WO2023187086A1 - Forme solide amorphe d'amcenestrant - Google Patents

Forme solide amorphe d'amcenestrant Download PDF

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WO2023187086A1
WO2023187086A1 PCT/EP2023/058351 EP2023058351W WO2023187086A1 WO 2023187086 A1 WO2023187086 A1 WO 2023187086A1 EP 2023058351 W EP2023058351 W EP 2023058351W WO 2023187086 A1 WO2023187086 A1 WO 2023187086A1
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Prior art keywords
amcenestrant
solid form
amorphous solid
anyone
process according
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PCT/EP2023/058351
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English (en)
Inventor
David BALTES
Damien Bonneau
Jessie-Laure HARDY
Xavier Lubeigt
Benoit Robert
Ouafa YASSA
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Sanofi
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Publication of WO2023187086A1 publication Critical patent/WO2023187086A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • 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:
  • 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.
  • ER estrogen receptor
  • HER2 human epidermal growth factor receptor 2
  • amcenestrant is developed in a solid form for oral administration.
  • Figure 1 is a X-ray powder diagram of the amorphous solid form of amcenestrant as obtained in example 1 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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:
  • 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.
  • impurity 1 said impurity is called “impurity 1”.
  • 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:
  • 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.
  • impurity 2 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:
  • 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.
  • impurity 3 said impurity
  • 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:
  • 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.
  • impurity 4 said impurity is called “impurity 4”.
  • 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:
  • 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.
  • impurity 5 said impurity is called “impurity 5”.
  • the purity measurement is performed by Ultra High Performance Liquid Chromatography (UHPLC).
  • UHPLC Ultra High Performance Liquid Chromatography
  • an amorphous solid form of amcenestrant substantially free from residual solvents is provided. “Substantially free” is defined herein as a content of no more than 1.1 % by weight of residual solvents.
  • 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.
  • GC Gas Chromatography
  • 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).
  • an amorphous solid form of amcenestrant containing not more than 0.50 % by weight of acetone.
  • an amorphous solid form of amcenestrant containing not more than 0.50 % by weight of methyl-tetrahydrofuran.
  • 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.
  • an amorphous solid form of amcenestrant with a particle size distribution having a D50 value of not more than 50 p.m and a D90 value of not more than 180
  • PSD particle size distribution
  • an amorphous solid form of amcenestrant with a particle size distribution having a D50 value of not more than 40 .m, more particularly not more than 30 .m, and for example not more than 20
  • PSD particle size distribution
  • said PSD is determined by means of laser light diffraction.
  • the herein disclosed amorphous amcenestrant may be further characterized by X-Ray Powder Diffraction and by its glass transition temperature.
  • 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.
  • 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.
  • 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.
  • organic solvent such as dichloromethane
  • 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.
  • amcenestrant is under an anhydrate crystalline form 2 as described in WO2021/1 16074.
  • the organic solvent for the preparation of the amorphous solid form of amcenestrant as described above is dichloromethane.
  • amcenestrant is dissolved or solubilized in an organic solvent, such as dichloromethane, at a concentration of about 3.2 V.
  • 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).
  • the solubilization of amcenestrant in an organic solvent 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.
  • 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.
  • 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).
  • 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).
  • the drum drying step is performed under a vacuum of 100 mbars +/- 20 mbars, so in a range of 80 to 120 mbars.
  • 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.
  • the drum drying step is followed by a sieving step.
  • 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.
  • drum drying and sieving steps are then followed by a drying step.
  • 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.
  • the drying step is performed under vacuum.
  • the drying step is performed under stirring.
  • 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.
  • step (a) 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),
  • step (b) 3. a sieving step of the powder as obtained in step (b) with sieves of about 200 to 630 p.m grid size, and
  • step (c) 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.
  • 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.
  • alternative techniques may also be used for obtaining amcenestrant in amorphous form, such as spray drying or precipitation.
  • amorphization by spray drying comprises the following steps:
  • 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;
  • the spray drying step is performed with a two-fluid nozzle equipped spray dryer or with a pressure nozzle system equipped spray dryer.
  • 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.
  • 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).
  • an organic solvent such as dichloromethane
  • the spray drying step is followed by a drying step.
  • 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.
  • the drying step is performed under vacuum, for example in a tray dryer, conical dryer, bicone, paddle dryer, and more particularly tray dryer.
  • 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.
  • a process for the preparation of anhydrate crystalline form 2 of amcenestrant, using the crystallization by evaporation technique comprises at least the following steps:
  • 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;
  • step 2 2) leaving the solution obtained in step 1 ) at the same temperature as the one set in step 1 ) for almost complete evaporation;
  • a pharmaceutical composition comprising amorphous amcenestrant as described above.
  • medicaments comprising amorphous amcenestrant as described above and at least one pharmaceutically acceptable excipient.
  • 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.
  • amorphous amcenestrant as described above for the manufacture of a medicament for treating a disease involving inhibition and degradation of estrogen receptors.
  • Example 1 Preparation of amcenestrant amorphous form by drum drying
  • Anhydrate crystalline form 2 of amcenestrant as described above 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 m 2 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.
  • 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:
  • 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
  • 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 .
  • Particle size 1.7 pm (Waters manufacturer); Column dimensions: 150 mm x 2.1 mm i.d.
  • 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
  • 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.
  • the purity of the amorphous amcenestrant obtained in example 1 was 101 .0 % (expressed on an anhydrous and solvent-free basis).
  • impurities 1 ⁇ 0.07 impurity 2: ⁇ 0.05 impurity 3: ⁇ 0.05 impurity 4: ⁇ 0.05 impurity 5: ⁇ 0.05
  • 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).
  • GC temperature-programmed capillary gas chromatography
  • FID flame ionization detector
  • Solvent amounts for dichloromethane, acetone, 2-methyltetrahydrofuran (2- MeTHF) were determined by internal standardization.
  • Carrier gas helium, at a constant flow rate of 2.0 mL/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 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.
  • the equipment was a Malvern Mastersizer 2000:
  • Size range 0.02 to 2000 microns
  • 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.
  • the particles size distribution is reported as density distribution by volume.
  • 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.
  • 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.
  • 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.
  • solvent system dichloromethane
  • 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.
  • 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 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.

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Abstract

L'invention concerne une forme solide amorphe d'amcenestrant. L'invention concerne en outre un procédé de fabrication d'une forme solide amorphe d'amcenestrant, une composition pharmaceutique comprenant ladite forme solide amorphe d'amcenestrant et l'amcenestrant amorphe destiné à être utilisé en tant que médicament, en particulier pour une utilisation dans le traitement de maladies dans lesquelles sont impliqués les récepteurs des œstrogènes, plus particulièrement le cancer.
PCT/EP2023/058351 2022-03-31 2023-03-30 Forme solide amorphe d'amcenestrant WO2023187086A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009140484A1 (fr) * 2008-05-15 2009-11-19 Sanofi-Aventis Procédés de préparation d’une substance médicamenteuse amorphe
WO2017140669A1 (fr) 2016-02-15 2017-08-24 Sanofi Dérivés de 6,7-dihydro-5h-benzo[7]annulène utilisés en tant que modulateurs de récepteurs des oestrogènes
WO2020049153A1 (fr) 2018-09-07 2020-03-12 Sanofi Procédé de préparation de méthyl 6-(2,4-dichlorophényl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphényl]-8,9-dihydro-7h-benzo[7]annulène-2-carboxylate
WO2021116074A1 (fr) 2019-12-09 2021-06-17 Sanofi Forme cristalline d'un dérivé d'acide 7h-benzo[7]annulène-2-carboxylique

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