WO2018224063A2

WO2018224063A2 - Solid forms of elagolix

Info

Publication number: WO2018224063A2
Application number: PCT/CZ2018/050031
Authority: WO
Inventors: Ruzena Vlasakova; Igor CERNA; Iva OBADALOVA; Lukas KREJCIK; Ondrej Dammer; Jaroslava SVOBODOVA; Filip SEMBERA
Original assignee: Zentiva, K.S.
Priority date: 2017-06-08
Filing date: 2018-06-06
Publication date: 2018-12-13
Also published as: WO2018224063A3

Abstract

The invention provides novel solid forms of elagolix and its esters, optionally with acids or with polymers, method of preparation and use thereof. These solid forms are particularly suitable as intermediates of synthesis of elagolix or as components of pharmaceutical formulations.

Description

Solid forms of elagolix

Field of Art

The present invention relates to novel solid forms of elagolix. Solid forms include free acid, salts, esters, and crystalline forms. The invention provides methods of preparation of said novel forms, and use thereof.

Background Art

Elagolix, or (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl- 2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)butanoic acid is a highly active second generation selective non-peptidic antagonist of the gonadotropin-releasing hormone receptor (GnRHR). The drug is currently in phase III of clinical tests and is destined for the treatment of endometriosis and uterine myoma. Endometriosis is a frequent cause of infertility, connected with a chronic pelvic and peri- menstrual pain.

The molecule of elagolix was first described, together with its sodium salt, in an international patent application WO 2005/007165. The sodium salt was obtained in amorphous form by lyofilization. Later on, in WO 2009/062087, a more detailed description of the method of synthesis of said drug was described. It involves the formation of elagolix ethylester (lb) and its hydrolysis to yield the free acid or the sodium salt. The elagolix sodium salt is then obtained by spray drying in amorphous form.

<^la) (^lb>

The method of synthesis of elagolix, as described in WO 2009/062087, is a process comprising a number of steps leading to the final compound. From the point of view of the process as a whole, the one -before- last step of the synthesis resulting in the ethylester (lb) is particularly interesting. This step has a low yield and the ethylester (lb) is prepared in a relatively low purity grade. The hydrolysis of the ethylester (lb) yields elagolix in the form of free acid or in the form of sodium salt, depending on the conditions. However, due to low purity of the starting ethylester (lb), the final product contains a significant amount of undesirable impurities.

Low stability of elagolix (la) and to some extent also of its ethylester (lb) represent a significant problem. Both compounds easily undergo intramolecular cyclization to form a lactam (II). This impurity is formed at 25 °C in a relatively short time, and the transformation is irreversible. Sodium salt of elagolix does not form the lactam so easily, but it is also obtained exclusively in amorphous form which could not be crystallized from any solvent.

(II)

The aim of the invention is thus to increase the stability and decrease the reactivity of elagolix or its ester towards intramolecular cyclization. WO 2009/062087 mentions this problem and suggests formation of solid solutions with polymers (e.g, Kollidon, HPMC).

Elagolix belongs among poorly soluble substances. Its amorphous sodium salt shows a better solubility, and is thus considered as the solid form to be used in the pharmaceutical final form. However, it is still far from perfect, because even in its amorphous form it still shows a relatively low solubility and a chemical instability involving intramolecular cyclization and lactam formation. The aim of the invention is thus to provide novel solid forms of elagolix which have the dissolution properties at least as good as the amorphous sodium salt, or have a better solubility, together with chemical stability.

Furthermore, currently there are no crystalline forms of elagolix and esters and salts thereof, hence, it is not possible to purify elagolix in any form by crystallization purification. A further aim of the invention is thus the provision of solid forms having crystalline forms and usable for purificitaion of elagolix by crystallization in the form of a suitable solid form.

Disclosure of the Invention Object of the invention are solid forms selected from the group comprising:

- solid forms of compound of formula (I)

(I) wherein R represents an alkaline earth metal, an alkali metal, H, C1-C6 alkyl, C6-C20 aryl or C7-C24 aralkyl, and

- solid forms of compound of formula (I) with an acid,

- solid solutions of compound of formula (I) with a polymer

whereas in the solid forms of compound of formula (I) without an acid and without a polymer, R is not H and R is not ethyl;

whereas the alkali metal may be sodium only in solid solution with a polymer, and

whereas when R is ethyl, the acid is not HC1. The alkali metals are lithium, sodium, and potassium. The alkali earth metals are magnesium, calcium.

Preferred alkali earth metals and alkali metals are calcium, magnesium, potassium, and lithium. These solid forms of elagolix are often amorphous. In one preferred embodiment, the alkali earth metal is calcium. The calcium salt of elagolix (R = Ca) is a particularly suitable form for use in a final pharmaceutical formulation.

Amorphous calcium salt of elagolix preferably shows

a) X-ray powder diffraction spectrum showing an amorphous halo with band maxima at 9.5; 15.5 and 22.2 ± 0.2 °2Theta, and/or

b) glass transition temperature as measured by diffraction scanning calorimetry being 114 °C to 119 °C.

In one preferred embodiment, the alkali metal is potassium. Amorphous potassium salt of elagolix (R = K) preferably shows

a) X-ray powder diffraction spectrum showing an amorphous halo with band maxima at 9.4; 16.0 and 22.6 ± 0.2 °2Theta, and/or

b) glass transition temperature as measured by diffraction scanning calorimetry being 61 °C to 67 °C.

Preferred acids are pamoic acid, 2,3-dibenzoyl-tartaric acid (in particular (+)-2,3-dibenzoyl-D-tartaric acid), and sulfonic acids.

In one preferred embodiment, R represents H, C1-C6 alkyl, C6-C20 aryl or C7-C24 aralkyl, and the solid form is a solid form of the compound of formula (I) with an acid, wheras when R is ethyl, the acid is not HC1. In one preferred embodiment, R represents C1-C6 alkyl, C6-C20 aryl or C7-C24 aralkyl; and the solid form is a solid form of the compound of formula (I) with an organic acid. In a preferred embodiment, the compound of formula (I) is elagolix ethylester, i.e. R is ethyl, in a solid form with an acid. When R is C1-C6 alkyl, e.g. ethyl, the acid is preferably selected from pamoic acid and (+)-2,3-dibenzoyl-D-tartaric acid. In one preferred embodiment of the invention, the solid form is a solid form of elagolix ethylester (lb) with pamoic acid, preferably in a crystalline form. In a particularly preferred embodiment, the solid form

2: 1.

Pamoic acid In one preferred embodiment, the compound of formula (I) is elagolix, i.e. R is H. Preferably, the acid is then selected from the group comprising pamoic acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid.

In another preferred embodiment, the compound of formula (I) is elagolix ethylester, i.e., R is ethyl. When R is C1-C6 alkyl, e.g. ethyl, the acid is preferably selected from the group comprising pamoic acid, 2,3-dibenzoyl-tartaric acid (in particular (+)-2,3-dibenzoyl-D-tartaric acid), hydrobromic acid, phosphoric acid, p-toluenesulfonic acid, citric acid, maleic acid.

In one preferred embodiment, the solid form is a solid form of elagolix (R=H) with pamoic acid, preferably in a crystalline form. In a particularly preferred embodiment, the solid form contains elagolix and pamoic acid in the ratio 1 : 1.

In a particularly preferred embodiment, the solid form of elagolix with pamoic acid shows:

a) characteristic reflections in X-ray powder diffraction spectrum: 7.7 ± 0.2; 9.4 ± 0.2; 15.6 ± 0.2; 19.3 ± 0.2; 20.6 ± 0.2 and 26.2 ± 0.2° 2-theta, measured using CuKa radiation, or

b) a DSC peak at the temperature of 154 ± 2 °C.

A complete list of reflections in X-ray powder diffraction spectrum for the solid form of elagolix with pamoic acid is disclosed in the following table. The characteristic diffraction peaks of the solid form of elagolix with pamoic acid according to the present invention, using CuKa, are: 7.7 ± 0.2; 9.4 ± 0.2; 15.6 ± 0.2; 19.3 ± 0.2; 20.6 ± 0.2 and 26.2 ± 0.2° 2-theta.

In one preferred embodiment, the solid form is a solid form of elagolix ethylester (lb) with pamoic acid, preferably in crystalline form. In a particularly preferred embodiment, the solid form contains the elagolix ethylester and pamoic acid in the ratio 2: 1.

Pamoic aclid In a preferred embodiment, the solid form of elagolix ethylester with pamoic acid shows: a) characteristic reflections in X-ray powder diffraction spectrum: 4.1 ; 7.5; 15.0; 23.3 and 26.8 ± 0.2° 2- theta, measured using CuKa radiation, or

b) DSC peak at the temperature 123 + 2 °C.

A complete list of reflections in X-ray powder diffraction spectrum for the solid form of elagolix ethylester with pamoic acid is disclosed in the following table. The characteristic diffraction peaks of the solid form of elagolix ethylester with pamoic acid according to the present invention, using CuKa, are: 4.1 ; 7.5; 15.0; 23.3 and 26.8 ± 0.2° 2-theta, further peaks are: 10.1 ; 14.0; 16.8; 21.3 and 24.2 ± 0.2° 2- theta.

In a further preferred embodiment of the invention, the solid form is a solid form of elagolix ethylester (lb) with (+)-2,3-dibenzoyl-D-tartaric acid, preferably in crystalline form. In a particularly preferred embodiment, the solid form contains elagolix ethylester and (+)-2,3-dibenzoyl-D-tartaric acid in the ratio 2: 1.

lb (÷^2_;3-ds:€:nzoyl-D-iarta:ric acid

In a particularly preferred embodiment, the solid form of elagolix ethylester with (+)-2,3-dibenzoyl-D- tartaric acid shows:

a) characteristic reflections in X-ray powder diffraction spectrum: 6.2; 7.4; 9.2; 15.0; 18.0 and 22.4 ± 0.2° 2-theta, measured using CuKa irradiation, or

b) DSC peak at the temperature 93 + 2 °C.

A complete list of reflections in X-ray powder diffraction spectrum for the solid form of elagolix ethylester with (+)-2,3-dibenzoyl-D-tartaric acid is disclosed in the following table. The characteristic diffraction peaks of the solid form of elagolix ethylester with (+)-2,3-dibenzoyl-D-tartaric acid according to the present invention, using CuKa, are: 6.2; 7.4; 9.2; 15.0; 18.0 and 22.4 ± 0,2° 2-theta, further peaks are: 9.0; 12.1; 16.0; 19.4 and 24.0 ± 0.2° 2-theta.

