WO2023187086A1

WO2023187086A1 - Amorphous solid form of amcenestrant

Info

Publication number: WO2023187086A1
Application number: PCT/EP2023/058351
Authority: WO
Inventors: David BALTES; Damien Bonneau; Jessie-Laure HARDY; Xavier Lubeigt; Benoit Robert; Ouafa YASSA
Original assignee: Sanofi
Priority date: 2022-03-31
Filing date: 2023-03-30
Publication date: 2023-10-05

Abstract

Herein is provided an amorphous solid form of amcenestrant. It is furthermore herein provided a process for manufacturing an amorphous solid form of amcenestrant, a pharmaceutical composition comprising said amorphous solid form of amcenestrant and the amorphous amcenestrant for use as a medicine, in particular for use in the treatment of diseases wherein estrogen receptors are involved, more particularly cancer.

Description

AMORPHOUS SOLID FORM OF AMCENESTRANT

Herein is provided an amorphous solid form of amcenestrant, processes for obtaining it, methods of using amcenestrant amorphous solid form and pharmaceutical compositions comprising it.

Amcenestrant, or 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-f luoropropyl)pyrrolidin- 3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, is an orally available selective estrogen receptor degrader (SERD). It has the following structure:

This compound and its processes of synthesis are disclosed in the patent application WO 2017/140669. An alternative process for synthesizing amcenestrant is also disclosed in the patent application WO 2020/049153. Furthermore, an anhydrate crystalline form 2 of amcenestrant is described in WO 2021/1 16074.

Amcenestrant is currently in clinical development for the treatment of breast cancer, more particularly in postmenopausal women with estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative, locally advanced or metastatic breast cancer. In this context, amcenestrant is developed in a solid form for oral administration.

For an active ingredient in a medicinal product in a solid form, there is a need to obtain said active ingredient in a form displaying a high purity, especially in terms of residual solvents, and with physico-chemical parameters allowing to reach an acceptable in vivo bioavailability. There is also a need to provide a reproducible, robust and scalable process for manufacturing said solid form. To this end, disclosed herein is a novel solid form of amcenestrant, pharmaceutical compositions comprising amcenestrant amorphous solid form, and methods of using and manufacturing the same.

Disclosed herein is an amorphous solid form of amcenestrant of high purity.

Figure 1 is a X-ray powder diagram of the amorphous solid form of amcenestrant as obtained in example 1 .

In the context of the present specification, the terms below have the following definitions unless otherwise mentioned throughout the instant specification:

The “amorphous phase of a compound” is a solid that lacks the long-range order that is characteristic of a crystal. Consequently, the X-ray diffraction pattern of an amorphous phase does not show diffraction peaks.

The term “crystalline” refers to any solid substance exhibiting three-dimensional order, which, in contrast to an amorphous solid substance, gives a distinctive XRPD pattern with more or less sharp peaks.

By “high purity”, it is meant herein an active ingredient which is substantially free from reaction impurities, starting materials, reagents, side products, unwanted solvents, and/or other processing impurities arising from the preparation and/or isolation and/or purification of said active ingredient.

By “high purity” of an amorphous solid form of amcenestrant, it is meant herein a purity comprised between 96.2% and 102.0% (w/w), assessed on an anhydrous and solvent-free basis. Such a purity range takes into account the precision of the analytical method (variability estimated equal to 2% in the measurements) and the total content of impurities, set as being inferior or equal to 1 .8% (w/w).

In an embodiment, herein is provided an amorphous solid form of amcenestrant containing not more than 0.15 % by weight of 8-(2,4-dichlorophenyl)-9-(4-{[(3S)-1 '-(3- fluoropropyl)[1 ,3'-bipyrrolidin]-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3- carboxylic acid, of formula below:

In a more particular embodiment, herein is provided an amorphous solid form of amcenestrant containing not more than 0.12 % by weight, more particularly not more than 0.10 % by weight, for example not more than 0.07 % by weight, of 8-(2,4- dichlorophenyl)-9-(4-{[(3S)-1 '-(3-fluoropropyl)[1 ,3'-bipyrrolidin]-3-yl]oxy}phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid.

In the following description, said impurity is called “impurity 1”.

