ of azilsartan medoxomil comprising dissolving azilsartan medoxomil in mixture of chlorinated solvent and ester such as dichloromethane and ethyl acetate and allowed to cool to obtain crystalline Form J₄ of azilsartan medoxomil.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of novel crystalline Form J₄ of azilsartan medoxomil 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 novel crystalline Form J₄ of azilsartan medoxomil 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.

An embodiment of the present invention provides novel crystalline form J₅ of azilsartan medoxomil. Another embodiment of the present invention provides crystalline Form J₅ of azilsartan medoxomil, which is characterized by PXRD pattern, as depicted in FIG. 13.

Yet another embodiment of the present invention provides crystalline Form J₅ of azilsartan medoxomil, which is characterized by infrared absorption spectrum, as depicted in FIG. 14.

Further embodiment of the present invention provides crystalline Form J₅ of azilsartan medoxomil, which is characterized by DSC thermogram, as depicted in FIG. 15.

Yet further embodiment of the present invention provides crystalline Form J₅ of azilsartan medoxomil, which is characterized by TGA analysis, as depicted in FIG. 16.

An embodiment of the invention provides the crystalline Form J₅ of azilsartan medoxomil, which is obtained through solvent precipitation by using polar-nonpolar solvent systems i.e. by solvent - anti solvent method. The polar solvent is the "solvent" which can be selected from the group comprising of ketones, esters, alcohols, mixture of alcohols and chlorinated solvents, or the mixtures thereof. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone etc. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Chlorinated solvents are selected from the group comprising of dichloromethane, chloroform, dichloroethane, chlorobenzene and the like. The non polar solvent (antisolvent) can be selected from the group comprising of hydrocarbons viz. aliphatic or aromatic hydrocarbons. Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected from the group comprising of toluene, xylene and the like.

An another embodiment of the present invention provides a process for preparing crystalline Form J₅ of azilsartan medoxomil comprising dissolving azilsartan medoxomil in esters such as ethyl acetate, followed by addition of antisolvent such as hydrocarbons like cyclohexane to obtain crystalline Form J₅ of azilsartan medoxomil.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of novel crystalline Form J₅ of azilsartan medoxomil 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 novel crystalline Form J₅ of azilsartan medoxomil 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.

An embodiment of the present invention provides novel crystalline form J₆ of azilsartan medoxomil.

Another embodiment of the present invention provides crystalline Form J₆ of azilsartan medoxomil, which is characterized by PXRD pattern, as depicted in FIG. 17.

Yet another embodiment of the present invention provides crystalline Form J₆ of azilsartan medoxomil, which is characterized by infrared absorption spectrum, as depicted in FIG. 18.

Further embodiment of the present invention provides crystalline Form J₆ of azilsartan medoxomil, which is characterized by DSC thermogram, as depicted in FIG. 19.

Yet further embodiment of the present invention provides crystalline Form J₆ of azilsartan medoxomil, which is characterized by TGA analysis, as depicted in FIG. 20.

According to yet another embodiment of the present invention there is provided a process for the preparation of crystalline Form J₆ of azilsartan medoxomil. Accordingly, azilsartan medoxomil is dissolved in one or more solvents and recovering said crystalline form of azilsartan medoxomil by the addition of anti solvent such as water and recovering the azilsartan medoxomil in the crystalline form by the removal of solvent through convenient methods such as by filtration, decantation etc.

The solvents are selected from the group comprising of alcohols, ethers, ketones, esters, nitriles, amides, dimethyl sulfoxide or the mixtures thereof. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Ethers are selected from the group comprising of tetrahydrofuran, diethyl ether, diisopropyl ether and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone etc. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. The nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Amides can be selected from dimethylformamide, dimethylacetamide, N-methyl formamide and the like.

An another embodiment of the present invention provides a process for preparing crystalline Form J₆ of azilsartan medoxomil comprising dissolving azilsartan medoxomil in alcohol selected from the group the comprising of methanol, ethanol, isopropyl alcohol, n-butanol etc. and adding antisolvent such as water to obtain crystalline Form J₆ of azilsartan medoxomil.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of novel crystalline Form J₆ of azilsartan medoxomil 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 novel crystalline Form J₆ of azilsartan medoxomil 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. An embodiment of the present invention provides novel crystalline form J₇ of azilsartan medoxomil.

Another embodiment of the present invention provides crystalline Form J₇ of azilsartan medoxomil, which is characterized by PXRD pattern, as depicted in FIG. 21.

