WO2017028802A1 - Crystal form of 5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihydrochloride and preparation method thereof - Google Patents

Abstract

The invention relates to a crystal salt of a 5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihydrochloride and a preparation method thereof, and specifically, to a dihydrochloride having Crystal form I or Crystal form II. The crystal forms have favorable stability, increased solubility, and decreased hygroscopicity, possessing a significant value in future drug development and optimization.

Description

Crystal form of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihydrochloride and preparation method thereof Technical field

The present invention relates to the field of chemical medicine, in particular to 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihydrochloride Crystal form and preparation method thereof.

Background technique

5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine (compound of formula I), also known as BKM120 (Buparlisib), is New drug for breast cancer developed by Novartis. At present, the drug treatment of metastatic breast cancer is in the phase III clinical and confirmatory I/II clinical stage. BKM120 is a reversible inhibitor of class I phosphoinositide-3 kinase (PI3K). The clinical results show that it has anti-tumor activity against ER-positive breast cancer cell lines and implanted tumors, and can be used alone or in combination with endocrine therapy.

Polymorphism is widespread in medicine. Different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, the comprehensive systematic polymorph screening in drug development and the selection of the most suitable crystal form are one of the important research contents that cannot be ignored.

Salt formation can improve certain undesirable physicochemical or biopharmaceutical properties of the drug, such as changing the solubility or dissolution of the drug, reducing the wettability, improving the stability, changing the melting point, improving the grinding performance, facilitating the preparation and purification, and improving the permeability. It has been reported that 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine can be stably present as a hydrochloride.

Patent CN103140479A discloses crystalline forms of the compounds of formula I and crystalline forms thereof. Specifically, the patent discloses a compound of formula I, a hemihydrate and an anhydride, a monohydrate of the compound of formula I, a monohydrate, an anhydride form A, a form B and a solvate form Sa, a form Sb, a form Sc, Form Sd and form Se.

Based on this, it is necessary to further carry out polymorphic screening of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine hydrochloride. Developed an anhydrate and hydrate crystal form with good stability and low wettability, which is suitable for industrial production, and provides a better choice for drug development.

Summary of the invention

Applicants are in the screening of polymorphs for 5-[2,6-bis(4-morpholinyl)-4-pyrimidin]-4-(trifluoromethyl)-2-pyridinamine monohydrochloride, Unexpectedly, 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihydrochloride was found. The form of the crystalline salt exists and has a polymorphic phenomenon. The new crystal form of the dihydrochloride has good stability and low wettability, and has higher solubility than the existing monohydrochloride crystal form, and is optimized for the future. And development is of great value.

One of the objects of the present invention is to provide a dihydrochloride of 5-[2,6-bis(4-morpholino)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine in crystalline form. The salt, the crystalline form of the dihydrochloride salt has good stability and low wettability, and has better solubility than the existing monohydrochloride salt crystal form, and is of great significance for improving the drug effect and reducing the drug load. .

The second object of the present invention is to provide a method for preparing the dihydrochloride salt in a crystalline form, and the method for preparing the crystalline form of the dihydrochloride salt of the present invention is simple and low in cost, and is important for optimization and development of the drug in the future. value.

To achieve the above object, the present invention adopts the following technical solutions:

a dihydrochloride salt of a compound of formula I,

This salt is a crystalline salt.

According to a particular aspect of the invention, the present invention provides a 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihalide salt The crystal form of the acid salt, designated as Form I, has an X-ray powder diffraction pattern at 25 ° C which is characterized by 2theta values of 24.1 ° ± 0.2 °, 19.1 ° ± 0.2 ° and 19.7 ° ± 0.2 °. peak.

Further, the X-ray powder diffraction pattern of Form I provided by the present invention has characteristic peaks at 2theta values of 9.9 ° ± 0.2 °, 8.8 ° ± 0.2 °, and 17.9 ° ± 0.2 °.

Further, the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at 2theta values of 22.2°±0.2°, 16.8°±0.2°, and 11.6°±0.2°.

