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WO2023287938A1 - Formes à l'état solide d'amcenestrant - Google Patents

Formes à l'état solide d'amcenestrant Download PDF

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Publication number
WO2023287938A1
WO2023287938A1 PCT/US2022/037052 US2022037052W WO2023287938A1 WO 2023287938 A1 WO2023287938 A1 WO 2023287938A1 US 2022037052 W US2022037052 W US 2022037052W WO 2023287938 A1 WO2023287938 A1 WO 2023287938A1
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WIPO (PCT)
Prior art keywords
amcenestrant
theta
degrees
crystalline
adipic acid
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PCT/US2022/037052
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English (en)
Inventor
Lorena KORDIĆ
Sanja MATEČIĆ MUŠANIĆ
Tea BARBARO
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Teva Pharmaceuticals International GmbH
Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
Original Assignee
Teva Pharmaceuticals International GmbH
Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
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Publication of WO2023287938A1 publication Critical patent/WO2023287938A1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure encompasses solid state forms of Amcenestrant, in embodiments crystalline polymorphs of Amcenestrant, processes for preparation thereof, and pharmaceutical compositions thereof.
  • Amcenestrant is reported to be a selective estrogen receptor degrader (SERD) which has estrogen receptor antagonist properties and accelerates the proteasomal degradation of the estrogen receptor. Amcenestrant is under clinical investigation as an anticancer agent, in particular for treatment of breast cancer.
  • SELD selective estrogen receptor degrader
  • Crystalline forms are described in International Publication No. WO 2021/116074.
  • Polymorphism the occurrence of different crystalline forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state ( 13 C) NMR spectrum.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • XRD X-ray diffraction
  • 13 C solid state
  • Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
  • New solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Amcenestrant.
  • the present disclosure provides solid state forms of Amcenestrant and salts thereof, in embodiments crystalline polymorphs of Amcenestrant, cocrystals of Amcenestrant, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid state forms of Amcenestrant, Amcenestrant salts and their solid state forms.
  • the present disclosure also provides uses of the said solid state forms of Amcenestrant and salts thereof in the preparation of other solid state forms of Amcenestrant or salts thereof. [0011] The present disclosure provides crystalline polymorphs of Amcenestrant and salts thereof for use in medicine, including for the treatment of cancer.
  • the present disclosure also encompasses the use of crystalline polymorphs of Amcenestrant and salts thereof of the present disclosure for the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs of Amcenestrant and salts thereof according to the present disclosure.
  • the present disclosure includes processes for preparing the above mentioned pharmaceutical compositions.
  • the processes include combining any one or a combination of the crystalline polymorphs of Amcenestrant and salts thereof with at least one pharmaceutically acceptable excipient.
  • the crystalline polymorph of Amcenestrant and salts thereof as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Amcenestrant and salts thereof may be used as medicaments, such as for the treatment of cancer.
  • the present disclosure also provides methods of treating cancer, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Amcenestrant and salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from cancer, or otherwise in need of the treatment.
  • the present disclosure also provides uses of crystalline polymorphs of Amcenestrant and salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating cancer.
  • Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of amorphous Amcenestrant.
  • Figure 2 shows a characteristic XRPD of Amcenestrant Form T1.
  • Figure 3 shows a characteristic XRPD of Amcenestrant Form T2.
  • Figure 4 shows a characteristic XRPD of Amcenestrant Form T3.
  • Figure 5 shows a characteristic XRPD of Amcenestrant Form T4.
  • Figure 6 shows a characteristic XRPD of Amcenestrant Form LI .
  • Figure 7 shows a characteristic XRPD of Amcenestrant hydrochloride Form L2.
  • Figure 8 shows a characteristic XRPD of Amcenestrant: adipic acid Form Al.
  • Figure 9 shows a characteristic XRPD of Amcenestrant: glutaric acid Form Gl.
  • Figure 10 shows a characteristic XRPD of Amcenestrant: glutaric acid Form G2.
  • Figure 11 shows a characteristic XRPD of Amcenestrant hydrochloride Form HI .
  • Figure 12 shows a characteristic XRPD of Amcenestrant bisulfate Form SI.
  • Figure 13 shows a characteristic XRPD of Amcenestrant napsylate Form N 1.
  • Figure 14 shows a characteristic solid state 13 C NMR spectrum for Amcenestrant: adipic acid Form Al.
  • the present disclosure encompasses solid state forms of Amcenestrant and salts thereof, including crystalline polymorphs of Amcenestrant, crystalline forms of Amcenestrant salts, cocrystals of Amcenestrant processes for preparation thereof, and pharmaceutical compositions thereof.
  • Solid state properties of Amcenestrant and crystalline polymorphs thereof can be influenced by controlling the conditions under which Amcenestrant and crystalline polymorphs thereof are obtained in solid form.
  • the solid state forms of Amcenestrant may be polymorphically pure, or substantially free of any other solid state (or polymorphic) forms.
  • the expression "substantially free of any other forms” will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD.