In another embodiment, herein is provided an amorphous solid form of amcenestrant containing not more than 0.20 % by weight of 9-(4-{[(3S)-1 -(3- fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3- carboxylic acid, of formula below:

In a more particular embodiment, herein is provided an amorphous solid form of amcenestrant containing not more than 0.15 % by weight, more particularly not more than 0.10 % by weight, for example not more than 0.05 % by weight, of 9-(4-{[(3S)-1 -(3- fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3- carboxylic acid.

In the following description, said impurity is called “impurity 2”. In another embodiment, herein is provided an amorphous solid form of amcenestrant containing not more than 0.25 % by weight of ((3S)-3-{4-[3-carboxy-8-(2,4- dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl]phenoxy}-1-(chloromethyl)-1-(3- fluoropropyl)pyrrolidinium, of formula below:

In a more particular embodiment, herein is provided an amorphous solid form of amcenestrant containing not more than 0.20 % by weight, more particularly not more than 0.10 % by weight, for example not more than 0.05 % by weight, of ((3S)-3-{4-[3- carboxy-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl]phenoxy}-1- (chloromethyl)-l -(3-fluoropropyl)pyrrolidinium.

In the following description, said impurity is called “impurity 3”.

In another embodiment, herein is provided an amorphous solid form of amcenestrant containing not more than 0.20 % by weight of methyl 6-(2,4-dichlorophenyl)- 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2- carboxylate, of formula below:

In a more particular embodiment, herein is provided an amorphous solid form of amcenestrant containing not more than 0.15 % by weight, more particularly not more than 0.10 % by weight, for example not more than 0.06 % by weight, of methyl 6-(2,4- dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H- benzo[7]annulene-2-carboxylate.

In the following description, said impurity is called “impurity 4”.

In another embodiment, herein is provided an amorphous solid form of amcenestrant containing not more than 0.15 % by weight of 9-(4-{[(3R)-1-{3-[(3S)-3-{4-[3- carboxy-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl]phenoxy}pyrrolidin-1- yl]propyl}pyrrolidin-3-yl]oxy}phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H- benzo[7]annulene-3-carboxylic acid, of formula below:

In a more particular embodiment, herein is provided an amorphous solid form of amcenestrant containing not more than 0.12 % by weight, more particularly not more than 0.10 % by weight, for example not more than 0.05 % by weight, of 9-(4-{[(3R)-1-{3- [(3S)-3-{4-[3-carboxy-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9- yl]phenoxy}pyrrolidin-1 -yl]propyl}pyrrolidin-3-yl]oxy}phenyl)-8-(2,4-dichlorophenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid.

In the following description, said impurity is called “impurity 5”.

In an embodiment, the purity measurement is performed by Ultra High Performance Liquid Chromatography (UHPLC). Example 2.1 herein after illustrates such a purity measurement by UHPLC.

In another embodiment, herein is provided an amorphous solid form of amcenestrant substantially free from residual solvents. “Substantially free” is defined herein as a content of no more than 1.1 % by weight of residual solvents. The term “residual solvents” designates herein the traces of solvents remaining in the active ingredient, coming from the solvents used during amcenestrant synthesis as a solid form, such as dichloromethane, acetone and methyltetrahydrofuran (2-methyl-tetrahydrofuran). These traces of solvents can be measured for example by Gas Chromatography (GC) or any other suitable analytical technique. Example 2.2 herein after illustrates such a residual solvents content measurement by Gas Chromatography (GC).

Herein is provided an amorphous solid form of amcenestrant containing not more than 1000 ppm by weight (not more than 0.10 %) of dichloromethane (also called methylene chloride).

Herein is provided an amorphous solid form of amcenestrant containing not more than 0.50 % by weight of acetone.

Herein is provided an amorphous solid form of amcenestrant containing not more than 0.50 % by weight of methyl-tetrahydrofuran.

Herein is provided an amorphous solid form of amcenestrant containing not more than 1000 ppm by weight of dichloromethane, not more than 0.50 % by weight of acetone, and not more than 0.50 % by weight of methyl-tetrahydrofuran.

The amorphous solid form of amcenestrant characterized by all the combinations of maximal weight percentage amount of reaction impurities, starting materials, reagents, side products and unwanted solvents as described herein also forms part of the present invention.

In another embodiment, herein is provided an amorphous solid form of amcenestrant with a particle size distribution (PSD) having a D50 value of not more than 50 p.m and a D90 value of not more than 180 |_im (i.e., wherein 50% of the particles have a size of 50 p.m or less and 90% of the particles have a size of 180 |_im or less).