According to a particular and preferred aspect of the invention, the X-ray powder diffraction pattern of Form I is also 2theta values of 9.9 ° ± 0.2 °, 8.8 ° ± 0.2 °, 17.9 ° ± 0.2 °, 22.2 ° ± 0.2 °, 16.8 ° There are characteristic peaks at both ±0.2° and 11.6°±0.2°. In According to a specific embodiment of the solution, the X-ray powder diffraction pattern of Form I is substantially as shown in FIG.

Preferably, the crystalline form I provided by the present invention begins to exhibit an endothermic peak near heating to 72 ° C, 167 ° C, and 214 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .

Preferably, the crystalline form I provided by the present invention has a weight loss gradient of about 21% when heated to 222 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.

According to the invention, the molar ratio of the compound of the formula I in the crystalline form I of the compound of the formula I to hydrochloric acid is from 1:1.89 to 2.10. That is, Form I is the dihydrochloride salt of a compound of Formula I.

According to still another specific aspect of the present invention, the present invention provides a 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine II The crystal form of the hydrochloride salt was designated as Form II, and the X-ray powder diffraction pattern of Form II had characteristic peaks at 2theta values of 22.9 ° ± 0.2 °, 10.1 ± 0.2 °, and 24.1 ° ± 0.2 °.

Further, the X-ray powder diffraction pattern of Form II provided by the present invention has a characteristic peak at a 2theta value of 26.3°±0.2°, 20.5°±0.2°, and 17.1°±0.2°.

Further, the X-ray powder diffraction pattern of Form II provided by the present invention has a characteristic peak at 2theta values of 22.7°±0.2°, 18.0°±0.2°, and 18.8°±0.2°.

According to a particular and preferred aspect of the invention, the X-ray powder diffraction pattern of Form II provided by the present invention is also 2theta value of 26.3° ± 0.2°, 20.5 ° ± 0.2 °, 17.1 ° ± 0.2 °, 22.7 ° ± 0.2 There are characteristic peaks at °, 18.0 ° ± 0.2 °, and 18.8 ° ± 0.2 °. In a specific embodiment according to this embodiment, the X-ray powder diffraction pattern of Form II is substantially as shown in FIG.

Preferably, the Form II is heated to 118 ° C, and an endothermic peak begins to appear near 196 ° C. The differential scanning calorimetry chart is substantially as shown in FIG. 9 .

Preferably, Form II has a weight loss gradient of about 14% when heated to 175 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.

According to the invention, the molar ratio of the compound of the formula I in the dihydrochloride salt form II of the compound of the formula I to hydrochloric acid is from 1: 1.95 to 2.10. That is, Form II is the dihydrochloride salt of a compound of Formula I.

Another object of the present invention is to provide a process for the preparation of Form I, which is obtained by the following method:

1) mixing the hydrochloride salt of the compound of the formula I with a cyclic ether solvent or a mixed solvent system thereof with water, and stirring and crystallization; or

2) obtaining a compound of the formula I and a hydrochloric acid in a cycloether solvent or a mixed solvent system with water to obtain a crystal; or

3) Mixing the hydrochloride of the compound of the formula I with a positive solvent, filtering to obtain a clear solution, adding an anti-solvent, and stirring and crystallization.

Further, the cyclic ether solvent is preferably 1,4 dioxane.

Further, the positive solvent is preferably a C1-C4 alcohol, that is, the positive solvent is methanol, ethanol, propanol, butanol, more preferably ethanol.

Further, the anti-solvent is preferably an alkyl ether solvent, more preferably methyl tert-butyl ether.

A third object of the present invention is to provide a process for the preparation of Form II which is obtained by the following method:

1) a hydrochloride of a compound of the formula I is obtained by stirring and crystallization in a ketone solvent, an ester solvent, a cyclic ether solvent or a mixed solvent system with water; or

2) stirring and crystallization of a compound of the formula I and hydrochloric acid in a ketone solvent, an ester solvent, a cyclic ether solvent or a mixed solvent system with water;

Wherein the cyclic ether solvent does not include 1,4 dioxane.