Pos. [°2Th.] d [A] Rel. Int. [%]

4.30 20.519 11.6

5.75 15.358 39.4

6.18 14.285 100.0

7.38 11.976 23.4

7.74 11.407 11.8

8.18 10.805 7.4

8.96 9.860 19.9

9.20 9.606 22.5

9.71 9.103 3.8

10.02 8.821 5.4

10.84 8.156 4.6

11.88 7.445 5.7

12.12 7.299 6.8

12.50 7.077 3.0

13.40 6.601 5.5

13.79 6.416 7.1

14.45 6.125 9.0

14.96 5.917 15.2

15.57 5.687 8.1

15.98 5.543 11.3

16.41 5.399 5.3

16.76 5.285 4.0

17.05 5.197 5.4 18.03 4.916 7.9

18.51 4.790 3.6

18.88 4.696 5.9

19.35 4.583 8.0

21.47 4.136 5.8

22.42 3.962 10.1

23.23 3.826 2.8

23.95 3.712 6.5

24.79 3.589 3.3

25.31 3.516 5.1

25.60 3.477 4.4

27.08 3.290 4.0

28.05 3.179 2.7

Solid forms of elagolix esters with organic acids in crystalline forms can be used for selective purification of the ester intermediate of the synthesis of elagolix (such as elagolix ethylester), due to their crystallinity. The purification removes the above-mentioned impurities and assists in obtaining elagolix with high purity. This could not be achieved with amorphous elagolix esters or elagolix salts.

The organic acid can be monovalent or multivalent. Preferably, the acid has a pKa < 5, more preferably a pKa < 3. Preferred organic acids include multivalent organic acids, in particular 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. Most preferred are pamoic acid and (+)-2,3- dibenzoyl-D-tartaric acid.

In a further embodiment, object of the invention is elagolix in amorphous solid form with a sulfonic acid. The sulfonic acid is typically a compound of formula R'-S0₃H, wherein R' is preferably selected from the group comprising C1-C4 alkyl, C6-C10 aryl, C6-C12 polycyclic alkyl or aryl, whereas R' may optionally be substituted by C1-C4 alkyl, halogen, S0₃H. Suitable sulfonic acids include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1- naphthalenesulfonic acid, 2-naphthalenesulfonic acid and camphorsulfonic acid.

In a preferred embodiment, the sulfonic acid is benzenesulfonic acid. Amorphous solid form of elagolix with benzenesulfonic acid preferably shows a glass transition temperature as measured by differential scanning calorimetry being 91 °C to 102 °C.

In a further preferred embodiment, the sulfonic acid is 2-naphthalenesulfonic acid. Amorphous solid form of elagolix with 2-naphthalenesulfonic acid preferably shows a glass transition temperature as measured by differential scanning calorimetry being 101 °C to 113 °C. In a further embodiment, the solid form is a solid solution in which an amorphous form of alkali metal or alkali earth metal salt of elagolix, preferably sodium salt of elagolix, is stabilized using a polymer in a weight ratio in the range of 1 :0.5 to 1:2.5, preferably in the range of 1 : 1 to 1 :2, more preferably in the weight ratio of about 1 : 1 or about 1 :2.

Suitable pharmaceutically acceptable polymers include homopolymers and copolymers of polyalkyleneoxids, in particular polyethylene glycol and polypropylene glycol; homopolymers and copolymers of N-vinyllactams, in particular of N-vinylpyrrolidone, such as polyvinylpyrrolidone (PVP) and of N-vinylcaprolactam; homopolymers and copolymers of acrylic acid and derivatives thereof; homopolymers and copolymers of methacrylic acid and derivatives thereof, in particular of methylmethacrylate; and cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxy ethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose; starch derivatives, etc. Preferably, the polymer is selected from a group consisting of polyvinylpyrrolidone, vinylpyrrolidone and vinylacetate copolymer (preferably Kollidon such as Kollidon K30 or Kollidon VA64), copolymer of polyvinylcaprolactam, polyvinylacetate and polyethylene glycol (preferably Soluplus), copolymer of methacrylic acid and methylmethacrylate (preferably Eudragit such as Eudragit LI 00 or Eudragit SI 00), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS).

In a preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with polyvinylpyrrolidone (Kollidon K30) in a weight ratio of about 1 : 1, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 14.5 and 21.3 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 130 °C to 132 °C.

In a preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with polyvinylpyrrolidone (Kollidon K30) in a weight ratio of about 1 : 2, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 13.6 and 21.1 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 135 °C to 137 °C.

A particularly preferred solid form for use in a pharmaceutical formulation are solid solutions of sodium salt of elagolix with polyvinylpyrrolidone (Kollidon VA64) in the ratio of about 1 : 1 or about 1 : 2. In a preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with polyvinylcaprolactame, polyvinylacetate and polyethyleneglycol copolymer (Soluplus) in a weight ratio of about 1 : 1, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 9.8 and 18.0 (flat maximum) ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 52 °C to 54 °C.

In a preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with polyvinylcaprolactame, polyvinylacetate and polyethyleneglycol copolymer (Soluplus) in a weight ratio of about 1 : 2, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 10.0 a 18.4 (flat maximum) ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 59 °C to 61 °C. In a preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with methacrylic acid and methyl methacrylate copolymer (about 1 : 1 by weight) (Eudragit L100) in a weight ratio of about 1 : 2, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 14.8 and 30.5 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 144 °C to 146 °C.

In a preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with methacrylic acid and methyl methacrylate copolymer (about 1 :2 by weight) (Eudragit S100) in a weight ratio of about 1 : 2, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 14.7 and 30.5 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 143 °C to 146 °C.

In a preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with HPMC in a weight ratio of about 1 : 1, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 9.4 and 20.0 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 111 °C to 114 °C.

In a preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with HPMC in a weight ratio of about 1 : 2, said solid solution preferably showing a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 8.0 and 20.3 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 113 °C to 116 °C. In a preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with HPMC AS in a weight ratio of about 1 : 2, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 9.9 and 19.8 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 108 °C to 111 °C.

In a particularly preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with vinylpyrrolidone and vinylacetate copolymer (ratio 3:2) (Kollidon VA64) in a weight ratio of about 1 : 1, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 9.6; 14.4 and 21.8 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 62 °C to 64 °C.

In a particularly preferred embodiment, the solid form is a solid solution of amorphous sodium salt of elagolix with vinylpyrrolidone and vinylacetate copolymer (ratio 3:2) (Kollidon VA64) in a weight ratio of about 1 : 2, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 14.2 and 21.5 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 106 °C to 108 °C. Another object of the invention is the use of the solid form selected from the group comprising:

- solid forms of compound of formula (I)

(I)

wherein R represents an alkaline earth metal, an alkali metal, H, C1-C6 alkyl, C6-C20 aryl or C7-C24 aralkyl, and

- solid forms of compound of formula (I) with an acid, - solid solutions of compound of formula (I) with a polymer,

whereas when R is ethyl, the acid is not HC1;

as intermediates of preparation of elagolix or ester thereof, and/or as components of pharmaceutical formulations.

A further object of the invention is the use of solid form of elagolix ester with (+)-2,3-dibenzoyl-D- tartaric acid for chiral removal of the (S)-enantiomer of elagolix ester, i.e., for obtaining a chirally pure (R)-enantiomer of elagolix ester. (+)-2,3-dibenzoyl-D-tartaric acid does not form a solid crystalline form with the (S)-enantiomer of elagolix ester, thus the said solid form is useful for chiral separation.

The inventors of the present invention have found that from a physical mixture of the (R)- and (S)- enantiomers of elagolix ethylester, only solid crystalline form of (R)-enantiomer is isolated after addition of (+)-2,3-dibenzoyl-D-tartaric acid (as confirmed by chiral HPLC). It was also ascertained that the (S)- enantiomer of elagolix ethylester, prepared according to WO 2009/062087 using (+)-N-Boc-L-a- phenylglycinol instead of the (-)-D analogue, form a solid crystalline form only with (-)-2,3-dibenzoyl-L- tartaric acid. Within the framework of the present invention it was found that the most suitable method of crystallization purification involves crystallization of esters of elagolix, preferably the ethylester of elagolix. Crystalline solid forms of ethylester of elagolix with pamoic acid or (+)-2,3-dibenzoyl-D-tartaric acid are suitable derivatives to be used for crystallization purification. With regard to physico-chemical properties of elagolix, the most suitable process seems to be the crystallization of esters of elagolix, preferably the ethylester of elagolix. Crystalline solid forms of ethylester of elagolix with pamoic acid or (+)-2,3-dibenzoyl-D-tartaric acid are suitable derivatives to be used for crystallization purification. These solid forms of elagolix may be used for selective removal of impurities. The solid form with pamoic acid (in particular in ratio 2: 1) can preferably be used to remove the desfluoro impurity (III). The amounts of other impurities can be successfully decreased by crystallization of the solid form of elagolix with (+)-dibenzoyl-D-tartaric acid.

Another object of the invention are crystallization and precipitation of salts and solid forms of ethylester of elagolix in order to increase their chemical purity.

Another object of the invention is a method of preparation of the above mentioned solid forms of the compound of formula (I), optionally together with acid, which includes the following steps: a) dissolving or suspending the compound of formula (I)

(I)

optionally together with an acid,

b) removal of the solvent, yielding the solid form.

In the method of preparation of solid forms of esters of elagolix, an ester of elagolix can be used in step a), wherein R is C1-C6 alkyl, C6-C20 aryl or C7-C24 aralkyl, preferably ethyl. The solvent in step a) may be an organic solvent or water. Preferably, the acid is other than HC1.

Organic solvent is preferably selected from the group consisting of ketones, alcohols, esters, ethers and mixtures thereof. Preferably, the solvent is selected from the group consisting of C3-C5 ketones, C1-C4 alcohols, acetic acid esters with C1-C4 alcohols, tetrahydrofurane, dioxane, halogenated alkanes and mixtures of said solvents. In a preferred embodiment, the compound of formula (I) is dissolved or suspended in a solvent, and an acid is optionally added in the amount of at least 0.5 equivalent, preferably 0.5 to 3 equivalents, most preferably 0.5 to 2.1 equivalents. The solution or suspension is preferably incubated and/or stirred for 1 to 24 hours, at the temperature of -30 °C to boiling point of the solvent, more preferably at the temperature 0 to 130 °C, most preferably at the temperature of 20 to 80 °C.

In step b), the solvent is preferably removed by filtration, centrifugation or evaporation, or the solution or suspension is first partially evaporated and/or another solvent is added as an anti-solvent, and the solvent is subsequently removed by filtration. A suitable antisolvent may be C2-C8 ether (e.g., diethylether, tert- butylmethylether, diisopropylether), C5-C7 cycloalkane, or C5-C7 alkane.

Preferably, the solution prepared in step a) is then cooled to the temperature in the range of 0 to 40 °C and then the solvent is removed. The resulting solid form is precipitated or crystallized from the solvent which is preferably removed by filtration, centrifugation or evaporation, free evaporation or evaporation at an increased temperature, e.g. 40 or 80 °C, and/or at a reduced pressure, e.g. 10 kPa (100 mbar). Alternatively, the solution or suspension may first be partially evaporated and/or another solved is added as an anti-solvent.

Another object of the invention is a method of preparation of the above mentioned solid forms of the compound of formula (I) with an acid, which includes at least the following steps:

a) dissolving or suspending a compound of formula (IV)

wherein R' is selected from H, a cation of a base (in particular alkali metals, alkali earth metals, ammonium), C1-C6 alkyl, C6-C20 aryl and C7-C24 aralkyl,

and an acid in an organic solvent and/or water, and

b) removal of the solvent, yielding the solid form.