  • a crystalline polymorph of Amcenestrant described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Amcenestrant.
  • the described crystalline polymorph of Amcenestrant may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of the same Amcenestrant.
  • the solid state forms of Amcenestrant e.g. Amcenestrant, Amcenestrant salts or Amcenestrant cocrystals
  • Amcenestrant e.g. Amcenestrant, Amcenestrant salts or Amcenestrant cocrystals
  • the expression “substantially free of any other enantiomer” will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other enantiomer of the subject compound as measured, for example, by chiral HPLC.
  • a crystalline polymorph of Amcenestrant described herein as substantially free of any other enantiomer would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject enantiomer of crystalline polymorph of Amcenestrant.
  • the described crystalline polymorph of Amcenestrant may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other enantiomer of crystalline polymorph of the same Amcenestrant.
  • the crystalline polymorphs of Amcenestrant of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.
  • a solid state form such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
  • the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone.
  • a crystal form of Amcenestrant referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Amcenestrant characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
  • crystalline Amcenestrant adipic acid is a distinct molecular species.
  • Crystalline Amcenestrant: adipic acid may be a co-crystal of Amcenestrant and adipic acid.
  • crystalline Amcenestrant: adipic acid may be a salt.
  • crystalline Amcenestrant glutaric acid is a distinct molecular species.
  • Crystalline Amcenestrant glutaric acid may be a co-crystal of Amcenestrant and glutaric acid.
  • crystalline Amcenestrant glutaric acid may be a salt.
  • Co-Crystal or “Cocrystal” as used herein is defined as a crystalline material including two or more molecules in the same crystalline lattice and associated by non-ionic and non-covalent bonds. In some embodiments, the cocrystal includes two molecules which are in natural state.
  • Cocrystal former or “crystal former” as used herein is defined as a molecule that forms a cocrystal with Amcenestrant or salts thereof, for example adipic acid.
  • solid state forms or crystalline polymorphs or crystal forms of Amcenestrant relates to solid state forms of Amcenestrant and Amcenestrant salts and include co-crystal forms of Amcenestrant (and salts thereof) and a crystal former.
  • anhydrous in relation to crystalline forms of Amcenestrant, relates to a crystalline form of Amcenestrant which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA.
  • solvate refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate.” The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.
  • the term "isolated" in reference to crystalline polymorph of Amcenestrant of the present disclosure corresponds to a crystalline polymorph of Amcenestrant that is physically separated from the reaction mixture in which it is formed.
  • XRPD measurements are taken using copper Ka radiation wavelength 1.54187 A.
  • a thing e.g., a reaction mixture
  • room temperature or “ambient temperature,” often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located.
  • room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
  • the amount of solvent employed in a chemical process may be referred to herein as a number of “volumes” or “vol” or “V.”
  • a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
  • this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent.
  • v/v may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.
  • a process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.
  • reduced pressure refers to a pressure that is less than atmospheric pressure.
  • reduced pressure is about 10 mbar to about 50 mbar.
  • ambient conditions refer to atmospheric pressure and a temperature of 22-24°C.
  • the present disclosure includes an amorphous form of Amcenestrant.
  • the amorphous form of Amcenestrant may be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1.
  • the present disclosure includes a crystalline polymorph of Amcenestrant, designated Form Tl.
  • the crystalline Form T1 of Amcenestrant may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 4.7, 11.0, 12.0, 16.8 and 22.2 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form Tl of Amcenestrant may be further characterized by an X-ray powder diffraction pattern having peaks at 4.7, 11.0, 12.0, 16.8 and 22.2 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 13.7, 14.5 and 18.4 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form Tl of Amcenestrant is isolated.
  • Crystalline Form Tl of Amcenestrant may be characterized by an X-ray powder diffraction pattern having peaks at 4.7, 11.0, 12.0, 13.7, 14.5, 16.8, 18.4 and 22.2 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form Tl of Amcenestrant may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 4.7,
  • the present disclosure includes a crystalline polymorph of Amcenestrant, designated Form T2.
  • the crystalline Form T2 of Amcenestrant may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 6.3, 7.8, 10.5, 21.1 and 29.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form T2 of Amcenestrant may be further characterized by an X-ray powder diffraction pattern having peaks at 6.3, 7.8, 10.5, 21.1 and 29.9 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from
  • crystalline Form T2 of Amcenestrant is isolated.
  • Crystalline Form T2 of Amcenestrant may be a solvate.
  • Crystalline Form T2 of Amcenestrant may be THF/water solvate and/or ethanol/heptane solvate.
  • Crystalline Form T2 of Amcenestrant may be characterized by an X-ray powder diffraction pattern having peaks at 4.7, 6.3, 7.8, 10.5, 11.0, 13.0, 15.5, 18.8, 21.1 and 29.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form T2 of Amcenestrant may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.3,
  • the present disclosure includes a crystalline polymorph of Amcenestrant, designated Form T3.
