DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

PROCESS FOR THE PREPARATION OF AMORPHOUS LESINURAD

INTRODUCTION
Aspects of the present application relates to the processes for the preparation of amorphous Lesinurad.

Lesinurad is a selective uric acid re-absorption inhibitor (SURI). Lesinurad is used for reducing serum uric acid level and for the treatment of gout and hyperurecemia. Lesinurad is chemically known as 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid and has following structural formula (I).

I
US8546436B2 discloses crystalline Forms 1 and 2 of Lesinurad and their processes for preparation. Similarly, US8524754B2 discloses crystalline forms A, B, B’, C, D and E of Lesinurad sodium and their processes for preparation.
WO2015075561A1 assigned to Crystal Pharmatech Co Ltd & Suzhou pengxu harmatech co. ltd., discloses crystalline forms III, IV, V, and VI of Lesinurad and their process for preparation.
CN104557748 A assigned to Guangdong East Sunshine Pharmaceutical Co., Ltd., discloses crystalline forms a, ß of Lesinurad and their process for preparation.
WO2015095703 A1 assigned to Crystal Pharmatech Co Ltd & Suzhou pengxu harmatech co. ltd., discloses co-crystal of Lesinurad and proline, co-crystal of Lesinurad and glycolic acid.
WO2016203436 A1 assigned to Dr.Reddy’s Laboratories, discloses amorphous form of Lesinurad and its process for preparation.

In general, polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices. Thus, “polymorphs” refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting points, solubilities, etc. The variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form. For these reasons, regulatory authorities require drug manufacturing companies to put efforts into identifying all different solid forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.

The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, “Tricky Business,” Science News, Vol. 166(8), August 2004.

Hence, there remains a need for alternate process for the preparation of amorphous Lesinurad, which are amenable to scale up for the larger production quantities and may yield both formulation and therapeutic benefits.

SUMMARY
In an aspect, the present application provides process for preparing amorphous form of Lesinurad comprising:
a) dissolving Lesinurad in a suitable solvent or mixture thereof;
b) optionally, heating the solution of step (a);
c) adding water as an anti-solvent to the solution of Lesinurad; or adding solution of Lesinurad to water;
d) isolating amorphous form of Lesinurad.

In another aspect, the present application provides for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) spray drying the resultant solution obtained from step a);
c) isolating amorphous form of Lesinurad.

In another aspect, the present application provides for preparing amorphous form of Lesinurad comprising:
a) dissolving Lesinurad in a suitable solvent or mixture thereof;
b) optionally, heating the solution of step (a);
c) adding water as an anti-solvent to the solution of Lesinurad; or adding solution of Lesinurad to water;
d) lyophilizing the resultant slurry obtained from step c);
e) isolating amorphous form of Lesinurad.

In another aspect, the present application provides for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) evaporating the solvent in rotavapor obtained from step a);
c) isolating amorphous form of Lesinurad.

In another aspect, the present application provides for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) adding a base to the solution of step a);
c) acidifying the solution obtained from step b) with acid;
d) isolating amorphous form of Lesinurad.

In another aspect, the present application provides for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) adding sodium hydroxide to the solution of step a);
c) acidifying the solution obtained from step b) with hydrochloric acid;
d) isolating amorphous form of Lesinurad.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is an illustrative X-ray powder diffraction of amorphous form of Lesinurad prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction of amorphous form of Lesinurad prepared by the method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction of amorphous form of Lesinurad prepared by the method of Example-3.
Figure 4 is an illustrative X-ray powder diffraction of amorphous form of Lesinurad prepared by the method of Example-4.
Figure 5 is an illustrative X-ray powder diffraction of amorphous form of Lesinurad prepared by the method of Example-5.
Figure 6 is an illustrative X-ray powder diffraction of amorphous form of Lesinurad prepared by the method of Example-6.
Figure 7 is an illustrative X-ray powder diffraction of amorphous form of Lesinurad prepared by the method of Example-7.
Figure 8 is an illustrative X-ray powder diffraction of amorphous form of Lesinurad prepared by the method of Example-8.
Figure 9 is an illustrative X-ray powder diffraction of amorphous form of Lesinurad prepared by the method of Example-9.

DETAILED DESCRIPTION

In an aspect, the present application provides process for preparing amorphous form of Lesinurad comprising:
a) dissolving Lesinurad in a suitable solvent or mixture thereof;
b) optionally, heating the solution of step (a);
c) adding water as an anti-solvent to the solution of Lesinurad; or adding solution of Lesinurad to water;
d) isolating amorphous form of Lesinurad.