Yet another embodiment of the present invention provides crystalline Form J₇ of azilsartan medoxomil, which is characterized by infrared absorption spectrum, as depicted in FIG. 22.

Further embodiment of the present invention provides crystalline Form J₇ of azilsartan medoxomil, which is characterized by DSC thermogram, as depicted in FIG. 23.

Yet further embodiment of the present invention provides crystalline Form J₇ of azilsartan medoxomil, which is characterized by TGA analysis, as depicted in FIG. 24.

According to yet another embodiment of the present invention there is provided a process for the preparation of crystalline Form J₇ of azilsartan medoxomil. Accordingly; azilsartan medoxomil is dissolved in one or more solvents and recovering said crystalline form of azilsartan medoxomil by the addition of water and recovering the azilsartan medoxomil in the crystalline form by the removal of solvent through convenient methods such as by filtration, decantation etc.

The solvents are selected from the group comprising of alcohols, ethers, ketones, esters, nitriles, amides, dimethylsulfoxide or the mixtures thereof. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Ethers are selected from the group comprising of tetrahydrofuran, diethyl ether, diisopropyl ether and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone etc. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. The nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Amides can be selected from dimethylformamide, dimethylacetamide, N-methyl formamide and the like.

An another embodiment of the present invention provides a process for preparing crystalline Form J₇ of azilsartan medoxomil comprising dissolving azilsartan medoxomil in ether such as tetrahydrofuran and followed by addition of antisolvent such as water to obtain crystalline Form J₇ of azilsartan medoxomil.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of novel crystalline Form J₇ of azilsartan medoxomil 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 novel crystalline form J₇ of azilsartan medoxomil 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.

An embodiment of the present invention provides novel crystalline form J₈ of azilsartan medoxomil.

Another embodiment of the present invention provides crystalline form J₈ of azilsartan medoxomil, which is characterized by PXRD pattern, as depicted in FIG. 25.

Yet another embodiment of the present invention provides crystalline form J₈ of azilsartan medoxomil, which is characterized by infrared absorption spectrum, as depicted in FIG. 26.

Further embodiment of the present invention provides crystalline form J₈ of azilsartan medoxomil, which is characterized by DSC thermogram, as depicted in FIG. 27.

Yet further embodiment of the present invention provides crystalline form J₈ of azilsartan medoxomil, which is characterized by TGA analysis, as depicted in FIG. 28.

According to yet another embodiment of the present invention there is provided a process for the preparation of crystalline Form J₈ of azilsartan medoxomil. Accordingly, azilsartan medoxomil is dissolved in one or more solvents and cooled to obtain the crystalline Form J through convenient methods such as filtration, decantation etc.

The solvents are selected from the group comprising of ketones, esters, nitriles, alcohols, amides, dimethysulfoxide, ethers, water, mixture of esters and chlorinated solvents, mixture of esters and ketones or the mixtures thereof. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone etc. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Chlorinated solvents are selected from the group comprising of dichloromethane, chloroform, dichloroethane, chlorobenzene and the like. Ethers can be selected from diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like. Amides can be selected from dimethylformamide, dimethylacetamide, N-methyl formamide and the like.

An another embodiment of the present invention provides a process for preparing crystalline Form Jg of azilsartan medoxomil comprising dissolving azilsartan medoxomil in nitriles such as acetonitrile and evaporating the solvent to obtain crystalline Form J₈ of azilsartan medoxomil.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of novel crystalline Form Jg of azilsartan medoxomil 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 novel crystalline Form J₈ of azilsartan medoxomil 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.

An embodiment of the present invention provides novel crystalline form J₉ of azilsartan medoxomil. An embodiment of the present invention provides novel crystalline form J₉ of azilsartan medoxomil.

Another embodiment of the present invention provides crystalline form J₉ of azilsartan medoxomil, which is characterized by PXRD pattern, as depicted in FIG. 35.

Yet another embodiment of the present invention provides crystalline form J₉ of azilsartan medoxomil, which is characterized by infrared absorption spectrum, as depicted in FIG. 36.

Further embodiment of the present invention provides crystalline form J₉ of azilsartan medoxomil, which is characterized by DSC thermogram, as depicted in FIG. 37.

According to yet another embodiment of the present invention there is provided the process for the preparation of crystalline form J₉ of azilsartan medoxomil. Accordingly, azilsartan medoxomil is dissolved in one or more solvents. By using convenient method, the solvent is evaporated in order to obtain crystalline form of azilsartan medoxomil.