  • the crystalline Form T3 of Amcenestrant may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 6.4, 14.1, 15.5, 17.6 and 21.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form T3 of Amcenestrant may be further characterized by an X-ray powder diffraction pattern having peaks at 6.4, 14.1, 15.5, 17.6 and 21.0 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from
  • crystalline Form T3 of Amcenestrant is isolated.
  • Crystalline Form T3 of Amcenestrant may be characterized by an X-ray powder diffraction pattern having peaks at 6.4, 8.8, 9.3, 13.2, 14.1, 15.5, 17.1, 17.6, 19.1 and 21.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form T3 of Amcenestrant may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.4,
  • the present disclosure includes a crystalline polymorph of Amcenestrant, designated Form T4.
  • the crystalline Form T4 of Amcenestrant may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 12.7, 15.1, 16.5, 19.8 and 23.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form T4 of Amcenestrant may be further characterized by an X-ray powder diffraction pattern having peaks at 12.7, 15.1, 16.5, 19.8 and 23.0 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 8.3, 10.6, 14.2, 17.2 and 20.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form T4 of Amcenestrant is isolated.
  • Crystalline Form T4 of Amcenestrant may be characterized by an X-ray powder diffraction pattern having peaks at 8.3, 10.6, 12.7, 14.2, 15.1, 16.5, 17.2, 19.8, 20.9 and 23.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form T4 of Amcenestrant may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 12.7,
  • the present disclosure provides a crystalline form of Amcenestrant, designated Form LI.
  • the crystalline Form LI of Amcenestrant may be characterized by an X-ray powder diffraction having peaks at 8.6, 10.3 and 18.8 degrees two-theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form LI of Amcenestrant may be further characterized by an X-ray powder diffraction pattern having any one, two, three, four, five, six or seven additional peaks selected from: 13.9, 14.6, 16.0, 20.6, 21.1, 22.8 and 26.2 degrees two-theta ⁇ 0.2 degrees two-theta.
  • Crystalline Form LI of Amcenestrant may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 8.6, 10.3, 18.8, 20.6 and 21.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form LI of Amcenestrant may be further characterized by an X-ray powder diffraction pattern having peaks at 8.6, 10.3, 18.8, 20.6 and 21.1 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 13.9, 14.6, 16.0, 22.8 and 26.2 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • the crystalline Form LI of Amcenestrant may be characterized by an X-ray powder diffraction pattern having peaks at 8.6, 10.3, 13.9, 14.6, 16.0, 18.8, 20.6, 21.1,
  • crystalline Amcenestrant Form LI is characterized by an XRPD pattern substantially as depicted in Figure 6.
  • crystalline Form LI of Amcenestrant is isolated.
  • the present disclosure provides a crystalline form of Amcenestrant HC1 salt, designated Form L2.
  • the crystalline Form L2 of Amcenestrant HC1 may be characterized by an X-ray powder diffraction having peaks at 13.0, 17.3 and 20.2 degrees two-theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form L2 of Amcenestrant HC1 may be further characterized by an X- ray powder diffraction pattern having any one, two, three, four, five, six or seven additional peaks selected from: 13.8, 16.8, 18.7, 20.7, 24.4, 24.7 and 25.7 degrees two-theta ⁇ 0.2 degrees two-theta.
  • Crystalline Form L2 of Amcenestrant HC1 may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 13.0, 17.3, 20.2, 20.7 and 25.7 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form L2 of Amcenestrant HC1 may be further characterized by an X-ray powder diffraction pattern having peaks at 13.0, 17.3, 20.2, 20.7 and 25.7 degrees 2- theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 13.8, 16.8, 18.7, 24.4 and 24.7 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • the crystalline Form L2 of Amcenestrant HC1 may be characterized by an X-ray powder diffraction pattern having peaks at 13.0, 13.8, 16.8, 17.3, 18.7, 20.2, 20.7, 24.4, 24.7 and 25.7 degrees two-theta ⁇ 0.2 degrees two-theta.
  • crystalline Amcenestrant HC1 Form L2 is characterized by an XRPD pattern substantially as depicted in Figure 7.
  • crystalline Form L2 of Amcenestrant HC1 is isolated.
  • the present disclosure further provides crystalline Amcenestrant: adipic acid.
  • Crystalline Amcenestrant: adipic acid may be a co-crystal of Amcenestrant and adipic acid.
  • crystalline Amcenestrant: adipic acid may be a salt, i.e., Amcenestrant adipate.
  • Amcenestrant: adipic acid may be in a ratio between about 2: 1 to about 1 :2 of Amcenestrant and adipic acid.
  • Amcenestrant: adipic acid may be in a 1:1 ratio of Amcenestrant and adipic acid.
  • the present disclosure provides a crystalline form of Amcenestrant: adipic acid, designated Form Al.