For the preparation of the elagolix solid forms, elagolix or a salt therof with a base may be used in step a). Such salts preferably include salts of elagolix with alkali metals or alkali earth metals, for example a sodium salt of elagolix. For elagolix salts, the solvent in step a) may be an organic solvent or water.

Organic solvent is preferably selected from the group consisting of ketones, alcohols, esters, ethers and mixtures thereof. Preferably, the solvent is selected from the group consisting of C3-C5 ketones, C1-C4 alcohols, acetic acid esters with C1-C4 alcohols, tetrahydrofurane, dioxane, halogenated alkanes and mixtures of said solvents.

In step b), the solvent is preferably removed by filtration, centrifugation or evaporation, or the solution or suspension is first partially evaporated and/or another solvent is added as an anti-solvent, and the solvent is subsequently removed by filtration. A suitable antisolvent may be, e.g. diethylether, tert- butylmethylether, diisopropylether or C5-C7 alkane.

In a preferred embodiment, the compound of formula (IV), wherein R is selected from H, a cation of a base (in particular alkali metal, alkaline earth metal and ammonium), C1-C6 alkyl, C6-C20 aryl and C7- C24 aralkyl, is dissolved in a solvent, and an acid is added in the amount of at least 0.9 equivalent, preferably in the amount of 0.9 to 3 equivalents, most preferably in the amount 0.9 to 2.1 equivalent. The solution or suspension is preferably incubated for 1 to 24 hours, at the temperature of from 30 °C to the boiling point of the solvent, preferably at the temperature of 0 to 130 °C and most preferably at the temperature of 20 to 80 °C. The resulting solution is further cooled to the temperature within the range of 0 to 40 °C and the solvent is then removed. The resulting solid form is precipitated or crystallized from the solvent which is preferably removed by filtration, centrifugation or evaporation, freely or at an increased temperature, e.g. 40 to 80 °C, and/or at a reduced pressure, e.g. 10 kPa (100 mbar). Alternatively, the solution or suspension is first partially evaporated and/or another solvent is used as an antisolvent. A suitable antisolvent may be, e.g. diethylether, tert-butylmethylether, diisopropylether or C5-C7 alkane.

Another object of the invention is a method of crystallizing and re -crystallizing solid forms of elagolix of formula (I), preferably of ethylester of elagolix, with organic acids, which comprises at least the following steps:

a) dissolving or suspending a compound of formula (I) and an organic acid,

b) free or disturbed crystallization and/or crystallization using an antisolvent,

c) removal of the solvent, yielding the solid form.

Organic solvent or water may be used in step a). The organic solvent is preferably selected from the group consisting of ketones, alcohols, esters, ethers and mixtures thereof. Preferably, the organic solvent is selected from the group consisting of C3-C5 ketones, C1-C4 alcohols, acetic acid esters with C1-C4 alcohols, tetrahydrofurane, dioxane halogenated alkanes and mixtures thereof. In step b), the solution is cooled to a temperature within the range of 0 to 40 °C, freely or in a controlled manner. A suitable antisolvent for use in the alternative step b) is C2-C8 ether (e.g., diethylether, tert-butylmethylether, diisopropylether), C5-C7 cycloalkane, or C5-C7 alkane. The step b) may preferably be repeated several times. In step c) the solvent is preferably removed by filtration, centrifugation or evaporation, or the solution or suspension is first partially evaporated and/or another solvent is added as an antisolvent, and the solvent is then removed by filtration.

Another object of the invention is a method of preapration of elagolix or elagolix ester, for example ethyl ester of elagolix, wherein a solid form of the compound of formula (I) with an organic acid is prepared, the said solid form is then subjected to crystallization and removal of the mother liquor containing the impurities, and subsequently the re-crystallized solid form is converted into an elagolix ester or an elagolix salt, in particular into ethyl ester of elagolix, or elagolix sodium salt. The conversion to the elagolix salt may be carried out in particular by basic hydrolysis. Ethyl ester of elagolix or elagolix sodium salt may be obtained for example by removing the solvent or by precipitation by the antisolvent. The step of re-crystallization and of removal of the mother liquor with the impurities may preferably be repeated several times. Solid forms of esters of elagolix with organic acids may be used for selective removal of impurities. For example, the solid form with pamoic acid (2: 1) may preferably be used for decreasing the amount of the desfluoro impurity (III). The amount of other impurities may be successfully decreased by crystallization of solid form of ester of elagolix with (+)-dibenzoyl-D-tartaric acid.

Solid forms with calcium, magnesium, potassium and lithium are chemically stable and have the dissolution properties at least as good as the amorphous sodium salt, typically they are even more soluble. Also solid solutions with polymers have a very good dissolution properties and a high chemical stability.

Solid forms with acids increase the stability against intramolecular cyclization.

The term„about" preceding a numerical value or a numerical ratio means common deviations from the exact numerical value or the exact numerical ratio, such as deviations ±10 %. These common deviations may be caused for example by deviations in weighing, manufacturing deviations, manufacturing inhomogeneities, etc.

The term„C1-C6 alkyl", as used herein, means a univalent saturated hydrocarbyl residue containing one to six carbon atoms in the chain which may be linear, branched or cyclic. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, 1- ethylpropyl, 3-methyl-2-butyl, 2-methylbutyl, 2-methylbutan-2-yl (t-pentyl), 3 -methyl- 1 -butyl (isopentyl/isoamyl), 2,2-dimethylpropyl (neopentyl), n-hexyl, 4-methyl-2-pentyl, cyclopentyl and cyclohexyl. Particularly preferred alkyl groups are methyl, ethyl, isopropyl, tert-butyl and 3-methyl-l- butyl.

The term„C6-C20 aryl", as used herein, means a univalent aromatic hydrocarbyl chain containing six to twenty carbon atoms in the chain which may be monocyclic, bicyclic or tricyclic. Preferred monocyclic aryls contain 5 or 6 carbon atoms. Preferred bicyclic aryls contain 8 to 10 carbon atoms. Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl and similar.

The term„C7-C24 aralkyl", as used herein, means a univalent hydrocarbyl residue containing one to six carbon atoms in alkyl chain, linear or branched, which is substituted by one or more aryl groups defined above. Examples of aralkyl groups include benzyl, trityl (triphenylmethyl), 1-phenylethyl, 2-phenylethyl, diphenylmethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl etc. Particularly preferred aralkyl groups are benzyl and trityl. The term„solid form of compound of formula (I) with an acid" means in the context of the present invention a solid form of elagolix, elagolix salt, elagolix ester, with an acid, e.g., a salt or a co-crystal with the acid in solid form. The components may be present preferably in the molar ratio of the elagolix ester to the acid 3: 1 to 1 :3, more preferably 2: 1 to 1 :2, in a particularly preferred embodiment, the molar ratios of 2: 1 and 1 : 1 are preferred. In one particualrly preferred embodiment, the solid form contains elagolix and pamoic acid in the ratio 1: 1.

The acid may be any inorganic or organic acid which may be monovalent or multivalent. Preferably, the acid has a pKa < 5, more preferably a pKa < 3. Preferred inorganic acids include strong inorganic acids, in particular hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Preferred organic acids include sulfonic acid, in particular methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, 1-naphthalenesulfonic, 2-naphthalenesulfonic, camphorsulfonic acid, and multivalent orgnaic acids, in particular pamoic, citric, maleic, fumaric, oxalic, malonic, succinic, malic, tartaric, asparagic, glutamic and 2,3-dibenzoyl-tartaric (in particular (+)-2,3-dibenzoyl-D-tartaric) acid.

Solid forms of the compound of formula (I) may be prepared in suitable ratios and yields, with a high chemical purity in crystalline form, amorphous form or in a mixture of a crystalline and amorphous solid form. This particularly applies for the solid forms of esters of elagolix, which can be especially prepared in crystalline form.

The prepared solid forms of the compounds of formula (I) may have different internal configuration (polymorphism) with different physicochemical properties depending on the conditions of their preparation. The invention relates to both crystalline and amorphous forms and mixtures thereof. Another object of the invention is a pharmaceutical composition comprising one of the above solid forms of elagolix and at least one pharmaceutically acceptable excipient. The active compound content in the pharmaceutical composition is 1 to 1 ,000 mg in unit dose, preferably the amount corresponding to 50 to 200 mg, or 50 to 250 mg, or 50, 100, 150, 200 or 250 mg of elagolix (free acid). The composition further comprises one or more pharmaceutically acceptable excipients which serve, in particular, as fillers, binders, lubricants, surfactants, disintegrants, dyes, solvents, antimicrobials or taste and smell corrigens. Preferably, the composition comprises at least one excipient selected from the group consisting of lactose, microcrystalline cellulose, sodium carboxymethyl starch, magnesium stearate, and combinations thereof.

The pharmaceutical composition can be prepared in virtually any solid dosage form, e.g. in the form of tablets, capsules, powders, pellets or granules. A preferred dosage form is a capsule or tablet or a coated tablet. This may preferably be prepared by mixing the solid form of elagolix with acid with pharmaceutically acceptable excipients, and then it is subjected to tableting, optionally followed by coating.

The compounds of formula (I) act as gonadotropin-releasing hormone (GnRH) receptor antagonists. Therefore, the above-mentioned solid forms of elagolix, in free acid or in ester or salt form, optionally with an acid or polymer, for use as a medicament, preferably for use as antagonists of the GnRH receptor, particularly for treating diseases such as endometriosis, uterine fibroids and prostate hyperplasia, or in the treatment of prostate, breast or ovarian cancer, are also the object of the present invention.

Description of the Drawings

Fig. 1 shows X-ray spectrum of amorphous forms of solid forms of elagolix ethylester (lb) with acids

Fig. 2 shows X-ray spectrum of amorphous forms of solid forms of elagolix (la) with acids

Fig. 3 shows DSC curve of solid form of elagolix ethylester (lb) and hydrobromic acid

Fig. 4 shows DSC curve of solid form of elagolix ethylester (lb) and p-toluenesulfonic acid

Fig. 5 shows DSC curve of solid form of elagolix ethylester (lb) and citric acid

Fig. 6 shows DSC curve of solid form of elagolix ethylester (lb) and maleic acid

Fig. 7 shows DSC curve of solid form of elagolix ethylester (lb) and phosphoric acid

Fig. 8 shows DSC curve of solid form of elagolix (la) with hydrochloric acid

Fig. 9 shows DSC curve of solid form of elagolix (la) with hydrobromic acid

Fig. 10 shows DSC curve of solid form of elagolix (la) with nitric acid

Fig. 11 shows DSC curve of solid form of elagolix (la) with sulfuric acid

Fig. 12 shows DSC curve of solid form of elagolix (la) with phosphoric acid

Fig. 13 shows X-ray spectrum of solid form of elagolix (la) with pamoic acid

Fig. 14 shows DSC curve of solid form of elagolix (la) with pamoic acid

Fig. 15 XRPD spectrum of amorphous form of free elagolix

Fig. 16 XRPD spectrum of amorphous sodium salt of elagolix

Fig. 17 XRPD spectrum of amorphous potassium salt of elagolix

Fig. 18 XRPD spectrum of amorphous calcium salt of elagolix

Fig. 19 XRPD spectrum of solid solution of sodium salt of elagolix with Kollidon VA 64 (1 : 1)