Further, the ketone solvent includes, but is not limited to, one or two of acetone and 4-methyl-2-pentanone; and the ester solvent includes, but not limited to, ethyl acetate and isopropyl acetate. One or two; the cyclic ether solvent includes, but is not limited to, 2-methyltetrahydrofuran, tetrahydrofuran.

The compound of formula (I) in the present invention may be in the form of a solid, semi-solid, wax or oil of the compound of formula (I).

A fourth object of the present invention is to provide a pharmaceutical composition comprising an effective amount of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4- (Trifluoromethyl)-2-pyridinamine dihydrochloride and a pharmaceutically acceptable adjuvant. That is, the active ingredient in the pharmaceutical composition may be 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridine in any crystalline form. The mixing of one or more of the amine dihydrochloride species may, in particular, be Form I, Form II or a mixture of the two.

In the present invention, a therapeutically effective amount of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihydrochloride is generally used. The crystalline salt is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation which is prepared in a manner well known in the pharmaceutical art.

Further, the pharmaceutical composition of the present invention can be used for the treatment of metastatic breast cancer.

A fifth object of the present invention is to provide a crystalline form of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine II. The use of hydrochloride for the preparation of a pharmaceutical preparation for the treatment of metastatic breast cancer.

A sixth object of the present invention is to provide a crystalline form of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine II. Use of hydrochloride in the treatment of metastatic breast cancer.

The beneficial effects of the invention are:

The dihydrochloride salt crystal salt provided by the invention has good stability, can well avoid the occurrence of crystal transformation during drug storage and development, thereby avoiding bioavailability and drug effect change. The crystal form provided by the invention has higher solubility, and is of great significance for improving the drug effect and reducing the drug load. The crystal form provided by the invention has low wettability, is not easily affected by high humidity and deliquesces, and is convenient for long-term storage and placement of the medicine. The crystalline crystal provided by the invention has complete morphology, high crystallinity and moderate particle size, and is favorable for filtration drying in the subsequent industrial production process. The crystal form provided by the invention has simple preparation operation and low cost, and is valuable for the optimization and development of the drug in the future.

DRAWINGS

1 is an XRPD pattern of Form I prepared in Example 1;

2 is a DSC chart of Form I prepared in Example 1;

3 is a TGA diagram of Form I prepared in Example 1;

4 is a DVS diagram of Form I prepared in Example 1;

5 is a comparison diagram of the stability XRPD of Form I prepared in Example 2 at a temperature of 4 ° C for 90 days (the XRPD pattern of the former Form I before the top view, and the XRPD diagram of the Form I after the placement) ;

6 is a comparison diagram of the stability XRPD of Form I prepared in Example 2 under the condition of 25° C./60% relative humidity for 90 days (the XRPD pattern of the former Form I is placed in the above figure, and the figure below shows the crystal form after standing. I XRPD map);

Figure 7 is a comparison diagram of the stability XRPD of the Form I prepared in Example 2 under the condition of 40 ° C / 75% relative humidity for 90 days (the XRPD pattern of the former Form I is placed in the above figure, and the figure below shows the crystal form after placement) I XRPD map);

Figure 8 is an XRPD pattern of Form II prepared in Example 3;

Figure 9 is a DSC chart of Form II prepared in Example 3;

Figure 10 is a TGA diagram of Form II prepared in Example 3;

Figure 11 is a PLM diagram of Form II prepared in Example 3;

Figure 12 is a DVS diagram of Form II prepared in Example 3;

Figure 13 is an XRPD pattern of Form II before and after standing for 90 days at 25 ° C / 60% relative humidity (the XRPD pattern of the former Form II is placed in the above figure, and the XRPD pattern of Form II is placed in the figure below);

Figure 14 is an XRPD pattern of Form II before and after leaving for 90 days at 40 ° C / 75% relative humidity (the XRPD pattern of the former Form II is placed in the above figure, and the XRPD pattern of Form II is placed in the figure below).

detailed description

The invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Field The skilled artisan may make modifications to the method of preparation and use of the instrument within the scope of the claims, and such modifications are also considered to be within the scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

In the following examples, the test methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4- The starting material of (trifluoromethyl)-2-pyridinamine hydrochloride or the free base is obtained by a commercially available method.