In a more particular embodiment, herein is provided an amorphous solid form of amcenestrant with a particle size distribution (PSD) having a D50 value of not more than 40 .m, more particularly not more than 30 .m, and for example not more than 20 |_im and a D90 value of not more than 140 .m, more particularly not more than 100 |_im and for example not more than 80 .m. Example 4 herein after illustrates such a particle size distribution (PSD) measurement. In one embodiment, said PSD is determined by means of laser light diffraction.

As illustrated in example 1 herein after, the herein disclosed amorphous amcenestrant may be further characterized by X-Ray Powder Diffraction and by its glass transition temperature.

An X-Ray Powder Diffraction representative of an amorphous form was obtained in example 1 and is provided in Figure 1.

The Tg (glass transition temperature) value determined by DSC (Differential Scanning Calorimetry) of the amorphous amcenestrant, for example as obtained in example 1 , is about 113-1 14°C.

Herein are also provided processes for the preparation of the amorphous solid form of amcenestrant as described above.

In one embodiment, herein is provided a process for manufacturing an amorphous solid form of amcenestrant as defined above, wherein it comprises a step of amorphisation of a crystalline form of amcenestrant by drum drying, by spray drying or by precipitation.

In said embodiment, amcenestrant may be solubilized under a crystalline form in an organic solvent, such as dichloromethane, followed by either drum drying, spray drying, or precipitation by addition of a non-solvent.

In an embodiment, the process comprises a step of solubilizing amcenestrant under a crystalline form in an organic solvent, optionally followed by a filtration step and a cooling step to about 5°C, such as in the range of 2°C to 8°C, and followed by a drum drying step.

In an embodiment, amcenestrant is under an anhydrate crystalline form 2 as described in WO2021/1 16074.

In another embodiment, the organic solvent for the preparation of the amorphous solid form of amcenestrant as described above is dichloromethane. In another embodiment, amcenestrant is dissolved or solubilized in an organic solvent, such as dichloromethane, at a concentration of about 3.2 V. In another embodiment, amcenestrant is dissolved in an organic solvent, such as dichloromethane, at a concentration of 3.0 to 5.3 V, more particularly 3.0 to 3.4 V (3.2 +/- 0.2 V).

In another embodiment, the solubilization of amcenestrant in an organic solvent, such as dichloromethane, is performed at a temperature of 17°C to 23°C, such as at about 20°C.

Said solubilization is followed by a drum drying step. This consists in a flash evaporation of a solution containing the active ingredient on heated and rotated cylinders. All equipment classically used by the man skilled in the art may be implemented, such as double drum drying equipment. Said drum drying step converts the solution as obtained in the preceding step into powder.

In another embodiment, the drum drying step is performed with a feed flow of the solution of 8.7 to 10.9 kg per hour, in particular of about 9.5 kg per hour.

In another embodiment, the drum drying step is performed at a drum temperature of 72°C to 84°C. In another embodiment, the drum drying step is performed at a drum temperature of 80 to 84°C (82°C +/- 2°C).

In another embodiment, the drum drying step is performed with a speed rotation of the rollers of 2 rpm to 4 rpm (rotations per minute), more particularly 2.5 rpm to 3.5 rpm (3 rpm +/- 0.5 rpm).

In another embodiment, the drum drying step is performed under a vacuum of 100 mbars +/- 20 mbars, so in a range of 80 to 120 mbars.

In another embodiment, the drum drying step is preceded by a filtration step and a cooling step to about 5°C, such as in the range of 2°C to 8°C, after amcenestrant is dissolved in dichloromethane.

In another embodiment, the drum drying step is followed by a sieving step.

In an embodiment, the sieving step is carried out with sieves of about 200 to 630 p.m grid size. In another embodiment, the sieving step is carried out with sieves of about 630 p.m grid size. In one embodiment, the sieving step is performed under agitation, for example by means of an oscillator rotor.

In another embodiment, the drum drying and sieving steps are then followed by a drying step.

In an embodiment, the drying step is performed at a temperature lower than 80°C, such as at 40°C to 65°C, more particularly 55°C to 61 °C. In another embodiment, the drying step is performed at a temperature of about 58°C.

In another embodiment, the drying step is performed under vacuum.

In another embodiment, the drying step is performed under stirring.

In another embodiment, the drying step is performed under vacuum and under stirring.