Suitable solvents of step a) for dissolving Lesinurad include, but are not limited to alcohols such as methanol, ethanol, propanol, isopropanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as chloroform, dichloromethane and mixtures thereof.
In an embodiment, water as an anti-solvent may be added to the reaction solution obtained in either step (a) or step (b) of the present invention by drop wise or in a single lot based on the solvent used in step (a) of the present invention. Optionally, the solution obtained in step (a) or step (b) may be added to water.
The temperature at which the above steps may be carried out in between about -70 °C and about 100 °C, based on the solvent or mixture of solvent used in particular step.
The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.

In another aspect, the present application provides for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) spray drying the resultant solution obtained from step a);
c) isolating amorphous form of Lesinurad.
Providing a solution of Lesinurad in step a) includes:
i) direct use of a reaction mixture containing Lesinurad that is obtained in the course of its synthesis; or
ii) dissolving Lesinurad in a solvent.

Suitable solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. Examples of such solvents include, but are not limited to: esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; alcohols, such as methanol, ethanol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, ?,?-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide; sulfoxides, such as dimethylsulfoxide; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; or any mixtures of two or more solvents thereof.
The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted. The concentration of Lesinurad in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
The isolation of step c) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures. The amorphous form of Lesinurad as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.
The temperature at which the above steps may be carried out in between about 20 °C and about 100 °C, based on the solvent or mixture of solvent used in particular step.

In another aspect, the present application provides for preparing amorphous form of Lesinurad comprising:
a) dissolving Lesinurad in a suitable solvent or mixture thereof;
b) optionally, heating the solution of step (a);
c) adding water as an anti-solvent to the solution of Lesinurad; or adding solution of Lesinurad to water;
d) lyophilizing the resultant slurry obtained from step c);
e) isolating amorphous form of Lesinurad.

Suitable solvents of step a) for dissolving Lesinurad include, but are not limited to alcohols such as methanol, ethanol, propanol, isopropanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as chloroform, dichloromethane and mixtures thereof.
In an embodiment, water as an anti-solvent may be added to the reaction solution obtained in either step (a) or step (b) of the present invention by drop wise or in a single lot based on the solvent used in step (a) of the present invention. Optionally, the solution obtained in step (a) or step (b) may be added to water.
The temperature at which the above steps may be carried out in between about -70 °C and about 100 °C, based on the solvent or mixture of solvent used in particular step.
The isolation of step e) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.

In another aspect, the present application provides for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) evaporating the solvent in rotavapor obtained from step a);
c) isolating amorphous form of Lesinurad.
Providing a solution of Lesinurad in step a) includes:
i) direct use of a reaction mixture containing Lesinurad that is obtained in the course of its synthesis; or
ii) dissolving Lesinurad in a solvent.

Suitable solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. Examples of such solvents include, but are not limited to: esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; alcohols, such as methanol, ethanol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, ?,?-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide; sulfoxides, such as dimethylsulfoxide; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; or any mixtures of two or more solvents thereof.
The temperature at which the above steps may be carried out in between about 10 °C and about 100 °C, based on the solvent or mixture of solvent used in particular step.
The isolation of step c) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.

In another aspect, the present application provides for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) adding a base to the solution of step a);
c) acidifying the solution obtained from step b) with acid;
d) isolating amorphous form of Lesinurad.
Providing a solution of Lesinurad in step a) includes:
i) direct use of a reaction mixture containing Lesinurad that is obtained in the course of its synthesis; or
ii) dissolving Lesinurad in a solvent.

Suitable solvents of step a) for dissolving Lesinurad include, but are not limited to water, alcohols such as methanol, ethanol, propanol, isopropanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as chloroform, dichloromethane and mixtures thereof.
Suitable base used in step b) include, but are not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
Suitable acid used in step c) include, but are not limited to hydrochloric acid, hydrobromic acid, nitric acid, hydroiodic acid, sulfuric acid, acetic acid and the like.

The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.

In another aspect, the present application provides for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) adding sodium hydroxide to the solution of step a);
c) acidifying the solution obtained from step b) with hydrochloric acid;
d) isolating amorphous form of Lesinurad.
Suitable solvents of step a) for dissolving Lesinurad include, but are not limited to water, alcohols such as methanol, ethanol, propanol, isopropanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as chloroform, dichloromethane and mixtures thereof.
The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.

Lesinurad that is used as starting material for the preparation of any of the solid forms of present application may be purified before using employing any of the purification techniques known in the art such as recrystallization, slurrying or chromatography or according to the procedures described or exemplified in the instant application.
Starting material may be either in a Lesinurad crystalline form 1 or Lesinurad crystalline form 2 or an alternate crystalline form of Lesinurad known in the art.
All PXRD data reported herein are obtained using a PANalytical X-ray Diffractometer with copper Ka radiation.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
EXAMPLES

Example-1: Preparation of amorphous form of Lesinurad.
Lesinurad (1 g) was dissolved in methanol (20 mL) at 60°C. The clear solution was added dropwise to water (100 mL) at -10°C and maintained for 2 hours. The solid was filtered and was dried at 25-30°C under vacuum to provide the title compound.