The abbreviations used in the present invention are explained as follows:

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric analysis

DVS: Dynamic moisture adsorption

PLM: polarized light microscope

The X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer at a temperature of about 25 °C. The method parameters of the X-ray powder diffraction described in the present invention are as follows:

X-ray reflection parameters: Cu, Kα

1.540598；

1.544426

1.540598;

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 volts (kV)

Current: 40 milliamps (mA)

Scan range: from 3.0 to 40.0 degrees

The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:

Scan rate: 10 ° C / min

Protective gas: nitrogen

The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:

Scan rate: 10 ° C / min

Protective gas: nitrogen

The dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.). The method parameters of the dynamic moisture adsorber are as follows:

Temperature: 25 ° C

Carrier gas, flow rate: N ₂ , 200 ml / min

Unit time quality change: 0.002% / minute

Relative humidity range: 0%RH-95%RH

Example 1

Preparation method of crystal form I:

1) 80.3 mg of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine monohydrochloride powder was added to 5.0 mL of anhydrous In ethanol, a clear solution was obtained by filtration.

2) The obtained solution of 1) was placed at room temperature (25 ± 3 ° C) on a magnetic stirrer at a rate of 500 rpm, and 15.0 mL of methyl t-butyl ether was added dropwise.

3) The suspension obtained in 2) was placed on a magnetic stirrer and stirred at a rate of 500 rpm for 2 days, and the lower layer solid was centrifuged.

4) The solid obtained in 3) was dried at 25 ° C overnight, and the obtained solid was Form I.

The X-ray powder diffraction data of Form I obtained in this example is shown in Table 1. Its XRPD diagram is shown in Figure 1. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 24.13°, 19.14° and 19.74° are characteristic peaks, and the 2theta values are 9.93° and 8.81°. The diffraction peak at 17.91° is an important peak, and the diffraction peak at 2theta values of 22.15°, 16.75°, and 11.62° is the second most important peak.

Table 1

2theta d interval strength% 8.81 10.04 65.40 9.93 8.91 71.07 11.62 7.61 32.56 12.12 7.30 25.38 13.64 6.49 25.65 14.07 6.30 21.34 15.91 5.57 23.34 16.75 5.29 37.93 17.91 4.95 59.82 18.63 4.76 15.65 19.14 4.64 76.33 19.74 4.50 74.05 21.62 4.11 26.74 22.15 4.01 51.58 22.70 3.92 17.73 23.42 3.80 29.92 23.98 3.71 62.53 24.13 3.69 100.00 24.82 3.59 20.64 26.08 3.42 10.93 26.71 3.34 32.37 27.02 3.30 20.69 27.58 3.23 32.32

28.00 3.19 23.65 28.26 3.16 21.06 29.76 3.00 12.38 30.17 2.96 10.31 30.62 2.92 18.94 31.32 2.86 19.75 33.92 2.64 12.11

The DSC of Form I is as shown in Figure 2, and an endothermic peak begins to appear near 72 ° C, 167 ° C, and 214 ° C.

The TGA pattern of Form I is shown in Figure 3 and has a weight loss gradient of about 20.86% when heated to 222 °C.

1.448 mg of Form I was dissolved in 10 ml of water to prepare a solution, and the content of free base and chloride ion in the sample was determined by high performance liquid chromatography and ion chromatography, respectively. The results are shown in Table 2.

Table 2 Crystal Form I Determination of molar ratio data by ion chromatography

Example 2

Preparation method of crystal form I:

18.0 mg of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinium monohydrochloride powder was added to 0.4 mL 1,4 In the dioxane, a suspension was obtained. The suspension was stirred at 50 ° C for two days, filtered, and the resulting filter cake was dried overnight in a 25 ° C constant temperature oven to obtain a crystalline form I.

