FIELD OF THE INVENTION
The present invention relates to the novel process for the preparation of amorphous form of Elagolix sodium (1) with purity greater than 99.0% (w/w).
BACKGROUND OF THE INVENTION
Elagolix Sodium is a nonpeptide small molecule and gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis. Chemically, it is described as sodium 4-({(lR)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl) phenyl] methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)- yl]-l-phenylethyl} amino) butanoate. It was approved in US for medical use in July 2018 and being sold under the brand name ORILISSA.
US8765948 patent discloses process for preparation of Elagolix sodium. It further discloses amorphous form of Elagolix sodium isolated by lyophilization, spray drying, co-spraying, precipitation or co-precipitation and use of excipients and polymers to stabilize amorphic material. It further discloses preparation of solid dispersion of Elagolix sodium with different polymers in 3-fold amount with respect to the active substance, which significantly increases the total weight and volume of tablet or a capsule and may cause difficulty in administration.
US9949973 patent discloses Elagolix as amorphous and hygroscopic solid having poor flowability (ffc < 2), and low bulk density (< 0.25 g/mlj) and a variable particle size distribution due to the agglomeration of sub-micron primary particles. It further discloses that Elagolix drug substance was employed in form of its sodium salt.
WO2018189213 application discloses amorphous solid dispersion of Elagolix sodium, and at least one silicon-based inorganic compound.
WO2019115019 application discloses process for preparation of Elagolix Sodium and crystalline forms of intermediates used in the process.

WO2018198086 discloses process for the preparation of Elagolix and different pharmaceutical^ acceptable salts of Elagolix of formula (I).
There is need to develop novel process for preparing amorphous Elagolix sodium salt. Hence, the present inventors hereby disclose novel process for preparing amorphous Elagolix sodium salt.
OBJECTIVE OF THE INVENTION
In one object, the present invention provides a novel process for the preparation of amorphous form of Elagolix sodium (1).
In another object, the present invention provides process for the preparation of different salts of Elagolix and converting into Elagolix sodium.
In another object, the present invention provides a process for preparing Elagolix of formula (I) or pharmaceutically acceptable salt thereof, preferably potassium salt of Elagolix.
In another embodiment, the present invention provides process for the purification of Elagolix by isolating as potassium salts and purifying from a suitable solvent.
In another object, the present invention provides amorphous form of Elagolix sodium (1) with purity greater than 99.0%.
SUMMARY OF THE INVENTION
Accordingly, in one aspect the present invention provides a novel process for the preparation of amorphous form of Elagolix sodium (1).
In another aspect, the present invention provides a novel process for the preparation of amorphous form of Elagolix sodium (1), comprising:
a) providing a solution of Elagolix sodium (1) in a suitable solvent or mixture of solvents;
b) removing the solvent using a suitable technique; and

c) isolating amorphous Elagolix sodium (1).
In another aspect, the present invention provides alternative process for the preparation of amorphous form of Elagolix sodium (1), comprising:
a) providing a solution of Elagolix sodium (1) in a suitable first solvent;
b) adding the reaction mixture to a suitable second solvent; and
c) isolating the amorphous Elagolix sodium (1) using a suitable technique.
In another aspect, the present invention provides alternative process for the preparation of amorphous form of Elagolix sodium (1), comprising:
a) providing a solution of Elagolix sodium (1) in a suitable first solvent;
b) removing the solvent using a suitable technique;
c) adding a suitable second solvent to the concentrate; and
d) isolating the amorphous Elagolix sodium (1).
In another aspect, the present invention provides alternative process for the preparation of amorphous form of Elagolix sodium (1), comprising:
a) providing a solution of Elagolix sodium (1) in a suitable solvent;
b) transferring the solution to a Petri plate; and
c) isolating amorphous Elagolix sodium (1).
In another aspect, the present invention provides amorphous form of Elagolix sodium (1) prepared herein is having purity more than 99.0% by HPLC.
In some aspect, the present invention provides, process for the preparation of different salts of Elagolix, comprising:
a) adding Elagolix free base to a suitable solvent or mixture of solvents;
b) adding suitable base or suitable acid to the solvent mixture;
c) extracting with a suitable mixture of solvents; and
d) isolating the desired acid addition salt or base addition salt of Elagolix .
In another aspect, the present invention provides process for the preparation of potassium salt of Elagolix and its purification thereof.

