Crystalline form of 7h-benzo[7]annulene-2-carboxylic acid derivative

Abstract

To provide a compound for use as a medicine.SOLUTION: Provided are a compound of formula (1) as an anhydrate which is in a crystalline Form 2, characterized by having a powder X-ray diffractogram presenting peaks expressed as degree 2θ angles at about 9.5, 11.8, 14.1, 14.6, 17.7, and 18.5, and a solid form thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Provided herein is 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (hereinafter referred to as the compound of formula (1)) as an anhydrate in crystalline form 2. Also provided herein are processes for its preparation and the anhydrate crystalline form 2 for use as a pharmaceutical, particularly in the treatment of cancer. [Background technology]

[0002] The compound of formula (1) shown below is a selective estrogen receptor degrader (SERD), which has the properties of an estrogen receptor antagonist and promotes the proteasomal degradation of the estrogen receptor. It can be used, in particular, as an anticancer agent. An amorphous form of this compound is disclosed in Patent Document 1. [ka]

[0003] In addition to its efficacy, a pharmaceutically active agent must comply with various additional requirements. For example, its stability under various environmental conditions, its stability during the production of pharmaceutical preparations, or its stability in the final pharmaceutical composition. In addition, when a pharmaceutically active agent is used to prepare a pharmaceutical composition, it must be as pure as possible, and its stability during long-term storage must be guaranteed under various environmental conditions. For example, this reduces or avoids the risk that the content of the active substance in the pharmaceutical is less than the specified amount.

[0004] Typically, compounds of formula (1) are not optimally suited for handling on an industrial scale, as they must be stored under refrigerated conditions in order to maintain long-term stability in amorphous form. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2017 / 140669 Summary of the Invention [Problem to be solved by the invention]

[0006] There is therefore a need to provide the compound of formula (1) in a form that is thermodynamically most stable at least under ambient conditions of temperature and pressure, and that allows for its use and storage on an industrial scale.

[0007] Furthermore, the hygroscopicity of the pharmaceutically active agent should be only slight. In fact, moisture absorption reduces the amount of the pharmaceutically active agent as a result of the weight gain caused by water uptake. Generally, pharmaceutical compositions that tend to absorb moisture must be protected from moisture during storage, for example, by adding a suitable desiccant or by storing the drug in a moisture-protected environment.

[0008] There is also a need to provide the compound of formula (1) in a form that exhibits low hygroscopicity and does not require the addition of desiccants or the imposition of harsh conditions for storage.

[0009] Furthermore, the availability of well-defined crystalline forms allows for purification of the drug substance by recrystallization. [Means for solving the problem]

[0010] The present disclosure relates to stable crystalline forms of compounds of formula (1) that satisfy the important above characteristics.

[0011] Provided herein is novel 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid as the anhydrate in crystalline Form 2, characterized by having a powder X-ray diffraction pattern exhibiting peaks expressed as 2θ angles of about 9.5; 11.8; 14.1; 14.6; 17.7, and 18.5 degrees (each time ±0.2), optionally further exhibiting peaks expressed as 2θ angles of about 15.5; 15.9; 16.6, and 22.2 degrees (each time ±0.2), optionally further characterized by a powder X-ray diffraction pattern substantially as illustrated in FIG. 1 .

[0012] Also provided herein is a solid form which is anhydrous crystalline Form 2 of the compound of formula (1).

[0013] Further provided herein is a method for preparing anhydrous crystalline Form 2 of the compound of Formula (1).

[0014] Also provided herein are medicaments comprising anhydrous crystalline Form 2 of the compound of Formula (1), and pharmaceutical compositions comprising anhydrous crystalline Form 2 of the compound of Formula (1) and at least one pharmaceutically acceptable excipient.

[0015] In certain embodiments, in the pharmaceutical composition, the anhydrous crystalline Form 2 is substantially pure and substantially free of alternative forms.

[0016] In another particular embodiment, in the pharmaceutical composition, the anhydrous crystalline Form 2 is at least 90 percent by weight of all forms.

[0017] As used herein, the term "substantially pure" means that the crystalline form contains at least 90 weight percent, preferably at least 95 weight percent, more preferably at least 97 weight percent, and most preferably at least 99 weight percent of the indicated crystalline form. Alternatively, "substantially pure" will be understood to mean that the crystalline form contains less than 10 weight percent, preferably less than 5 weight percent, more preferably less than 3 weight percent, and most preferably less than 1 weight percent of impurities (including other polymorphs, solvates, or amorphous forms).

[0018] The present invention relates to compounds for use as pharmaceuticals, for use as inhibitors and degraders of estrogen receptors, and for use in treating various diseases in which the estrogen receptor is involved, more particularly in the treatment of diseases in which the estrogen receptor is involved. Further disclosed is anhydrous crystalline Form 2 of the compound of formula (1), particularly for use in the treatment of cancer.

[0019] Further disclosed herein is the use of anhydrous crystalline Form 2 of the compound of formula (1) for the manufacture of a medicament for treating a disease involving estrogen receptor inhibition and degradation.

[0020] Further disclosed herein is the use of anhydrous crystalline Form 2 of the compound of formula (1) for the manufacture of a medicament for treating cancer.

[0021] Further disclosed herein is a method for treating a disease involving estrogen receptor inhibition and degradation, comprising administering to a subject in need thereof a therapeutically effective amount of anhydrous crystalline Form 2 of the compound of formula (1).

[0022] Further disclosed herein is a method of treating cancer, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of anhydrous crystalline Form 2 of the compound of formula (1).

[0023] As used herein, the terms "ambient temperature" or "room temperature" refer to a temperature range of 18°C ​​to 25°C, unless otherwise specified. [Brief explanation of the drawings]

