WO2016206619A1 - Novel crystalline forms of volasertib and trihydrochloride thereof - Google Patents

Abstract

The present invention provides novel crystalline forms of Volasertib and Volasertib trihydrochloride, preparation methods therefor, medical uses thereof and compositions comprising same. Compared with the known crystalline forms, the novel crystalline forms of the present invention have significantly improved fluidity. Furthermore, the crystalline forms of the present invention have relatively good storage stability, are good supplements for the known crystalline forms and have important application values. The preparation methods of the present novel crystalline forms are simple, low-cost and adaptable to industrialization.

Description

New crystal form of Volasertib and its trihydrochloride Technical field

The invention relates to the field of chemical medicine, in particular to a new crystal form of Volasertib and its salt and a preparation method thereof.

Background technique

Volasertib (a compound of formula I) is a drug developed by Boehringer Ingelheim Pharmaceuticals for the treatment of acute myeloid leukemia (AML). Volasertib is currently in Phase III clinical development and is currently eligible for orphan drug status from the US FDA and the European Commission. Volasertib is an experimental Polo-like kinase (Plk) inhibitor, and Plk is an enzyme that regulates cell division (mitosis). This inhibition will prolong cell cycle arrest and ultimately lead to cell death (apoptosis).

The chemical name of Volasertib is N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6 ,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide, the structure As follows:

Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on drug stability, bioavailability, and efficacy. Therefore, in the development of drugs, the issue of drug polymorphism should be fully considered.

At present, the patent CN101379064B discloses the trihydrochloride trihydrate form of the compound of formula (I) and the anhydrous form of the trihydrochloride. Patent WO2009019205A1 discloses an anhydrous crystalline form of the free base of the compound of formula (I). There are no other companies that disclose other crystal forms of the compound of formula (I). These reported Volasertib crystal forms and Volasertib trihydrochloride crystal forms are less fluid and have poor stability under certain conditions.

Summary of the invention

One of the objects of the present invention is to provide a new crystalline form of Volasertib with good fluidity, named Volasertib Form A.

A second object of the present invention is to provide two new crystalline forms of Volasertib trihydrochloride with good fluidity, designated Volasertib Trihydrochloride Form I and Volasertib Trihydrochloride Form II, respectively.

A third object of the present invention is to provide a process for the preparation of the above Volasertib Form A, Volasertib Trihydrochloride Form I and Volasertib Trihydrochloride Form II.

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

The Volasertib crystal form A provided by the present invention, that is, the crystal form A of the compound of the formula (I),

The X-ray powder diffraction pattern of this Form A has characteristic peaks at 2theta values of 4.9 ° ± 0.2 °, 8.6 ° ± 0.2 °, and 9.2 ° ± 0.2 °.

Further, the crystal form A provided by the present invention has an X-ray powder diffraction pattern having a characteristic peak at a 2theta value of 6.7 ° ± 0.2 °, 14.1 ° ± 0.2 °, and 16.9 ° ± 0.2 °.

Further, the crystal form A provided by the present invention has an X-ray powder diffraction pattern having a characteristic peak at a 2theta value of 5.2 ° ± 0.2 °, 10.4 ° ± 0.2 °, and 20.9 ° ± 0.2 °.

According to a particular aspect of the invention, the X-ray powder diffraction pattern of Form A provided by the present invention is substantially as shown in FIG.

The invention provides a preparation method of Volasertib crystal form A, wherein the compound A of the formula (I) is added to a mixed solvent of an alcohol and water, stirred, or the compound of the formula (I) is dissolved in an alcohol or a ring. It is obtained by mixing and stirring with an ether solvent.

Further, the alcohol solvent includes methanol and ethanol; and the cyclic ether solvent includes tetrahydrofuran and 1,4-dioxane.

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of Volasertib Form A and a pharmaceutically acceptable adjuvant. Generally, a therapeutically effective amount of Volasertib Form A 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. . The pharmaceutical composition is preferably a pharmaceutical preparation for the treatment of acute myeloid leukemia.

Further, in the pharmaceutical composition of the present invention, Volasertib Form A can be used for the preparation of a pharmaceutical preparation for treating acute myeloid leukemia.

The crystal form I of Volasertib trihydrochloride provided by the present invention, that is, the trihydrochloride salt form I of the compound of the formula (I),

The X-ray powder diffraction pattern of this Form I has characteristic peaks at 2theta values of 10.1 ± 0.2 °, 22.9 ° ± 0.2 °, and 24.4 ° ± 0.2 °.

Further, the Volasertib Trihydrochloride Form I of the present invention has an X-ray powder diffraction pattern having a characteristic peak at a 2theta value of 7.6 ° ± 0.2 °, 11.2 ° ± 0.2 °, and 21.7 ° ± 0.2 °.

Further, the Volasertib trihydrochloride Form I provided by the present invention has an X-ray powder diffraction pattern having a characteristic peak at a 2theta value of 13.5°±0.2°, 19.0°±0.2°, and 26.9°±0.2°.

According to a particular aspect of the invention, the X-ray powder diffraction pattern of Volasertib Trihydrochloride Form I of the present invention is substantially as shown in FIG.

