Crystalline forms of 7H-benzo[7]annulene-2-carboxylic acid derivatives

Abstract

The present disclosure relates to a compound of formula (1) as an anhydrate in crystalline form 2, characterized by having a powder X-ray diffraction pattern showing peaks expressed as degrees 2θ at about 9.5, 11.8, 14.1, 14.6, 17.7 and 18.5; and solid forms thereof. The present disclosure also relates to methods for its preparation, and to medicaments and pharmaceutical compositions comprising it. The present disclosure further relates to anhydrous crystalline form 2 of the compound of formula (1), which is useful as a medicament, more particularly for the treatment of cancer.

Description

[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 anhydrous form of crystalline form 2. Also provided herein is a method for preparing the anhydrous crystalline form 2 and a method for using the anhydrous crystalline form 2 as a medicament, particularly for treating cancer.

[0002] The compound of formula (1) depicted below is a selective estrogen receptor degrader (SERD) having estrogen receptor antagonist properties and promoting proteasomal degradation of estrogen receptors. It can be used in particular as an anticancer agent. This compound in amorphous form is disclosed in application WO2017 / 140669.

[0003]

[0004] In addition to its pharmaceutical efficacy, a pharmaceutically active agent must also meet a variety of other requirements. For example, its stability under various environmental conditions, its stability during the production of the pharmaceutical preparation, or its stability in the final pharmaceutical composition. In addition, when a pharmaceutically active agent is used to prepare a pharmaceutical composition, it should be as pure as possible and its long-term storage stability must be guaranteed under various environmental conditions. For example, this reduces or avoids the risk that the content of the active substance in the drug is less than the specified content.

[0005] Generally, the compound of formula (1) in amorphous form is not optimal for handling on an industrial scale, since it needs to be stored under refrigerated conditions to maintain its stability over time.

[0006] It would therefore be desirable to provide the compound of formula (1) in a form which is the most thermodynamically stable form at least under ambient conditions of temperature and pressure and which allows its use and storage on an industrial scale.

[0007] Furthermore, the pharmaceutically active agent should be only slightly hygroscopic. In fact, moisture absorption reduces the amount of the pharmaceutically active agent due to the weight increase caused by the absorption of water. Usually, pharmaceutical compositions that tend to absorb moisture must be protected from moisture during storage, for example by adding suitable desiccants or by storing the drug in a moisture-proof environment.

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

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

[0010] The present disclosure relates to a stable crystalline form of a compound of formula (1) that satisfies the above-mentioned important features.

[0011] Provided herein is a 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 an anhydrate in crystalline Form 2, characterized by having a powder X-ray diffraction pattern exhibiting peaks expressed as angles in degrees 2θ at about 9.5, 11.8, 14.1, 14.6, 17.7 and 18.5 (each ± ​​0.2), the powder X-ray diffraction pattern optionally further exhibiting the following peaks expressed as angles in degrees 2θ at about 15.5, 15.9, 16.6 and 22.2 (each ± ​​0.2); optionally further characterized by being substantially as Figure 1 Powder X-ray diffraction pattern shown.

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

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

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

[0015] In a specific embodiment, in the pharmaceutical composition, the anhydrous crystalline Form 2 is substantially pure and substantially free of substituted forms.

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

[0017] As used herein, the term "substantially pure" means that the crystalline form contains at least 90%, preferably at least 95%, more preferably at least 97%, most preferably at least 99% by weight of the indicated crystalline form. Alternatively, it should be understood that "substantially pure" means that the crystalline form contains less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1% by weight of impurities, including other polymorphic forms, solvated forms or amorphous forms.

[0018] Further disclosed herein is the anhydrous crystalline Form 2 of the compound of formula (1) for use as a medicament, as an inhibitor and degrader of estrogen receptors, and for use in the treatment of various diseases involving estrogen receptors, more particularly cancer.

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

[0020] Further disclosed herein is the use of the 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 of treating a disease involving inhibition and degradation of estrogen receptors, 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 a therapeutically effective amount of the anhydrous crystalline form 2 of the compound of formula (1) to a subject, particularly a human, in need thereof.

[0023] As used herein, unless otherwise specified, the term "ambient temperature" or "room temperature" refers to a temperature ranging from 18°C ​​to 25°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is an X-ray powder pattern 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.

[0025] Figure 2 It 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.

[0026] Figure 3 is a dynamic vapor sorption (DVS) isotherm plot 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 (adsorption step).

[0027] Figure 4 is an X-ray powder pattern 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 measured at room temperature.

[0028] Figure 5 It is a thermogram 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.

[0029] Figure 6 is a dynamic vapor sorption (DVS) isotherm 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 measured at 25°C (adsorption step).

[0030] Figure 7 is an X-ray powder pattern 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 room temperature.

[0031] Figure 8 It is a thermogram 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.

[0032] Fig. 9 is a dynamic vapor sorption (DVS) isotherm 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 (adsorption step).

[0033] Fig.10 is an X-ray powder pattern 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 room temperature.

[0034] Fig.11 It is a thermogram 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.

[0035] Fig.12 is a dynamic vapor sorption (DVS) isotherm plot 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 (adsorption step).

[0036] Fig.13a is an X-ray powder pattern of an ethanol solvate of the compound of formula (1) measured at room temperature under ethanol vapor.

[0037] Fig.13b is an X-ray powder pattern measured at room temperature, which includes three X-ray powder patterns of the ethanol solvate of the compound of formula (1), from bottom to top: (a) under ethanol vapor (solid line); (b) at 40°C (dashed line); and (c) after exposure to moisture (bold line).

[0038] Fig.14a is an X-ray powder pattern of an acetone solvate of the compound of formula (1) under acetone vapor measured at room temperature.

[0039] Fig.14b is an X-ray powder pattern measured at room temperature, which includes two X-ray powder patterns of the acetone solvate of the compound of formula (1), from bottom to top: (a) under acetone vapor (solid line); and (b) after exposure to nitrogen (bold line).