In yet another aspect, the present invention provides process for the conversion of potassium salt of Elagolix to Elagolix sodium.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates XRD pattern of amorphous form of Elagolix sodium (1) prepared by example 1.
Figure 2 illustrates XRD pattern of amorphous form of Elagolix sodium (1) prepared by example 2.
Figure 3 illustrates XRD pattern of amorphous form of Elagolix sodium (1) prepared by example 3.
Figure 4 illustrates XRD pattern of amorphous form of Elagolix sodium (1) prepared by example 4.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment the present invention provides a novel process for the preparation of amorphous form of Elagolix sodium (1).
In another embodiment, the present invention provides a novel process for the preparation of amorphous form of Elagolix sodium (1), comprising:
a) providing a solution of Elagolix sodium (1) in a suitable solvent or mixture of solvents;
b) removing the solvent using a suitable technique; and
c) isolating amorphous Elagolix sodium (1).
Elagolix sodium (1) may be dissolved in a mixture of suitable solvents and the excess solvent removed using a suitable technique, preferably by distillation. The solid obtained may be dried and amorphous Elagolix sodium (1) may be isolated. The reaction may be carried out at a temperature range of 20-70 °C, preferably at 25-30 °C in some instances and 50-60 °C in other instances.

In another embodiment, the present invention provides alternative process for the preparation of amorphous form of Elagolix sodium (1), comprising:
a) providing a solution of Elagolix sodium (1) in a suitable first solvent;
b) adding the reaction mixture to a suitable second solvent; and
c) isolating the amorphous Elagolix sodium (1) using a suitable technique.
Elagolix sodium (1) may be dissolved in a mixture of suitable first solvent and filtered. The filtrate was then added to a second solvent. The solid formed was filtered and dried using a suitable technique to yield amorphous Elagolix sodium (1). The reaction may be carried out at a temperature range of 20-50 °C, preferably at 25-35 °C.
In another embodiment, the present invention provides alternative process for the preparation of amorphous form of Elagolix sodium (1), comprising:
e) providing a solution of Elagolix sodium (1) in a suitable first solvent;
f) removing the solvent using a suitable technique;
g) adding a suitable second solvent to the concentrate; and h) isolating the amorphous Elagolix sodium (1).
Elagolix sodium (1) may be dissolved in a suitable solvent and the excess solvent removed using a suitable technique, preferably by distillation. A suitable second solvent may be added to the concentrate and dried to yield amorphous Elagolix sodium (1). The reaction may be carried out at a temperature range of 20-70 °C, preferably at 25-30 °C in some instances and 50-60 °C in other instances.
In another embodiment, the present invention provides alternative process for the preparation of amorphous form of Elagolix sodium (1), comprising:
d) providing a solution of Elagolix sodium (1) in a suitable solvent;
e) transferring the solution to a Petri plate; and
f) isolating the amorphous Elagolix sodium (1).
Elagolix sodium (1) may be dissolved in a suitable solvent. The clear solution obtained may be added transferred to a petri plate for open air drying. The reaction mass so

obtained may be dried under vacuum to yield amorphous Elagolix sodium (1). The reaction may be carried out at a temperature range of 20-70 °C, preferably at 25-30 °C in some instances and 50-60 °C in other instances.
In another embodiment, the present invention provides amorphous form of Elagolix sodium (1) prepared herein is having purity more than 99.0% by HPLC.
In some aspect, the present invention provides, process for the preparation of different salts of Elagolix, comprising:
a) providing Elagolix free base in a suitable solvent or mixture of solvent;
b) adding the suitable base or suitable acid;
c) extracting with a suitable mixture of solvents; and
d) isolating to the suitable pharmaceutically acceptable salt of Elagolix.
The term "pharmaceutically acceptable salt" may comprise of acid or base addition salts. Acid addition salts of the present invention may be formed from organic and inorganic acids. Suitable acids may be selected from but not limited to maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methane sulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. The base used to prepare base addition salts may be selected from a group comprising of organic or inorganic bases. Inorganic bases may be selected from a group comprising of sodium hydroxide, potassium hydroxide or the like. Organic bases may be selected from a group comprising of methylamine, ethylamine, triethylamine, n-propylamine, isopropyl amine, butylamine, dibenzyl ammonium, benzyl ammonium, ammonium hydroxide or the like.
In another embodiment, the present invention provides a process for preparing the sodium and potassium salt of Elagolix.