The drying step may for example be performed in a conical dryer, under maximum vacuum and with a peripheric speed of the stirring of 35 to 75 rpm, more particularly 65 to 75 rpm, for example at about 70 rpm.

Said drying step may alternatively be performed in a static oven.

In an embodiment is provided a process for the preparation of the amorphous solid form of amcenestrant as described above, comprising:

1 . a solubilizing step of amcenestrant under a crystalline form in an organic solvent, such as dichloromethane, at a concentration of 3.0 to 5.3 V, more particularly 3.0 to 3.4 V, optionally followed by a filtration step and a cooling step to about 5°C, such as in the range of 2°C to 8°C,

2. a drum drying step of the solution prepared in step (a) at a drum temperature of 72°C to 84°C with a speed rotation of the rollers of 2 rpm to 4 rpm, more particularly 2.5 rpm to 3.5 rpm (3 rpm +/- 0.5 rpm),

3. a sieving step of the powder as obtained in step (b) with sieves of about 200 to 630 p.m grid size, and

4. a drying step of the sieved powder as obtained in step (c) under vacuum at a temperature lower than 80°C, such as at 40°C to 65°C, more particularly 55°C to 61 °C. In addition to the drum drying technique described above, alternative techniques may also be used for obtaining amcenestrant in amorphous form, such as spray drying or precipitation.

In one embodiment, amorphization by spray drying comprises the following steps:

1. preparing a solution of amcenestrant, by dissolving amcenestrant in crystalline form, for example as anhydrate crystalline form 2 as described above, in an organic solvent, such as dichloromethane, at a concentration of 10 to 20% w/w;

2. spray drying this solution;

3. optionally, drying the powder obtained under conventional technique, for example using a tray dryer at about 40°C.

In another embodiment, the spray drying step is performed with a two-fluid nozzle equipped spray dryer or with a pressure nozzle system equipped spray dryer.

In another embodiment, the spray drying step is performed under nitrogen atmosphere. Nitrogen may for example be introduced at 100% capacity. The nitrogen flow rate may for example be about 20 kg/h to about 50 kg/h, for example 20 kg/h to about 35 kg/h.

In one embodiment, amorphization by precipitation comprises a step of solubilizing amcenestrant in crystalline form, for example as anhydrate crystalline form 2 as described above, in an organic solvent, such as dichloromethane, followed by a step of adding a non-solvent, such as heptane in a 4-fold volume, followed by a cooling step (such as about -20°C during an hour), a filtration step and a drying step (such as at 45°C, under vacuum, during about a day).

In another embodiment, the spray drying step is followed by a drying step.

In an embodiment, the drying step is performed at a temperature lower than 70°C, such as at 30°C to 65°C, more particularly 35°C to 60°C. In another embodiment, the drying step is performed at a temperature of about 40°C.

In another embodiment, the drying step is performed under vacuum, for example in a tray dryer, conical dryer, bicone, paddle dryer, and more particularly tray dryer. In an embodiment, amcenestrant used as a starting material in the manufacturing processes as described above is under an anhydrate crystalline form 2 as described in WO 2021/116074.

The anhydrate crystalline form 2 of amcenestrant is characterized by having a powder-X-ray diffractogram displaying peaks expressed as degree 2-Theta angles at about 9.5; 1 1.8; 14.1 ; 14.6; 17.7 and 18.5 (each time ± 0.2), which optionally further shows the following peaks expressed as degree 2-Theta angles at: about 15.5; 15.9; 16.6 and 22.2 (each time ± 0.2).

The anhydrate crystalline form 2 of amcenestrant has a differential scanning calorimetry (DSC) showing a melting endotherm at about 204°C onset (± 2°C).

The anhydrate crystalline form 2 of amcenestrant may be obtained by conventional crystallization techniques known to one of skill in the Art, such as crystallization by evaporation, crystallization by cooling, or crystallization by adding a nonsolvent such as water or heptane.

For example, a process for the preparation of anhydrate crystalline form 2 of amcenestrant, using the crystallization by evaporation technique, comprises at least the following steps:

1 ) solubilizing the amcenestrant in amorphous form, typically as obtained in implementing the process as described in WO 2017/140669 or WO 2020/049153 in a solvent selected from alcohols, ketones, acetates, ethers and acetonitrile, optionally in admixture with water, at a set temperature ranging from 18°C to 80°C;

2) leaving the solution obtained in step 1 ) at the same temperature as the one set in step 1 ) for almost complete evaporation;

3) isolating the anhydrate crystalline form 2 of amcenestrant formed in step 2).