To obtain the crystalline form, the solvents such as nitriles, mixture of nitrile and water. The nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.

The solvent can be removed to the extent, wherein the crystalline form J₉ is obtained. In the further embodiment, the crystalline form J₉ can be obtained by dissolving azilsartan medoxomil in one or more solvents and recovering the azilsartan medoxomil in the crystalline form J₉ by adding suitable antisolvent. To obtain the crystalline form J₉, the solvents such as nitriles, mixture of nitrile and water. The nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. The antisolvent can be selected from the group comprising of aliphatic or aromatic hydrocarbon such as pentane, hexane, heptane, cyclohexane, toluene and the like.

An embodiment of the present invention provides novel amorphous form of azilsartan medoxomil. Another embodiment of the present invention provides novel amorphous form of azilsartan medoxomil, which is characterized by PXRD pattern, as depicted in FIG. 29.

Yet another embodiment of the present invention provides novel amorphous form of azilsartan medoxomil, which is characterized by infrared absorption spectrum, as depicted in FIG. 30.

Further embodiment of the present invention provides novel amorphous form of azilsartan medoxomil, which is characterized by TGA analysis, as depicted in FIG. 31.

Another embodiment of the present invention provides novel amorphous form of azilsartan medoxomil, which is characterized by PXRD pattern, as depicted in FIG. 32.

Yet another embodiment of the present invention provides novel amorphous form of azilsartan medoxomil, which is characterized by infrared absorption spectrum, as depicted in FIG. 33.

Further embodiment of the present invention provides novel amorphous form of azilsartan medoxomil, which is characterized by TGA analysis, as depicted in FIG. 34.

An embodiment of the present invention the process for the preparation of the amorphous form of azilsartan medoxomil is disclosed. The process comprises of dissolving azilsartan medoxomil in one or more solvents; and recovering the azilsartan medoxomil in the amorphous form by the removal of solvent through convenient methods.

The solvents are selected from the group comprising of ketones, nitriles, chlorinated solvents, esters, alcohols, mixture of alcohols and chlorinated solvents, or the mixtures thereof. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone etc. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Chlorinated solvents are selected from the group comprising of dichloromethane, chloroform, dichloroethane, chlorobenzene and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Ethers can be selected from the group comprising of diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like. Amides can be selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide and the like. Dialkyl sulfoxide can be selected from the group comprising of dimethyl sulfoxide, diethyl sulfoxide, dibutyl sulfoxide and the like.

The method for removal the solvent can be selected to obtain the amorphous form of azilsartan medoxomil. The method can be selected from the processes comprising of spray drying, distillation under vacuum, roller drying, freeze drying i.e. lyophilization, thin film drying and the like.

An another embodiment of the present invention provides a process for preparing amorphous form of azilsartan medoxomil comprising dissolving azilsartan medoxomil in solvent selected from the group comprising of acetone, dichloromethane, acetonitrile etc. followed by spray drying to obtain amorphous form of azilsartan medoxomil.

In another embodiment the azilsartan medoxomil is milled by grinding action between two surfaces till the time amorphous azilsartan medoxomil is obtained. Such milling can be carried out by using a traditional technique of compounding using a pestle and mortar or by milling machines that essentially work on the same principle. Examples of such milling machines can be selected from the group comprising of ball mills, roller mills, jet mills, gyratory mills, and the like.

In further embodiment the amorphous form of azilsartan medoxomil is obtained through solvent precipitation by using polar-nonpolar solvents i.e. by solvent-antisolvent technique. The polar solvent is selected from the group consisting of ketones, esters, alcohols, mixture of alcohols and chlorinated solvents, or the mixtures thereof. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone etc. Esters are selected from the group comprising of ethyl acetate, propyl acetate and . the like. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Chlorinated solvents are selected from the group comprising of dichloromethane, chloroform, dichloroethane, chlorobenzene and the like. The non polar solvent can be selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, cyclohexane, cyclopentane, toluene, xylene and the like.

In other embodiment the invention provides a method for preparation of physical forms of azilsartan medoxomil by quenching a melt of azilsartan medoxomil.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of novel amorphous form of azilsartan medoxomil 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 novel amorphous form of azilsartan medoxomil 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.