In another embodiment, the present invention provides a process for preparing Elagolix sodium (1) by treating potassium salt of Elagolix with a suitable acid. Optionally, the potassium salt of Elagolix may be purified from using suitable solvents or mixtures thereof. The Elagolix free base formed, may be further treated with a suitable sodium salt, preferably sodium hydroxide to yield Elagolix sodium (1). The suitable acid may be selected from a group comprising of organic or inorganic acids. Organic acids may be selected from a group comprising of pamoic acid, (+)-2,3- dibenzoyl-D-tartaric acid, citric acid, maleic acid, fumaric acid, oxalic acid, malonic acid, succinic acid, malic acid, tartaric acid, aspartic acid, glutamic acid. Inorganic acids may be selected from a group comprising of hydrochloric acid, sulfuric acid, phosphoric acid or the like.
In another embodiment, the suitable solvents used in the present invention was selected from a group comprising of protic, aprotic solvents or mixtures thereof. The protic solvents may be selected from a group comprising of water, methanol, ethanol, isopropyl alcohol, isobutyl alcohol, dimethyl sulfoxide, or the like, preferably water and methanol were used in the present invention ; the aprotic solvents may be selected from a group comprising of acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, butyl acetate ,N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toluene, tetrahydrofuran or the like, preferably acetone, ethyl acetate and hexane were used in the present invention.
In another embodiment, the suitable techniques used for the isolation of amorphous forms of Elagolix sodium (1) may be selected from a group comprising of solvent evaporation, distillation, lyophilization or freeze drying, spray drying, agitated thin film drying (ATFD), air tray drying (ATD), cooling the solvent, adding anti-solvent to the reaction mixture and combination thereof. Preferably, solvent evaporation by distillation and air tray drying (ATD) were used in the present invention.

Yet, in another embodiment, the amorphous forms of Elagolix sodium (1) obtained by any of the above methods may be characterized by the X-ray powder diffraction pattern as shown in figure 1, figure 2, figure 3 and figure 4.
Yet, in another embodiment, the amorphous forms of Elagolix sodium (1) obtained by any of the above methods is having particle size less than 200 microns, preferably less than 100 microns and more preferably less than 50 microns.
In another embodiment Elagolix sodium (1) obtained by any of the above methods is having surface area less than 0.5%.
In another embodiment Elagolix sodium (1) obtained by any of the above methods is having moisture content less than 10% (w/w).
In another embodiment Elagolix sodium (1) obtained by any of the above methods is having total impurities less than l%(w/w), preferably less than 0.5% (w/w).
The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES
EXAMPLE 1: Preparation of amorphous form of Elagolix sodium (1)
l.Ogm of Elagolix sodium (1) was added to 20mL mixture of ethyl acetate and methanol in the ratio of 8:2 at 25-35 °C. The solvent was distilled below 60 °C and the solid formed was isolated and dried under vacuum to yield amorphous form of Elagolix sodium (1). Yield: 90%, XRD: Figure 1.

EXAMPLE 2: Alternate process for the preparation of amorphous form of Elagolix sodium (1)
15.0gm of Elagolix sodium (1) was added to a 50mL ethyl acetate at 25-35 °C, stirred
and filtered. The filtrate was then added to 200mL of n-hexane with the formation of
solid. The solid formed was filtered and dried in air tray dryer (ATD) below 35 °C to
yield amorphous form of Elagolix sodium (1). Yield: 80%, XRD: Figure 2.
EXAMPLE 3: Alternate process for the preparation of amorphous form of
Elagolix sodium (1)
l.Ogm of Elagolix sodium (1) was added to 10 mL of water at 25-35 °C and stirred.
The solvent was distilled of below 60 °C. 40 mL of acetone was added to the
concentrate. The solid formed was collected and dried to yield amorphous form of
Elagolix sodium (1). Yield: 80%, XRD: Figure 3.
EXAMPLE 4: Alternate process for the preparation of amorphous form of
Elagolix sodium (1)
l.Ogm of Elagolix sodium (1) was added to 10 mL of water at 25-35 °C and stirred.
The reaction solution was poured into a Petri plate. The solvent was evaporated at 25-
30 °C for 2days. The solid formed was collected and dried to yield amorphous form of
Elagolix sodium (1). Yield: 80%, XRD: Figure 4.
EXAMPLE 5: Process for the preparation of Elagolix potassium salt (1)
l.Ogm of Elagolix free base was dissolved in a mixture of tetrahydrofuran and water.
1.6g of solid potassium hydroxide was added and the resulting mixture was heated at
50° C. The mixture was cooled, layers separated, and citric acid was added to the
aqueous solution to maintain a pH of 3. The reaction mixture was then extracted with
ethyl acetate and solvent removed by evaporation. The reaction mass was then passed
through a cation-exchange column to convert to potassium salt of Elagolix. Yield: 65%.
EXAMPLE 6: Alternate process for the preparation of Elagolix sodium (1)
Elagolix ester was dissolved in ethanol and a solution of sodium hydroxide added at
25-30 °C. The solvent was removed by distillation and water added to the concentrated
mass and filtered. Ethyl acetate was added to the filtrate and the mixture heated to 55