In another embodiment, herein is provided a pharmaceutical composition comprising amorphous amcenestrant as described above.

In another embodiment, herein is provided medicaments comprising amorphous amcenestrant as described above and at least one pharmaceutically acceptable excipient. Herein are further disclosed the amorphous amcenestrant as described above for use as a medicine, for use as an inhibitor and degrader of estrogen receptors, and for use in the treatment of various diseases wherein estrogen receptors are involved, more particularly cancer.

Herein is further disclosed use of the amorphous amcenestrant as described above for the manufacture of a medicament for treating a disease involving inhibition and degradation of estrogen receptors.

Herein is further disclosed use of the amorphous amcenestrant as described above for the manufacture of a medicament for treating cancer.

Herein is further disclosed method of treating a disease involving inhibition and degradation of estrogen receptors, comprising administering to a subject in need thereof a therapeutically effective amount of the amorphous amcenestrant as described above.

Herein is further disclosed method of treating cancer, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of the amorphous amcenestrant as described above.

The following examples describe processes for obtaining amcenestrant in amorphous form and the physical analyses thereof.

Example 1 : Preparation of amcenestrant amorphous form by drum drying

Anhydrate crystalline form 2 of amcenestrant as described above (55 kg) was dissolved in dichloromethane (3.2 V per kg of amcenestrant) at 20°C. The solution was filtered, cooled to 5°C and concentrated to a wet powder by drum drying, using a drum dryer displaying a 0.19 m² of total drying surface area (commercial name: Buflovak) under a vacuum of 100 mbars, drums temperature of 82°C and drums speed of 3 rotations per minute, with a feed flow of 9.5 kg/h. Said drum drying step gave a yield of 58 kg of the wet amorphous form of amcenestrant.

The recovered wet powder was sieved on 630 pm grids and the product was finally dried under vacuum in a conical dryer of 350 L (commercial name: De Dietrich) at a temperature of 58°C to yield 51.6 kg (yield: 93%) of amcenestrant drug substance in amorphous form.

The X-Ray Powder Diffraction (XRPD), acquired at room temperature using a DRX D8 advantage - Brucker equipment, was representative of an amorphous form of the compound obtained (Figure 1 ). The Tg (glass transition temperature) value determined by DSC (Differential Scanning Calorimetry) was 114°C.

Of note, in example 1 herein and in example 4 below, identification of the amorphous form of amcenestrant by XRPD was performed by recording diffractograms using the Bragg-Brentano (vertical 0-20 configuration) parafocusing geometry diffractometer, coupled with a position sensitive detector. The configuration used was as follows:

• Copper anticathode (ACuKal = 1.54056 A).

• SSD 160 type detector.

The proposed reference diagram has been acquired under the following parameters:

- Generator power supply: voltage: 40 kV; intensity: 40 mA

- Initial sweep angle: 14 degrees 2e

- Final sweep angle: 23.5 degrees 2e

- Step: 0.006 degrees 2

- Step duration: 2 seconds

- Sample rotation: 30 revolutions/min

• Sample holder for about 400 mg of powder.

The diffractogram of the sample was compared to the diffractogram of an amorphous compound.

Example 2: Analyses of amcenestrant amorphous form obtained in example 1

2.1 : UHPLC method for evaluating drug substance purity and content in impurities Materials and methods

The analysis was carried out by reversed phase UHPLC in gradient elution mode using an instrument equipped with a pump, an automatic injector, a column oven capable of maintaining a temperature of 40°C, and a UV spectrophotometric detector set to 252 nm.

The reagents used were as shown in Table 1 .

Table 1 - Reagents

Test and standard solutions were prepared at a concentration of 0.20 mg/mL in a mixture of water/acetonitrile/formic acid 50/50/0.1 (V/V/V). A gradient Ultra High Performance Liquid Chromatographic (UHPLC) system in accordance with Ph. Eur. 2.2.29 was used, under the following analytical conditions:

Stationary phase

Stationary phase: Acquity UPLC CSH® Phenyl-Hexyl;

Particle size: 1.7 pm (Waters manufacturer); Column dimensions: 150 mm x 2.1 mm i.d.