[0040] Fig.15a is an X-ray powder pattern of a butanol solvate of the compound of formula (1) under butanol vapor measured at room temperature.

[0041] Fig.15b is an X-ray powder pattern measured at room temperature, which includes two X-ray powder patterns 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).

[0042] Fig.16 is an X-ray powder pattern of the DCM solvate of the compound of formula (1) under DCM vapor measured at room temperature.

[0043] Fig.17 is an X-ray powder pattern of a THF solvate of the compound of formula (1) under THF vapor measured at room temperature.

[0044] Fig.18 is a HR (high resolution) X-ray powder pattern of the 2-propanol solvate of the compound of formula (1) measured at room temperature.

[0045] Fig.19 is an X-ray powder pattern of the methyl tert-butyl ether (MTBE) solvate of the compound of formula (1) measured at room temperature.

[0046] Fig.20a is an X-ray powder pattern of the 1,4-dioxane solvate of the compound of formula (1) measured at room temperature.

[0047] Fig.20b : is an X-ray powder pattern, which includes two X-ray powder patterns of the 1,4-dioxane solvate of the compound of formula (1), from bottom to top: measured at room temperature (solid line); and measured after one week at room temperature (bold line).

[0048] Anhydrous crystalline form of the compound of formula (1) 2 and comparative anhydrous forms and solvates of compounds of formula (1)

[0049] Anhydrous crystalline form 2 of the compound of formula (1)

[0050] As explained above, provided herein is an anhydrous crystalline form of Form 2 of the compound of formula (1)

[0051]

[0052] Characterized by having a powder X-ray diffraction pattern exhibiting peaks expressed as degrees 2θ at about 9.5, 11.8, 14.1, 14.6, 17.7 and 18.5 (each ± ​​0.2), the powder X-ray diffraction pattern optionally further exhibiting the following peaks expressed as degrees 2θ at about 15.5, 15.9, 16.6 and 22.2 (each ± ​​0.2); optionally further characterized by being substantially as Figure 1 Powder X-ray diffraction pattern shown.

[0053] 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 expressed in degrees 2θ at about 9.5.

[0054] More specifically, the characteristic X-ray powder diffraction pattern of the anhydrous crystalline form 2 of the compound of formula (1) can be substantially Figure 1 The characteristic signals are summarized in the following Table 1:

[0055] Table I

[0056]

[0057]

[0058] In one embodiment, the anhydrous crystalline Form 2 of the compound of formula (1) has a differential scanning calorimetry (DSC) showing a melting endotherm at about 204°C onset (±2°C), and is optionally further characterized by being substantially as follows Figure 2 The thermal spectrum shown.

[0059] like Figure 2 As indicated, this melting point temperature is associated with a relatively high melting enthalpy ΔH f (close to 70 J / g).

[0060] Furthermore, advantageously, exposure to temperature changes does not alter the crystal structure prior to its melting.

[0061] In another embodiment, the anhydrous crystalline Form 2 of the compound of formula (1) is characterized by showing a weight gain of less than 0.2 wt. %, particularly less than 0.1 wt. %, based on the weight of the crystalline Form 2 anhydrate, as determined by dynamic vapor sorption (DVS) in the range of 0% to 95% relative humidity at a temperature of about 25° C. (±0.2° C.); and optionally is further characterized by being substantially as Figure 3 DVS isotherm diagram shown.

[0062] Basically corresponds to Figure 3 The characteristic data are summarized in Table II below:

[0063] Table II

[0064]

[0065]

[0066] These results demonstrate that the anhydrous crystalline form 2 of the compound of formula (1) exhibits no hygroscopicity (water absorption of 0.06% at 95% relative humidity, substantially the same as Figure 3 shown).

[0067] Thus, in the sense of the present disclosure and according to the European Pharmacopoeia, the term "non-hygroscopic" as used herein means that the compound shows a weight gain of less than 0.2 wt.-% based on the weight of the compound when measured in the range from 0 to 95 % relative humidity at about 25°C (±0.2°C).

[0068] Furthermore, the inventors have observed that the anhydrous crystalline form 2 of the compound of formula (1) does not transform into another crystalline form upon exposure to moisture. Furthermore, exposure to temperature changes does not alter the crystal structure prior to its melting.

[0069] All these factors demonstrate the stability of the anhydrous Form 2.

[0070] As shown in the experimental part, the inventors have also intensively studied the possibility of the compound of formula (1) to 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).

[0071] Polymorphism is the ability of a single compound to exist in more than one form or crystal structure. Different polymorphs represent unique solids with the same molecular formula, but each polymorph may have unique physical properties. A single compound can produce multiple polymorphic forms, each of which may have different and unique physical properties, such as different solubility curves, different thermodynamic stabilities, different crystallization behaviors, different filterabilities, different melting point temperatures, and / or different X-ray diffraction peaks. The differences in physical properties of different polymorphic forms are caused by different orientations of adjacent molecules in the solid and intermolecular interactions. Polymorphic forms of a compound can be distinguished by X-ray diffraction.

[0072] "Solvate" refers to an association or complex of one or more solvent molecules and the compound of formula (1).

[0073] The amorphous phase of a compound is a solid that lacks the long-range order that is characteristic of a crystal. Therefore, the X-ray diffraction pattern of the amorphous phase does not show diffraction peaks.

[0074] The term "crystalline" refers to any solid material that exhibits three-dimensional order, which results in a distinctive XRPD pattern with more or less sharp peaks compared to an amorphous solid material.

[0075] The term "anhydrate" refers to a crystalline form of a substance that does not contain water in its structure. By extension, the term "anhydrate" generally refers to a crystalline form of a substance that does not contain water and / or solvent in its structure.

[0076] The term "heterosolvate" refers to a crystalline form that includes more than one type of solvent in the crystal lattice.

[0077] The characterization (XRPD, DSC and DVS) and certain properties of these comparative anhydrous Forms 1, 3 and 4 and the solvates are detailed below.

[0078] As explained below, the 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 shown in the examples.