Illustrative of the invention is a pharmaceutical composition made by mixing novel solid state forms of azilsartan medoxomil according to the invention and a pharmaceutically acceptable carrier. A further embodiment of the invention is a process for making a pharmaceutical composition comprising mixing novel solid state forms of azilsartan medoxomil according to the invention and a pharmaceutically acceptable carrier. An example of the invention is a method for the treatment of an angiotensin type II receptor mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of novel solid state forms of azilsartan medoxomil according to any of the embodiments of the invention or pharmaceutical compositions described above. Also included in the invention is the use of novel solid state forms of azilsartan medoxomil, for the preparation of a medicament for treating an angiotensin type II receptor mediated disorder in a subject in need thereof.

Pharmaceutical formulations of the present invention contain novel solid state forms of azilsartan medoxomil. It is preferred that the novel solid state forms of azilsartan medoxomil are substantially pure, but this is non-limiting to the working of composition for a variety of purposes. Diluents increase the bulk of a solid pharmaceutical composition and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel(R)), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit(R)), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol(R)), carboxymethyl cellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel(R)), hydroxypropyl methyl cellulose (e.g. Methocel(R)), liquid glucose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, povidone (e.g. Kollidon(R), Plasdone(R)), pregelatinized starch, sodium alginate and starch. The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di-Sol(R), Primellose(R)), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon(R), Polyplasdone(R)), guar gum, magnesium aluminium silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate(e.g.Explotab(R)) and starch. Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powderedcellulose, starch, talc and tribasic calcium phosphate.

When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some dioxide, magnesium trisilicate, powderedcellulose, starch, talc and tribasic calcium phosphate.

When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearylfumarate, stearicacid, talc and zincstearate.

Flavouring agents and flavour enhancers make the dosage form more palatable to the patient. Common flavouring agents and flavour enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethylvanillin, menthol, citricacid, fumaricacid, ethylmaltol and tartaric acid.

Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colourant to improve their appearance and/or facilitate patient identification of the product and unit dosage level. In liquid pharmaceutical compositions of the present invention, azilsartan medoxomil and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may further contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel or organoleptic qualities of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid, bentonite, carbomer, carboxymethyl cellulose calcium or sodium, Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste. Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improve storage stability.

According to the present invention, a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.

Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.

The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colourant. The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.

A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.

A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the active and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.

As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose; spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting; however, they are not subjected to a final tableting step.

In yet another aspect of the invention, the azilsartan medoxomil or salts thereof has particles size having d_{0 9} less than 200 micrometer, do.₅ less than 50 micrometer and do_.i less than 10 micrometer.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of novel crystalline Forms such as J_2; J_3i J_4> J₅, J₆, J_7;

J_8j J₉ and amorphous form of azilsartan medoxomil 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 novel crystalline Forms such as J₂,

J_3j J_4i J₅_ J₆₎ J_7; J_8; J₉ and amorphous form of azilsartan medoxomil 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 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 examples are directed to novel solid state forms of azilsartan medoxomil, the principles described in this example can be applied to other salts / hydrates / solvates of azilsartan medoxomil. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description.

Examples

Example 1:

Preparation of crystalline Form J₂ of azilsartan medoxomil.

Azilsartan medoxomil (0.5 gm) was dissolved in methanol (50 ml) at 15-20°C and resulting solution was filtered. The solvent was evaporated to obtain 0.35 g of crystalline Form J₂ of azilsartan medoxomil. XRD as provided in Fig. l .

Example 2:

Preparation of crystalline Form J3 of azilsartan medoxomil.

Azilsartan medoxomil (0.3 gm) was dissolved in acetonitrile (30 ml) at 15- 20°C and resulting solution was filtered. The solvent was evaporated at a temperature of about 15-20°C for 24 hrs to obtain 0.25 g of crystalline Form J₃ of azilsartan medoxomil. XRD as provided in Fig.5.

Example 3:

Preparation of crystalline Form J4 of azilsartan medoxomil. Azilsartan medoxomil (0.5 gm) was dissolved in acetone (10 ml) at 40-45°C and it was filtered. The resulting solution was stirred over a period of 10 min at 40- 45°C and cyclohexane (20 ml) was added to the solution in 10 min at 40-45°C. The reaction mixture was stirred for another 15 min at 40-45 °C and then cooled to 20- 25°C. The solid thus obtained was filtered and suck dried to obtain 0.37 g of crystalline Form J₄ of azilsartan medoxomil. XRD as provided in Fig.9. Example 4:

Preparation of crystalline Form J₄ of azilsartan medoxomil.

Azilsartan medoxomil (0.5 gm) was dissolved in mixture of acetone (7.5 ml) and ethyl acetate (7.5 ml) at 40-45°C. The resulting solution was filtered and then cooled to 0-5°C and stirred. The solid thus obtained was filtered and dried under vacuum to obtain 0.17 g of crystalline Form J₄ of azilsartan medoxomil. XRD as provided in Fig.9.