[0024] [Figure 1] X-ray powder diagram of the stable anhydrous crystalline form 2 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid measured at room temperature. [Figure 2] 1 is a thermogram of the stable anhydrous crystalline Form 2 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid. [Figure 3] FIG. 1 is a dynamic vapor sorption (DVS) isotherm plot (sorption process) of the stable anhydrous crystalline Form 2 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid measured at 25° C. [Figure 4] X-ray powder diagram of the anhydrous crystalline Form 1 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid measured at room temperature. [Figure 5] 1 is a thermogram of anhydrous crystalline Form 1 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid. [Figure 6]FIG. 1 is a dynamic vapor sorption (DVS) isotherm plot (sorption process) of the anhydrous crystalline Form 1 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid measured at 25° C. [Figure 7] X-ray powder diagram of the anhydrous crystalline Form 3 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid measured at room temperature. [Figure 8] 1 is a thermogram of anhydrous crystalline Form 3 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid. [Figure 9] FIG. 1 is a dynamic vapor sorption (DVS) isotherm plot (sorption process) of anhydrous crystalline Form 3 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid measured at 25° C. [Figure 10] X-ray powder diagram of the anhydrous crystalline Form 4 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid measured at room temperature. [Figure 11] 1 is a thermogram of anhydrous crystalline Form 4 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid. [Figure 12]FIG. 1 is a dynamic vapor sorption (DVS) isotherm plot (sorption process) of anhydrous crystalline Form 4 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid measured at 25° C. [Figure 13a] FIG. 1 is an X-ray powder diagram of the ethanol solvate of compound of formula (1) measured under ethanol vapor at room temperature. [Figure 13b] FIG. 1 is an X-ray powder diagram including three X-ray powder diagrams measured at room temperature of the ethanol solvate of the compound of formula (1): (a) under ethanol vapor (solid line), (b) at 40° C. (dotted line), and (c) after exposure to moisture (bold line), from bottom to top, respectively. [Figure 14a] FIG. 1 is an X-ray powder diagram of the acetone solvate of compound of formula (1) measured under acetone vapor at room temperature. [Figure 14b] FIG. 1 shows two X-ray powder diagrams of the acetone solvate of the compound of formula (1) measured at room temperature, from bottom to top: (a) under acetone vapor (solid line) and (b) after exposure to nitrogen (bold line). [Figure 15a] FIG. 1 is an X-ray powder diagram of the butanol solvate of compound of formula (1) measured under butanol vapor at room temperature. [Figure 15b] 1 is an X-ray powder diagram including two X-ray powder diagrams measured at room temperature of the butanol solvate of the compound of formula (1), from bottom to top, (a) under butanol vapor (solid line) and (b) after exposure to ambient conditions (bold line). [Figure 16] FIG. 1 is an X-ray powder diagram of the DCM solvate of compound of formula (1) measured under DCM vapor at room temperature. [Figure 17] FIG. 1 is an X-ray powder diagram of the THF solvate of compound of formula (1) measured under THF vapor at room temperature. [Figure 18] FIG. 1 is a HR (high resolution) X-ray powder diagram of the 2-propanol solvate of the compound of formula (1) measured at room temperature. [Figure 19]FIG. 1 is an X-ray powder diagram of the methyl tert-butyl ether (MTBE) solvate of the compound of formula (1) measured at room temperature. [Figure 20a] FIG. 1 is an X-ray powder diagram of the 1,4-dioxane solvate of the compound of formula (1), measured at room temperature. [Figure 20b] FIG. 1 is an X-ray powder diagram including two X-ray powder diagrams of the 1,4-dioxane solvate of the compound of formula (1), measured at room temperature (solid line) and after one week at room temperature (bold line), from bottom to top, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0025] Anhydrous Crystalline Form 2 of the Compound of Formula (1), and Comparative Anhydrous Forms and Solvates of the Compound of Formula (1) Anhydrous Crystalline Form 2 of the Compound of Formula (1) As explained above, herein, Form 2 is the anhydrous crystalline form of the compound of formula (1). The state is provided, [ka]

[0026] It is characterized by having a powder X-ray diffraction pattern exhibiting peaks expressed as 2θ angles of about 9.5; 11.8; 14.1; 14.6; 17.7 and 18.5 degrees (each time ±0.2), and optionally further exhibiting peaks expressed as 2θ angles of about 15.5; 15.9; 16.6 and 22.2 degrees (each time ±0.2), and optionally further characterized by a powder X-ray diffraction pattern substantially as illustrated in FIG. 1.

[0027] According to one embodiment, the anhydrous crystalline Form 2 of the compound of formula (1) has an X-ray powder diffraction pattern comprising a peak at about 9.5 degrees 2-theta.

[0028] More specifically, the characteristic X-ray powder diffraction pattern of the anhydrous crystalline Form 2 of the compound of formula (1) can be substantially given in Figure 1, and its characteristic signals are summarized in Table I below.

[0029] [Table 1]

[0030] In one embodiment, the anhydrous crystalline Form 2 of the compound of formula (1) has a differential scanning calorimetry (DSC) exhibiting a melting endotherm with an onset of about 204°C (±2°C), and optionally further characterized by a thermogram substantially as illustrated in Figure 2.

[0031] As shown in Figure 2, this melting point temperature is due to the relatively high enthalpy of fusion, ΔH f (approximately 70 J / g).

[0032] Moreover, advantageously, exposure to temperature changes does not alter its crystalline structure prior to melting.

[0033] In another embodiment, anhydrous crystalline Form 2 of the compound of formula (1) is characterized by exhibiting a weight gain of less than 0.2 wt. %, particularly less than 0.1 wt. %, relative to the weight of crystalline Form 2 anhydrous, as determined by dynamic vapor sorption (DVS) at a temperature of about 25° C. (±0.2° C.) and in the range of 0% to 95% relative humidity, and optionally further characterized by a DVS isotherm plot substantially as shown in FIG. 3.

[0034] Characterization data substantially corresponding to FIG. 3 are summarized below in Table II.

[0035] [Table 2]

[0036] These results indicate that the anhydrous crystalline Form 2 of the compound of formula (1) does not exhibit hygroscopicity (0.06% water uptake at 95% relative humidity, as substantially shown in Figure 3).

[0037] Thus, within the meaning of this disclosure and in accordance with the European Pharmacopoeia, the term "non-hygroscopic" as used herein refers to a compound that exhibits a weight gain of less than 0.2% by weight relative to the weight of the compound when measured at about 25°C (±0.2°C) in the range of 0 to 95% relative humidity.

[0038] Additionally, the inventors have observed that anhydrous crystalline Form 2 of the compound of formula (1) does not convert to another crystalline form after exposure to moisture. Furthermore, exposure to temperature changes does not alter the crystalline structure prior to its melting.

[0039] All these factors indicate the stability of the anhydrate form 2.

[0040] As shown in the experimental section, the inventors have also investigated in depth the possibility that the compound of formula (1) may form polymorphs (anhydrous forms, more specifically anhydrous crystalline forms 1, 3 and 4) and pseudopolymorphs (solvates, more specifically ethanol, acetone, butanol, tetrahydrofuran (THF), dichloromethane (DCM), 2-propanol, methyl tert-butyl ether (MTBE) and 1,4 dioxane solvates).