Fig. 20 XRPD spectrum of solid solution of sodium salt of elagolix with Kollidon VA 64 (1 : 2)

Fig. 21 XRPD spectrum of solid solution of sodium salt of elagolix with Kollidon K 30 (1 : 1)

Fig. 22 XRPD spectrum of solid solution of sodium salt of elagolix with Kollidon K 30 (1 : 2)

Fig. 23 XRPD spectrum of solid solution of sodium salt of elagolix with Soluplus (1 : 1)

Fig. 24 XRPD spectrum of solid solution of sodium salt of elagolix with Soluplus (1 : 2)

Fig. 25 XRPD spectrum of solid solution of sodium salt of elagolix with Eudragit L 100 (1 : 2)

Fig. 26 XRPD spectrum of solid solution of sodium salt of elagolix with Eudragit S 100 (1 : 2) Fig. 27 XRPD spectrum of solid solution of sodium salt of elagolix with HPMC (1 : 1)

Fig. 28 XRPD spectrum of solid solution of sodium salt of elagolix with HPMC (1 : 2)

Fig. 29 XRPD spectrum of solid solution of sodium salt of elagolix with HPMC AS (1 : 2)

Fig. 30 shows X-ray spectrum of solid form of elagolix ethylester with pamoic acid (2: 1)

Fig. 31 shows DSC curve of solid form of elagolix ethylester with pamoic acid (2:1)

Fig. 32 shows X-ray spectrum of solid form of elagolix ethylester with (+)-2,3-dibenzoyl D-tartaric acid (2: 1)

Fig. 33 shows DSC curve of solid form of elagolix ethylester with (+)-2,3-dibenzoyl D-tartaric acid (2: 1) Examples

The following exemplary embodiments only serve to illustrate and explain the invention and they should not be construed as limiting the scope of protection which is defined exclusively by the claims.

Overview of polymers used:

Kollidon VA 64 - copolymer of vinylpyrrolidone and vinyl acetate in a ratio of 3 : 2

Kollidon K 30 - polyvinyl pyrrolidone

Soluplus - copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol

Eudragit L 100 - copolymer of methacrylic acid and methyl methacrylate in a ratio of 1 : 1

Eudragit S 100 - copolymer of methacrylic acid and methyl methacrylate in a ratio of 1 : 2

HPMC - hydroxypropyl methylcellulose

HPMC AS - hydroxypropyl methylcellulose acetate succinate

Example 1

Preparation of sodium salt of elagolix (comparative example)

Ethyl-(R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6- dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)butanoate (10 g) was dissolved in 50 ml of ethanol and then an aqueous solution of NaOH (1.97 g of NaOH in 50 ml of water) was added. The mixture was stirred at 40 °C for 2 h, then the reaction volume was reduced to ca 50 ml by distilling off the solvent, 85 ml of water was added and the mixture was again concentrated to ca 50 ml. Ethyl acetate was added (85 ml) and the layers were separated. The aqueous layer was washed with 30 ml of ethyl acetate. To the aqueous layer was added 45 g of NaCl and the product was extracted into ethyl acetate (1 x 80 ml, 1 x 40 ml). The organic layer was dried over Na₂S0₄, concentrated by evaporation of the solvent on a rotary vacuum evaporator to ca 40 ml and filtered through diatomaceous earth. The resulting solution was added dropwise into 100 ml of chilled (15 °C) heptane and 7.69 g of Na salt of elagolix was obtained with purity of 97.19 % by HPLC.

¾ NMR (500.13 MHz, DMSO): δ = 7.65 (d, / = 7.7Hz, 1H), 7.63 - 7.54 (overlap, 2H), 7.27 - 7.11 (m, 7H), 6.75 (m, 0.5H), 6.59 (m, 0.5H), 5.38 - 5.27 (overlap, 2H), 4.06 - 3.93 (m, 1H), 3.93 - 3.82 (overlap, 2H), 3.85 (s, 3H), 2.27 - 2.20 (m, 1H), 2.20 - 2.12 (m, 1H), 2.08 (d, / = 2.7Hz, 3H), 1.84 - 1.71 (overlap, 2H), 1.53 - 1.36 (m, 2H).

Example 2

Preparation of solid forms of elagolix ethylester with acid

Ethyl-(R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6- dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)butanoate (340 mg) was dissolved in 1 ml of ethanol. To the solution 1.0 eq of appropriate acid (hydrobromic, p-toluenesulfonic, citric, maleic, and phosphoric) in 1 ml of ethanol was added at 25 °C. Evaporation of the solvent on the vacuum rotary evaporator gave the desired solid form. In the described manner, the following solid forms of elagolix ethylester were prepared: a) Solid form with hydrobromic acid (395 mg)

¾ NMR (500.13 MHz, DMSO): δ 9.19 - 8.98 (overlap, 2H), 7.67 - 7.52 (overlap, 3H), 7.42 - 7.30 (overlap, 5H), 7.20 - 7.13 (overlap, 2H), 6.70 (m, 0.5H), 6.51 (m, 0.5H), 5.29 - 5.25 (overlap, 2H), 4.63 - 4.55 (m, 1H), 4.55 - 4.43 (m, 1H), 4.29 - 4.21 (m, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.91 (m, 1H), 2.63 (m, 1H), 2.37 - 2.29 (overlap, 2H), 2.11 (s, 1.5H), 2.10 (s, 1.5H), 1.84 - 1.73 (overlap, 2H). 1.13 (t, J=.7.1 Hz, 3H).

The X-ray spectrum is on Fig. 1, DSC curve on Fig. 3; it is an amorphous form with Tg=93 °C. b) Solid form with p-toluenesulfonic acid (423 mg)

¾ NMR (500.13 MHz, DMSO): δ 9.15 - 8.93 (overlap, 2H), 7.67 - 7.53 (overlap, 3H), 7.47 (d, J = 8.10 Hz, 2H), 7.42 - 7.29 (overlap, 5H), 7.21 - 7.13 (overlap, 2H), 7.11 (d, J = 8.10 Hz, 2H), 6.70 (m, 0.5H), 6.51 (m, 0.5H), 5.30 - 5.24 (overlap, 2H), 4.62 - 4.55 (m, 1H), 4.52 - 4.40 (m,lH), 4.29 - 4.20 (m, 1H), 4.00 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.90 (m, 1H), 2.64 (m, 1H), 2.35 - 2.29 (overlap, 2H), 2.28 (s, 3H), 2.11 (s, 1.5H), 2.10 (s, 1.5H), 1.83 - 1.72 (overlap, 2H). 1.13 (t, J=.7.1 Hz, 3H).

The X-ray spectrum is on Fig. 1, DSC curve on Fig. 4; it is an amorphous form with Tg=83 °C. c) Solid form with citric acid (432 mg)

¾ NMR (500.13 MHz, DMSO): δ 7.68 - 7.53 (overlap, 3H), 7.34 - 7.24 (overlap, 5H), 7.21 - 7.13 (overlap, 2H), 6.71 (m, 0.5H), 6.54 (m, 0.5H), 5.33 - 5.28 (overlap, 2H), 4.29 - 4.05 (overlap, 3H), 4.00 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 2.68 - 2.53 (overlap, 5H), 2.46 (m, 1H), 2.30 - 2.27 (overlap, 2H), 2.10 (s, 1.5H), 2.09 (s, 1.5H), 1.68 - 1.60 (overlap, 2H), 1.13 (t, J=.7.1 Hz, 3H).

The X-ray spectrum is on Fig. 1, DSC curve on Fig. 5; it is an amorphous form with Tg=61 °C d) Solid form with maleic acid (397 mg) ¾ NMR (500.13 MHz, DMSO): δ 9.16 - 8.93 (overlap, 2H), 7.67 - 7.52 (overlap, 3H), 7.41 - 7.29 (overlap, 5H), 7.20 - 7.13 (overlap, 2H), 6.70 (m, 0.5H), 6.51 (m, 0.5H), 6.04 (s, 2H), 5.30 - 5.26 (overlap, 2H), 4.61 - 4.37 (overlap, 2H), 4.27 - 4.19 (m, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.89 (m, 1H), 2.62 (m, 1H), 2.36 - 2.30 (overlap, 2H), 2.11 (s, 1.5H), 2.10 (s, 1.5H), 1.81 - 1.72 (overlap, 2H), 1.13 (t, J=.7.1 Hz, 3H).

The X-ray spectrum is on Fig. 1 , DSC curve on Fig. 6; it is an amorphous form with Tg=59 °C. e) Solid form with phosphoric acid (385 mg)

¾ NMR (500.13 MHz, DMSO): δ 7.67 - 7.52 (overlap, 3H), 7.33 - 7.25 (overlap, 5H), 7.19 - 7.12 (overlap, 2H), 6.72 (m, 0.5H), 6.55 (m, 0.5H), 5.32 - 5.25 (overlap, 2H), 4.30 - 4.08 (overlap, 3H), 4.00 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 3.07 (s, 1H), 2.55 (m, 1H), 2.47 (m, 1H), 2.30 - 2.26 (overlap, 2H), 2.10 (s, 1.5H), 2.09 (s, 1.5H), 1.72 - 1.62 (overlap, 2H), 1.12 (t, J=.7.1 Hz, 3H), 1.10 (s, 3H).

The X-ray spectrum is on Fig. 1 , DSC curve on Fig. 7; it is an amorphous form with Tg=16 °C.

Example 3

Preparation of solid forms of elagolix free acid

Sodium salt of (R)-4-((2-(5-(2-fluoro-3-phenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6- dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l -phenylethyl)amino)butanoic acid (300 mg) was dissolved in 3 ml of water. This solution was added dropwise at 25 °C to an aqueous solution of the appropriate acid (hydrochloric, hydrobromic, nitric, sulfuric, and phosphoric). The precipitated solid was filtered and washed with water. If phosphoric acid is used, the resulting solid form is well soluble in water and therefore it was isolated by evaporation of the solvent on the vacuum rotary evaporator. In the described manner, the following solid forms of elagolix were prepared: a) Solid form with hydrochloric acid (210 mg)

¾ NMR (500.13 MHz, DMSO): δ 7.65 - 7.51 (overlap, 3H), 7.39 - 7.30 (overlap, 5H), 7.19 - 7.12 (overlap, 2H), 6.71 (m, 0.5H), 6.50 (m, 0.5H), 5.29 - 5.21 (overlap, 2H), 4.60 - 4.50 (overlap, 2H), 4.29 - 4.23 (m, 1H), 3.85 (s, 3H), 2.82 (m, 1H), 2.59 (m, 1H), 2.27 - 2.22 (overlap, 2H), 2.10 (s, 1.5H), 2.09 (s, 1.5H), 1.86 - 1.83 (overlap, 2H). The X-ray spectrum is on Fig. 2, DSC curve on Fig. 8; it is an amorphous form with Tg=l 19 °C. b) Solid form with hydrobromic acid (255 mg)

¾ NMR (500.13 MHz, DMSO): δ 7.65 - 7.51 (overlap, 3H), 7.42 - 7.33 (overlap, 5H), 7.19 - 7.12 (overlap, 2H), 6.71 (m, 0.5H), 6.51 (m, 0.5H), 5.32 - 5.24 (overlap, 2H), 4.61 - 4.46 (overlap, 2H), 4.29 - 4.23 (m, 1H), 3.85 (s, 3H), 2.89 (m, 1H), 2.63 (m, 1H), 2.27 - 2.22 (overlap, 2H), 2.10 (s, 1.5H), 2.09 (s, 1.5H), 1.83 - 1.71 (overlap, 2H).