The X-ray powder diffraction data of Form I obtained in this example is shown in Table 3. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 24.16°, 19.14° and 19.74° are characteristic peaks, and the 2theta values are 9.93° and 8.81°. The diffraction peak at 17.91° is an important peak, and the diffraction peak at 2theta values of 22.16°, 16.75°, and 11.62° is the second most important peak.

table 3

2theta d interval strength% 8.81 10.04 100.00 9.23 9.58 17.93 9.93 8.91 61.02 11.62 7.61 36.72 12.12 7.31 24.48 13.64 6.49 15.49 14.06 6.30 15.12 15.92 5.57 20.97 16.75 5.29 20.78 17.91 4.95 34.43 18.66 4.76 10.76 19.14 4.64 53.30

19.74 4.50 67.98 20.25 4.39 10.99 21.60 4.11 16.19 22.16 4.01 32.77 22.72 3.91 11.04 23.40 3.80 24.38 23.99 3.71 47.16 24.16 3.68 64.75 24.81 3.59 12.26 25.20 3.53 7.27 26.12 3.41 5.60 26.72 3.34 28.48 27.03 3.30 11.61 27.60 3.23 25.60 28.00 3.19 18.23 28.26 3.16 14.67 28.71 3.11 5.97 29.76 3.00 7.28 30.16 2.96 6.39 30.62 2.92 12.31 31.33 2.86 12.72 33.88 2.65 5.85 35.36 2.54 3.07

Example 3

Preparation method of Form II:

0.99 g of the compound of formula (I) was added to 10 mL of acetone/water solution (95/5, v/v), stirred at room temperature (25±3 ° C) for 0.5 h, and dissolved; 16 mL of 0.1 mol/L hydrochloric acid acetone solution (95/5) , v / v), added crystal form II seed crystal, constant 0.5h. Then add 33mL 0.1mol / L hydrochloric acid acetone / water solution (95 / 5, v / v), added within 0.5h, stirred for 12h, filtered, the filter cake was placed in a constant temperature drying oven at 25 ° C overnight, the resulting solid is crystal Type II.

The X-ray powder diffraction data of Form II obtained in this example is shown in Table 4. Its XRPD diagram is shown in Figure 8. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 22.92°, 10.13° and 24.13° are characteristic peaks, and the 2theta values are 26.35° and 20.52°. The diffraction peak at 17.06° is an important peak, and the diffraction peak at 2theta values of 22.69°, 17.99°, and 18.78° is the second most important peak.

Table 4

2theta d interval strength% 8.92 9.91 14.93 10.13 8.73 85.18 11.04 8.02 10.62 13.29 6.66 22.54

14.79 5.99 6.92 17.06 5.20 39.35 17.38 5.10 24.31 17.64 5.03 9.84 17.99 4.93 29.79 18.78 4.73 24.51 19.89 4.46 23.42 20.28 4.38 23.65 20.52 4.33 41.09 21.52 4.13 5.34 22.33 3.98 8.60 22.69 3.92 34.34 22.92 3.88 100.00 24.13 3.69 59.97 24.56 3.63 15.96 25.69 3.47 8.55 26.35 3.38 49.50 26.82 3.32 9.30 27.31 3.27 16.23 28.44 3.14 9.64 29.17 3.06 15.68 30.32 2.95 10.03 31.06 2.88 11.94 32.81 2.73 17.17 33.38 2.68 13.96 36.09 2.49 2.74 37.34 2.41 2.12 38.15 2.36 2.61

The DSC pattern of Form II is shown in Figure 9. The endothermic peak begins to appear near 118 ° C and around 196 ° C.

The TGA pattern of Form II is shown in Figure 10. When heated to 175 ° C, it has a weight loss gradient of about 14%.

The PLM diagram of Form II is shown in Figure 11.