[0041] Polymorphism is the ability of a single compound to exist in multiple forms or crystalline structures. Different polymorphs represent distinct solids that share the same molecular formula, and each polymorph may have distinct physical properties. A single compound may produce various polymorphic forms, each of which may have different and distinct physical properties, such as different solubility profiles, different thermodynamic stabilities, different crystallization behaviors, different filterability, different melting point temperatures, and / or different X-ray diffraction peaks. The differences in physical properties between different polymorphic forms are due to the different orientations and intermolecular interactions of adjacent molecules within the solid. Polymorphic forms of a compound can be identified by X-ray diffraction.

[0042] "Solvate" refers to an association or complex of one or more solvent molecules and a compound of formula (1).

[0043] An "amorphous phase of a compound" is a solid that lacks the long-range order that is characteristic of a crystal. As a result, the X-ray diffraction pattern of an amorphous phase shows no diffraction peaks.

[0044] The term "crystalline" refers to any solid material that exhibits three-dimensional order, giving rise to a distinctive XRPD pattern with more or less sharp peaks, in contrast to amorphous solid materials.

[0045] The term "anhydrous" refers to a crystalline form of a substance that does not contain water in its structure. By extension, the term "anhydrous" usually refers to a crystalline form of a substance that does not contain water and / or solvent in its structure.

[0046] The term "heterolvate" refers to a crystalline form that contains more than one type of solvent in the lattice.

[0047] The characterization (XRPD, DSC, and DVS) and some properties of these comparative anhydrous forms 1, 3, and 4 and solvates are detailed below.

[0048] As explained below, anhydrous crystalline Form 2 of the compound of formula (1) is particularly advantageous over the other three identified anhydrous crystalline forms and solvates for several reasons, as detailed below and illustrated in the Examples.

[0049] Anhydrous Crystalline Form 1 of the Compound of Formula (1) The preparation of anhydrous crystalline Form 1 of the compound of formula (1) is detailed below in Comparative Example 6.

[0050] The anhydrous crystalline Form 1 of the compound of formula (1) was characterized by XRPD, DSC and DVS, the results of which are detailed below.

[0051] More specifically, the characteristic X-ray powder diffraction pattern of the anhydrous crystalline Form 1 of the compound of formula (1) can be substantially given in Figure 4, and its characteristic signals are summarized in Table III below.

[0052] [Table 3]

[0053] As substantially shown in Figure 5, anhydrous crystalline Form 1 of the compound of Formula (1) has a differential scanning calorimetry showing a melting endotherm with an onset of about 132°C (±2°C). This melting point temperature has a weaker enthalpy of fusion, ΔH, than anhydrous crystalline Form 2 of the compound of Formula (1). f (approximately 21 J / g).

[0054] Additionally, as substantially illustrated in Figure 6 and set forth in the table below, anhydrous crystalline Form 1 of the compound of formula (1) is characterized by a weight gain of 4.07% by weight relative to the weight of crystalline Form 1 anhydrous, as determined by dynamic vapor sorption at a temperature of about 25°C (±0.2°C) and 95% relative humidity.

[0055] Characterization data substantially corresponding to FIG. 6 are summarized below in Table IV.

[0056] [Table 4]

[0057] The DSC and DVS results show that anhydrous crystalline Form 2 advantageously has a higher melting point and is less hygroscopic than anhydrous crystalline Form 1. Indeed, as noted above, anhydrous crystalline Form 2 is not hygroscopic. Anhydrous crystalline Form 2 is stable, whereas anhydrous crystalline Form 1 is metastable, meaning that anhydrous crystalline Form 1 is expected to convert to Form 2 over time following changes in its environment.

[0058] Anhydrous crystalline form 3 of the compound of formula (1) The preparation of anhydrous crystalline Form 3 of the compound of formula (1) is detailed below in Comparative Example 7.

[0059] The anhydrous crystalline Form 3 of the compound of formula (1) was characterized by XRPD, DSC and DVS, the results of which are detailed below.

[0060] More specifically, the characteristic X-ray powder diffraction pattern of the anhydrous crystalline Form 3 of the compound of formula (1) can be substantially given in Figure 7, and its characteristic signals are summarized in Table V below.

[0061] [Table 5]

[0062] As substantially shown in Figure 8, anhydrous crystalline Form 3 of the compound of Formula (1) has a differential scanning calorimetry showing a melting endotherm with an onset of about 149°C (±2°C). This melting point temperature has a weaker enthalpy of fusion, ΔH, than anhydrous crystalline Form 2 of the compound of Formula (1). f (approximately 40 J / g).

[0063] Additionally, as substantially illustrated in Figure 9 and set forth in the table below, anhydrous crystalline Form 3 of the compound of formula (1) is characterized by a weight gain of 2.92% by weight relative to the weight of crystalline Form 3 anhydrous, as determined by dynamic vapor sorption at a temperature of about 25°C (±0.2°C) and 95% relative humidity.

[0064] Characterization data substantially corresponding to FIG. 9 are summarized below in Table VI.

[0065] [Table 6]

[0066] The DSC and DVS results show that anhydrous crystalline Form 2 advantageously has a higher melting point and is less hygroscopic than anhydrous crystalline Form 3. Indeed, as noted above, anhydrous crystalline Form 2 is not hygroscopic. Anhydrous crystalline Form 2 is stable, whereas anhydrous crystalline Form 3 is metastable, meaning that anhydrous crystalline Form 3 is expected to convert to Form 2 over time following changes in its environment.

[0067] Anhydrous crystalline form 4 of the compound of formula (1) The preparation of anhydrous crystalline Form 4 of the compound of formula (1) is detailed below in Comparative Example 8.

[0068] The anhydrous crystalline Form 4 of the compound of formula (1) was characterized by XRPD, DSC and DVS, the results of which are detailed below.

[0069] More specifically, the characteristic X-ray powder diffraction pattern of the anhydrous crystalline Form 4 of the compound of formula (1) can be substantially given in Figure 10, and its characteristic signals are summarized in Table VII below.

[0070] [Table 7]

[0071] As substantially shown in Figure 11, anhydrous crystalline Form 4 of the compound of Formula (1) has a differential scanning calorimetry showing a melting endotherm with an onset of about 130°C (±2°C). This melting point temperature has a weaker enthalpy of fusion, ΔH, than anhydrous crystalline Form 2 of the compound of Formula (1). f (approximately 22 J / g).

[0072] Additionally, as substantially illustrated in Figure 12 and set forth in Table VIII below, anhydrous crystalline Form 4 of the compound of formula (1) is characterized by exhibiting a weight gain of 0.75% by weight relative to the weight of crystalline Form 4 anhydrous, as determined by dynamic vapor sorption at a temperature of about 25°C (±0.2°C) and 90% relative humidity.