  • the crystalline Form A1 of Amcenestrant: adipic acid may be characterized by an X-ray powder diffraction having peaks at 10.5, 15.0 and 20.1 degrees two- theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form Al of Amcenestrant: adipic acid may be further characterized by an X-ray powder diffraction pattern having any one, two, three, four, five, six or seven additional peaks selected from: 9.4, 10.3, 17.1, 17.7, 18.8, 19.4 and 23.5 degrees two-theta ⁇ 0.2 degrees two-theta.
  • Crystalline Form Al of Amcenestrant adipic acid, may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 10.5, 15.0 and 20.1 degrees two-theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form Al of Amcenestrant: adipic acid may be further characterized by an X-ray powder diffraction pattern having any one, two, three, four, five or six additional peaks selected from: 9.4, 17.1, 17.7, 18.8, 19.4 and 23.5 degrees two-theta ⁇ 0.2 degrees two-theta.
  • Crystalline Form Al of Amcenestrant adipic acid, may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 10.5, 15.0, 18.8, 19.4 and 20.1 degrees 2- theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form Al of Amcenestrant: adipic acid may be further characterized by an X-ray powder diffraction pattern having peaks at 10.5, 15.0, 18.8, 19.4 and 20.1 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 9.4, 10.3, 17.1, 17.7 and 23.5 degrees 2-theta ⁇ 0.2 degrees 2- theta.
  • Crystalline Form Al of Amcenestrant adipic acid, may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 10.5, 15.0, 18.8, 19.4 and 20.1 degrees 2- theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form Al of Amcenestrant: adipic acid may be further characterized by an X-ray powder diffraction pattern having peaks at 10.5, 15.0, 18.8, 19.4 and 20.1 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 9.4, 17.1, 17.7 and 23.5 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • the crystalline Form A1 of Amcenestrant: adipic acid may be characterized by an X-ray powder diffraction pattern having peaks at 9.4, 10.5, 15.0, 17.1, 17.7, 18.8, 19.4, 20.1 and 23.5 degrees two-theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form A1 of Amcenestrant: adipic acid may be characterized by an X-ray powder diffraction pattern having peaks at 9.4, 10.3, 10.5, 15.0, 17.1, 17.7, 18.8, 19.4, 20.1 and 23.5 degrees two-theta ⁇ 0.2 degrees two-theta.
  • crystalline Amcenestrant adipic acid Form A1 is characterized by an XRPD pattern substantially as depicted in Figure 8.
  • crystalline Amcenestrant: adipic acid Form A1 can be characterized by a 13 C solid state NMR spectrum with characteristic peaks: 25.9, 38.1, 62.4, 153.9 and 177.8 ⁇ 0.2 ppm; or by a 13 C solid state NMR spectrum substantially as depicted in Figure 14.
  • crystalline Amcenestrant: adipic acid Form A1 can be characterized by a 13 C solid state NMR spectrum having characteristic chemical shift differences between peaks at 25.9, 38.1, 62.4, 153.9 and 177.8 ⁇ 0.2 ppm and a reference peak at 74.0 ⁇ 0.2 ppm of: 48.1, 35.9, 11.6, 79.9 and 103.8 ⁇ 0.1 ppm.
  • crystalline Form A1 of Amcenestrant: adipic acid is isolated.
  • crystalline Form A1 of Amcenestrant: adipic acid is polymorphically pure.
  • crystalline Form A1 of Amcenestrant: adipic acid is enantiomerically pure.
  • crystalline Form A1 of Amcenestrant: adipic acid may be an anhydrous form.
  • the present disclosure further provides crystalline Amcenestrant: glutaric acid.
  • Crystalline Amcenestrant: glutaric acid may be a co-crystal of Amcenestrant and glutaric acid.
  • crystalline Amcenestrant: adipic acid may be a salt, i.e., Amcenestrant glutarate.
  • the present disclosure provides a crystalline form of Amcenestrant: glutaric acid, designated Form Gl.
  • the crystalline Form G1 of Amcenestrant: glutaric acid may be characterized by an X-ray powder diffraction having peaks at 17.2, 18.0 and 24.1 degrees two- theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form G1 of Amcenestrant glutaric acid may be further characterized by an X-ray powder diffraction pattern having any one, two, three, four, five, six, seven or eight additional peaks selected from: 9.6, 14.4, 15.5, 19.4, 22.1, 22.7, 23.8 and 24.1 degrees two-theta ⁇ 0.2 degrees two-theta.
  • Crystalline Form G1 of Amcenestrant glutaric acid, may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 17.2, 18.0, 19.4, 23.8 and 24.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form G1 of Amcenestrant glutaric acid may be further characterized by an X-ray powder diffraction pattern having peaks at 17.2, 18.0,
  • the crystalline Form G1 of Amcenestrant glutaric acid may be characterized by an X-ray powder diffraction pattern having peaks at 9.6, 14.4, 15.5, 17.2, 18.0,
  • crystalline Amcenestrant glutaric acid Form G1 is characterized by an XRPD pattern substantially as depicted in Figure 9.
  • crystalline Form G1 of Amcenestrant glutaric acid is isolated.