The invention provides a preparation method of Volasertib trihydrochloride salt form I, wherein Volasertib trihydrochloride salt form I is obtained by stirring a compound of formula (I) and hydrochloric acid in an alcohol solvent.

Preferably, the alcohol solvent is isobutanol.

The Volasertib trihydrochloride salt form II provided by the present invention, that is, the trihydrochloride salt form II of the compound of the formula (I),

The X-ray powder diffraction pattern of the Form II has characteristic peaks at 2theta values of 7.5 ° ± 0.2 °, 7.7 ° ± 0.2 °, and 22.5 ° ± 0.2 °.

Further, the X-ray powder diffraction pattern of Volasertib Trihydrochloride Form II also has characteristic peaks at 2theta values of 13.3 ° ± 0.2 °, 17.9 ° ± 0.2 °, 25.8 ° ± 0.2 °.

Further, the X-ray powder diffraction pattern of Volasertib Trihydrochloride Form II also has characteristic peaks at 2theta values of 8.4 ° ± 0.2 °, 12.3 ° ± 0.2 °, and 23.2 ° ± 0.2 °.

According to a particular aspect of the invention, the X-ray powder diffraction pattern of Volasertib Trihydrochloride Form II is substantially as shown in FIG.

The present invention provides a process for preparing Volasertib trihydrochloride salt form II by dissolving the trihydrochloride salt trihydrate of the compound of formula (I) in an alcohol solvent with a halogenated hydrocarbon and/or an aromatic hydrocarbon solvent. Crystallization in a mixed solvent gave Volasertib Trihydrochloride Form II.

According to a specific and preferred aspect, the mixed solvent of the alcohol solvent and the halogenated hydrocarbon is a mixed solvent of methanol and chloroform. According to still another specific and preferred aspect, the mixed solvent of the alcohol and the aromatic hydrocarbon is a mixed solvent of methanol and toluene.

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of Volasertib Trihydrochloride Form I or Form II or a mixture thereof and a pharmaceutically acceptable adjuvant. Typically, a therapeutically effective amount of Volasertib Trihydrochloride Form I or Form II or a mixture thereof is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation, the pharmaceutical composition or formulation It is prepared in a manner well known in the pharmaceutical art. The pharmaceutical composition is preferably a pharmaceutical preparation for the treatment of acute myeloid leukemia.

Further, in the pharmaceutical composition of the present invention, Volasertib Trihydrochloride Form I or Form II or a mixture thereof is used for the preparation of a pharmaceutical preparation for treating acute myeloid leukemia.

Further, the Volasertib crystal form A of the present invention, the Volasertib trihydrochloride salt form I of the present invention, and the Volasertib trihydrochloride salt form II can be used in combination to prepare a medicament for treating acute myeloid leukemia. preparation.

The beneficial effects of the invention are:

The three new crystal forms provided by the present invention have significantly improved flow properties compared to existing crystal forms. Moreover, the crystal form of the present invention itself has good storage stability, wherein it has been confirmed that the Volasertib crystal form A of the present invention and the Volasertib crystal form ratio reported by WO2009019205A1 are more stable under certain circumstances; the Volasertib trihydrochloride salt form of the present invention Compared with the crystal form of Volasertib trihydrochloride reported by CN101379064B, it is more stable under certain circumstances. Therefore, the novel crystal form provided by the present invention has important application value.

DRAWINGS

Figure 1 is an XRPD pattern of Volasertib crystal form A;

Figure 2 is a ¹ H NMR chart of Volasertib Form A;

Figure 3 is an infrared spectrum of Volasertib crystal form A;

Figure 4 is an XRPD pattern of Volasertib trihydrochloride Form I;

Figure 5 is a DSC chart of Volasertib trihydrochloride Form I;

Figure 6 is a TGA diagram of Volasertib trihydrochloride Form I;

Figure 7 is an infrared spectrum of Volasertib trihydrochloride Form I;

Figure 8 is a ¹ H NMR of Volasertib trihydrochloride Form I;

Figure 9 is an XRPD pattern of Volasertib Trihydrochloride Form II;

Figure 10 is an infrared spectrum of Volasertib trihydrochloride Form II;

Figure 11 is a PLM diagram of Volasertib crystal form A;

Figure 12 is a PLM diagram of Volasertib trihydrochloride Form I;

Figure 13 is a PLM diagram of Volasertib Trihydrochloride Form II;

Figure 14 is a PLM diagram of the Volasertib crystal form reported in WO2009019205A1;

Figure 15 is a PLM diagram of the crystal form of Volasertib trihydrochloride trihydrate reported by CN101379064B;

Figure 16 is a comparison of XRPD before and after the Volasertib crystal form A accelerated stability test;

Figure 17 is a comparison of XRPD before and after the Volasertib Trihydrochloride Form I accelerated stability test;

Figure 18 is a comparison of XRPD before and after the Volasertib Trihydrochloride Form II accelerated stability test (25 ° C / 60% RH for 3 months);

Figure 19 is a comparison of XRPD before and after the Volasertib Trihydrochloride Form II accelerated stability test (40 ° C / 75% RH for 15 days).

detailed description

The invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Improvements in the method of preparation and use of the apparatus may be made by those skilled in the art 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 described are generally carried out under conventional conditions or conditions recommended by the manufacturer.