[0079] Anhydrous crystalline form 1 of the compound of formula (1)

[0080] The preparation of the anhydrous crystalline form 1 of the compound of formula (1) is described in detail in Comparative Example 6 below.

[0081] The anhydrous crystalline Form 1 of the compound of formula (1) was characterized by XRPD, DSC and DVS, and the results are detailed below.

[0082] More specifically, the characteristic X-ray powder diffraction pattern of the anhydrous crystalline form 1 of the compound of formula (1) can be substantially Figure 4 Its characteristic signals are summarized in the following Table III:

[0083] Table III

[0084]

[0085] Basically Figure 5 As indicated, the anhydrous crystalline form 1 of the compound of formula (1) has a differential scanning calorimetry showing a melting endotherm at an onset of about 132°C (±2°C). This melting point temperature is weaker than the melting enthalpy ΔH of the anhydrous crystalline form 2 of the compound of formula (1). f (close to 21 J / g).

[0086] In addition, basically Figure 6 As shown and detailed in the table below, anhydrous crystalline Form 1 of the compound of formula (1) is characterized by exhibiting a weight gain of 4.07 wt % based on the weight of crystalline Form 1 anhydrate, as determined by dynamic vapor sorption at a temperature of about 25°C (±0.2°C) and at 95% relative humidity.

[0087] Basically corresponds to Figure 6 The characteristic data are summarized in Table IV below:

[0088] Table IV

[0089] Target RH (%) Quality change (%) 0 0.00 10 0.20 20 0.54 30 0.99 40 1.54 50 2.09 60 2.57 70 2.99 80 3.36 90 3.76 95 4.07

[0090] From the results of DSC and DVS, it can be seen that the anhydrous crystalline form 2 advantageously has a higher melting point and less hygroscopicity than the anhydrous crystalline form 1. In fact, as mentioned above, the anhydrous crystalline form 2 is not hygroscopic. The anhydrous crystalline form 2 is stable, while the anhydrous crystalline form 1 is metastable, which means that over time, the anhydrous crystalline form 1 is expected to transform into form 2 due to changes in its environment.

[0091] Anhydrous crystalline form 3 of the compound of formula (1)

[0092] The preparation of the anhydrous crystalline form 3 of the compound of formula (1) is described in detail in Comparative Example 7 below.

[0093] The anhydrous crystalline Form 3 of the compound of formula (1) was characterized by XRPD, DSC and DVS, and the results are detailed below.

[0094] More specifically, the characteristic X-ray powder diffraction pattern of the anhydrous crystalline form 3 of the compound of formula (1) can be substantially Figure 7 Its characteristic signals are summarized in the following Table V:

[0095] Table V

[0096]

[0097]

[0098] Basically Figure 8 As indicated, the anhydrous crystalline form 3 of the compound of formula (1) has a differential scanning calorimetry showing a melting endotherm at an onset of about 149°C (±2°C). This melting point temperature is weaker than the melting enthalpy ΔH of the anhydrous crystalline form 2 of the compound of formula (1). f (close to 40 J / g).

[0099] In addition, basically Fig. 9 As shown and detailed in the table below, anhydrous crystalline Form 3 of the compound of formula (1) is characterized by exhibiting a weight gain of 2.92 wt % based on the weight of the crystalline Form 3 anhydrate, as determined by dynamic vapor sorption at a temperature of about 25°C (±0.2°C) and at 95% relative humidity.

[0100] Basically corresponds to Fig. 9 The characteristic data are summarized in Table VI below:

[0101] Table VI

[0102]

[0103] From the results of DSC and DVS, it can be seen that the anhydrous crystalline Form 2 advantageously has a higher melting point and less hygroscopicity than the anhydrous crystalline Form 3. In fact, as mentioned above, the anhydrous crystalline Form 2 is not hygroscopic. The anhydrous crystalline Form 2 is stable, while the anhydrous crystalline Form 3 is metastable, which means that over time, the anhydrous crystalline Form 3 is expected to transform into Form 2 due to changes in its environment.

[0104] Anhydrous crystalline form 4 of the compound of formula (1)

[0105] The preparation of the anhydrous crystalline form 4 of the compound of formula (1) is described in detail in Comparative Example 8 below.

[0106] The anhydrous crystalline Form 4 of the compound of formula (1) was characterized by XRPD, DSC and DVS, and the results are detailed below.

[0107] More specifically, the characteristic X-ray powder diffraction pattern of the anhydrous crystalline form 4 of the compound of formula (1) can be substantially Fig.10 and its characteristic signals are summarized in the following Table VII:

[0108] Table VII

[0109] Angle (2θ°) (±0.2) 9.2 14.1 14.6 15.7 17.5 17.9 19.8

[0110] Basically Fig.11 As indicated, the anhydrous crystalline form 4 of the compound of formula (1) has a differential scanning calorimetry showing a melting endotherm at an onset of about 130°C (±2°C). This melting point temperature is weaker than the melting enthalpy ΔH of the anhydrous crystalline form 2 of the compound of formula (1). f (close to 22 J / g).

[0111] In addition, basically Fig.12 As shown and detailed in Table VIII below, anhydrous crystalline Form 4 of the compound of formula (1) is characterized by exhibiting a weight gain of 0.75 wt % based on the weight of crystalline Form 4 anhydrate, as determined by dynamic vapor sorption at a temperature of about 25° C. (±0.2° C.) at 90% relative humidity.

[0112] Basically corresponds to Fig.12 The characteristic data are summarized in Table VIII below:

[0113] Table VIII

[0114]

[0115]

[0116] From the results of DSC and DVS, it can be seen that the anhydrous crystalline Form 2 advantageously has a higher melting point and less hygroscopicity than the anhydrous crystalline Form 4. In fact, as mentioned above, the anhydrous crystalline Form 2 is not hygroscopic. The anhydrous crystalline Form 2 is stable, while the anhydrous crystalline Form 4 is metastable, which means that over time, the anhydrous crystalline Form 4 is expected to transform into Form 2 due to changes in its environment.