  • the present disclosure provides a crystalline form of Amcenestrant: glutaric acid, designated Form G2.
  • the crystalline Form G2 of Amcenestrant: glutaric acid may be characterized by an X-ray powder diffraction having peaks at 14.9, 19.4 and 20.2 degrees two- theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form G2 of Amcenestrant: glutaric acid may be further characterized by an X-ray powder diffraction pattern having any one, two, three, four, five, six or seven additional peaks selected from: 8.2, 10.5, 15.5, 17.1, 17.6, 23.0 and 27.4 degrees two-theta ⁇ 0.2 degrees two-theta.
  • Crystalline Form G2 of Amcenestrant glutaric acid, may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 10.5, 14.9, 19.4, 20.2 and 23.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form G2 of Amcenestrant glutaric acid may be further characterized by an X-ray powder diffraction pattern having peaks at 10.5, 14.9,
  • the crystalline Form G2 of Amcenestrant glutaric acid may be characterized by an X-ray powder diffraction pattern having peaks at 8.2, 10.5, 14.9, 15.5, 17.1,
  • crystalline Amcenestrant glutaric acid Form G2 is characterized by an XRPD pattern substantially as depicted in Figure 10.
  • crystalline Form G2 of Amcenestrant glutaric acid is isolated.
  • the present disclosure further provides crystalline Amcenestrant hydrochloride.
  • the present disclosure provides a crystalline form of Amcenestrant hydrochloride, designated Form HI.
  • the crystalline Form HI of Amcenestrant hydrochloride may be characterized by an X-ray powder diffraction having peaks at 13.0, 17.3, 20.2, 20.7 and 24.4 degrees two-theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form HI of Amcenestrant hydrochloride may be further characterized by an X-ray powder diffraction pattern having any one, two, three, four or five additional peaks selected from: 13.8, 16.8, 17.7, 18.7 and 24.5 degrees two-theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form HI of Amcenestrant hydrochloride may be characterized by an X-ray powder diffraction pattern having peaks at 13.0, 13.8, 16.8, 17.3, 17.7,
  • crystalline Amcenestrant hydrochloride Form HI is characterized by an XRPD pattern substantially as depicted in Figure 11.
  • crystalline Form HI of Amcenestrant hydrochloride is isolated.
  • the present disclosure further provides crystalline Amcenestrant bisulfate.
  • the present disclosure provides a crystalline form of Amcenestrant bisulfate, designated Form SI.
  • the crystalline Form SI of Amcenestrant bisulfate may be characterized by an X-ray powder diffraction having peaks at 8.8, 11.7, 13.2, 15.4 and 20.6 degrees two-theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form SI of Amcenestrant bisulfate may be further characterized by an X-ray powder diffraction pattern having any one, two, three, four or five additional peaks selected from: 13.9, 14.7, 16.3, 17.8 and 19.0 degrees two-theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form SI of Amcenestrant bisulfate may be characterized by an X-ray powder diffraction pattern having peaks at 8.8, 11.7, 13.2, 13.9, 14.7, 15.4, 16.3, 17.8, 19.0 and 20.6 degrees two-theta ⁇ 0.2 degrees two-theta.
  • crystalline Amcenestrant bisulfate Form SI is characterized by an XRPD pattern substantially as depicted in Figure 12.
  • crystalline Form SI of Amcenestrant bisulfate is isolated.
  • the present disclosure further provides crystalline Amcenestrant napsylate.
  • the present disclosure provides a crystalline form of Amcenestrant napsylate, designated Form Nl.
  • the crystalline Form N1 of Amcenestrant napsylate may be characterized by an X-ray powder diffraction having peaks at 7.4, 14.8, 18.0, 19.9 and 20.7 degrees two-theta ⁇ 0.2 degrees two-theta.
  • the crystalline Form Nl of Amcenestrant napsylate may be further characterized by an X-ray powder diffraction pattern having any one, two, three, four or five additional peaks selected from: 8.6, 9.9, 11.1, 13.4 and 15.5 degrees two-theta ⁇ 0.2 degrees two- theta.
  • the crystalline Form Nl of Amcenestrant napsylate may be characterized by an X-ray powder diffraction pattern having peaks at 7.4, 8.6, 9.9, 11.1, 13.4, 14.8, 15.5, 18.0, 19.9 and 20.7 degrees two-theta ⁇ 0.2 degrees two-theta.
  • crystalline Amcenestrant napsylate Form Nl is characterized by an XRPD pattern substantially as depicted in Figure 13.
  • crystalline Form Nl of Amcenestrant napsylate is isolated.
  • the above crystalline polymorphs can be used to prepare other crystalline polymorphs of Amcenestrant, Amcenestrant salts and their solid state forms.
  • the present disclosure encompasses a process for preparing other solid state forms of Amcenestrant, Amcenestrant salts and their solid state forms thereof.
  • the process includes preparing any one of the Amcenestrant (salts) and solid state forms of Amcenestrant by the processes of the present disclosure, and converting it to other Amcenestrant salt(s).