Eluting conditions

Phase A: Water/Methanol/Formic acid (90:10:0.1 ; V/V/V)

Phase B: Acetonitrile/Methanol/Formic acid (90:10:0.1 ; V/V/V) Table 2

Flow rate: 0.4 mL/min

Column temperature: 40°C

Sample temperature: 10°C

Injection volume: 3 pL

The assay (amcenestrant content) was determined by external standardization on as-is basis; it was then corrected for the sum of water and solvents content to express the amcenestrant assay on anhydrous and solvent-free basis.

The reversed phase assay UHPLC method enabled the separation of the related impurities from the drug substance. The content of each individual impurity was determined based on its area percent of total area of all peaks equal or greater than their reporting threshold (normalized area percent method). UV correction factors were applied when the relative UV response of the impurity versus amcenestrant drug substance was outside the range of [0.8-1.2] pursuant to the Ph. Eur. chapter 2.2.46 (Chromatographic separation techniques).

The reporting limit was 0.05% for specified and unspecified impurities, except for impurity 1 for which the reporting limit was 0.07%.

Typical retention times and relative retentions for the drug substance amcenestrant and for the impurities to be assessed are given in the following table 3. Table 3 - Typical retention times and relative retention times

Results

The purity of the amorphous amcenestrant obtained in example 1 was 101 .0 % (expressed on an anhydrous and solvent-free basis).

The contents in impurities of the amorphous amcenestrant obtained in example 1 were as follows (UHPLC, m/m %): impurity 1 : < 0.07 impurity 2: < 0.05 impurity 3: < 0.05 impurity 4: < 0.05 impurity 5: < 0.05

2.2: Evaluation of residual solvents content by GC

Materials and methods

The drug substance was examined as a solution by temperature-programmed capillary gas chromatography (GC) using a split injection and a flame ionization detector (FID).

The procedure was performed according to the methods described in the Ph. Eur. 2.2.28 (gas chromatography) and the following procedure. Table 4 - Reagents

also called 3-pentanone

Solvent amounts for dichloromethane, acetone, 2-methyltetrahydrofuran (2- MeTHF) were determined by internal standardization.

Standard solutions

The standard solutions were prepared in DMF containing diethyl ketone as internal standard at 0.1% (v/v): 0.05 mg/mL dichloromethane, 0.25 mg/mL acetone and 0.25 mg/mL MeTHF corresponding to respective contents of 0.10% (= 1000 ppm) dichloromethane, 0.50% acetone and 0.50% MeTHF in a drug substance sample.

Sample solution

A 50 mg/mL solution in N,N-dimethylformamide (DMF) with diethyl ketone (3- pentanone) as internal standard at 0.1% (v/v) was prepared, using the amorphous amcenestrant obtained in example 1 .

Analytical conditions

Column: VF-200ms Agilent (phase: trifluoropropylmethyl polysiloxane), 30 m length and 0.25 mm i.d. coated with a 1.0 pm film thickness. Alternatively, the columns referenced RTX-200 or RTX-200 MS (Restek) could also be used.

Carrier gas: helium, at a constant flow rate of 2.0 mL/min.

Column oven temperature: 35°C (hold 5 min), to 90°C at 15°C/min, to 120°C at 20°C/min, to 160°C at 40°C/min, hold 1 min at 160°C then to 240°C at 40°C/min.

Injector: 150°C; 1 pL with a split ratio 1/20.

Detector: FID at 280°C, air 400 mL/min, hydrogen 30 mL/min, helium make-up ca 30 mL/min.

Results

Results were calculated for each solvent by comparing the ratio of the solvent peak area to the internal standard area in the sample solution with the ratio of the solvent peak area to the internal standard area in the standard solution, and applying appropriate corrections for weights and dilutions.

According to the method as described above, the following residual solvents evaluated by gas chromatography were obtained for the amorphous amcenestrant as prepared in example 1 above: acetone: not quantified (less than 0.015% by weight); methyl-tetrahydrofuran (MeTHF): 0.02% by weight; dichloromethane: 260 ppm.

2.3: Particle Size Distribution

Materials and methods

Laser light diffraction was used for the measurement of the particle size distribution (PSD). The particle size distribution was measured according to the Ph. Eur. 2.9.31 (Particle size analysis by laser light diffraction) chapter by laser diffraction in liquid phase.

The equipment was a Malvern Mastersizer 2000:

• Size range: 0.02 to 2000 microns;

• Cell liquid pathways: Hydro 2000S; • Speed/ stir pump: 2000 rpm.