[0117] Ethanol solvate of the compound of formula (1)

[0118] The preparation of this ethanol solvate is detailed below in Comparative Example 9. This solvate was characterized by XRPD, and the results are detailed below.

[0119] More specifically, the characteristic X-ray powder diffraction pattern of the ethanol solvate of the compound of formula (1) under ethanol vapor measured at room temperature can be substantially Fig.13a The characteristic signals are summarized in the following Table IX:

[0120] Table IX

[0121]

[0122]

[0123] 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 anhydrous Form 1, substantially as Fig.13b Alternatively, ethanol vapor attached to a partially desolvated sample would produce the initial ethanol solvate.

[0124] Therefore, this ethanol solvate is unstable.

[0125] Acetone solvate of the compound of formula (1)

[0126] The preparation of this acetone solvate is detailed below in Comparative Example 10. This solvate was characterized by XRPD and the results are detailed below.

[0127] More specifically, the characteristic X-ray powder diffraction pattern of the acetone solvate of the compound of formula (1) under acetone vapor measured at room temperature can be substantially Fig.14a Its characteristic signals are summarized in the following Table X:

[0128] Table X

[0129]

[0130] The inventors have observed that this acetone solvate is physically unstable and generally converts to a low crystalline material upon exposure to ambient conditions or dry nitrogen, substantially as Fig.14b shown.

[0131] Butanol solvate of the compound of formula (1)

[0132] The preparation of this butanol solvate is detailed below in Comparative Example 11. This solvate was characterized by XRPD, and the results are detailed below.

[0133] More specifically, the characteristic X-ray powder diffraction pattern of the butanol solvate of the compound of formula (1) under butanol vapor measured at room temperature can be substantially Fig.15a and its characteristic signals are summarized in the following Table XI:

[0134] Table XI

[0135]

[0136] The inventors have observed that this butanol solvate must more accurately be considered a heterosolvate (1:2:1 water:butanol:active pharmaceutical ingredient) which is physically unstable and generally converts to an amorphous form upon exposure to ambient conditions or dry nitrogen, essentially as Fig.15b shown.

[0137] Dichloromethane (DCM) solvate of the compound of formula (1)

[0138] The preparation of this DCM solvate is detailed below in Comparative Example 12. This solvate was characterized by XRPD and the results are detailed below.

[0139] More specifically, the characteristic X-ray powder diffraction pattern of this DCM solvate of the compound of formula (1) under DCM vapor measured at room temperature can be substantially Fig.16 and its characteristic signals are summarized in the following Table XII:

[0140] Table XII

[0141]

[0142]

[0143] The inventors have observed that exposure of the DCM solvate to heat and / or moisture generally results in the formation of the anhydrous form 1. The inventors have observed that exposure of the DCM solvate to heat and / or N2 generally results in the formation of the anhydrous form 4. Therefore, the DCM solvate is unstable.

[0144] Tetrahydrofuran (THF) solvate of the compound of formula (1)

[0145] The preparation of this THF solvate is detailed below in Comparative Example 13. This solvate was characterized by XRPD, and the results are detailed below.

[0146] More specifically, the characteristic X-ray powder diffraction pattern of the THF solvate of the compound of formula (1) under THF vapor measured at room temperature can be substantially Fig.17 and its characteristic signals are summarized in the following Table XIII:

[0147] Table XIII

[0148]

[0149]

[0150] The inventors have observed that exposure of the THF solvate to heat and / or moisture generally results in the formation of the anhydrous Form 1. Therefore, the THF solvate is unstable.

[0151] 2-Propanol solvate of the compound of formula (1)

[0152] The preparation of this 2-propanol solvate is detailed below in Comparative Example 14. This solvate was characterized by HR XRPD, and the results are detailed below.

[0153] More specifically, the characteristic HR X-ray powder diffraction pattern of the 2-propanol solvate of the compound of formula (1) measured at room temperature can be substantially Fig.18 and its characteristic signals are summarized in the following Table XIV:

[0154] Table XIV

[0155]

[0156] The inventors have observed that upon heating, this 2-propanol solvate typically converts to the anhydrous form 3, which itself typically converts to the anhydrous form 2.

[0157] Methyl tert-butyl ether (MTBE) solvate of the compound of formula (1)

[0158] The preparation of this MTBE solvate is detailed below in Comparative Example 15. This solvate was characterized by XRPD, and the results are detailed below.

[0159] More specifically, the characteristic X-ray powder diffraction pattern of this MTBE solvate of the compound of formula (1) measured at room temperature can be substantially Fig.19 and its characteristic signals are summarized in the following Table XV:

[0160] Table XV

[0161]

[0162]

[0163] Based on XRPD analysis, this MTBE solvate is the least crystalline of the other disclosed solvates.

[0164] The inventors have also observed that this MTBE solvate generally melts at 80°C upon heating, with a melting enthalpy ΔH close to 10 J / g. f Related.

[0165] 1,4-dioxane solvate of the compound of formula (1)

[0166] The preparation of this 1,4-dioxane solvate is detailed below in Comparative Example 16. This solvate was characterized by XRPD, and the results are detailed below.

[0167] More specifically, the characteristic X-ray powder diffraction pattern of the 1,4-dioxane solvate of the compound of formula (1) measured at room temperature can be substantially Fig.20a and its characteristic signals are summarized in the following Table XVI:

[0168] Table XVI

[0169]

[0170] The inventors have observed that this 1,4-dioxane solvate is physically unstable and often transforms into an unknown poorly crystalline solid form at room temperature. The instability of the 1,4-dioxane solvate after one week at room temperature is essentially as follows: Fig.20b shown.

[0171] in conclusion

[0172] In view of the results provided above, it has been demonstrated that the anhydrous crystalline form 2 of the compound of formula (1) has more favorable properties than the anhydrous crystalline forms 1, 3 and 4 of the compound of formula (1) and the solvates (ethanol, acetone, butanol, THF, DCM, 2-propanol, MTBE and 1,4-dioxane solvates) of the compound of formula (1), particularly in terms of stability under at least ambient conditions of temperature and pressure, stability under humidity conditions (hygroscopicity), melting point value, etc.