Example 5:

Preparation of crystalline Form J4 of azilsartan medoxomil.

Azilsartan medoxomil (0.5 gm) was dissolved in mixture of dichloromethane (15 ml) and ethyl acetate (15 ml) at 40-45°C. The resulting solution was filtered and then cooled to 0-5°C and stirred. The solid thus obtained was filtered and dried under vacuum to obtain 0.25 g of crystalline Form J₄ of azilsartan medoxomil. XRD as provided in Fig.9.

Example 6:

Preparation of crystalline Form J5 of azilsartan medoxomil.

Azilsartan medoxomil (0.5 gm) was dissolved in ethyl acetate (45 ml) at 40- 45°C and cyclohexane (90 ml) was added to the solution over a period of 10-15 min at 20-25°C, resulting solution was stirred. The solid thus obtained was filtered and dried under vacuum to obtain 0.21 g of crystalline Form J₅ of azilsartan medoxomil. XRD as provided in Fig. 13.

Example 7:

^Preparation of crystalline Form J₆ of azilsartan medoxomil.

Azilsartan medoxomil (0.5 gm) was dissolved in methanol (15 ml) at 40-45°C and it was filtered. The resulting solution was allowed to cool at 20-25°C and water (30 ml) was added to the solution over a period of 10 min at 20-25°C. The solid thus obtained was filtered and dried under vacuum at 40-45°C to obtain 0.35 g of crystalline Form J₆ of azilsartan medoxomil. XRD as provided in Fig. 17.

Example 8:

Preparation of crystalline Form J₆ of azilsartan medoxomil. Azilsartan medoxomil (0.5 gm) was dissolved in isopropyl alcohol (35 ml) at 40-45°C and it was filtered. The resulting solution was cooled to 20-25°C and water (70 ml) was added to the solution over a period of 10 min at 20-25°C. The solid thus obtained was filtered and dried under vacuum at 40-45°C to obtain 0.37 g of crystalline Form J₆ of azilsartan medoxomil. XRD as provided in Fig. 17.

Example 9:

Preparation of crystalline Form J₇ of azilsartan medoxomil.

Azilsartan medoxomil (0.5 gm) was dissolved in tetrahydrofuran (15 ml) at 40-45°C and it was filtered .The resulting solution was cooled to 20-25°C and water (30 ml) was added to the solution over a period of 10 min at 20-25°C. The solid thus obtained was filtered and dried under vacuum at 40-45°C to obtain 0.41 g of crystalline Form J₇ of azilsartan medoxomil. XRD as provided in Fig. 21.

Example 10:

Preparation of crystalline Form Js of azilsartan medoxomil. Azilsartan medoxomil (0.5 gm) was dissolved in acetonitrile (50 ml) at 40-

45°C and resulting solution was filtered. The solvent was evaporated at a temperature of about 10-15 °C for 72 hrs to obtain 0.35 g of crystalline Form J₈ of azilsartan medoxomil. XRD as provided in Fig. 25.

Example 11:

Preparation of crystalline Form J9 of azilsartan medoxomil.

Azilsartan medoxomil (0.37 g) was dissolved in acetonitrile (17 ml) at 50- 55°C and the solution was stirred at 50-55°C for 15 min. Acetonitrile was evaporated under vacuum at 65 to 70°C to obtain 0.34 g of crystalline azilsartan medoxomil. XRD as provided in Fig.35.

Example 12:

Preparation of amorphous form of azilsartan medoxomil.

Azilsartan medoxomil (5 gm) was dissolved in dichloromethane (500 ml) and resulting solution was filtered. The solvent was subjected to spray drying to obtain 0.90 g of amorphous form of azilsartan medoxomil. XRD as provided in Fig. 29.

Example 13:

Preparation of amorphous form of azilsartan medoxomil. Azilsartan medoxomil (5 gm) was dissolved in acetone (500 ml) and resulting solution was filtered. The solvent was subjected to spray drying to obtain 1 g of amorphous form of azilsartan medoxomil. XRD as provided in Fig. 29.

Example 14:

Preparation of amorphous form of azilsartan medoxomil.

Azilsartan medoxomil (5 gm) was dissolved in acetonitrile (500 ml) and resulting solution was filtered. The solvent was subjected to spray drying to obtain 0.10 g of amorphous form of azilsartan medoxomil. XRD as provided in Fig. 29.