  • the present disclosure provides the above described crystalline polymorphs of Amcenestrant and salts thereof for use in the preparation of pharmaceutical compositions comprising Amcenestrant and salts thereof and/or crystalline polymorphs thereof.
  • the present disclosure encompasses the use of the above described solid state forms of Amcenestrant and salts thereof, for the preparation of a pharmaceutical composition in the form of a solid dispersion comprising Amcenestrant or salt thereof.
  • the present disclosure also encompasses the use of crystalline polymorphs of Amcenestrant and salts thereof of the present disclosure for the preparation of pharmaceutical compositions of Amcenestrant and salts thereof and/or crystalline polymorphs thereof.
  • the present disclosure encompasses the above described solid state forms of Amcenestrant and salts thereof, for the preparation of a pharmaceutical composition or formulation, preferably an oral formulation in the form of a solid dispersion comprising Amcenestrant or salt thereof.
  • the present disclosure includes processes for preparing the above mentioned pharmaceutical compositions.
  • the processes include combining any one or a combination of the crystalline polymorphs of Amcenestrant and salts thereof of the present disclosure with at least one pharmaceutically acceptable excipient.
  • compositions of the present disclosure contain any one or a combination of the solid state forms of Amcenestrant and salts thereof of the present disclosure.
  • the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
  • Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g., Avicel®
  • microfme cellulose lactose
  • starch pregelatinized starch
  • calcium carbonate calcium sulfate
  • sugar dextrates
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g.
  • Methocel® liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.
  • povidone e.g. Kollidon®, Plasdone®
  • pregelatinized starch sodium alginate, and starch.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.
  • alginic acid e.g., Ac- Di-Sol®, Primellose®
  • colloidal silicon dioxide e.g., croscarmellose sodium
  • crospovidone e.g., Kollidon®, Polyplasdone®
  • guar gum e.g., magnesium aluminum silicate
  • methyl cellulose e.g., microcrystalline cellulose
  • polacrilin potassium ed
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet is made by the compaction of a powdered composition
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • Amcenestrant and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.
  • a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • the solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral.
  • the dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.
  • the dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell.
  • the shell can be made from gelatin and optionally contain a plasticizer such as glycerin and/or sorbitol, an opacifying agent and/or colorant.
  • compositions and dosage forms can be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filling can be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size.
  • the granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition can be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.
  • a blended composition can be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.
  • a pharmaceutical formulation of Amcenestrant can be administered.
  • Amcenestrant may be formulated for administration to a mammal, in embodiments to a human, by injection.
  • Amcenestrant can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection.
  • the formulation can contain one or more solvents.
  • a suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity.
  • Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others.
  • Ansel et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
  • the crystalline polymorphs of Amcenestrant and salts thereof and the pharmaceutical compositions and/or formulations of Amcenestrant of the present disclosure can be used as medicaments, in embodiments in the treatment of cancer.
  • the present disclosure also provides methods of treating cancer by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Amcenestrant and salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.
  • Crystalline Amcenestrant adipic acid.
  • Crystalline Amcenestrant adipic acid which is a co-crystal. 3. Crystalline Amcenestrant adipate salt.
  • a 1 characterized by the XRPD pattern having peaks at 10.5, 15.0 and 20.1 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having one, two, three, four, five, six or seven additional peaks selected from 9.4, 10.3, 17.1, 17.7, 18.8, 19.4 and 23.5 degrees two theta ⁇ 0.2 degrees two theta.
  • Al characterized by the XRPD pattern having peaks at 10.5, 15.0 and 20.1 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having one, two, three, four, five or six additional peaks selected from 9.4, 17.1, 17.7, 18.8, 19.4 and 23.5 degrees two theta ⁇ 0.2 degrees two theta.
  • a crystalline product according to Clause 1, 2, or 3, designated Form Al which is characterized by data selected from one or more of the following: a) an XRPD pattern having peaks at 10.5, 15.0, 18.8, 19.4 and 20.1 degrees 2-theta ⁇ 0.2 degrees 2-theta; b) an XRPD pattern as depicted in Figure 8; and c) combinations of these data.
  • a crystalline product according to any of Clauses 1, 2, 3 or 7, designated form Al characterized by the XRPD pattern having peaks at 10.5, 15.0, 18.8, 19.4 and 20.1 degrees 2- theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 9.4, 17.1, 17.7 and 23.5 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • a crystalline product according to any of Clauses 1, 2, 3, 4, 5, 6, 7,8 or 9 designated form Al characterized by the XRPD pattern having peaks at 9.4, 10.3, 10.5, 15.0, 17.1, 17.7, 18.8, 19.4, 20.1 and 23.5 degrees two-theta ⁇ 0.2 degrees two-theta.
  • a crystalline product according to any of Clauses 1, 2, 3, 4, 6 or 7 designated form Al, characterized by the XRPD pattern having peaks at 9.4, 10.5, 15.0, 17.1, 17.7, 18.8, 19.4, 20.1 and 23.5 degrees two-theta ⁇ 0.2 degrees two-theta.