0.611 mg of Form II was dissolved in 10 ml of water to prepare a solution, and the content of free base and chloride ion in the sample was determined by high performance liquid chromatography and ion chromatography, respectively. The results are shown in Table 5.

Table 5 Crystal Form II Determination of molar ratio data by ion chromatography

Example 4

Study on the conversion relationship between crystal form I and crystal form II:

Form I is added to a suitable solvent, stirred at room temperature (25 ± 3 ° C) for 6 h, and filtered to give a crystalline solid. See Table 6 for detailed solvents and amounts. The experimental results show that the stirring of Form I under a specific solvent is converted to Form II.

Table 6

Example 5

Study on the stability of crystal form I:

Three samples of Form I prepared in Example 2 were placed at 4 ° C, exposed to openness at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 90 days, and then sampled for XRPD, HPLC. . The results are shown in Table 7:

Table 7

Form I was kept at a temperature of 4 ° C, 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, leaving the crystal form unchanged for 90 days. The above test results show that Form I has good stability.

Example 6

Stability study of Form II:

Three samples of Form II prepared in Example 3 were placed at 4 ° C, exposed to openness at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 90 days, and then sampled for XRPD, HPLC. . The results are shown in Table 8:

Table 8

Form II remained unchanged at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 90 days. The above test results show that Form II has good stability.

Example 7

Study on the relationship between the dihydrochloride salt form II and the monohydrochloride form A of the patent CN103140479A:

1) Add 50 mg of the monohydrochloride salt form of patent CN103140479A to 2 mL of acetone/water (95/5, v/v) to obtain a suspension, stir at room temperature (25 ± 3 ° C) for 24 h, and two salts appear in the system. The salt form II of the acid salt indicates the tendency of the monohydrochloride form A to be converted to the dihydrochloride salt form II.

2) Add 50 mg of the monohydrochloride salt form of CN103140479A to 2 mL of acetone/water (95/5, v/v) to obtain a suspension, add appropriate amount of concentrated hydrochloric acid, stir at room temperature for 24 h, monohydrochloride form Conversion of A to dihydrochloride salt form II indicates a tendency for the monohydrochloride form A to be converted to the dihydrochloride salt form II.

Example 8

Study on the wettability of Form I and Form II:

The crystal form I prepared in Example 1 of the present invention and the crystal form II obtained in Example 3 were about 10 mg, and the wettability was measured by a dynamic moisture adsorption (DVS) instrument. The experimental results are shown in Table 9. The DVS diagram of the wettability experiment is shown in Figures 4 and 12.

Table 9

Defining the characteristics of wettability and the definition of wetting weight gain (Chinese Pharmacopoeia 2010 edition Appendix XIX J drug hygroscopicity Test guidelines, experimental conditions: 25 ° C ± 1 ° C, 80% relative humidity):

Deliquescence: absorb enough water to form a liquid

Very hygroscopic: the wetting weight gain is not less than 15%

Humidity: Wet weight gain is less than 15% but not less than 2%

Slightly wettability: wetting gain is less than 2% but not less than 0.2%

No or almost no wettability: wetting gain is less than 0.2%

The results show that the crystal form I and the crystal form II of the present invention have low wettability.

Example 9

Comparative study on the solubility of dihydrochloride salt and monohydrochloride salt:

Form I prepared in Example 1 of the present invention, Form II obtained in Example 3, and Monohydrochloride Form A in Patent CN103140479 were respectively used at pH 5.0 FeSSIF (simulated intestinal juice in simulated feeding state), pH 6 .5FaSSIF (simulated artificial intestinal juice in the fasting state) was prepared as a saturated solution, and the content of the sample in the saturated solution was determined by high performance liquid chromatography after 4 hours and 24 hours. The experimental results are shown in Table 10.

Table 10

The results showed that the dihydrochloride crystalline salt was more soluble than the monohydrochloride crystalline salt after being placed in FaSSIF and FeSSIF for 4 hours and 24 hours.