[0073] Characterization data substantially corresponding to FIG. 12 are summarized below in Table VIII.

[0074] [Table 8]

[0075] The DSC and DVS results show that anhydrous crystalline Form 2 advantageously has a higher melting point and is less hygroscopic than anhydrous crystalline Form 4. Indeed, as noted above, anhydrous crystalline Form 2 is not hygroscopic. Anhydrous crystalline Form 2 is stable, whereas anhydrous crystalline Form 4 is metastable, meaning that anhydrous crystalline Form 4 is expected to convert to Form 2 over time following changes in its environment.

[0076] Ethanol solvate of the compound of formula (1) The preparation of this ethanol solvate is detailed below in Comparative Example 9. This solvate was characterized by XRPD, the results of which are detailed below.

[0077] More specifically, the characteristic X-ray powder diffraction pattern of this ethanol solvate of compound of formula (1) under ethanol vapor measured at room temperature can be substantially given in Figure 13a, and its characteristic signals are summarized in Table IX below.

[0078] [Table 9]

[0079] The inventors have observed that exposure of this ethanol solvate to heat (e.g., 40°C) and / or moisture generally results in the formation of the anhydrous Form 1, as substantially shown in Figure 13b. Additionally, ethanol vapor on a partially desolvated sample leads to the original ethanol solvate.

[0080] Therefore, this ethanol solvate is unstable.

[0081] Acetone solvate of the compound of formula (1) The preparation of this acetone solvate is detailed below in Comparative Example 10. This solvate was characterized by XRPD, the results of which are detailed below.

[0082] More specifically, the characteristic X-ray powder diffraction pattern of this acetone solvate of compound of formula (1) under acetone vapor measured at room temperature can be substantially given in Figure 14a, and its characteristic signals are summarized in Table X below.

[0083] [Table 10]

[0084] We have observed that this acetone solvate is physically unstable and generally converts to a poorly crystalline material when exposed to ambient conditions or dry nitrogen, as substantially shown in Figure 14b.

[0085] Butanol solvate of the compound of formula (1) The preparation of this butanol solvate is detailed below in Comparative Example 11. This solvate was characterized by XRPD, the results of which are detailed below.

[0086] More specifically, the characteristic X-ray powder diffraction pattern of this butanol solvate of compound of formula (1) under butanol vapor measured at room temperature can be substantially given in Figure 15a, and its characteristic signals are summarized in Table XI below.

[0087] [Table 11]

[0088] The inventors have observed that this butanol solvate, which should be considered a heterosolvate (1:2:1 water:butanol:active pharmaceutical ingredient), is physically unstable and generally converts to an amorphous form when exposed to ambient conditions or dry nitrogen, as substantially shown in Figure 15b.

[0089] Dichloromethane (DCM) solvate of the compound of formula (1) The preparation of this DCM solvate is detailed below in Comparative Example 12. This solvate was characterized by XRPD, the results of which are detailed below.

[0090] More specifically, the characteristic X-ray powder diffraction pattern of this DCM solvate of compound of formula (1) under DCM vapor measured at room temperature can be substantially given in Figure 16, and its characteristic signals are summarized in Table XII below.

[0091] [Table 12]

[0092] The inventors have observed that exposure of this DCM solvate to heat and / or moisture generally results in the formation of anhydrous Form 1. The inventors have observed that exposure of this DCM solvate to heat and / or N2 generally results in the formation of anhydrous Form 4. Thus, this DCM solvate is unstable.

[0093] Tetrahydrofuran (THF) solvate of the compound of formula (1) The preparation of this THF solvate is detailed below in Comparative Example 13. This solvate was characterized by XRPD, the results of which are detailed below.

[0094] More specifically, the characteristic X-ray powder diffraction pattern of this THF solvate of compound of formula (1) under THF vapor measured at room temperature can be substantially given in Figure 17, and its characteristic signals are summarized in Table XIII below.

[0095] [Table 13]

[0096] The inventors have observed that exposure of this THF solvate to heat and / or moisture generally results in the formation of the anhydrous Form 1. Thus, this THF solvate is unstable.

[0097] 2-Propanol solvate of the compound of formula (1) The preparation of this 2-propanol solvate is detailed below in Comparative Example 14. This solvate was characterized by HR XRPD, the results of which are detailed below.

[0098] More specifically, the characteristic HR X-ray powder diffraction pattern of this 2-propanol solvate of compound of formula (1), measured at room temperature, can be substantially given in Figure 18, and its characteristic signals are summarized in Table XIV below.

[0099] [Table 14]

[0100] We have observed that this 2-propanol solvate generally converts to the anhydrous form 3 upon heating, which itself generally converts to the anhydrous form 2.

[0101] Methyl tert-butyl ether (MTBE) solvate of the compound of formula (1) The preparation of this MTBE solvate is detailed below in Comparative Example 15. This solvate was characterized by XRPD, the results of which are detailed below.

[0102] More specifically, the characteristic X-ray powder diffraction pattern of this MTBE solvate of compound of formula (1), measured at room temperature, can be substantially given in Figure 19, and its characteristic signals are summarized in Table XV below.

[0103] [Table 15]

[0104] According to XRPD analysis, this MTBE solvate is the least crystalline of the other solvates disclosed.

[0105] The inventors also found that this MTBE solvate generally exhibits an enthalpy of fusion, ΔH, of approximately 10 J / g upon heating. f It was observed to melt at 80°C accompanied by

[0106] 1,4-Dioxane solvate of the compound of formula (1) The preparation of this 1,4-dioxane solvate is detailed below in Comparative Example 16. This solvate was characterized by XRPD, the results of which are detailed below.

[0107] More specifically, the characteristic X-ray powder diffraction pattern of this 1,4-dioxane solvate of compound of formula (1), measured at room temperature, can be substantially given in Figure 20a, and its characteristic signals are summarized in Table XVI below.

[0108] [Table 16]

[0109] We observed that this 1,4-dioxane solvate was physically unstable and generally converted to an unknown, poorly crystallized solid form at room temperature. The instability of the 1,4-dioxane solvate after one week at room temperature is substantially illustrated in Figure 20b.

[0110] conclusion In view of the results given above, it has been demonstrated that the anhydrous crystalline Form 2 of the compound of formula (1) has advantageous properties over the anhydrous crystalline Forms 1, 3 and 4 of the compound of formula (1) and the solvates of the compound of formula (1) (ethanol, acetone, butanol, THF, DCM, 2-propanol, MTBE and 1,4-dioxane solvates), in particular with regard to stability at least under ambient conditions of temperature and pressure, stability under humid conditions (hygroscopicity), melting point value, etc.