  • Crystalline Amcenestrant glutaric acid.
  • Crystalline Amcenestrant glutaric acid which is a co-crystal.
  • a crystalline product according to Clause 1, 2, or 3, designated Form Gl which is characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 17.2, 18.0 and 24.1 degrees 2-theta ⁇ 0.2 degrees 2-theta; b. an XRPD pattern as depicted in Figure 9; and c. combinations of these data.
  • a crystalline product according to Clause 1, 2, or 3, designated Form Gl which is characterized by data selected from one or more of the following: d) an XRPD pattern having peaks at 17.2, 18.0, 19.4, 23.8 and 24.1 degrees 2-theta ⁇ 0.2 degrees 2-theta; e) an XRPD pattern as depicted in Figure 9; and f) combinations of these data.
  • Crystalline Amcenestrant glutaric acid.
  • Crystalline Amcenestrant glutaric acid which is a co-crystal.
  • a crystalline product according to Clause 1, 2, or 3, designated Form Gl which is characterized by data selected from one or more of the following: d. an XRPD pattern having peaks at 14.9, 19.4 and 20.2 degrees 2-theta ⁇ 0.2 degrees 2-theta; e. an XRPD pattern as depicted in Figure 10; and f. combinations of these data.
  • G2 characterized by the XRPD pattern having peaks at 14.9, 19.4 and 20.2 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having one, two, three, four, five, six or seven additional peaks selected from 8.2, 10.5, 15.5, 17.1, 17.6, 23.0 and 27.4 degrees two theta ⁇ 0.2 degrees two theta.
  • a crystalline product according to Clause 1, 2, or 3, designated Form G2 which is characterized by data selected from one or more of the following: g) an XRPD pattern having peaks at 10.5, 14.9, 19.4, 20.2 and 23.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; h) an XRPD pattern as depicted in Figure 10; and i) combinations of these data.
  • Solid state NMR spectra were measured at 11.7 T using a Bruker Avance III HD 500 US/WB NMR spectrometer (Karlsruhe, Germany, 2013) with a 4- or 3.2-mm probehead.
  • the 13 C CP/MAS NMR spectra employing cross-polarization were acquired standard cross-polarization pulse scheme at spinning frequency of 18 kHz.
  • the cross-polarization contact time was 2 ms.
  • the dipolar decoupling SPINAL64 was applied during the data acquisition. The number of scans was set for the signal-to-noise ratio SINO reach at least the value ca. 50.
  • the measurements were conducted at room temperature.
  • the recycle delay D1 was optimized experimentally by the measurement of 1H MAS NMR spectra with variable repetition delay.
  • the build-up of intensity of 1H NMR signals was monitored. The whole procedure was finished when the constant (equilibrium) signal intensity was reached.
  • the repetition delay D1 used for the measurement of ss-NMR spectra was set to be 80% of the obtained equilibrium value.
  • Amcenestrant can be prepared according to methods known from the literature, for example U.S. Patent No. 9,714,221.
  • Example 1 Preparation of amorphous Amcenestrant
  • Amcenestrant (20 mg, prepared according to U.S. Patent No. 9,714,221) was dissolved in ethyl acetate (0.2 mL) at room temperature (25°C). Solution was left in opened flask at RT for 16 days, until all the solvent evaporated. Obtained solid was analyzed by XRPD. Amcenestrant amorphous was obtained.
  • Amcenestrant (200 mg, amorphous) was suspended in solvent mixture methanol/water 1:2 (2 mL) at room temperature (25°C). Obtained suspension was mixed additionally for 1 day at 25°C. The solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T1 was obtained.
  • Amcenestrant (50 mg, amorphous) was suspended in solvent mixture acetone/water 1:2 (0.5 mL) at room temperature (25°C). Obtained suspension was mixed additionally for 9 days at 25°C. The solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T1 was obtained.
  • Amcenestrant 50 mg, amorphous was suspended in solvent mixture acetone/water 1:5 (0.5 mL) at room temperature (25°C). Obtained suspension was mixed additionally for 7 days at 25°C. The solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T1 was obtained.
  • Amcenestrant (50 mg, amorphous) was suspended in solvent mixture 2-PrOH/water 1:5 (0.5 mL) at room temperature (25°C). Obtained suspension was mixed additionally for 7 days at 25°C. The solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T1 was obtained.
  • Amcenestrant (200 mg, amorphous) was suspended in solvent mixture ethanol/water 1:2 (2 mL) at room temperature (25°C). Obtained suspension was mixed additionally for 1 day at 25°C. The solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T1 was obtained.
  • Example 7 Preparation of Amcenestrant Form T1
  • Amcenestrant (200 mg, amorphous) was suspended in solvent mixture THF/water 1:5 (2 mL) at room temperature (25°C). Obtained suspension was mixed additionally for 1 day at 25°C. The solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T1 was obtained.