The X-ray spectrum is on Fig. 2, DSC curve on Fig. 9; it is an amorphous form with Tg=l 17 °C. c) Solid form with nitric acid (287 mg)

¾ NMR (500.13 MHz, DMSO): δ 12,23, 9.17 - 8.97 (overlap, 2H), 7.67 - 7.52 (overlap, 3H), 7.42 - 7.31 (overlap, 5H), 7.20 - 7.13 (overlap, 2H), 6.71 (m, 0.5H), 6.53 (m, 0.5H), 5.31 - 5.24 (overlap, 2H), 4.60 (br.s, 1H), 4.53 - 4.42 (overlap, 1H), 4.30 - 4.24 (m, 1H), 3.85 (s, 3H), 2.90 (m, 1H), 2.64 (m, 1H), 2.27 - 2.22 (overlap, 2H), 2.10 (s, 1.5H), 2.09 (s, 1.5H), 1.81 - 1.71 (overlap, 2H).

The X-ray spectrum is on Fig. 2, DSC curve is on Fig. 10; it is an amorphous form with Tg=103 °C. d) Solid form with sulfuric acid (268 mg)

¾ NMR (500.13 MHz, DMSO): δ 9.57, 7.67 - 7.52 (overlap, 3H), 7.35 - 7.28 (overlap, 5H), 7.20 - 7.13 (overlap, 2H), 6.72 (m, 0.5H), 6.54 (m, 0.5H), 5.32 - 5.25 (overlap, 2H), 4.43 - 4.25 (overlap, 2H), 4.24 - 4.14 (m, 1H), 3.85 (s, 3H), 2.70 (m, 1H), 2.53 (m, 1H), 2.25 - 2.20 (overlap, 2H), 2.10 (s, 1.5H), 2.09 (s, 1.5H), 1.74 - 1.63 (overlap, 2H).

The X-ray spectrum is on Fig. 2, DSC curve is on Fig. 11 ; it is an amorphous form with Tg=124 °C. e) Solid form with phosphoric acid (256 mg)

¾ NMR (500.13 MHz, DMSO): δ 12.05, 10.11 - 9.12, 7.66 - 7.51 (overlap, 3H), 7.39 - 7.30 (overlap, 5H), 7.19 - 7.12 (overlap, 2H), 6.70 (m, 0.5H), 6.50 (m, 0.5H), 5.30 - 5.21 (overlap, 2H), 4.64 - 4.53 (overlap, 2H), 4.32 - 4.24 (m, 1H), 4.03 (q, J = 7.1 Hz, 2H) 3.85 (s, 3H), 2.84 (m, 1H), 2.59 (m, 1H), 2.27 - 2.22 (overlap, 2H), 2.08 (s, 1.5H), 2.07 (s, 1.5H), 1.99 (s, 1H), 1.87 - 1.73 (overlap, 2H), 1.17 (t, J=.7.1 Hz, 3H).

The X-ray spectrum is on Fig. 2, DSC curve is on Fig. 12; it is an amorphous form with Tg=89 °C. Example 4

Preparation of solid form of elagolix free acid with pamoic acid (1 :1)

1 g of elagolix free acid with purity of 97.19 % by HPCL and 630 mg (1,0 eq.) of pamoic acid were weighted into the flask. Then 20 ml of methanol was added. The suspension was stirred for 3 h at 60 °C and then for 16 h at 25 °C. Filtration yielded 1.5 g of crystalline solid form with purity of 98.70 % by HPLC.

¾ NMR (250 MHz, DMSO): S = 8.37 (s, 2H), 8.17 (d, / = 8.7Hz, 2H), 7.79 (d, / = 8.2Hz, 2H), 7.64 (td, / = 7.5, 2.0 Hz, 1H), 7.60 - 7.48 (overlap, 2H), 7.39 (d, / = 3.0 Hz, 4H), 7.32 - 7.23 (m, 2H), 7.22 - 7.08 (overlap, 4H), 6.79 (td, / = 6.1, 3.2 Hz, 0.5H), 6.60 - 6.50 (m, 0.5H), 5.28 (q, / = 17.2 Hz, 2H), 4.77 (s, 2H), 4.71- 4.58 (m, 1H), 4.52 - 4.26 (overlap, 2H), 3.86 (s, 3H), 3.00 - 2.82 (m, 1H), 2.74 - 2.57 (m, 1H), 2.27 (t, / = 7.0 Hz, 2H), 1.97 (d, / = 2.0 Hz, 3H), 1.89 - 1.71 (overlap, 2H).

The X-ray spectrum is on Fig. 13, DSC curve is on Fig. 14; T_t=154 °C

Example 5 Preparation of the solid form of elagolix free acid with pamoic acid (1: 1)

One gram of elagolix free acid with purity of 88.9 % by HPCL and 630 mg (1,0 eq.) of pamoic acid were weighted into the flask. Then 20 ml of methanol was added. The suspension was stirred for 3 h at 60 °C and then for 16 h at 25 °C. Filtration yielded 1.5 g of crystalline solid form with purity of 98.13 % by HPCL.

¾ NMR, RTG and DSC records are identical to the crystalline solid form obtained in Example 4. Example 6

Comparison of the stability of elagolix ester (lb) and free acid (la) with the stability of their salts

One hundred mg of the selected substance (elagolix ethylester and its solid forms with hydrobromic and maleic acids, elagolix, its sodium salt and solid form with hydrochloric acid) was weighted into the vials. The substances were dissolved in 1 ml of methyl ethyl ketone and stirred at 25 °C. The concentration of the solution was 100 mg/ml. Samples were taken at 0 h, 24 h and 168 h and analysed by HPLC. The following tables show the HPCL values (%) of content for the individual samples.

Elagolix stability as compared to its salts

Elagolix ethylester stability as compared to its salts

From the results, it can be seen that elagolix in the form of free acid or alkali metal salt is in the solution relatively easily and rapidly transformed into lactam which is the main impurity. However, when present in the form of a solid with an acid, the formation of lactam is greatly suppressed. Elagolix ethylester undergoes the same degradation to lactam, albeit to a lesser extent. Certainly, the effect of increased stability by forming a solid form with an acid is also undisputed here. Similar results were obtained with other prepared solid forms. Example 7

Preparation of elagolix sodium salt

The solution of 26 g of NaOH (0.65 mol) in 800 ml of water was added to 1,500 ml of alcoholic solution containing 200 g of elagolix ethylester (0.3 mol). The resulting mixture was stirred at room temperature for approximately 6 h. On a rotary vacuum evaporator, the mixture was then concentrated and, after addition of 1 ,500 ml of water, filtered. To the filtrate was added 1 ,450 ml of methyl isobutyl ketone, the mixture was heated to 55 °C, stirred at this temperature for about 10 to 15 minutes and then, after cooling, the layers were separated. To the aqueous layer, 1,450 ml of methyl isobutyl ketone was added with stirring at room temperature, followed by the solution of 185 g of NaOH in 200 ml of water. The mixture was stirred for several minutes, then the layers were separated and the aqueous layer was extracted with 2 x 400 ml of methyl isobutyl ketone. The combined organic layers were agitated with a solution of 180 g of sodium chloride in 500 ml of water and concentrated on the rotary vacuum evaporator to about 2/3 of the original volume. The concentrated mixture was filtered and the filtrate was added to a mechanically stirred reactor with 2,000 ml of heptane at 20 °C. The mixture was stirred for 2 h, the resulting solid was filtered, washed twice with 70 ml of heptane and dried in a vacuum oven first at 20 °C and then the temperature was gradually increased up to 40 °C. At 40 °C, the amorphous elagolix sodium salt was dried in the vacuum oven for 24 h, 146 g of product was obtained.

The X-ray spectrum of elagolix sodium salt shows classic amorphous halo with band maxima at 9.0, 15.8 and 22.6 °2Theta. The differential scanning calorimetry curve of elagolix sodium salt exhibits the glass transition temperature of 52 °C to 57 °C.

Example 8

Preparation of elagolix sodium salt

The free form of elagolix (5 g) was stirred in 80 ml of water/methyl isobutyl ketone (1 : 1). To this mixture, a solution of 3.2 g of NaOH in 5 ml of water was added with stirring. The mixture was stirred for 1 h at 60 °C. After cooling to room temperature, the layers were separated and the aqueous layer was extracted with 20 ml of methyl isobutyl ketone. The combined organic layers were agitated with a solution of 4.5 g of sodium chloride in 15 ml of water and concentrated on the rotary vacuum evaporator to about 2/3 of the original volume. The concentrated mixture was filtered and the filtrate was added to a mechanically stirred flask with 50 ml of heptane at 20 °C. The mixture was stirred for 2 h, the resulting solid was filtered, washed twice with 5 ml of heptane and dried in a vacuum oven first at 20 °C and then the temperature was gradually increased up to 40 °C. At 40 °C, the amorphous elagolix sodium salt was dried in the vacuum oven for 24 h, 3.7 g of product was obtained. Example 9

Preparation of elagolix potassium salt The solution of 36.4 g of KOH (0.65 mol) in 800 ml of water was added to 1,500 ml of alcoholic solution containing 200 g of elagolix ethylester (0.3 mol). The resulting mixture was stirred at room temperature for approximately 6 h. On the rotary vacuum evaporator, the mixture was then concentrated and, after addition of 1 ,500 ml of water, filtered. To the filtrate was added 1 ,450 ml of methyl isobutyl ketone, the mixture was heated to 55 °C, stirred at this temperature for about 10 to 15 minutes and then, after cooling, the layers were separated. To the aqueous layer was added 1,450 ml of methyl isobutyl ketone, followed by the solution of 259 g of KOH in 280 ml of water, while stirring at room temperature. The mixture was stirred for several minutes, then the layers were separated and the aqueous layer was extracted with 2 x 400 ml of methyl isobutyl ketone. The combined organic layers were agitated with a solution of 180 g of sodium chloride in 500 ml of water and concentrated on the rotary vacuum evaporator to about 2/3 of the original volume. The concentrated mixture was filtered and the filtrate was added to a mechanically stirred reactor with 2,000 ml of heptane at 20 °C. The mixture was stirred for 2 h, the resulting solid was filtered, washed twice with 5 ml of heptane and dried in the vacuum oven first at 20 °C and then the temperature was gradually increased up to 40 °C. At 40 ° C, the amorphous elagolix potassium salt was dried in the vacuum oven for 24 h, 151 g of product was obtained.

The X-ray spectrum of elagolix potassium salt shows a classic amorphous halo with band maxima at 9.4, 16.0 and 22.6 °2Theta. The differential scanning calorimetry curve of elagolix potassium salt exhibits the glass transition temperature of 61 °C to 67 °C.