°C. The layers were separated, and the aqueous layer treated with ethyl acetate. Further potassium hydroxide was added, and the reaction mass stirred. The total organic layer was separated and concentrated. The concentrated reaction mixture solution was filtered through a 0.2-micron filter and added to hexane. The reaction mass was then cooled to 20 °C, filtered to yield potassium salt of Elagolix. Elagolix potassium, was then treated with hydrochloric acid and finally converted to Elagolix sodium (1) using sodium hydroxide.
EXAMPLE 7: Alternate process for the preparation of Elagolix sodium (1) l.Ogm of Elagolix free base was dissolved in a mixture of 30 mL tetrahydrofuran and 30 mL water. 1.6g of solid sodium hydroxide was added and the resulting mixture was heated at 50° C. The mixture was cooled and extracted with ethyl acetate. The organic layer was separated and distilled off under vacuum to yield Elagolix sodium (1). Yield: 80%.
EXAMPLE 8: Alternate process for the preparation of Elagolix sodium (1) l.Ogm of Elagolix free base was dissolved in a mixture of 30 mL tetrahydrofuran and 30 mL water. 1.6g of solid sodium hydroxide was added and the resulting mixture was heated at 50 °C. The mixture was cooled and extracted with ethyl acetate. The organic layer was separated, and hexane was added. The precipitated solid was filtered and dried under vacuum to yield Elagolix sodium (1). Yield: 85%.

We Claim:
1. A process for the preparation of amorphous form of Elagolix sodium (1),
comprising:
a) providing a solution of Elagolix sodium (1) in a suitable solvent or mixture of solvents;
b) removing the solvent using a suitable technique; and
c) isolating amorphous Elagolix sodium (1).
2. An alternative process for the preparation of amorphous form of Elagolix
sodium (1), comprising:
a) providing a solution of Elagolix sodium (1) in a suitable first solvent;
b) adding the reaction mixture to a suitable second solvent; and
c) isolating the amorphous Elagolix sodium (1) using a suitable technique.
3. An alternative process for the preparation of amorphous form of Elagolix
sodium (1), comprising:
a) providing a solution of Elagolix sodium (1) in a suitable first solvent;
b) removing the solvent using a suitable technique;

c) adding a suitable second solvent to the concentrate; and
d) isolating amorphous Elagolix sodium (1).
4. The process according to claim 1, claim 2 and claim 3, wherein the suitable
techniques used for isolation is selected from a group comprising of solvent
evaporation, distillation, lyophilization or freeze drying, spray drying, agitated
thin film drying (ATFD), air tray drying (ATD), precipitating , cooling the
solvent, adding anti-solvent to the reaction mixture and combination thereof.
5. A process for the preparation of different suitable pharmaceutically acceptable
salts of Elagolix, comprising:
a) providing Elagolix free base in a suitable solvent or mixture of solvent;
b) adding the suitable base or suitable acid;
c) extracting with a suitable mixture of solvents; and
d) isolating the suitable pharmaceutically acceptable salt of Elagolix.

6. The process according to claim 1, claim 2 and claim 3 and claim 5 wherein, the suitable solvents is selected from a group comprising of water, methanol, ethanol, isopropyl alcohol, isobutyl alcohol, dimethyl sulfoxide, acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, butyl acetate ,N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toluene, tetrahydrofuran or mixtures thereof.
7. The process, according to claim 5, wherein the pharmaceutically acceptable salt of Elagolix may be acid addition salt or base addition salts.
8. The process, according to claim 5, wherein the suitable bases is selected from a group comprising of sodium hydroxide, potassium hydroxide, methylamine, ethylamine, triethylamine, n-propylamine, isopropyl amine, butylamine, ammonium hydroxide, dibenzyl ammonium and benzyl ammonium.
9. The process, according to claim 7, wherein the suitable acid is selected from a group comprising of ascorbic acid , acetic acid, trifluoroacetic acid, aspartic acid benzoic acid, citric acid , cinnamic acid , fumaric acid, glycolic acid , glutamic acid , gluconic acid, lactic acid , (+)-2,3- dibenzoyl-D-tartaric acid, tartaric acid , maleic acid, , mandelic acid, malic acid , oxalic acid, malonic acid, succinic acid, salicylic acid, stearic acid, propionic acid , palmitic acid , pamoic acid , methane sulfonic acid , benzenesulfonic acid , hydrochloric acid, hydrobromic acid , sulfuric acid, nitric acid or phosphoric acid.,
10. The process, according to claim 1, claim 2 and claim 3, wherein, the Elagolix
sodium (1) is having particle size less than 200 microns.