An obscuration range of 10% to 25% was selected.

Silicone oil (polydimethylsiloxane silicon oil V20 or equivalent) was used for obtaining a wet dispersion of amcenestrant: about 40 mg of amorphous amcenestrant as obtained in example 1 were dispersed in 10 mL, manually shaked, then poured into the cell and stirred at 2000 rpm for 1 minute.

Results

The particles size distribution is reported as density distribution by volume.

The mean of the results obtained from three test suspensions obtained from the amorphous amcenestrant as prepared in example 1 was as follows:

D90: 65 pm

D50: 18 pm

Example 3: Preparation of amcenestrant amorphous form by spray drying

- Solution preparation:

In several assays performed, the feed solution was prepared in a glass flask of 1 I (laboratory trials) to 2 I (“demo batch”), by dissolving anhydrate crystalline form 2 of amcenestrant as described above in the required amount of dichloromethane to achieve a yellowish solution; the concentrations tested were 10 and 20% w/w. The mixture was stirred to achieve a homogeneous solution. If not used immediately, the solution was stored at 2-8 °C.

- Spray drying:

A laboratory scale spray dryer, (commercial name: BLICH I, model B-290 Advanced), with nominal drying gas capacity of 40 kg/h equipped with a two-fluid nozzle was used in the laboratory trials. Nozzle cap and diameter were 1.5 and 0.7 mm, respectively. Trials were executed operating the spray drying in closed cycle mode, with the aspirator blowing nitrogen at 100% of capacity, corresponding to a flow rate of the drying nitrogen of approximately 20 kg/h. The flow rate of atomization nitrogen was adjusted to the target value.

The demo batch was produced in a larger lab scale unit (spray dryer) in closed loop mode and using a pressure nozzle system (commercial name: SK 82/106 commercialized by Spraying Systems Co). Nozzle cap and diameter were 82 and 106 mm, respectively. A high-performance cyclone was used to collect the dried product. The spray drier was operated in a closed cycle mode, with the aspirator blowing nitrogen at 100% of capacity, corresponding to a flow rate of the drying nitrogen of approximately 35 kg/h.

Before initiating each trial, the spray dryer was stabilized with the corresponding solvent system (dichloromethane). During the stabilization period, the inlet temperature was adjusted to attain the target outlet temperature. After stabilization of the outlet temperature, the feed of the spray dryer was commuted to the feed solution and the trial initiated.

At the end, the feed was swapped back to stabilization solvent to rinse the feed line and to carry out a controlled shutdown of the unit. The dry product in the collection flask under the cyclone was weighed and the yield calculated as the mass percentage of the wet product in relation to the total solids in the solution fed to the spray dryer (90 to 103% w/w). After each test, the equipment was washed with dichloromethane to avoid the accumulation of product for the following tests.

- Secondary drying:

A lab vacuum tray dryer was used for the secondary drying step of the lab trials. Secondary drying was conducted under vacuum and nitrogen sweeping until a final level of dichloromethane below 600 ppm was achieved. The secondary drying temperature was set at 40°C. This secondary drying step produces a dry bulk powder.

The absence of crystallinity of this powder was confirmed by X-ray powder diffraction (XRPD).

The Tg (glass transition temperature) was determined by Differential Scanning Calorimetry (DSC) and was measured at about 1 13 to 1 14°C in all trials.

The purity of the amorphous amcenestrant batches obtained in example 3 ranged from 98.0 to 98.6%, with a dichloromethane content of less than 1000 ppm, more particularly of less than about 600 ppm.

Claims

1 . An amorphous solid form of amcenestrant.

2. An amorphous solid form of amcenestrant according to anyone of the preceding claims, characterized in that it contains not more than 0.15 % by weight of 8-(2,4- dichlorophenyl)-9-(4-{[(3S)-1 '-(3-fluoropropyl)[1 ,3'-bipyrrolidin]-3-yl]oxy}phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid.

3. An amorphous solid form of amcenestrant according to anyone of the preceding claims, characterized in that it contains not more than 0.20 % by weight of 9-(4-{[(3S)-1 -(3- fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3- carboxylic acid.

4. An amorphous solid form of amcenestrant according to claim 1 or 2, characterized in that it contains not more than 0.25 % by weight of ((3S)-3-{4-[3-carboxy-8-(2,4- dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl]phenoxy}-1 -(chloromethyl)-1 -(3- fluoropropyl)pyrrolidinium.