[0111] Therefore, the anhydrous crystalline form 2 of the compound of formula (1) appears to be the most suitable product for use and storage on an industrial scale. Indeed, the anhydrous crystalline form 2 of the compound of formula (1) is non-hygroscopic and stable (melting point value, enthalpy of fusion value, etc.), as shown above.

[0112] Process for preparing anhydrous crystalline form 2 of the compound of formula (1) As indicated above, also provided herein is a method for preparing anhydrous crystalline Form 2 of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.

[0113] The anhydrous crystalline Form 2 of the compound of formula (1) can be obtained by conventional crystallization techniques known to those skilled in the art, such as crystallization by evaporation, crystallization by cooling, or crystallization by adding a non-solvent such as water or heptane.

[0114] Optionally, step 1 of the process described below can also be carried out by carrying out seeding, i.e., by using seed crystals of the anhydrous form 2 of the compound of formula (1) obtained previously. Example 5 illustrates a synthetic route using seeding.

[0115] In the sense of the present disclosure, a "set temperature" means a temperature that remains the same during the corresponding step.

[0116] In the context of the present disclosure, the expression "almost complete evaporation" of the solvent means that the evaporation is not complete, i.e. the amount of evaporated solvent is reduced but still present in a very low content, in other words, the evaporation should not be to dryness.

[0117] Crystallization by evaporation According to one embodiment, the method for preparing anhydrous crystalline Form 2 of the compound of formula (1) comprises at least: 1) solubilizing the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, acetates, ethers and acetonitrile, optionally mixed 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 set in step 1) until it evaporates almost completely; 3) isolating the anhydrous crystalline Form 2 of the compound of formula (1) formed in step 2); Includes.

[0118] In certain embodiments, the solvent in step 1) is selected from methanol, methanol / water mixtures, ethanol, ethanol / water mixtures, 2-propanol, 1-propanol, 1-propanol / water mixtures, 1-butanol, 1-butanol / water mixtures, acetone, acetone / water mixtures, 2-butanone (also known as methyl ethyl ketone or MEK), 2-butanone / water mixtures, methyl isobutyl ketone (also known as MIBK), methyl isobutyl ketone / water mixtures, methyl acetate, methyl acetate / water mixtures, ethyl acetate, ethyl acetate / water mixtures, isopropyl acetate, isopropyl acetate / water mixtures, isobutyl acetate, isobutyl acetate / water mixtures, acetonitrile, and methyl tert-butyl ether (also known as MTBE).

[0119] In more specific embodiments, the solvent in step 1) is selected from methanol, methanol / water mixtures, ethanol, ethanol / water mixtures, 2-propanol, 1-propanol, 1-propanol / water mixtures, 1-butanol / water mixtures, acetone, acetone / water mixtures, 2-butanone, 2-butanone / water mixtures, methyl isobutyl ketone / water mixtures, methyl acetate, methyl acetate / water mixtures, ethyl acetate, ethyl acetate / water mixtures, isopropyl acetate / water mixtures, isobutyl acetate, isobutyl acetate / water mixtures, and acetonitrile.

[0120] In yet another embodiment, the solvent in step 1) is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, acetonitrile, methanol / water mixture, ethanol / water mixture, 1-propanol / water mixture, 1-butanol / water mixture, 2-butanone / water mixture, methyl isobutyl ketone / water mixture, methyl acetate / water mixture, ethyl acetate / water mixture, isopropyl acetate / water mixture, isobutyl acetate / water mixture, and methyl isobutyl ketone / water mixture.

[0121] When the solvent in step 1) is mixed with water, the solvent / water volume ratio is typically 99 / 1.

[0122] According to another embodiment, the set temperatures for steps 1) and 2) are selected from the temperature range of 20°C to 80°C, or even 25°C to 80°C.

[0123] Crystallization by cooling According to another embodiment, the method for preparing anhydrous crystalline Form 2 of the compound of formula (1) comprises at least: 1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, acetates, ethers and acetonitrile at a set temperature, which is room temperature; 2) optionally purifying the solution or suspension obtained in step 1) by heating it at a set temperature in the range of 60°C to 80°C, stirring and filtering the solution or suspension; 3) heating the solution or suspension obtained in step 1) or step 2) at a set temperature in the range of 60°C to 80°C; 4) cooling the solution or suspension obtained in step 2) to a set temperature in the range of -20°C to 25°C; 5) isolating the anhydrous crystalline form 2 of the compound of formula (1) formed in step 4); Includes.

[0124] Optional step 2) advantageously makes it possible to remove impurities or bacteria that may be present in the solution or suspension.

[0125] In certain embodiments, the solvent in step 1) is selected from ethanol, 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone (also known as methyl ethyl ketone or MEK), methyl isobutyl ketone (also known as MIBK), isopentyl methyl ketone (also known as MIAK), methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, acetonitrile, and methyl tert-butyl ether (also known as MTBE).

[0126] In one embodiment, the solvent in step 1) is acetone.

[0127] According to one variant, the set temperature of step 1) is the same as that of step 4).

[0128] According to another variant, the set temperature of step 1) is the same as that of step 4) and the set temperature of step 2) is the same as that of step 3).

[0129] Crystallization by adding water as a non-solvent According to another embodiment, the method for preparing anhydrous crystalline Form 2 of the compound of formula (1) comprises at least: 1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, acetates, and diethyl ether at a set temperature, which is room temperature; 2) optionally filtering the solution or suspension obtained in step 1); 3) adding water as a non-solvent; 4) isolating the anhydrous crystalline form 2 of the compound of formula (1) formed in step 3); Includes.

[0130] The optional filtering step 2) advantageously makes it possible to remove impurities or bacteria that may be present in the solution or suspension.

[0131] In certain embodiments, the solvent in step 1) is selected from 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isopentyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, and diethyl ether.

[0132] Optionally, step 3) is followed by leaving the solvent to evaporate.

[0133] Crystallization by adding heptane as a non-solvent According to another embodiment, the method for preparing anhydrous crystalline Form 2 of the compound of formula (1) comprises at least: 1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, and acetates at a set temperature, which is room temperature; 2) optionally filtering the solution or suspension obtained in step 1); 3) adding heptane as a non-solvent; 4) isolating the anhydrous crystalline form 2 of the compound of formula (1) formed in step 3); Includes.

[0134] The optional filtering step 2) advantageously makes it possible to remove impurities or bacteria that may be present in the solution or suspension.