[0173] 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. In fact, as indicated above, the anhydrous crystalline form 2 of the compound of formula (1) is not hygroscopic and is stable (melting point values, melting enthalpy values, etc.).

[0174] Process for preparing anhydrous crystalline form 2 of the compound of formula (1)

[0175] As indicated above, also provided herein is a process 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.

[0176] 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.

[0177] Optionally, step 1 of the process described below can also be carried out by implementing seeding, ie by using previously obtained seeds of the anhydrous form 2 of the compound of formula (1). Example 5 illustrates the synthetic route using seeding.

[0178] In the sense of the present disclosure, "setting the temperature" means maintaining the same temperature during the corresponding step.

[0179] In the context of the present disclosure, the expression that the solvent is "almost completely evaporated" means that the evaporation is not completely carried out, that is, the evaporated amount of the solvent is reduced, but is still present in a very low content. In other words, the evaporation cannot be carried out dryly.

[0180] Crystallization by evaporation

[0181] According to one embodiment, the process for preparing the anhydrous crystalline form 2 of the compound of formula (1) comprises at least the following steps:

[0182] 1) dissolving a compound of formula (1) in an 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.;

[0183] 2) allowing the solution obtained in step 1) to evaporate almost completely at the same temperature as the temperature set in step 1);

[0184] 3) isolating the anhydrous crystalline form 2 of the compound of formula (1) formed in step 2).

[0185] In a specific embodiment, the solvent of 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).

[0186] In a more specific embodiment, the solvent of 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.

[0187] In still another embodiment, the solvent of 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 mixtures, ethanol / water mixtures, 1-propanol / water mixtures, 1-butanol / water mixtures, 2-butanone / water mixtures, methyl isobutyl ketone / water mixtures, methyl acetate / water mixtures, ethyl acetate / water mixtures, isopropyl acetate / water mixtures, isobutyl acetate / water mixtures, and methyl isobutyl ketone / water mixtures.

[0188] When the solvent of step 1) is mixed with water, the volume ratio of solvent / water is usually 99 / 1.

[0189] According to another embodiment, the set temperatures of step 1) and step 2) are selected from a temperature range of from 20°C to 80°C or even from 25°C to 80°C.

[0190] Crystallization by cooling

[0191] According to another embodiment, the process for preparing the anhydrous crystalline form 2 of the compound of formula (1) comprises at least the following steps:

[0192] 1) dissolving or suspending a compound of formula (1) in an amorphous form in a solvent selected from alcohols, ketones, acetates, ethers and acetonitrile at a set temperature of room temperature;

[0193] 2) optionally purifying the solution or suspension obtained in step 1) by heating, stirring and filtering the solution or suspension at a set temperature ranging from 60° C. to 80° C.;

[0194] 3) heating the solution or suspension obtained in step 1) or step 2) at a set temperature ranging from 60° C. to 80° C.;

[0195] 4) cooling the solution or suspension obtained in step 2) to a set temperature ranging from -20°C to 25°C;

[0196] 5) isolating the anhydrous crystalline form 2 of the compound of formula (1) formed in step 4).

[0197] Optional step 2) allows advantageously removing impurities or microorganisms that may be present in the solution or suspension.

[0198] In a specific embodiment, the solvent of 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), isoamyl methyl ketone (also known as MIAK), methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, acetonitrile and methyl tert-butyl ether (also known as MTBE).

[0199] In one embodiment, the solvent of step 1) is acetone.

[0200] According to a variant, the set temperature of step 1) is the same as the set temperature of step 4).

[0201] According to another variant, the set temperature of step 1) is the same as the set temperature of step 4), and the set temperature of step 2) is the same as the set temperature of step 3).

[0202] Crystallization was performed by adding water as a non-solvent.

[0203] According to another embodiment, the process for preparing the anhydrous crystalline form 2 of the compound of formula (1) comprises at least the following steps:

[0204] 1) dissolving or suspending a compound of formula (1) in an amorphous form in a solvent selected from alcohols, ketones, acetates and diethyl ether at a set temperature of room temperature;

[0205] 2) optionally filtering the solution or suspension obtained in step 1);

[0206] 3) Adding water as a non-solvent;

[0207] 4) isolating the anhydrous crystalline form 2 of the compound of formula (1) formed in step 3).

[0208] The optional filtration step 2) allows advantageously removing impurities or microorganisms that may be present in the solution or suspension.

[0209] In a specific embodiment, the solvent of step 1) is selected from 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isoamyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate and diethyl ether.

[0210] Optionally, after step 3), the solvent is evaporated.

[0211] Crystallization was performed by adding heptane as non-solvent.

[0212] According to another embodiment, the process for preparing the anhydrous crystalline form 2 of the compound of formula (1) comprises at least the following steps:

[0213] 1) dissolving or suspending a compound of formula (1) in an amorphous form in a solvent selected from alcohols, ketones and acetates at a set temperature of room temperature;

[0214] 2) optionally filtering the solution or suspension obtained in step 1);

[0215] 3) adding heptane as a non-solvent;

[0216] 4) isolating the anhydrous crystalline form 2 of the compound of formula (1) formed in step 3).

[0217] The optional filtration step 2) allows advantageously removing impurities or microorganisms that may be present in the solution or suspension.

[0218] In a specific embodiment, the solvent of step 1) is selected from ethanol, 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isoamyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate and isobutyl acetate.

[0219] Crystallization was performed by seeding.

[0220] 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 seeds of the previously obtained anhydrous crystalline form 2). Seeding is a crystallization technique well known in the art. Such a seeding method may, for example, comprise the following steps:

[0221] 1) dissolving the compound of formula (1) in an amorphous form in an organic solvent such as 2-methyltetrahydrofuran or dichloromethane;

[0222] 2) Adding seed crystals of the anhydrous crystalline form 2 of the compound of formula (1).