Example 15

Preparation of amorphous form of azilsartan medoxomil.

Azilsartan medoxomil (0.4 g) was dissolved in acetone (17 ml) at 50-55°C and the solution was stirred at 50-55°C for 10 min. The solution was distilled and dried under vacuum at 65°C to obtain 0.38 g of amorphous azilsartan medoxomil. XRD as provided in Fig. 32.

Example 16:

Purification of (5-methyl-2-oxo-l, 3-dioxol-4yl) methyl 2-ethoxy-l-[[2'-(4, 5- dihydro-5-oxo-4H-l, 2, 4-oxadiazol-3-yl) biphenyl-4-yl] methyl]-2-ethoxy-lH- benzimidazole-7-carboxylate (Azilsartan medoxomil) The crude azilsartan medoxomil (20 gm) was suspended in dichloromethane (40 ml) and ethyl acetate (40 ml) at 40-45°C for 10-15 mins and then cooled to 10°- 15°C and stirred. The solid thus obtained was filtered and further suspended in a mixture of dichloromethane (15 ml) and ethyl acetate (15 ml) at 40-45°C and then cooled to 10°-15°C and stirred .The solid thus obtained was filtered and dried to obtain title compound. The particle size obtained is d_0.i=1.8 μηη d_{0 5}=6.1 pm and do.9=14.4 Mm.

Claims

1. Crystalline form J₂ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 6.1 , 7.2, 17.5 ± 0.2 degrees 2Θ.

2. The crystalline form J₂ according to claim 1, wherein the X-ray powder diffraction pattern further comprising peaks at about 13.3, 16.0, 23.3, 24.1 , 27.7 ± 0.2 degrees 2Θ.

3. The crystalline form J₂ of azilsartan medoxomil, having an X-ray powder diffraction pattern in accordance with FIG. 1.

4. The crystalline form J according to claim 1, having an IR spectrum in accordance with FIG.2

5. The crystalline form J₂ according to claim 1 , having differential scanning calorimetry (DSC) in accordance with FIG. 3.

6. The crystalline form J₂ according to claim 1 , having thermo-gravimetric analysis (TGA) in accordance with FIG. 4.

7. The process for preparing crystalline form J₂ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 6.1, 7.2, 17.5 ± 0.2 degrees 2Θ comprising the steps of:

(i) providing a solution of azilsartan medoxomil in alcohol

(ii) removing solvent; and

(iii) isolating crystalline form J₂

8. The₍ process according to claim 7, wherein alcohol is selected from the group comprising methanol, ethanol, isopropyl alcohol, n-butanol; preferably methanol.

9. Crystalline form J₃ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 4.6, 13.2, 29.2 ± 0.2 degrees 2Θ.

10. The crystalline form J₃ according to claim 9, wherein the X-ray powder diffraction pattern further comprising peaks at about 8.8, 13.2, 19.7, 22.6, 23.8 ± 0.2 degrees 2Θ.

1 1. The crystalline form J₃ of azilsartan medoxomil, having an X-ray powder diffraction pattern in accordance with FIG. 5.

12. The crystalline form J₃ according to claim 9, having an IR spectrum in accordance with FIG.6.

13. The crystalline form J₃ according to claim 9, having differential scanning calorimetry (DSC) in accordance with FIG. 7.

14. The crystalline form J₃ according to claim 9, having thermo-gravimetric analysis (TGA) in accordance with FIG. 8.

15. The process for preparing crystalline form J₃ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 4.6, 13.2, 29.2 ± 0.2 degrees 2Θ comprising the steps of :

(i) providing a solution of azilsartan medoxomil in a nitrile solvent

(ii) removing solvent; and

(iii) isolating crystalline form J₃

16. The process according to claim 15, wherein nitrile is selected from the group comprising acetonitrile, propionitrile, butyronitrile; preferably acetonitrile.

17. Crystalline form J₄ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 4.5, 10.7, 26.3 ± 0.2 degrees 2Θ.

18. The crystalline form J₄ according to claim 17, wherein the X-ray powder diffraction pattern further comprising peaks at about 16.6, 18.2, 22.8, 25.2, 26.4 ± 0.2 degrees 2Θ.

19. The crystalline form J₄ of azilsartan medoxomil, having an X-ray powder diffraction pattern in accordance with FIG. 9.

20. The crystalline form J according to claim 17, having an IR spectrum in accordance with FIG.10

21. The crystalline form J₄ according to claim 17, having differential scanning calorimetry (DSC) in accordance with FIG. 1 1.