Example-2: Preparation of amorphous form of Lesinurad.
Lesinurad (3 g) was dissolved in methanol (60 mL) at 60°C and filtered the solution to make it particle free. The clear solution was added dropwise to water (300 mL) at 5°C and maintained for upto 28 hours between 0 to -5°C. The solid was filtered and was dried at 25-30°C under vacuum to provide the title compound.

Example-3: Preparation of amorphous form of Lesinurad.
Lesinurad (3 g) was dissolved in methyl acetate (140 mL) at 25°C and filtered the solution to make it particle free. The clear solution was spray dried with 75% aspirator, inlet temperature of 40°C and out let temperature of 31-33°C to obtain 1.7 g of the title compound.

Example-4: Preparation of amorphous form of Lesinurad.
Lesinurad (3 g) was dissolved in ethyl acetate (150 mL) at 30°C and filtered the solution to make it particle free. The clear solution was spray dried with 75% aspirator, inlet temperature of 40-43°C and out let temperature of 31-34°C to obtain 1.2 g of the title compound.

Example-5: Preparation of amorphous form of Lesinurad.
Lesinurad (5 g) was dissolved in ethyl acetate (500 mL) at 30°C and filtered the solution to make it particle free. The clear solution was spray dried with 75% aspirator, inlet temperature of 40-44°C and out let temperature of 29-33°C to obtain 2.4 g of the title compound.

Example-6: Preparation of amorphous form of Lesinurad.
Lesinurad (1 g) was dissolved in ethyl acetate (100 mL) at 25°C and stirred for 5-10 minutes. Clear solution was taken in buchi flask in rotavapor and temperature raised to 35°C and vacuum pump started. Solids isolated on solvent evaporation gave title compound.

Example-7: Preparation of amorphous form of Lesinurad.
Lesinurad (1 g) was dissolved in methanol (15 mL) at 60°C. The clear solution was added dropwise to cold water (100 mL) and slurry kept in dry ice bath to freeze. The frozen slurry was lyophilized to obtain the title compound.

Example-8: Preparation of amorphous form of Lesinurad.
Lesinurad (1 g) and water (50 mL) were charged in to the reactor and cooled to 10°C. 1N sodium hydroxide solution (2mL) was added to the resultant slurry at 10°C. 37% HCl (4 drops) was added dropwise to the above solution. Solids isolated were filtered and dried obtained title compound.

Example-9: Preparation of amorphous form of Lesinurad.
Water (50 mL) was charged in to the reactor and cooled to 10°C and Lesinurad (3 g) was charged into the water at 10°C. 1N sodium hydroxide solution (4.5 mL) was added to the resultant slurry at 10°C. 37% HCl (1mL) was added dropwise to the above solution. Water (30 mL) was added to the above solution, and pH observed to be 5. 37% HCl (0.3mL) was added dropwise to the above solution to make pH is 3 and the slurry maintained for approx 60 minutes. Filtered and dried the obtained title compound.
,CLAIMS:WE CLAIM:
1) A process for preparing amorphous form of Lesinurad comprising:
a) dissolving Lesinurad in a suitable solvent or mixture thereof;
b) optionally, heating the solution of step (a);
c) adding water as an anti-solvent to the solution of Lesinurad; or adding solution of Lesinurad to water;
d) isolating amorphous form of Lesinurad.

2) A process for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) spray drying the resultant solution obtained from step a);
c) isolating amorphous form of Lesinurad.

3) A process for preparing amorphous form of Lesinurad comprising:
a) dissolving Lesinurad in a suitable solvent or mixture thereof;
b) optionally, heating the solution of step (a);
c) adding water as an anti-solvent to the solution of Lesinurad; or adding solution of Lesinurad to water;
d) lyophilizing the resultant slurry obtained from step c);
e) isolating amorphous form of Lesinurad.

4) A process for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) evaporating the solvent in rotavapor obtained from step a);
c) isolating amorphous form of Lesinurad.

5) A process for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) adding a base to the solution of step a);
c) acidifying the solution obtained from step b) with acid;
d) isolating amorphous form of Lesinurad.

6) A process for preparing amorphous form of Lesinurad comprising:
a) providing a solution of Lesinurad in a solvent;
b) adding sodium hydroxide to the solution of step a);
c) acidifying the solution obtained from step b) with hydrochloric acid;
d) isolating amorphous form of Lesinurad.