[0223] In one embodiment, the seeding process is carried out at a temperature between room temperature and mild heating, for example at about 28° C. (±3° C.). In another embodiment, the seeding process includes a solvent exchange step 3), which includes the step of adding a non-solvent such as acetone. The crystals of the anhydrous crystalline form 2 of the compound of formula (1) are then recovered by filtering the reaction medium and drying. Example

[0224] Materials and Methods

[0225] I. Differential Scanning Calorimetry (DSC)

[0226] DSC analysis was performed on a Q1000 analyzer (TA Instruments). A few milligrams of sample pieces were deposited in unsealed aluminum pans and the atmosphere was regulated by a constant nitrogen flow. The analysis has been performed at a scanning rate of 5°C / min.

[0227] II. X-ray powder diffraction (XRPD)

[0228] The analysis was performed on a Brucker D4 Endeavor instrument using Bragg-Brentano parafocusing geometry at room temperature. A sealed copper anode X-ray tube (λCuKα average = 1.54178 ). A LynxEye linear detector completed the setup. For each sample analysis, a count time of a few seconds per step was used over an angular range from a few degrees 2θ to tens of degrees 2θ, with a 2θ step size of 0.016°.

[0229] For each experiment, the powder was deposited on the surface of the sample holder.

[0230] III. Water adsorption isotherms using dynamic vapor sorption (DVS)

[0231] Experiments were performed on a DVS automatic gravimetric vapor sorption analyzer (Surface Measurement Systems Ltd., London, UK). The water absorption and water loss of the samples were measured gravimetrically using an ultra-microbalance with a mass resolution of ± 0.1 μg. Controlled relative humidity was generated by mixing different proportions of dry and water-saturated carrier gas streams. The temperature was kept constant at 25.0°C ± 0.2°C by enclosing the entire system in a temperature-controlled thermostat. Sample amounts between 5 and 20 mg were used. Before exposure to any water vapor, the samples were dried at 0% relative humidity (RH) to remove most of the surface moisture present, and a dry baseline mass was established. Next, the samples were exposed to increasing relative humidity from 0 to 95% RH in a gradient of 5% RH.

[0232] IV. High Resolution X-Ray Powder Diffraction (HR-XRPD)

[0233] High-resolution diffraction patterns were recorded on a PANanalytical X'Pert Pro MPD powder diffractometer under ambient conditions using a Bragg-Brentano (vertical θ-2θ configuration) parafocusing geometry coupled to an X'Celerator detector. A sealed copper anode X-ray tube was used. The incident beam monochromator produced pure Cu Kα1 radiation (λ = 1.5406 ). The angular range extends from a few degrees 2θ to tens of degrees 2θ, with a 2θ step size of 0.017°.

[0234] Example 1: Preparation of the anhydrous crystalline Form 2 of the compound of formula (1) via recrystallization by evaporation.

[0235] Scenario 1: A 10 mg / mL solution of the amorphous compound of formula (1) was prepared at room temperature (50 mg amorphous solid in 5 mL solvent, 20 mL vial). The solution / suspension was allowed to evaporate almost completely at the selected temperature (open 20 mL vial).

[0236] According to Scheme 1, methanol at about 20°C, 40°C or 80°C (±2°C each time), ethanol / H2O (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) is used as the solvent, respectively.

[0237] Example 2: Preparation of the anhydrous crystalline Form 2 of the compound of formula (1) via recrystallization by cooling.

[0238] Scenario 2: A 100 mg / mL solution / suspension (depending on the solvent used) of the amorphous compound of formula (1) was prepared at room temperature (100 mg of amorphous solid in 1 mL of solvent, 4 mL in a vial). The solution / suspension was then heated to 80° C. The latter was heated again to 80° C. The solution was then cooled to room temperature, 5° C. or -20° C.

[0239] According to Scheme 2, acetone (through a cooling step for a temperature of about -20°C, 5°C or 20°C (±2°C each time)) or methyl acetate (through a cooling step for a temperature of about 5°C or 20°C (±2°C each time)) is used as a solvent, respectively.

[0240] Example 3: Preparation of anhydrous crystals of the compound of formula (1) by recrystallization with the addition of water as a non-solvent Crystal form 2.

[0241] Scenario 3: A 50 mg / mL solution / suspension (depending on the solvent used) of the amorphous compound of formula (1) was prepared at room temperature (50 mg amorphous solid in 1 mL solvent, 4 mL in a vial). The latter was kept at room temperature to add the non-solvent (here water).

[0242] According to Scheme 3, MIBK at about 20°C (±2°C) or isobutyl acetate at about 20°C (±2°C) was used as the solvent, respectively.

[0243] Example 4: Preparation of anhydrous form of the compound of formula (1) by recrystallization with the addition of heptane as a non-solvent Crystalline Form 2.

[0244] Solution 4:A 200 mg / mL solution / suspension (depending on the solvent used) of the amorphous compound of formula (1) was prepared at room temperature (50 mg amorphous solid in 250 μL solvent, 4 mL vial). The latter was kept at room temperature for the addition of the non-solvent (here heptane).

[0245] According to Scheme 4, 1-butanol at about 20° C. (±2° C.), acetone at about 20° C. (±2° C.), or isopropyl acetate at about 20° C. (±2° C.) was used as a solvent, respectively.

[0246] Characterization of anhydrous crystalline form 2

[0247] The anhydrous crystalline form 2 of the compound of formula (1) is characterized by being substantially as follows Figure 1 The XRPD shown is substantially as Figure 2 The DSC shown is essentially the same as Figure 3 DVS shown.

[0248] Example 5: Preparation of anhydrous crystalline Form 2 of the compound of formula (1) by seeding.