[0135] In certain embodiments, the solvent in step 1) is selected from ethanol, 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isopentyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, and isobutyl acetate.

[0136] Seeded crystallization According to another embodiment, the anhydrous crystalline Form 2 of the compound of formula (1) can be obtained by a seeding method, i.e., by using seed crystals of previously obtained anhydrous crystalline Form 2. Seeding is a crystallization technique well known in the art. Such a seeding method can, for example, comprise the following steps: 1) solubilizing the compound of formula (1) in amorphous form in an organic solvent such as 2-methyltetrahydrofuran or dichloromethane; 2) Seeding with anhydrous crystalline Form 2 of the compound of formula (1).

[0137] In one embodiment, the seeding process is carried out at a temperature comprised between room temperature and mild heating, for example, about 28°C (±3°C). In another embodiment, the seeding process comprises step 3) of solvent exchange, which comprises adding a non-solvent such as acetone. Crystals of anhydrous crystalline Form 2 of the compound of Formula (1) are then recovered by filtration and drying of the reaction medium. [Example]

[0138] material and method I. Differential Scanning Calorimetry (DSC) DSC analysis was performed on a Q1000 analyzer (TA Instruments). A few mg of sample mass was deposited in an unsealed aluminum pan, and the atmosphere was controlled by a constant nitrogen flow. The analysis was performed at a scan rate of 5°C / min.

[0139] II. X-ray Powder Diffraction (XRPD) The analysis was performed at room temperature on a Brucker D4 Endeavor instrument using Bragg-Brentano parafocusing geometry. A sealed copper anode X-ray tube was used (λ CuKα average = 1.54178 Å). The setup was completed with an ynxEye linear detector, using a step size of 0.016° in 2θ and counting times of a few seconds per step over an angular range of a few to several tens of 2θ degrees for each sample analysis.

[0140] In each experiment, the powder was deposited on the surface of a sample holder.

[0141] III. Water Sorption Isotherms Using Dynamic Vapor Sorption (DVS) Experiments were performed on a DVS automated gravimetric vapor sorption analyzer (Surface Measurement Systems Ltd., London, UK). Water uptake and loss by the samples were measured gravimetrically using an ultramicrobalance with a mass resolution of ±0.1 μg. Controlled relative humidity was generated by mixing various ratios of dry and water-saturated carrier gas streams. The temperature was maintained constant at 25.0 ±0.2 °C by enclosing the entire system inside a temperature-controlled incubator. Sample sizes ranging from 5 to 20 mg were used. Prior to exposure to water vapor, samples were dried at 0% relative humidity (RH) to remove most of the surface water present and establish a dry baseline mass. Samples were then exposed to increasing relative humidity in 5% RH steps from 0% to 95% RH.

[0142] IV. High resolution X-ray powder diffraction (HR-XRPD) High-resolution images were recorded at ambient conditions using a PANanalytical X'Pert Pro MPD powder diffractometer using a Bragg-Brentano (vertical θ-2θ configuration) parafocusing geometry coupled with an X'Celerator detector. A sealed copper anode X-ray tube was used. An incident beam monochromator produced pure CuKα radiation (λ = 1.5406 Å). The angular range extended from a few 2θ degrees to several tens of 2θ degrees, with a step size of 0.017° in 2θ.

[0143] Example 1: Preparation of anhydrous crystalline form 2 of the compound of formula (1) by evaporative recrystallization Protocol 1: A 10 mg / mL solution of the amorphous compound of formula (1) (50 mg of solid amorphous in 5 mL of solvent, 20 mL vial) was prepared at room temperature. This solution / suspension was left at a selected temperature to allow for near complete evaporation (20 mL open vial).

[0144] According to Protocol 1, the following solvents were used: methanol at about 20°C, 40°C, or 80°C (± 2°C each time); ethanol / HO (99 / 1) at about 20°C (± 2°C each time); 2-butanone at about 20°C, 40°C, or 80°C (± 2°C each time); ethyl acetate at about 20°C, 40°C, or 80°C (± 2°C each time); or acetonitrile at about 20°C, 40°C, or 80°C (± 2°C each time).

[0145] Example 2: Preparation of anhydrous crystalline form 2 of the compound of formula (1) via cooling recrystallization Protocol 2: A 100 mg / mL solution / suspension (depending on the solvent used) of the amorphous compound of formula (1) (100 mg of solid amorphous in 1 mL of solvent, 4 mL vial) was prepared at room temperature. This solution / suspension was then heated to 80°C. The latter was then heated again to 80°C. The solution was then cooled to room temperature, 5°C, or -20°C.

[0146] According to Protocol 2, acetone was used as the solvent using temperatures of about −20° C., 5° C., or 20° C. (±2° C. each time) for the cooling step, or methyl acetate was used separately using temperatures of about 5° C. or 20° C. (±2° C. each time) for the cooling step.

[0147] Example 3: Preparation of anhydrous crystalline Form 2 of the compound of formula (1) via recrystallization by adding water as a non-solvent Protocol 3: Amorphous compound of formula (1) (50 mg of solid amorphous in 1 mL of solvent) A 50 mg / mL solution / suspension (depending on the solvent used) of rufus (4 mL vial) was prepared at room temperature. The latter was kept at room temperature for the addition of the non-solvent (here, water).

[0148] Protocol 3 was followed, using MIBK at about 20° C. (±2° C.) or isobutyl acetate at about 20° C. (±2° C.), respectively, as the solvent.

[0149] Example 4: Preparation of anhydrous crystalline Form 2 of the compound of formula (1) via recrystallization by adding heptane as a non-solvent Protocol 4: A 200 mg / mL solution / suspension (depending on the solvent used) of the amorphous compound of formula (1) (50 mg of solid amorphous in 250 μL of solvent, 4 mL vial) was prepared at room temperature. The latter was kept at room temperature for the addition of the non-solvent (here, heptane).

[0150] Protocol 4 was followed, and the solvents used were 1-butanol at about 20° C. (±2° C.), acetone at about 20° C. (±2° C.), or isopropyl acetate at about 20° C. (±2° C.), respectively.

[0151] Characterization of anhydrous crystalline form 2 Anhydrous crystalline Form 2 of the compound of formula (1) was characterized by XRPD, substantially as presented in FIG. 1, by DSC, substantially as illustrated in FIG. 2, and by DVS, substantially as illustrated in FIG. 3.