Example 10

Preparation of elagolix potassium salt

The free form of elagolix (5 g) was stirred in 80 ml of water/methyl isobutyl ketone (1: 1). To this mixture, a solution of 4.5 g of KOH in 5 ml of water was added with stirring. The mixture was stirred for 1 h at 60 °C. After cooling to room temperature, the layers were separated and the aqueous layer was extracted with 20 ml of methyl isobutyl ketone. The combined organic layers were agitated with a solution of 4.5 g of sodium chloride in 15 ml of water and concentrated on the rotary vacuum evaporator to about 2/3 of the original volume. The concentrated mixture was filtered and the filtrate was added to a mechanically stirred flask with 50 ml of heptane at 20 °C. The mixture was stirred for 2 h, the resulting solid was filtered, washed twice with 5 ml of heptane and dried in the vacuum oven first at 20 °C and then the temperature was gradually increased up to 40 °C. At 40 °C, the amorphous elagolix potassium salt was dried in the vacuum oven for 24 h, 3.7 g of product was obtained.

Example 11

Preparation of elagolix calcium salt

The free form of elagolix (5 g) was stirred in 80 ml of water/methyl isobutyl ketone (1: 1). To this mixture, a solution of 12.7 g of calcium acetate in 30 ml of water was added with stirring. The mixture was stirred for 1 h at 60 °C. After cooling to room temperature, the layers were separated and the aqueous layer was extracted with 20 ml of methyl isobutyl ketone. The combined organic layers were agitated with a solution of 4.5 g of sodium chloride in 15 ml of water and concentrated on the rotary vacuum evaporator to about 2/3 of the original volume. The concentrated mixture was filtered and the filtrate was added to a mechanically stirred flask with 50 ml of heptane at 20 °C. The mixture was stirred for 2 h, the resulting solid was filtered, washed twice with 5 ml of heptane and dried in the vacuum oven first at 20 °C and then the temperature was gradually increased up to 40 °C. At 40 °C, the amorphous elagolix calcium salt was dried in the vacuum oven for 24 h, 3.5 g of product was obtained.

The X-ray spectrum of elagolix calcium salt shows classic amorphous halo with band maxima at 9.5, 15.5 and 22.2 °2Theta. The differential scanning calorimetry curve of elagolix calcium salt exhibits the glass transition temperature of 114 °C to 119 °C.

Example 12

Preparation of the solid form of elagolix with benzenesulfonic acid

The free form of elagolix (900 mg) was stirred in 20 ml of methanol together with benzenesulfonic acid (227 mg). The resulting mixture was heated at 60 °C for 2 h, then allowed to cool and stirred at room temperature for 24 h. After evaporation of the solvent, 1.1 g of amorphous solid form of elagolix with benzenesulfonic acid was obtained.

The differential scanning calorimetry curve of the solid form of elagolix with benzenesulfonic acid exhibits the glass transition temperature of 91 °C to 102 °C

Example 13

Preparation of the solid form of elagolix with 2-naphtalenesulfonic acid

The free form of elagolix (900 mg) was stirred in 20 ml of methanol together with 2-naphtalenesulfonic acid (303 mg). The resulting mixture was heated at 60 °C for 4 h, then allowed to cool and stirred at room temperature for 24 h. After evaporation of the solvent, 1.2 g of amorphous solid form of elagolix with 2- naphtalenesulfonic acid was obtained.

The differential scanning calorimetry curve of the solid form of elagolix with 2-naphtalenesulfonic acid exhibits the glass transition temperature of 101 °C to 113 °C Example 14

Preparation of solid solutions of elagolix with polymers in a weight ratio of 1 : 1

Sodium salt of elagolix (200 mg) was dissolved in a mixture of dichloromethane and methanol using an ultrasound, together with 200 mg of polymer. The resulting solution was filtered and evaporated on the rotary evaporator until foaming occurs. The product was subsequently dried in the vacuum oven at 40 °C for approximately 48 h.

According to the above example, solid solutions were prepared with the following polymers: Polymer Amount and ratio of solvents used for dissolution

KoUidon VA 64 5 ml / methanol : dichloromethane 3 : 2

KoUidon K 30 8.5 ml / methanol : dichloromethane 6 : 1

Soluplus 4 ml / methanol : dichloromethane 2 : 1

Eudragit L 100 10.5 ml / methanol : dichloromethane 1 : 1

Eudragit S 100 8 ml / methanol : dichloromethane 4 : 5

HPMC 7.5 ml / methanol : dichloromethane 2 : 1

HPMC AS 8.5 ml / methanol : dichloromethane 1 : 2

The X-ray spectrum of the solid solution of elagolix sodium salt with KoUidon VA 64 in a weight ratio of 1 : 1 shows classic amorphous halo with band maxima at 9.4, 14.4 and 21.8 °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with KoUidon VA 64 in a weight ratio of 1 : 1 exhibits the glass transition temperature of 62 °C to 64 °C.

The X-ray spectrum of the solid solution of elagolix sodium salt with KoUidon K 30 in a weight ratio of 1 : 1 shows classic amorphous halo with band maxima at 14.5 and 21.3 °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with KoUidon K 30 in a weight ratio of 1 : 1 exhibits the glass transition temperature of 130 °C to 132 °C.

The X-ray powder diffraction spectrum of the solid solution of elagolix sodium salt with Soluplus in a weight ratio of 1 : 1 shows classic amorphous halo with band maxima at 9.8 and 18.0 (flat maximum) °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with Soluplus™ in a weight ratio of 1 : 1 exhibits the glass transition temperature of 52 °C to 54 °C. The X-ray powder diffraction spectrum of the solid solution of elagolix sodium salt with HPMC in a weight ratio of 1 : 1 shows classic amorphous halo with band maxima at 9.4 and 20.0 °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with HPMC in a weight ratio of 1 : 1 exhibits the glass transition temperature of 111 °C to 114 °C.

Example 15

Preparation of solid solutions of elagolix with polymers in a weight ratio of 1 : 2

Sodium salt of elagolix (100 mg) was dissolved in a mixture of dichloromethane and methanol using an ultrasound, together with 200 mg of polymer. The resulting solution was filtered and evaporated on the rotary evaporator until foaming occurs. The product was subsequently dried in the vacuum oven at 40 °C for approximately 48 h.

According to the above example, solid solutions were prepared with the following polymers:

Polymer Amount and ratio of solvents used for dissolution

KoUidon VA64 3 ml / methanol : dichloromethane 3 : 1 KoUidon K30 3,5 ml / methanol : dichloromethane 6 : 1

Soluplus 2,5 ml / methanol : dichloromethane 3 : 2

Eudragit LI 00 12,5 ml / methanol : dichloromethane 3 : 1

Eudragit SI 00 4,5 ml / methanol : dichloromethane 4 : 5

HPMC 5,5 ml / methanol : dichloromethane 2 : 1

HPMC AS 7,5 ml / methanol : dichloromethane 1 : 2

The X-ray powder diffraction spectrum of the solid solution of elagolix sodium salt with KoUidon VA 64 in a weight ratio of 1 : 2 shows classic amorphous halo with band maxima at 14.2 and 21.5 °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with KoUidon VA 64 in a weight ratio of 1 : 2 exhibits the glass transition temperature of 106 °C to 108 °C.

The X-ray powder diffraction spectrum of the solid solution of elagolix sodium salt with KoUidon K 30 in a weight ratio of 1 : 2 shows classic amorphous halo with band maxima at 13.6 and 21.1 °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with KoUidon K 30 in a weight ratio of 1 : 2 exhibits the glass transition temperature of 135 °C to 137 °C.

The X-ray powder diffraction spectrum of the solid solution of elagolix sodium salt with Soluplus in a weight ratio of 1 : 2 shows classic amorphous halo with band maxima at 10.0 and 18.4 (flat maximum) °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with Soluplus in a weight ratio of 1 : 2 exhibits the glass transition temperature of 59 °C to 61 °C.

The X-ray powder diffraction spectrum of the solid solution of elagolix sodium salt with Eudragit L 100 in a weight ratio of 1 : 2 shows classic amorphous halo with band maxima at 14.8 and 30.5 °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with Eudragit L 100 in a weight ratio of 1 : 2 exhibits the glass transition temperature of 144 °C to 146 °C.

The X-ray powder diffraction spectrum of the solid solution of elagolix sodium salt with Eudragit S 100 in a weight ratio of 1 : 2 shows classic amorphous halo with band maxima at 14.7 and 30.5 °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with Eudragit S 100 in a weight ratio of 1 : 2 exhibits the glass transition temperature of 143 °C to 146 °C.

The X-ray powder diffraction spectrum of the solid solution of elagolix sodium salt with HPMC in a weight ratio of 1 : 2 shows classic amorphous halo with band maxima at 8.0 and 20.3 °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with HPMC in a weight ratio of 1 : 2 exhibits the glass transition temperature of 113 °C to 116 °C.

The X-ray powder diffraction spectrum of the solid solution of elagolix sodium salt with HPMC AS in a weight ratio of 1 : 2 shows classic amorphous halo with band maxima at 9.9 and 19.8 °2Theta. The differential scanning calorimetry curve of the solid solution of elagolix sodium salt with HPMC AS in a weight ratio of 1 : 2 exhibits the glass transition temperature of 108 °C to 111 °C. Example 16

Preparation of solid solutions of elagolix with polymers in a weight ratio 1 : 1 by hot melt extrusion (HME)

A mixture of 3 g of elagolix sodium salt and 3 g of polymer was triturated, passed over a 0.5 mm sieve and thoroughly mixed. Thus homogenized mixture was extruded on a twin-screw extruder by Three -Tec at the appropriate temperature. The extrudate was milled on a hammer mill with a 0.6 mm sieve.

Example 17

Evaluation of dissolution behaviour

Dissolution behaviourw of the amorphous forms of elagolix salts, amorphous solid forms of elagolix with acids and solid elagolix solutions with polymers were compared. The dissolution behaviour was tested for true dissolutions and dissolutions from powder forms. However, the greatest emphasis when assessing the solubility of solid forms of elagolix was put on true dissolutions. The dissolution behaviour was tested on Sirius InForm instrument, medium was 40 ml of 10 mM hydrochloric acid, pH 2, 100 rpm, disc surface 0.28 cm² (disk diameter 6 mm).

Results of dissolution behaviour IDR (= Intrinsic dissolution rate):

It follows from the above values, that amorphous potassium salt, solid solutions of elagolix sodium salt with Kollidon K 30 in a ratio of 1 : 2 and HPMC in a ratio of 1 : 1 showed significantly higher dissolution than elagolix sodium salt. On the other hand, amorphous elagolix calcium salt and solid solutions of elagolix calcium salt with Kollidon VA 64 in a ratio of 1 : 1 and 1 : 2 showed similar dissolution behaviour in these tests as elagolix sodium salt.

Example 18

Pharmaceutical compositions containing elagolix salts

Amorphous sodium salt was used to prepare core tablets having strength of 150 mg of elagolix. After mixing thoroughly, the mixture of substances was processed by dry granulation, followed by sieving and tableting. The quantitative composition of the tablet is given in the table below:

In the same way, the core tablets containing other elagolix salts were prepared. The elagolix solid form charge was always calculated with respect to the content of elagolix in the given salt so that the final content of elagolix in the tablet was 150 mg. The amount of salt ranged from about 395 mg for elagolix sodium salt tablets to about 399 mg for tablets with elagolix potassium and calcium salts.