Claims (18)

a dihydrochloride salt of a compound of formula I,

It is characterized in that the salt is a crystalline salt. A dihydrochloride salt of a compound of formula I according to claim 1 wherein the crystalline salt is Form I having an X-ray powder diffraction pattern having a 2theta value of 24.1 ° ± 0.2 °, 19.1 ° ± 0.2 ° and There is a characteristic peak at 19.7 ° ± 0.2 °. The dihydrochloride salt of a compound of formula I according to claim 2, characterized in that the X-ray powder diffraction pattern of said Form I is also 2theta values of 9.9 ° ± 0.2 °, 8.8 ° ± 0.2 ° and 17.9 Characteristic peak at °±0.2°. The dihydrochloride salt of a compound of formula I according to claim 3, characterized in that the X-ray powder diffraction pattern of said Form I is also 2theta values of 22.2° ± 0.2°, 16.8° ± 0.2° and 11.6. Characteristic peak at °±0.2°. The dihydrochloride salt of the compound of formula I according to claim 1, wherein the crystalline salt is crystalline form II, and the X-ray powder diffraction pattern has a 2theta value of 22.9 ° ± 0.2 ° and 10.1 ° ± 0.2 °. There are characteristic peaks at 24.1 ° ± 0.2 °. The dihydrochloride salt of a compound of formula I according to claim 5, characterized in that the X-ray powder diffraction pattern of said Form II is also at 2theta values of 26.3° ± 0.2°, 20.5° ± 0.2°, 17.1. Characteristic peak at °±0.2°. The dihydrochloride salt of the compound of formula I according to claim 6, characterized in that the X-ray powder diffraction pattern of said Form II is also 2theta value of 22.7 ° ± 0.2 °, 18.0 ° ± 0.2 °, 18.8 Characteristic peak at °±0.2°. A process for the preparation of Form I according to any one of claims 2 to 4, wherein the Form I is obtained by the following method: 1) mixing the hydrochloride salt of the compound of the formula I with a cyclic ether solvent or a mixed solvent system thereof with water, and stirring and crystallization; or 2) obtaining a compound of the formula I and a hydrochloric acid in a cycloether solvent or a mixed solvent system with water to obtain a crystal; or 3) Mixing the hydrochloride of the compound of the formula I with a positive solvent, filtering to obtain a clear solution, adding an anti-solvent, and stirring and crystallization. The method for producing a crystalline form I according to claim 8, wherein the cyclic ether solvent is 1,4 dioxane. The method for producing Form I according to claim 8, wherein the positive solvent is a C1-C4 alcohol. A method of producing Form I according to claim 10, wherein the positive solvent is ethanol. The method for producing a crystalline form I according to claim 8, wherein the anti-solvent is an alkyl ether solvent. The method for producing Form I according to claim 12, wherein the anti-solvent is methyl tert-butyl ether. A method for producing a crystalline form II according to any one of claims 5 to 7, wherein the crystalline form II is obtained by the following method: 1) a hydrochloride of a compound of the formula I is obtained by stirring and crystallization in a ketone solvent, an ester solvent, a cyclic ether solvent or a mixed solvent system with water; or 2) stirring and crystallization of a compound of the formula I and hydrochloric acid in a ketone solvent, an ester solvent, a cyclic ether solvent or a mixed solvent system with water; Wherein the cyclic ether solvent does not include 1,4 dioxane. The method for preparing Form II according to claim 14, wherein the ketone solvent is acetone or 4-methyl-2-pentanone; and the ester solvent is ethyl acetate or isopropyl acetate. The cyclic ether solvent is 2-methyltetrahydrofuran or tetrahydrofuran. A pharmaceutical composition comprising the dihydrochloride salt of a compound of formula I according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient. Use of a crystalline dihydrochloride salt of a compound of formula I according to any one of claims 1 to 7 for the preparation of a pharmaceutical preparation for the treatment of metastatic breast cancer. Use of a crystalline dihydrochloride salt of a compound of formula I according to any one of claims 1 to 7 for the treatment of metastatic breast cancer.

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