[0249] Starting from 1 kg of methyl 6-(2,4-dichlorophenyl)-5-(4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl)-8,9-dihydro-7H-benzocycloheptene-2-carboxylate oxalate as described in patent application WO 2020 / 049153, the free base is obtained by adding an aqueous solution of potassium carbonate in MeTHF (also known as 2-methyltetrahydrofuran). The free base in the MeTHF solution is then saponified using NaOH in the presence of MeOH under conditions well known in the art. After several washings in an aqueous medium while maintaining the pH in the range of 5.0 to 6.6, the organic phase (consisting of MeTHF) is dehydrated by vacuum distillation 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 5V volume ratio of reaction medium (MeTHF) to starting material (the above oxalate), and the reaction medium is maintained at 28°C±3°C for at least one hour under stirring.

[0250] The MeTHF solvent was then exchanged with acetone at a constant volume under vacuum and at a temperature of up to 55° C. During this solvent exchange, the reaction medium became turbid, indicating the onset of crystallization. The distillation was performed until the MeTHF content was equal to or less than 2.0%.

[0251] The reaction medium is heated to 40°C-45°C and pure water is added at a ratio of 1.3V of pure water per kg of starting material (oxalate as described above). The reaction medium is cooled to 0°C±3°C under stirring for at least 4 hours. The anhydrous form 2 of the compound of formula (1) thus obtained is washed with acetone and water, filtered and then dried to obtain 0.77kg of the anhydrous form 2 of the compound of formula (1).

[0252] In another embodiment, the seeding method is also performed on a dry amorphous form of the compound of formula (1). The amorphous form is dissolved in 7.1 V of MeTHF and heated to about 55° C. until completely dissolved. The medium is concentrated in vacuo at a maximum jacket temperature of 55° C. and seeding is performed as described above. The yield is greater than 95%.

[0253] Comparative Example 6: Anhydrous crystalline form 1 of the compound of formula (1).

[0254] The anhydrous crystalline Form 1 of the compound of formula (1) is obtained by desolvation of the ethanol solvate.

[0255] The ethanol solvate form is obtained by slowly evaporating the ethanol solution at room temperature. The ethanol solvate thus obtained is then placed under vacuum at 40° C. The anhydrous crystalline Form 1 is then produced by desolvation of the ethanol solvate.

[0256] The anhydrous crystalline form 1 of the compound of formula (1) is characterized by being substantially as follows Figure 4 The XRPD shown is substantially as Figure 5 The DSC shown is essentially the same as Figure 6 DVS shown.

[0257] Comparative Example 7: Anhydrous crystalline form 3 of the compound of formula (1).

[0258] At room temperature, 40% by weight of water was slowly added to a 50 mg / ml acetone solution of the compound of formula (1). After several hours at room temperature, crystals of the anhydrous form 3 appeared.

[0259] The anhydrous crystalline form 3 of the compound of formula (1) is characterized by being substantially as follows Figure 7 The XRPD shown is substantially as Figure 8 The DSC shown is essentially the same as Fig. 9 DVS shown.

[0260] Comparative Example 8: Anhydrous crystalline form 4 of the compound of formula (1).

[0261] The anhydrous crystalline Form 4 of the compound of formula (1) was obtained by dynamic vapor sorption (DVS) of DCM solvate. The crystalline anhydrous Form 4 was prepared under a nitrogen flow (200 cm / min) at 25°C. 3) for several hours and then after two consecutive water sorption / desorption cycles from 0% to 95% relative humidity at 25°C, the anhydrous form 4 of the compound of formula (1) is obtained.

[0262] Comparative Example 9: Ethanol solvate of the compound of formula (1).

[0263] The ethanol solvate was obtained by dissolving in ethanol (50 mg / mL) at 40° C. and cooling at about 20° C. (±2° C.) The ethanol solvate stoichiometry was 1 molecule of solvent per molecule of the compound of formula (1).

[0264] The XRPD pattern of the ethanol solvate is basically as follows Fig.13a and Fig.13b shown.

[0265] Comparative Example 10: Acetone solvate of the compound of formula (1).

[0266] The acetone solvate is obtained by slow evaporation of a saturated solution at about 20° C. (±2° C.) The stoichiometry is 1 molecule of the compound of formula (1) to 1.5 molecules of the solvent.

[0267] The XRPD pattern of acetone solvate is basically as follows Fig.14a and Fig.14b shown.

[0268] Comparative Example 11: Butanol solvate of the compound of formula (1).

[0269] The butanol solvate was obtained by cooling a 20 mg / mL solution to -20° C. The latter is a heterosolvate (1:2:1 water:butanol:compound of formula (1)).

[0270] The XRPD pattern of butanol solvate is basically as follows Fig.15a and Fig.15b shown.

[0271] Comparative Example 12: DCM solvate of the compound of formula (1).

[0272] 2.5 volumes of a DCM solution of the compound of formula (1) were prepared at room temperature. The solution was then slowly evaporated at 5°C.

[0273] The XRPD pattern of DCM solvate is basically as Fig.16 shown.

[0274] Comparative Example 13: THF solvate of the compound of formula (1).

[0275] A 400 mg / ml THF solution of the compound of formula (1) was prepared at 40° C. The solution was then cooled at room temperature under magnetic stirring.

[0276] The XRPD pattern of the THF solvate is basically as follows Fig.17 shown.

[0277] Comparative Example 14: 2-Propanol solvate of the compound of formula (1).

[0278] The 2-propanol solvate is obtained by evaporating a mixed solvent of 2-propanol / water (99 / 1) at about 20° C. (±2° C.) The stoichiometry of the 2-propanol solvate is 1 molecule of the solvent per molecule of the compound of formula (1).

[0279] The XRPD pattern of 2-propanol solvate is basically as follows Fig.18 shown.

[0280] Comparative Example 15: MTBE solvate of the compound of formula (1).

[0281] The MTBE solvate was obtained by slowly releasing water from a 50 mg / mL solution using vapor phase diffusion at about 20°C (± 2°C).

[0282] The XRPD pattern of MTBE solvate is basically as follows Fig.19 shown.

[0283] Comparative Example 16: 1,4-dioxane solvate of the compound of formula (1).

[0284] The 1,4-dioxane solvate was obtained by cooling the 100 mg / mL solution to -20 °C.