[0152] Example 5: Preparation of anhydrous crystalline Form 2 of the compound of formula (1) by seeding. Starting from 1 kg of 6-(2,4-dichlorophenyl)-5-(4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl)-8,9-dihydro-7H-benzocycloheptene-2-carboxylic acid methyl ester oxalate, the free base is obtained by adding an aqueous solution of potassium carbonate in MeTHF (also known as 2-methyltetrahydrofuran), as described in patent application WO 2020 / 049153. The free base in solution in MeTHF is then saponified using NaOH in the presence of MeOH under conditions well known in the art. After several washes in aqueous medium, maintaining the pH in the range of 5.0 to 6.6, the organic phase (composed of MeTHF) is dehydrated by distillation under vacuum at a jacket temperature of up to 55 °C. Seed crystals of the anhydrous form 2 of the compound of formula (1) are introduced at 28 °C ± 3 °C in a volume ratio of 5 V of reaction medium (MeTHF) to starting material (the above oxalate). The reaction medium was maintained at 28°C ± 3°C with stirring for at least 1 hour.

[0153] The MeTHF solvent was then exchanged with a volume of acetone under vacuum at a maximum temperature of 55° C. During this solvent exchange, the reaction medium became cloudy, indicating the onset of crystallization. Distillation was carried out until the MeTHF content was 2.0% or less.

[0154] The reaction medium was heated to 40-45°C and purified water was added in a ratio of 1.3 V of purified water per kg of starting material (the oxalate salt). The reaction medium was cooled to 0°C ± 3°C with stirring for at least 4 hours. The anhydrous form 2 of the compound of formula (1) thus obtained was washed with acetone and water, filtered, and then dried to obtain 0.77 kg of anhydrous form 2 of the compound of formula (1).

[0155] In another embodiment, this seeding method was also carried out on the dry amorphous form of the compound of formula (1). The amorphous form was solubilized in 7.1 V MeTHF and heated to about 55°C until complete dissolution. The medium was concentrated under vacuum with a jacket temperature of up to 55°C, and seeding was carried out as described above. The yield was greater than 95%.

[0156] Comparative Example 6: Anhydrous Crystalline Form 1 of the Compound of Formula (1) Anhydrous crystalline Form 1 of the compound of formula (1) was obtained by desolvation of the ethanol solvate.

[0157] The ethanol solvate form was obtained by slowly evaporating the ethanol solution at room temperature. The ethanol solvate thus obtained was then placed under vacuum at 40° C. The anhydrous crystalline Form 1 was then produced by desolvation of the ethanol solvate.

[0158] Anhydrous crystalline Form 1 of the compound of formula (1) was characterized by XRPD, substantially as presented in FIG. 4, by DSC, substantially as illustrated in FIG. 5, and by DVS, substantially as illustrated in FIG. 6.

[0159] Comparative Example 7: Anhydrous Crystalline Form 3 of the Compound of Formula (1) To a 50 mg / mL solution of the compound of formula (1) in acetone was slowly added 40 wt% water at room temperature. Crystals of anhydrous Form 3 appeared after a few more hours at room temperature.

[0160] Anhydrous crystalline Form 3 of the compound of formula (1) was characterized by XRPD, substantially as presented in FIG. 7, by DSC, substantially as illustrated in FIG. 8, and by DVS, substantially as illustrated in FIG. 9.

[0161] Comparative Example 8: Anhydrous Crystalline Form 4 of the Compound of Formula (1) Anhydrous crystalline Form 4 of the compound of formula (1) was obtained by performing a water sorption isotherm using dynamic vapor sorption (DVS) of the DCM solvate in a nitrogen flow (200 cm per minute) at 25°C. 3 ) for several hours, followed by two successive cycles of water sorption / desorption from 0% to 95% relative humidity at 25 °C, the anhydrous form 4 of the compound of formula (1) was obtained.

[0162] Comparative Example 9: Ethanol solvate of the compound of formula (1). The ethanol solvate was obtained by dissolving in ethanol (50 mg / mL) at 40° C. and cooling to about 20° C. (±2° C.). The stoichiometry of the ethanol solvate is one molecule of solvent per molecule of the compound of formula (1).

[0163] The XRPD patterns of the ethanol solvate are substantially as presented in Figures 13a and 13b.

[0164] Comparative Example 10: Acetone solvate of the compound of formula (1). The acetone solvate was obtained by slow evaporation of the saturated solution at about 20° C. (±2° C.) with a stoichiometry of 1.5 molecules of solvent to 1 molecule of the compound of formula (1).

[0165] The XRPD patterns of the acetone solvate are substantially as presented in Figures 14a and 14b.

[0166] Comparative Example 11: Butanol solvate of the compound of formula (1). The butanol solvate was obtained by cooling a 20 mg / mL solution to −20° C. The latter is a heterosolvate (water:butanol:compound of formula (1)=1:2:1).

[0167] The XRPD patterns of the butanol solvate are substantially as presented in Figures 15a and 15b.

[0168] Comparative Example 12: DCM solvate of the compound of formula (1) A 2.5 volume solution of the compound of formula (1) was prepared in DCM at room temperature, and then the solution was allowed to slowly evaporate at 5°C.

[0169] The XRPD diagram of the DCM solvate is substantially as presented in FIG.

[0170] Comparative Example 13: THF solvate of the compound of formula (1). A 400 mg / mL solution of the compound of formula (1) was prepared in THF at 40° C. The solution was then cooled to room temperature under magnetic stirring.

[0171] The XRPD diagram of the THF solvate is substantially as presented in FIG.

[0172] Comparative Example 14: 2-propanol solvate of the compound of formula (1). The 2-propanol solvate was obtained by evaporation of the mixed solvent 2-propanol / water (99 / 1) at about 20° C. (±2° C.) The stoichiometry of the 2-propanol solvate is one molecule of solvent per molecule of the compound of formula (1).

[0173] The XRPD diagram of this 2-propanol solvate is substantially as presented in FIG.

[0174] Comparative Example 15: MTBE solvate of the compound of formula (1). The MTBE solvate was obtained by the slow release of water in a 50 mg / mL solution by vapor phase diffusion at about 20° C. (±2° C.).

[0175] The XRPD diagram of this MTBE solvate is substantially as presented in FIG.

[0176] Comparative Example 16: 1,4-dioxane solvate of the compound of formula (1). The 1,4-dioxane solvate was obtained by cooling a 100 mg / mL solution to -20°C.

[0177] The XRPD patterns of this 1,4 dioxane solvate are substantially as presented in Figures 20a and 20b.

[0178] As explained above, the inventors have demonstrated that Form 2 of the compound of formula (1) is thermodynamically more stable at room temperature and ambient pressure compared to the various forms identified above.