  • Amcenestrant 400 mg, amorphous was dissolved in solvent acetone (2.7 mL) at room temperature (25°C), and water (25°C) was added dropwise in solution (10.8 mL), and additionally stirred (magnetic stirrer) by 350 rpm for 7 days. Obtained solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T1 was obtained.
  • Amcenestrant (225 mg) was dissolved in solvent methanol (2.7 mL) at room temperature (25°C), and the solution was added dropwise in water (25°C, 3.0 mL), and additionally stirred (magnetic stirrer) by 350 rpm for 1 day. Obtained solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T1 was obtained.
  • Amcenestrant 250 mg, amorphous was suspended in solvent mixture acetone/water 2:1 (2.5 mL) at room temperature (25°C). Obtained suspension was mixed additionally for 1 day at 25°C. The solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T3 was obtained.
  • Amcenestrant form T3 (3.1 mg) was placed in open aluminum pan. Sample was subjected to thermal treatment in TGA Discovery TA instruments, according to following steps:
  • a suspension of Amcenestrant (amorphous, 250 mg) in MTBE (2.5 mL) was heated to boiling point (60°C). The suspension was cooled down to room temperature. The solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T4 was obtained.
  • Amcenestrant (amorphous, 500 mg) was dissolved in MTBE (8 mL) at 45 - 50°C. The solution was slowly cooled down and at temperature of about 34-29°C crystallization occurred. The suspension was additionally cooled down to room temperature and after 30 minutes it was additionally cooled down to 0°C. Cold suspension was left to stir at 0°C for 40 minutes. In addition, the suspension was left stirring at room temperature for 24 hours. The solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T4 was obtained.
  • Amcenestrant 50 mg, amorphous was dissolved in solvent mixture ethanol/heptane 1:9 (0.5 mL) at room temperature (25°C). Obtained solution was stirred additionally for 1 day at 25°C. The solution was then cooled to 10° and left stirring for 18 days. The solid was isolated by vacuum filtration. Obtained solid was analyzed by XRPD. Amcenestrant Form T2 was obtained.
  • Amcenestrant 400 mg, amorphous was suspended in deep eutectic solvent (choline chloride/lactic acid, 1 : 1 molar ratio) / water mixture 2: 1 (7.5 mL) at temperature of 50°C for 8 days. Obtained suspension is filtered off over blue ribbon filter paper and filtrate was washed with 3 mL of water. Obtained white powder was analyzed by XRPD. Amcenestrant HC1 Form L2 was obtained.
  • Amcenestrant (117 mg, amorphous) and glutaric acid (83 mg, 3eq.) were suspended in solvent mixture DMSO/water 1:1 (2 mL) at room temperature (25°C). Obtained suspension was stirred for 7 days at 25°C and then filtered off over blue ribbon filter paper. Obtained white powder was analyzed by XRPD. Amcenestranriglutaric acid Form G1 was obtained.
  • Amcenestrant (200 mg) was suspended in acetonitrile (2 mL) at room temperature. HC1 was added to the suspension (0.0361 mL, 1.2eq.). It was left to stir for 4 days at room temperature. Then it was filtered off over blue ribbon filter paper. Obtained powder was analyzed by XRPD. Amcenestrant HC1 Form HI was obtained.
  • Amcenestrant (200 mg) was suspended in acetonitrile (2 mL) at room temperature. Naphthalene-2-sulfonic acid was added to the suspension (0.024 mL, 1.2eq.). It was left to stir for 4 days at room temperature. Then it was filtered off over blue ribbon filter paper. Obtained powder was analyzed by XRPD. Amcenestrant bisulfate_Form SI was obtained.
  • Amcenestrant (200 mg) was suspended in acetonitrile (2 mL) at room temperature. Naphthalene-2-sulfonic acid was added to the suspension (90.12 mg, 1.2eq.). It was left to stir for 4 days at room temperature. Then it was filtered off over blue ribbon filter paper and dried for 4 hours at 80°C. Obtained powder was analyzed by XRPD. Amcenestrant napsylate Form N1 was obtained.

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Abstract

La présente invention concerne des formes à l'état solide d'Amcenestrant, dans des modes de réalisation, des polymorphes cristallins d'Amcenestrant, des procédés de préparation de ceux-ci, et des compositions pharmaceutiques de ceux-ci.
PCT/US2022/037052 2021-07-15 2022-07-14 Formes à l'état solide d'amcenestrant Ceased WO2023287938A1 (fr)

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US202263317996P 2022-03-09 2022-03-09
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9714221B1 (en) 2016-02-15 2017-07-25 Sanofi Substituted 6,7-dihydro-5H-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof
WO2021116074A1 (fr) 2019-12-09 2021-06-17 Sanofi Forme cristalline d'un dérivé d'acide 7h-benzo[7]annulène-2-carboxylique

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US9714221B1 (en) 2016-02-15 2017-07-25 Sanofi Substituted 6,7-dihydro-5H-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof
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
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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ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems"

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