[0285] The XRPD pattern of 1,4-dioxane solvate is basically as follows Fig.20a and Fig.20b shown.

[0286] As explained above, the inventors have demonstrated that Form 2 of the compound of formula (1) is thermodynamically more stable than the various forms identified above at room temperature and ambient pressure.

[0287] Anhydrous Form 2 also presents the advantage of being non-hygroscopic and does not convert to another crystalline form upon exposure to moisture. Furthermore, exposure to temperature changes does not alter the crystal structure prior to its melting. It should also 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 the Anhydrous Form 2 crystals.

[0288] With respect to solvates, all solvates are unstable under ambient conditions of temperature and pressure.

Claims

1. An anhydrous crystalline form of Form 2 of a compound of formula (1) Features Having a powder X-ray diffraction pattern exhibiting peaks expressed as degrees 2θ at 9.5±0.2, 11.8±0.2, 14.1±0.2, 14.6±0.2, 17.7±0.2 and 18.5±0.

2.

2. The anhydrous crystalline form 2 of the compound of formula (1) according to claim 1, which further shows the following peaks expressed as 2θ degrees at 15.5±0.2, 15.9±0.2, 16.6±0.2 and 22.2±0.

2.

3. The anhydrous crystalline form 2 of the compound of formula (1) according to claim 2, characterized in that Having a powder X-ray diffraction pattern substantially as shown in Figure 1.

4. The anhydrous crystalline Form 2 of the compound of formula (1) according to claim 1, wherein differential scanning calorimetry DSC shows a melting endotherm at an onset of 204±2°C.

5. The anhydrous crystalline form 2 of the compound of formula (1) according to claim 4, characterized in that Having a thermal spectrum substantially as shown in FIG. 2 .

6. The anhydrous crystalline form 2 of the compound of formula (1) according to claim 1, characterized in that The crystalline Form 2 anhydrate exhibits a weight gain of less than 0.2 wt % based on the weight of the crystalline Form 2 anhydrate as determined by dynamic vapor sorption (DVS) at a temperature of 25 ± 0.2 °C in the range of relative humidity from 0% to 95%.

7. The anhydrous crystalline form 2 of the compound of formula (1) according to claim 6, characterized in that There is a DVS isotherm diagram substantially as shown in FIG3 .

8. A solid form which is an anhydrous crystalline Form 2 of the compound of formula (1) according to any one of claims 1 to 7.

9. A method for preparing anhydrous crystalline form 2 of a compound of formula (1) according to any one of claims 1 to 7, comprising at least the following steps: 1) dissolving a compound of formula (1) in an 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) allowing the solution obtained in step 1) to evaporate almost completely at the same temperature as the temperature set in step 1); 3) isolating the anhydrous crystalline form 2 of the compound of formula (1) formed in step 2).

10. The method of claim 9, wherein the solvent is selected from the group consisting of 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, 2-butanone / water mixtures, methyl isobutyl ketone, 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.

11. The method according to claim 9 or 10, wherein the set temperature of step 1) and step 2) is selected from a temperature range of from 20°C to 80°C.

12. A method for preparing anhydrous crystalline form 2 of a compound of formula (1) according to any one of claims 1 to 7, comprising at least the following steps: 1) dissolving or suspending a compound of formula (1) in an amorphous form in a solvent selected from alcohols, ketones, acetates, ethers and acetonitrile at a set temperature of room temperature; 2) optionally purifying the solution or suspension obtained in step 1) by heating, stirring and filtering the solution or suspension at a set temperature ranging from 60° C. to 80° C.; 3) heating the solution or suspension obtained in step 1) or step 2) at a set temperature ranging from 60° C. to 80° C.; 4) cooling the solution or suspension obtained in step 3) to a set temperature ranging from -20°C to 25°C; 5) isolating the anhydrous crystalline form 2 of the compound of formula (1) formed in step 4).

13. The method of claim 12, wherein the solvent is selected from the group consisting of ethanol, 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isoamyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, acetonitrile and methyl tert-butyl ether.

14. A method for preparing anhydrous crystalline form 2 of a compound of formula (1) according to any one of claims 1 to 7, comprising at least the following steps: 1) dissolving or suspending a compound of formula (1) in an amorphous form in a solvent selected from alcohols, ketones, acetates and diethyl ether at a set temperature of 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).

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

16. A method for preparing anhydrous crystalline form 2 of a compound of formula (1) according to any one of claims 1 to 7, comprising at least the following steps: 1) dissolving or suspending a compound of formula (1) in an amorphous form in a solvent selected from alcohols, ketones and acetates at a set temperature of 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).

17. The method of claim 16, wherein the solvent is selected from the group consisting of ethanol, 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isoamyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate and isobutyl acetate.

18. A method for preparing anhydrous crystalline form 2 of a compound of formula (1) according to any one of claims 1 to 7, comprising at least the following steps: 1) dissolving or suspending the compound of formula (1) in an amorphous form in an organic solvent; 2) Adding seed crystals of the anhydrous crystalline form 2 of the compound of formula (1).

19. The method according to claim 18, wherein the steps after steps 1) and 2) are adding a non-solvent, followed by distillation, followed by cooling and drying.

20. A drug characterized in that It comprises the anhydrous crystalline form 2 of the compound of formula (1) according to any one of claims 1 to 7.

21. A pharmaceutical composition comprising the anhydrous crystalline form 2 of the compound of formula (1) according to any one of claims 1 to 7 and at least one pharmaceutically acceptable excipient.

22. The pharmaceutical composition of claim 21, wherein the anhydrous crystalline Form 2 is substantially pure and free of alternative forms, wherein substantially pure means that the crystalline form contains at least 90% by weight of the indicated crystalline form.

23. The pharmaceutical composition of claim 21, wherein the anhydrous crystalline Form 2 comprises at least 90% by weight of all forms.

24. Use of the anhydrous crystalline form 2 of the compound of formula (1) according to any one of claims 1 to 7 in the preparation of a medicament for the treatment of cancer.

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