5. An amorphous solid form of amcenestrant according to claim 1 , characterized in that it contains not more than 0.20 % by weight of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)- 1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2- carboxylate.

6. An amorphous solid form of amcenestrant according to anyone of the preceding claims, characterized in that it contains not more than 0.15 % by weight of 9-(4-{[(3R)-1 -{3- [(3S)-3-{4-[3-carboxy-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9- yl]phenoxy}pyrrolidin-1 -yl]propyl}pyrrolidin-3-yl]oxy}phenyl)-8-(2,4-dichlorophenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid.

7. An amorphous solid form of amcenestrant according to anyone of the preceding claims, characterized in that it contains not more than 1000 ppm by weight of dichloromethane.

8. An amorphous solid form of amcenestrant according to anyone of the preceding claims, characterized in that it contains not more than 0.50 % by weight of acetone.

9. An amorphous solid form of amcenestrant according to anyone of the preceding claims, characterized in that it contains not more than 0.50 % by weight of methyltetrahydrofuran.

10. An amorphous solid form of amcenestrant according to anyone of the preceding claims, characterized in that it has a purity comprised between 96.2% and 102.0% (w/w), on an anhydrous and solvent-free basis.

1 1 . An amorphous solid form of amcenestrant according to anyone of the preceding claims, characterized in that its particle size distribution has a D50 value of not more than 50 .m, in particular not more than 40 .m, more particularly not more than 30 .m, and for example not more than 20 |_im and a D90 value of not more than 180 p.m, in particular not more than 140 .m, more particularly not more than 100 |_im and for example not more than 80 .m.

12. An amorphous solid form of amcenestrant according to anyone of the preceding claims, characterized by a glass transition temperature determined by Differential Scanning Calorimetry of 113-1 14°C.

13. A process for manufacturing an amorphous solid form of amcenestrant as defined in anyone of the preceding claims, wherein it comprises a step of amorphisation of a crystalline form of amcenestrant by drum drying, by spray drying or by precipitation.

14. A process according to claim 13, comprising a step of solubilizing amcenestrant under a crystalline form in an organic solvent, such as dichloromethane, followed by either drum drying, spray drying, or precipitation by addition of a non-solvent.

15. A process according to claim 13 or 14, wherein it comprises a step of solubilizing amcenestrant under a crystalline form in an organic solvent, optionally followed by a filtration step and a cooling step to 5°C, such as in the range of 2°C to 8°C, and followed by a drum drying step.

16. The process according to claim 14 or 15, wherein amcenestrant is dissolved in an organic solvent, such as dichloromethane, at a concentration of 3.0 to 5.3 V, more particularly 3.0 to 3.4 V.

17. The process according to any of claims 14 to 16, wherein amcenestrant is dissolved at a temperature of 17°C to 23°C, such as at 20°C.

18. The process according to any of claims 13 to 17, wherein the drum drying step is performed with a feed flow of the solution of 9.5 kg per hour.

19. The process according to any of claims 13 to 18, wherein the drum drying step is performed with a speed rotation of the rollers of 2 rpm to 4 rpm, more particularly 2.5 rpm to 3.5 rpm.

20. The process according to any of claims 13 to 19, wherein the drum drying step is performed under a vacuum of 100 mbars +/- 20 mbars, so in a range of 80 to 120 mbars.

21 . The process according to any of claims 13 to 20, wherein the drum drying step is followed by a sieving step.

22. The process according to claim 21 , wherein the sieving step is carried out with sieves of 200 to 630 |_im grid size, in particular with sieves of 630 |_im grid size.

23. The process according to claim 21 or 22, wherein the sieving step is followed by a drying step.

24. The process according to claim 23, wherein the drying step is performed at a temperature lower than 80°C, such as at 40°C to 65°C, more particularly 55°C to 61 °C, for example at a temperature of 58°C.

25. The process according to claim 23 and 24, wherein the drying step is performed under vacuum and under stirring.

26. Pharmaceutical composition comprising amcenestrant as defined in anyone of claims 1 to 12.

27. The amorphous amcenestrant as defined in anyone of claims 1 to 12 for use as a medicine.

28. The amorphous amcenestrant as defined in anyone of claims 1 to 12 for use as an inhibitor and degrader of estrogen receptors, and for use in the treatment of diseases wherein estrogen receptors are involved, more particularly cancer.