[0179] Anhydrous Form 2 further offers the advantage of not being hygroscopic and not converting to another crystalline form after exposure to moisture. Furthermore, exposure to temperature changes does not result in a change in crystalline structure prior to melting. Furthermore, it should be noted that once Anhydrous Form 2 is obtained, it is not possible to recrystallize Anhydrous Form 1 by adding seed crystals, thus demonstrating the stability of Anhydrous Form 2 crystals.

[0180] As far as solvates are concerned, all solvates are unstable under ambient conditions of temperature and pressure.

Claims

1. An anhydrous crystalline form of the compound of formula (1) which is Form 2, 【Chemistry 1】 The anhydrous crystalline Form 2 is characterized by having a powder X-ray diffraction pattern exhibiting peaks expressed as 2-theta angles of approximately 9.5; 11.8; 14.1; 14.6; 17.7 and 18.5 degrees.

2. 2. Anhydrous crystalline Form 2 of the compound of formula (1) according to claim 1, having a powder X-ray diffraction pattern containing peaks expressed as 2θ angles of about 9.5 degrees.

3. 3. Anhydrous Crystalline Form 2 of the compound of formula (1) according to claim 1 or claim 2, further characterized by a powder X-ray diffraction pattern, optionally substantially as illustrated in Figure 1, further exhibiting peaks expressed as 2θ angles of about 15.5; 15.9; 16.6 and 22.2 degrees.

4. Anhydrous crystalline Form 2 of the compound of formula (1) according to any one of claims 1 to 3, wherein Differential Scanning Calorimetry DSC shows a melting endotherm with an onset of about 204°C, optionally further characterized by a thermogram substantially as illustrated in Figure 2.

5. Anhydrous crystalline Form 2 of the compound of formula (1) according to any one of claims 1 to 4, characterized by exhibiting a weight gain of less than 0.2 wt.%, in particular less than 0.1 wt.%, relative to the weight of crystalline Form 2 anhydrous, as determined by dynamic vapor sorption (DVS) at a temperature of about 25°C and in the range of 0% to 95% relative humidity, and optionally further characterized by a DVS isotherm plot substantially as shown in Figure 3.

6. A solid form of the compound of formula (1) according to any one of claims 1 to 5, which is anhydrous crystalline form 2.

7. A method for preparing anhydrous crystalline form 2 of the compound of formula (1) according to any one of claims 1 to 5, comprising at least 1) solubilizing the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, acetates, ethers and acetonitrile, optionally mixed 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 set in step 1) until it evaporates almost completely; 3) isolating the anhydrous crystalline Form 2 of the compound of formula (1) formed in step 2); The method comprising:

8. 8. The method of claim 7, wherein the solvent is selected from methanol, a methanol / water mixture, ethanol, an ethanol / water mixture, 2-propanol, 1-propanol, a 1-propanol / water mixture, 1-butanol, a 1-butanol / water mixture, acetone, an acetone / water mixture, 2-butanone, a 2-butanone / water mixture, methyl isobutyl ketone, a methyl isobutyl ketone / water mixture, methyl acetate, a methyl acetate / water mixture, ethyl acetate, an ethyl acetate / water mixture, isopropyl acetate, an isopropyl acetate / water mixture, isobutyl acetate, an isobutyl acetate / water mixture, acetonitrile, and methyl tert-butyl ether.

9. 9. The method according to claim 7 or 8, wherein the set temperatures of step 1) and step 2) are selected from the temperature range of 20°C to 80°C, or even 25°C to 80°C.

10. A method for preparing anhydrous crystalline form 2 of the compound of formula (1) according to any one of claims 1 to 5, comprising at least 1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, acetates, ethers and acetonitrile at a set temperature, which is room temperature; 2) optionally purifying the solution or suspension obtained in step 1) by heating at a set temperature in the range of 60°C to 80°C, stirring and filtering the solution or suspension; 3) heating the solution or suspension obtained in step 1) or step 2) at a set temperature in the range of 60°C to 80°C; 4) cooling the solution or suspension obtained in step 2) to a set temperature in the range of -20°C to 25°C; 5) isolating the anhydrous crystalline Form 2 of the compound of formula (1) formed in step 4); The method comprising:

11. 11. The method of claim 10, wherein the solvent is selected from ethanol, 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isopentyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, acetonitrile, and methyl tert-butyl ether.

12. A method for preparing anhydrous crystalline form 2 of the compound of formula (1) according to any one of claims 1 to 5, comprising at least 1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, acetates, and diethyl ether at a set temperature, which is room temperature; 2) optionally filtering the solution or suspension obtained in step 1); 3) adding water as a non-solvent; 4) isolating the anhydrous crystalline Form 2 of the compound of formula (1) formed in step 3); The method comprising:

13. 13. The method of claim 12, wherein the solvent is selected from 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isopentyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, and diethyl ether.

14. A method for preparing anhydrous crystalline form 2 of the compound of formula (1) according to any one of claims 1 to 5, comprising at least 1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, and acetates at a set temperature, which is room temperature; 2) optionally filtering the solution or suspension obtained in step 1); 3) adding heptane as a non-solvent; 4) isolating the anhydrous crystalline Form 2 of the compound of formula (1) formed in step 3); The method comprising:

15. 15. The method of claim 14, wherein the solvent is selected from ethanol, 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isopentyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, and isobutyl acetate.

16. A method for preparing anhydrous crystalline form 2 of the compound of formula (1) according to any one of claims 1 to 5, comprising at least 1) solubilizing or suspending the compound of formula (1) in amorphous form in an organic solvent; 2) seeding with anhydrous crystalline Form 2 of the compound of formula (1); The method comprising:

17. 17. The method of claim 16, wherein steps 1) and 2) are followed by a step of adding a non-solvent, then distillation, followed by cooling and drying.

18. A medicament comprising anhydrous crystalline form 2 of the compound of formula (1) according to any one of claims 1 to 5.

19. A pharmaceutical composition comprising anhydrous crystalline Form 2 of the compound of formula (1) according to any one of claims 1 to 5, and at least one pharmaceutically acceptable excipient.

20. 20. The pharmaceutical composition of claim 19, wherein the anhydrous crystalline Form 2 is substantially pure and substantially free of alternative forms.

21. 20. The pharmaceutical composition of claim 19, wherein the anhydrous crystalline Form 2 is at least 90 percent by weight of all forms.

22. Anhydrous crystalline Form 2 of the compound of formula (1) according to any one of claims 1 to 5 for use as a pharmaceutical.

23. Anhydrous crystalline Form 2 of the compound of formula (1) according to any one of claims 1 to 5 for use in the treatment of cancer.

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