22. The crystalline form J according to claim 17, having thermo-gravimetric analysis (TGA) in accordance with FIG. 12.

23. The process for preparing crystalline form J₄ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 4.5, 10.7, 26.3 ± 0.2 degrees 2Θ comprising the steps of:

(i) providing a solution of azilsartan medoxomil in ketone followed by addition of an antisolvent or providing a solution of azilsartan medoxomil in mixtures of ketone and ester or providing a solution of azilsartan medoxomil in mixtures of chlorinated solvent and ester.

(ii) Optionally removing solvent; and

(iii) isolating crystalline form J₄

24. The process according to claim 23, wherein ketone is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, preferably acetone ; ester is selected from ethyl acetate, propyl acetate, preferably ethyl acetate; chlorinated solvents is selected from dichloromethane, chloroform, dichloroethane, and chlorobenzene, preferably dichloromethane.

25. Crystalline form J₅ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 8.7, 9.9, 10.7, 18.2 ± 0.2 degrees 2Θ.

26. The crystalline form J₅ according to claim 25, wherein the X-ray powder diffraction pattern further comprising peaks at about 12.4, 19.8, 20.6, 22.8± 0.2 degrees 2Θ.

27. The crystalline form J₅ of azilsartan medoxomil, having an X-ray powder diffraction pattern in accordance with FIG. 13.

28. The crystalline form J₅ according to claim 25, having an IR spectrum in accordance with FIG.14

29. The crystalline form J₅ according to claim 25, having differential scanning calorimetry (DSC) in accordance with FIG. 15.

30. The crystalline form J₅ according to claim 25, having thermo-gravimetric analysis (TGA) in accordance with FIG. 16.

31. The process for preparing crystalline form J₅ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 8.7, 9.9, 10.7, 18.2 ± 0.2 degrees 2Θ comprising the steps of:

(i) providing a solution of azilsartan medoxomil in an ester.

(ii) addition of an antisolvent ; and

(iii) isolating crystalline form J₅

32. The process according to claim 34, wherein ester is selected from ethyl acetate, propyl acetate, preferably ethyl acetate.

33. Crystalline form J₆ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 9.2, 16.0, 20.3 ± 0.2 degrees 2Θ.

34. The crystalline form J₆ according to claim 33, wherein the X-ray powder diffraction pattern further comprising peaks at about 10.0, 13.3, 23.3, 25.1 ± 0.2 degrees 2Θ.

35. The crystalline form J₆ of azilsartan medoxomil, having an X-ray powder diffraction pattern in accordance with FIG. 17.

36. The crystalline form J₆ according to claim 37, having an IR spectrum in accordance with FIG.18

37. The crystalline form J according to claim 37, having differential scanning calorimetry (DSC) in accordance with FIG. 19.

38. The crystalline form J₆ according to claim 37, having thermo-gravimetric analysis (TGA) in accordance with FIG. 20.

39. The process for preparing crystalline form J₆ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 9.2, 16.0, 20.3 ± 0.2 degrees 2Θ comprising the steps of :

(i) providing a solution of azilsartan medoxomil in alcohol

(ii) addition of antisolvent; and

(iii) isolating crystalline form J₆

40. The process according to claim 39, wherein alcohol is selected from the group comprising methanol, ethanol, n-propanol, n-butanol, preferably n-propanol.

41. A process as claimed in any one of the preceding claims, wherein the antisolvent is hydrocarbon.

42. Crystalline form J₇ of Azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 10.5, 14.6, 18.5 ± 0.2 degrees 2Θ.

43. The crystalline form J₇ according to claim 42, wherein the X-ray powder diffraction pattern further comprises peaks at about having 1 1.0, 19.3, 20.9, 21.5, 22.2 ± 0.2 degrees 2Θ.

44. The crystalline form J₇ of azilsartan medoxomil, having an X-ray powder diffraction pattern in accordance with FIG. 21.

45. The crystalline form J₇ according to claim 42, having an IR spectrum in accordance with FIG.22

46. The crystalline form J₇ according to claim 42, having differential scanning calorimetry (DSC) in accordance with FIG. 23.

47. The crystalline form J₇ according to claim 42, having thermo-gravimetric analysis (TGA) in accordance with FIG. 24.

48. The process for preparing crystalline form J₇ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 10.5, 14.6, 18.5 ± 0.2 degrees 2Θ comprising the steps of :

(i) providing a solution of azilsartan medoxomil in ether

(ii) adding an antisolvent; and

(iii) isolating crystalline form J₇

49. The process according to claim 48, wherein ether is selected from tetrahydrofuran, diisopropyl ether, diethyl ether, preferably tetrahydrofuran and antisolvent is water.