Example 19

Pharmaceutical compositions containing solid solutions of elagolix sodium salt

Solid solution of elagolix sodium salt with Kollidon VA 64 in a ratio of 1: 1 was used to prepare core tablets having strength of 150 mg of elagolix. After mixing thoroughly, the mixture of substances was processed by dry granulation, followed by sieving and tableting. The quantitative composition of the tablet is given in the table below. The total weight of the core tablets was about 400 mg.

Substance Amount - core |mgl

Solid solution of elagolix with Kollidon VA 64 in a ratio of 1 : 1 300.0 mg

Microcrystalline cellulose 72.0 mg Sodium carboxymethyl starch 24.0 mg

Magnesium stearate 4.0 mg

In the same way, the core tablets containing the solid elagolix sodium salt solution with Kollidon VA 64 were prepared in a ratio of 1 : 2. In this case, the solid solution charge was 450 mg and the total weight of core tablets was approximately 550 mg.

Example 20: Preparation of the solid form of elagolix ethylester with pamoic acid (2: 1)

Elagolix ethylester with HPLC purity of 92.63 % (53.5 g) was dissolved in MeOH (800 ml); pamoic acid was added (15.76 g, 0.5 eq.). The suspension was heated at 60 °C for 3 h. Subsequently, the mixture was cooled to room temperature, allowed to cool to 25 °C, and placed for 1 h in an ice bath. Filtration, washing with MeOH (80 ml), and drying in the vacuum oven at 40 °C for 32 h gave 59.18 g (86 %) of a solid crystalline form of 2: 1 with a purity of 95.08 %.

NMR

Elagolix ethylester

'H-NMR (500 MHz, DMSO-i¼):

7.67 - 7.64 (1H, ovl, ArH), 7.60 - 7.51 (2Η, ovl, ArH), 7.40 - 7.36 (5Η, ovl, ArH), 7.19 - 7.09 (2Η, ovl,

ArH), 6.80 (0.5Η, m, ArH), 6.54 (0.5Η, m, ArH), 5.34+5.20 (1Η+1Η, dd+d, / = 17.2, 5.4 Hz, / = 17.2;

NCH₂), 4.56 (1Η, br, CH), 4.30 (2Η, br, NCH₂CH), 3.99 (2H, q, / = 7.0, OCH₂CH₃ ), 3.84 (3H, s, OCH₃),

2.58 (2H, br, NCH₂), 2.32 (2Η, m, CH₂CO), 2.00 - 1.90 (3Η, ovl, CH₃), 1.70 (2Η, br, CH₂CH₂CH₂), 1.10

(3H, t, J = 7.0 Hz, OCH₂<¾)

Pamoic acid (0.5 eq. )

'H-NMR (500 MHz, DMSO-<¾):

8.23 (1H, s, ArH), 8.17 (1Η, d, J = 8.6 Hz, ArH), 7.66 (1Η, d, J = 8.9 Hz, ArH), 7.11 (1Η, t, J = 7.6 Hz, ArH), 7.03 (1Η, t, J = 7.4 Hz, ArH), 4.71 (1Η, s, ArCH₂Ar).

The X-ray spectrum is on Fig. 30, DSC curve is on Fig. 31.

Example 21 : Crystallization of the solid form of ethylester elagolix with pamoic acid (2: 1)

The solid form (1 g) is crystallized by dissolving in boiling MeOH (ca. 45 ml). The mixture is then freely cooled to room temperature and then stirred at 0 °C for 1 h. The product is isolated by filtration.

¾ NMR, X-ray and DSC images are identical to the solid crystalline form obtained in Example 20.

Cleaning potential of the solid form of ethylester of elagolix with pamoic acid: Reduction of content of lactam (II) and desfluoro impurity (III) by repeated crystallization

Sample II (%) Ill (%)

Starting ester 1.22 1.44

Formation of a solid 0.46 0.82

1^st crystallization - 0.38 2^nd crystallization - 0.20

3^rd crystallization - 0.10

4^th crystallization - 0.06

Example 22: Preparation of the solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D-tartaric acid (2: 1)

A flask was filled with 1.2 g of elagolix ethylester with HPLC purity of 92.11%, which was then dissolved in ethanol (12 ml). The (+)-2,3-dibenzoyl-D-tartaric acid (0.358 g, 0.55 eq.) was dissolved in ethanol (1 ml) and added to the reaction mixture in one portion. The reaction mixture was stirred overnight to form fine white crystals. Filtration yielded 1.25 g (82 %) of crystalline solid form with HPLC purity of 96.25 %. NMR

Elagolix ethylester

lU NMR (500 Hz, DMSO-<¾: 7.68 - 7.61 (1H, ovl, ArH), 7.61 - 7.53 (2Η, ovl, ArH), 7.31 - 7.21 (5Η, ovl, ArH), 7.21 - 7.09 (2Η, ovl, ArH), 6.75 (0.5Η, m, ArH), 6.55 (0.5Η, m, ArH), 5.30 (2Η, m, NCH₂Ar), 4.29 - 4.01 (2Η + 1Η, ovl, NCH₂CH+ CH), 3.99 (1H, q, J = 7.0 Hz, OCH₂CH₃), 3.98 (1H, q, J = 7.0 Hz, OCH₂CH₃), 3.85 (3H, s, OCH₃), 2.37 (2H, m, NCH₂CH₂), 2.22 (2H, m, CH₂COOEt), 2.10 (1.5Η, s, CH₃), 2.09 (1.5Η, s, CH₃), 1.60 (2Η, m, CH₂CH₂CH₂), 1.12 (1.5H, t, 7.0 Hz, OCH₂C¾), 1.11 (1.5H, t, J = 7.0

( + )-2,3-dibenzoyl-D-tartaric acid (0.5 eq.)

lU NMR (500 Hz, DMSO-<¾): 7.95 (2H, d, J = 7.8 Hz, ArH), 7.63 (1Η, ovl, ArH), 7.50 (2Η, t, J = 7.8 Hz, ArH), 5.69 (1Η, s, CH)

The X-ray spectrum is on Fig.32, DSC curve is on Fig. 33

Example 23: Preparation of the solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D-tartaric acid (2: 1)

A flask was filled with 235 mg of elagolix ethylester with HPLC purity of 92.11 %, which was then dissolved in methanol (2 ml). The (+)-2,3-dibenzoyl-D-tartaric acid (70 g, 0.55 eq.) was dissolved in methanol (0.25 ml) and added to the reaction mixture in one portion. The reaction mixture was inoculated and stirred overnight to form fine white crystals. Filtration yielded 123 mg (41 %) of crystalline solid form with HPLC purity of 96.53 %.

¾ NMR, X-ray and DSC images are identical to the solid crystalline form obtained in Example 22.

Example 24: Preparation of the solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D-tartaric acid (2: 1) A flask was filled with 300 mg of elagolix ethylester with HPLC purity of 92.11 %, which was subsequently dissolved in acetone/water (3: 1, 4 ml). The (+)-2,3-dibenzoyl-D-tartaric acid (90 mg, 0.55 eq.) was dissolved in the same solvent mixture (0.25 ml) and added to the reaction mixture in one portion. The reaction mixture was stirred overnight to form fine white crystals. Filtration yielded 161 mg (54 %) of crystalline solid form with HPLC purity of 97.19 %.

Example 25: Crystallization of the solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D-tartaric acid (2: 1)

The solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D-tartaric acid (2:1) (200 mg) with HPLC purity of 96.25 % was dissolved in boiling ethanol (1 ml) and subsequently freely cooled to room temperature with stirring. Filtration yielded 159 mg of crystals with HPLC purity of 97.15 %.

Example 26: Re-crystallization of the solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D- tartaric acid (2: 1)

The solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D-tartaric acid (2:1) (200 mg) with HPLC purity of 96.25 % was dissolved in boiling isopropylalcohol (1 ml) and subsequently freely cooled to room temperature with stirring. Filtration yielded 173 mg of crystals with HPLC purity of 96.71 %.

Example 27: Re-crystallization of the solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D- tartaric acid (2: 1)

The solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D-tartaric acid (2:1) (200 mg) with HPLC purity of 96.25 % was dissolved in boiling methanol (1 ml) and subsequently freely cooled to room temperature with stirring. Filtration yielded 135 mg of crystals with HPLC purity of 97.52 %.

¾ NMR, X-ray and DSC images are identical to the solid crystalline form obtained in Example 22. Example 28: Crystallization of the solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D-tartaric acid (2: 1)

The solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D-tartaric acid (2:1) (200 mg) with HPLC purity of 96.25 % was dissolved in dichloromethane (1 ml) and subsequently w-heptane (4 ml) was added dropwise over 20 minutes. Filtration yielded 188 mg of crystals with HPLC purity of 96.83 %.

*H NMR, X -ray and DSC images are identical to the solid crystalline form obtained in Example 22.

Cleaning potential of the solid form of ethylester of elagolix with (+)-2,3-dibenzoyl-D-tartaric acid: V (%) (intermediate of

preparation with a free

Sample II (%) III ( ) amino group)

Starting ester 1.22 1.44 1.86

Formation of a solid 0.63 1.38 0.98

Example 25 0.36 1.37 0.57

Example 26 0.36 1.40 0.80

Example 27 0.18 1.34 0.31

Example 28 0.10 1.39 0.91

Example 29: Release of elagolix sodium salt from the solid form of ethylester of elagolix with pamoic acid (2: 1)

The solid form of ethylester of elagolix with pamoic acid (2: 1, HPLC purity 95.1 %, 19.9 g) was dissolved in EtOAc (170 ml) and 9% aqueous NaHC03 (63 ml) was added dropwise with vigorous stirring. The mixture was stirred for 1 h to remove the co-former from the organic phase. The phases were separated. The volume of the organic phase was distilled down to one third and then EtOH (170 ml) was added. The substitution of EtOAc for EtOH was made by distillation. The NaOH solution (2.35 g / 60 ml H₂0) was added to the ethanolic solution and the mixture was stirred for 1 h at 35 °C. Subsequently, the volume was vacuum reduced to a minimum and water (60 ml) was added. Most of the solvent was redistilled and 60 ml of water was added. The aqueous solution was washed with EtOAc (60 ml). Subsequently, the solution was saturated with NaCl (20 g) and after its dissolution the mixture was extracted with EtOAc (90 ml). The organic phase was dried azeotropically, filtered through a layer of diatomaceous earth and added dropwise over 20 min to n-heptane (150 ml) cooled to 5 °C. Filtration yielded the precipitated product in a yield of 65 % and HPLC purity of 99.72 %.

Example 30: Release of elagolix sodium salt from the solid form of ethylester of elagolix with (+)-2,3- dibenzoyl-D-tartaric acid (2: 1)

The reaction was carried out according to Example 10 from the solid form of elagolix ethylester with (+)- 2,3-dibenzoyl-D-tartaric acid (15.73 g) with HPLC purity of 99.3 %. Isolated was 6.44 g (53 %) of the elagolix sodium salt having a purity of 99.78 %.