50. Crystalline form J₈ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 6.0, 17.3, 21.3 ± 0.2 degrees 2Θ.

51. The crystalline form J according to claim 50, wherein the X-ray powder diffraction pattern further comprises peaks at about having 13.1 , 15.7, 22.3, 23.4, 24.8 ± 0.2 degrees 2Θ.

52. The crystalline form Jg of azilsartan medoxomil, having an X-ray powder diffraction pattern in accordance with FIG. 25.

53. The crystalline form J₈ according to claim 50, having an IR spectrum in accordance with FIG.26.

54. The crystalline form J₈ according to claim 50, having differential scanning calorimetry (DSC) in accordance with FIG. 27.

55. The crystalline form J₈ according to claim 50, having thermo-gravimetric analysis (TGA) in accordance with FIG. 28.

56. The process for preparing crystalline form J₈ of azilsartan medoxomil comprising of :

(i) providing a solution of azilsartan medoxomil in a nitrile solvent; and (ii) isolating crystalline form Jg

57. The process according to claim 56, wherein nitrile is selected from the group comprising of acetonitrile, propionitrile and butyronitrile, preferably acetonitrile.

58. Crystalline form J₉ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 1 1.3, 13.0, 22.3 ± 0.2 degrees 2Θ.

59. The crystalline form J₉ according to claim 58, wherein the X-ray powder diffraction pattern further comprises peaks at about having 8.7, 19.2, 20.4, 21.9, 23.5 ± 0.2 degrees 2Θ.

60. The crystalline form J₉ of azilsartan medoxomil, having an X-ray powder diffraction pattern in accordance with FIG. 35.

61. The crystalline form J₉ according to claim 58, having an IR spectrum in accordance with FIG.36.

62. The crystalline form J₉ according to claim 58, having differential scanning calorimetry (DSC) in accordance with FIG. 37.

63. The process for preparing crystalline form J₉ of azilsartan medoxomil having an X-ray powder diffraction pattern comprising peaks at about 1 1.3, 13.0, 22.3 ± 0.2 degrees 2Θ comprising the steps of :

(iii) providing a solution of azilsartan medoxomil in a nitrile solvent

(iv) removing solvent; and

(v) isolating crystalline form J₉

64. The process according to claim 63, wherein nitrile is selected from the group comprising acetonitrile, propionitrile and butyronitrile, preferably acetonitrile.

65. Amorphous azilsartan medoxomil

66. Amorphous azilsartan medoxomil having an X-ray powder diffraction pattern in accordance with FIG. 29.

67. Amorphous azilsartan medoxomil having an X-ray powder diffraction pattern in accordance with FIG. 32.

68. The process for preparing amorphous azilsartan medoxomil comprising :

(i) providing a solution of azilsartan medoxomil in one or more solvents (ii) removing solvent under vacuum ; and

(iii) isolating amorphous azilsartan medoxomil

69. The process according to claim 68, wherein solvent is selected from nitrile, chlorinated solvent, ester, alcohol and ether.

70. The process as claimed in claim 69, wherein nitrile can be selected from the group comprising acetonitrile, propionitrile, butyronitrile, preferably acetonitrile ; chlorinated solvent can be selected from dichloromethane, chloroform, dichloroethane, preferably dichloromethane; ketone can be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, preferably acetone; ester can be selected from ethyl acetate, propyl acetate; alcohol can be selected from methanol, ethanol, n-propanol, isopropanol, n-butanol; ether can be selected from diethyl ether, diisopropyl ether, and tetrahydrofuran.

71. The process according to claim 68, wherein the process for removal of solvent can be selected from the method comprising of spray drying, distillation under vacuum, freeze drying and roller drying.

72. Azilsartan medoxomil or pharmaceutically acceptable salts thereof having particle size distribution, wherein d₅₀ is less than about 10 μι^η and d₉₀ is less than about 20 μιη.

73. The process according to any of the preceeding claim, wherein azilsartan medoxomil is converted into its pharmaceutically acceptable salts thereof such as alkali or alkaline earth metal salts; more preferably monopotassium salt.

74. A pharmaceutical composition, which includes therapeutically effective amount of azilsartan medoxomil or salts thereof according to any of the preceeding claims.

75. Use of azilsartan medoxomil or salts thereof prepared according to any of the preceeding claims.