List of analytical methods X-ray measuring parameters: The diffractogram was obtained on X'PERT PRO MPD PANalytical Powder Diffractometer, CuKa radiation (λ = 1.542 A), excitation voltage 45 kV, anode current 40 niA, measured range 2 - 40° 2Θ, step size 0.01° 2Θ while staying on the reflection for 0.5 s. The measurement was carried out on a sample with surface/ thickness 10/0.5 mm. For the primary bundle correction, Soller diaphragms 0.02 rad, 10 mm mask and a fixed anti-dispersion diaphragm 1/4° were used. The irradiated sample surface area is 10 mm, programmable divergence slits were used. For the secondary bundle correction, Soller diaphragms 0.02 rad and anti-dispersion diaphragm 5.0 mm were used. Records of differential scanning calorimetry (DSC) were measured on Discovery DSC instrument from TA Instruments. Sample loading into a standard Al crucible (40 μΐ.) was between 3 to 5 mg and the heating rate was 5 °C/min. The temperature program used was composed of 1 stabilization minute at 0 °C and then heating up to 200 °C with the heating rate of 5 °C/min (amplitude = 0.8 °C and period = 60 s). The carrier gas was 5.0 N₂ at a flow rate of 50 ml/min.

*H NMR was measured on Bruker Avance 500 instruments, probe Prodigy 5 mm or Bruker Avance 250, probe QNP 250 MHz SB 5mm

Method for the determination of chemical purity by HPLC:

Mobile phase: A: 1 ml of trifluoroacetic acid in 1,000 ml of water

B: 1 ml of trifluoroacetic acid in 1,000 ml of acetonitrile

Elution: gradient

Column temperature: 29 °C

Detection: UV at 273 nm

Spray: 1.0 μΐ

Sample temperature: 20 °C

Length of measurement: 8.5 min

Instrument: Vyvoj 12

Column: UPLC-132 (BEH C18 1.7 μπι, 2.1 x 100 mm, part no. 186002352)

Sample preparation: Dissolve 5 mg of substance in 10 ml of 70% acetonitrile.

Claims

1. A solid form selected from the group comprising:

- solid forms of compound of formula (I)

(I)

- solid forms of compound of formula (I) with an acid,

- solid solutions of compound of formula (I) with a polymer

whereas when R is ethyl, the acid is not HC1.

2. Use of the solid form according to claim 1 as an intermediate of synthesis of elagolix or its ester, and/or as a component of pharmaceutical formulation.

3. The solid form of compound of formula (I) according to claim 1 or the use according to claim 2, wherein R is calcium, preferably the solid form is a calcium salt of elagolix, more preferably an amorphous calcium salt of elagolix having

b) glass transition temperature as measured by diffraction scanning calorimetry being 114 °C to 119 °C. 4. The solid form of compound of formula (I) according to claim 1 or the use according to claim 2, wherein R is potassium, preferably the solid form is amorphous potassium salt of elagolix having a) X-ray powder diffraction spectrum showing an amorphous halo with band maxima at 9.

4; 16.0 and 22.6 ± 0.2 °2Theta, and/or

5. The solid form of compound of formula (I) with an acid according to claim 1 or the use according to claim 2, wherein the acids are pamoic acid, 2,3-dibenzoyl-tartaric acid (in particular (+)-2,3-dibenzoyl-D- tartaric acid), sulfonic acids. 6. The solid form according to claim 1 or the use according to claim 2, wherein the solid form is a solid form of compound of formula (I), wherein R is H, with pamoic acid, having

a) characteristic reflections in X-ray powder diffraction spectrum: 7.7 ± 0.2; 9.4 ± 0.2; 15.6 ± 0.2; 19.3 ± 0.2; 20.

6 ± 0.2 and 26.2 ± 0.2° 2-theta, measured using CuKa radiation, or

b) a DSC peak at the temperature of 154 ± 2 °C.

7. The solid form of compound of formula (I) with acid according to claim 1 or the use according to claim 2, wherein R is C1-C6 alkyl, preferably ethyl, and the acid is selected from the group comprising pamoic acid, (+)-2,3-dibenzoyl-D-tartaric acid, hydrobromic acid, phosphoric acid, p-toluenesulfonic acid, citric acid, maleic acid.

8. The solid form according to claim 1 or the use according to claim 2, wherein the solid form is a solid form of compound of formula (I), wherein R is ethyl, with pamoic acid, preferably in ratio 2: 1 and/or preferably having

a) characteristic reflections in X-ray powder diffraction spectrum: 4.1 ; 7.5; 15.0; 23.3 and 26.8 ± 0.2° 2- theta, measured using CuKa radiation, or

b) DSC peak at the temperature 123 + 2 °C.

9. The solid form of compound of formula (I) according to claim 1 or the use according to claim 2, wherein the solid form is compound of formula (I), wherein R is H, in amorphous form with sulfonic acid, preferably selected from a group comprising amorphous solid form of compound of formula (I), wherein R is H, with benzenesulfonic acid, preferably showing a glass transition temperature 91 °C az 102 °C as measured by differential scanning calorimetry, and amorphous solid form of compound of formula (I), wherein R is H, with 2-naphthalenesulfonic acid, preferably showing a glass transition temperature 101 °C az 113 °C as measured by differential scanning calorimetry.

10. The solid form of compound of formula (I) with acid according to claim 1 or the use according to claim 2, wherein the solid form is a solid form of compound of formula (I), wherein R is ethyl, with (+)- 2,3-dibenzoyl-D-tartaric acid, preferably in the ratio 2: 1, and/or preferably a solid form of compound of formula (I), wherein R is ethyl, with (+)-2,3-dibenzoyl-D-tartaric acid having:

b) DSC peak at the temperature 93 + 2 °C.

11. The solid form according to claim 1 or the use according to claim 2, wherein the solid form is a solid solution in which an amorphous form of compound of formula (I), wherein R is an alkali metal or an alkali earth metal, preferably an amorphous form of sodium salt of elagolix, is stabilized by a polymer in a weight ratio in the range of 1:0.5 to 1:2.5, preferably in the range of 1 : 1 to 1 : 2, more preferably in the weight ratio of about 1:1 or about 1:2.

12. The solid form according to claim 1 or the use according to claim 2, wherein the solid form is selected from the group comprising:

- a solid solution of amorphous sodium salt of elagolix with polyvinylpyrrolidone in a weight ratio of about 1:1, said solid solution preferably showing

b) differential scanning calorimetry curve with glass transition temperature of 130 °C to 132 °C;

- a solid solution of amorphous sodium salt of elagolix with polyvinylpyrrolidone in a weight ratio of about 1 : 2, said solid solution preferably showing

b) differential scanning calorimetry curve with glass transition temperature of 135 °C to 137 °C;

- solid solutions of sodium salt of elagolix with polyvinylpyrrolidone in the ratio of about 1 : 1 or about 1 : 2;

- a solid solution of amorphous sodium salt of elagolix with polyvinylcaprolactame, polyvinylacetate and polyethyleneglycol copolymer in a weight ratio of about 1 : 1, said solid solution preferably showing a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 9.8 and 18.0 (flat maximum) ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 52 °C to 54 °C;

- a solid solution of amorphous sodium salt of elagolix with polyvinylcaprolactame, polyvinylacetate and polyethyleneglycol copolymer in a weight ratio of about 1 : 2, said solid solution preferably showing a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 10.0 a 18.4 (flat maximum) ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 59 °C to 61 °C;

- a solid solution of amorphous sodium salt of elagolix with methacrylic acid and methyl methacrylate copolymer (about 1:1 by weight) in a weight ratio of about 1 : 2, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 14.8 and 30.5 ±

0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 144 °C to 146 °C; - a solid solution of amorphous sodium salt of elagolix with methacrylic acid and methyl methacrylate copolymer (about 1:2 by weight) in a weight ratio of about 1 : 2, said solid solution preferably showing

b) differential scanning calorimetry curve with glass transition temperature of 143 °C to 146 °C;

- a solid solution of amorphous sodium salt of elagolix with HPMC in a weight ratio of about 1 : 1, said solid solution preferably showing

b) differential scanning calorimetry curve with glass transition temperature of 111 °C to 114 °C;

- a solid solution of amorphous sodium salt of elagolix with HPMC in a weight ratio of about 1 : 2, said solid solution preferably showing

a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 8.0 and 20.3 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 113 °C to 116 °C;

- a solid solution of amorphous sodium salt of elagolix with HPMC AS in a weight ratio of about 1 : 2, said solid solution preferably showing

b) differential scanning calorimetry curve with glass transition temperature of 108 °C to 111 °C;

- a solid solution of amorphous sodium salt of elagolix with vmylpyrrolidone and vinylacetate copolymer

(ratio 3:2) (Kollidon VA64) in a weight ratio of about 1 : 1, said solid solution preferably showing a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 9.6; 14.4 and 21.8 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 62 °C to 64 °C;

(ratio 3:2) (Kollidon VA64) in a weight ratio of about 1 : 2, said solid solution preferably showing a) X-ray powder diffraction spectrum having an amorphous halo with band maxima at 14.2 and 21.5 ± 0.2 °2Theta, and/or

b) differential scanning calorimetry curve with glass transition temperature of 106 °C to 108 °C.

13. A method of preparation of the solid form of claim 1, characterized in that it contains at least the following steps:

a) dissolving or suspending the compound of formula (I)

b) removal of the solvent, yielding the solid form.

14. A method of preparation of the solid form of claim 1, characterized in that it contains at least the following steps:

a) dissolving or suspending a compound of formula (IV)

wherein R' is selected from H, a cation of a base, C1-C6 alkyl, C6-C20 aryl and C7-C24 aralkyl, and an acid in an organic solvent and/or water, and

b) removal of the solvent, yielding the solid form.

15. A method of crystallizing and/or re -crystallizing solid forms of compound of formula (I), wherein R represents C1-C6 alkyl, C6-C20 aryl or C7-C24 aralkyl, with an organic acid, characterized in that it contains at least the following steps:

a) dissolving or suspending a compound of formula (I), wherein R represents C1-C6 alkyl, C6-C20 aryl or C7-C24 aralkyl, and the organic acid,

c) removal of the solvent, yielding the solid form.

16. A method of preapration of elagolix or elagolix ester, characterized in that a solid form of the compound of formula (I) with an acid is prepared, in particular wherein R is C1-C6 alkyl, C6-C20 aryl or C7-C24 aralkyl and the acid is an organic acid, the said solid form is then subjected to crystallization, and subsequently the re-crystallized solid form is converted into an elagolix ester or an elagolix salt, in particular into ethyl ester of elagolix, or elagolix sodium salt, preferably the re-crystallized solid form is converted into elagolix sodium salt by basic hydrolysis.

17. Use of the solid form of elagolix ester of formula (I)

(I)

wherein R represents C1-C6 alkyl, C6-C20 aryl or C7-C24 aralkyl,

with (+)-2,3-dibenzoyl-D-tartaric acid for obtaining a chirally pure (R)-enantiomer of elagolix ester.

18. The solid form according to any one of claims 1 and 3 to 12 for use as a medicament, in particular in the treatment of diseases selected from the group comprising endometriosis, uterine myomas, prostate hyperplasia, prostate, breast and ovarian cancers.