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

XRPD: X-ray powder diffraction

¹ H NMR: liquid NMR

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

X-ray reflection parameters: Cu, Kα

Kα1

1.540598; Kα2

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

Example 1

Preparation method of Volasertib crystal form A:

101.4 mg of the free base of the compound of the formula (I) was weighed, and 10 mL of water and 0.75 mL of ethanol were successively added thereto, and the mixture was stirred at room temperature for 4 days, and dried by filtration to give a white solid. The solid was collected, and was determined to be Volasertib crystal form A.

The Volsertib crystal form A prepared by the above method has a ¹ H NMR spectrum as shown in Fig. 2, and the ¹ H NMR identification data is as follows: ¹ H NMR (400 MHz, CDCl 3 ) δ 8.52 (d, J = 8.4 Hz, 1H), 7.65 ( s, 1H), 7.60 (s, 1H), 7.40 (d, J = 1.7 Hz, 1H), 7.21 (dd, J = 8.5, 1.7 Hz, 1H), 5.87 (d, J = 7.9 Hz, 1H), 4.77-4.63 (m, 1H), 4.28 (dd, J = 7.7, 3.3 Hz, 1H), 3.98-3.84 (m, 4H), 3.31 (s, 3H), 2.69 (s, 7H), 2.31 (t, J = 7.9 Hz, 3H), 2.17 (d, J = 12.2 Hz, 2H), 1.99 (d, J = 11.7 Hz, 2H), 1.90 (ddd, J = 14.4, 7.5, 3.4 Hz, 1H), 1.45 ( Dd, J = 22.6, 8.7 Hz, 6H), 1.34 (d, J = 6.9 Hz, 3H), 1.32-1.17 (m, 4H), 0.85 (t, J = 7.5 Hz, 4H), 0.56 - 0.46 (m) , 2H), 0.11 (q, J = 5.0 Hz, 2H).

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1. Its XRPD diagram is shown in Figure 1, its infrared The spectrum is shown in Figure 3.

Table 1

2theta	d interval	strength%
4.80	18.42	80.08
5.22	16.93	44.21
6.69	13.22	38.45
8.22	10.75	28.29
8.58	10.30	52.71
9.28	9.53	100.00
9.63	9.18	62.40
10.44	8.48	7.75
11.77	7.52	4.79
13.39	6.61	4.77
14.16	6.26	37.31
14.76	6.00	16.35
17.00	5.22	18.99
18.59	4.77	9.24
19.99	4.44	6.93
20.95	4.24	19.26
22.16	4.01	3.10
23.63	3.77	2.95
25.35	3.51	5.35
27.29	3.27	3.19
28.25	3.16	4.55

Example 2

Preparation method of Volasertib crystal form A:

7.8 mg of the free base of the compound of the formula (I) was weighed and dissolved in 25 μL of methanol, 2.0 mL of water was added dropwise, and a solid precipitated. Stirring was continued for 24 hours at room temperature, and dried by filtration to give a white solid, which was collected, which was obtained as Volasertib crystal form A.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 2.

Table 2

2theta	d interval	strength%
4.49	19.68	48.89
4.77	18.53	100.00
5.17	17.11	22.80
6.71	13.17	14.95
8.20	10.78	19.30

8.58	10.31	25.01
9.31	9.50	28.96
9.59	9.22	28.50
10.47	8.45	8.03
11.85	7.47	9.15
13.37	6.62	7.26
14.20	6.24	18.25
14.76	6.00	11.36
15.95	5.56	8.41
17.05	5.20	12.48
18.77	4.73	8.92
19.61	4.53	9.34
21.07	4.22	13.97
21.91	4.06	7.88
22.32	3.98	7.44
23.68	3.76	11.91
24.66	3.61	5.71
25.71	3.47	11.42
27.43	3.25	9.03
28.33	3.15	10.46
30.88	2.90	1.15
32.85	2.73	0.36

Example 3

Preparation method of Volasertib crystal form A:

101.1 mg of the free base of the compound of the formula (I) was weighed, and 10 mL of water and 0.75 mL of methanol were successively added thereto, and the mixture was stirred at room temperature for 4 days, and dried by filtration to give a white solid. Upon examination, the solid obtained in this example was Volasertib crystal form A.

Example 4

Preparation method of Volasertib crystal form A:

7.8 mg of the free base of the compound of the formula (I) was weighed and dissolved in 25 μL of ethanol, 2.0 mL of water was added dropwise, and a solid precipitated. Stirring was continued for 24 hours at room temperature and dried by filtration to give a white solid. Upon examination, the solid obtained in this example was Volasertib crystal form A.

Example 5

Preparation method of Volasertib crystal form A:

7.7 mg of the free base of the compound of the formula (I) was weighed and dissolved in 25 μL of tetrahydrofuran, and 2.0 mL of water was added dropwise thereto to precipitate a solid. Stirring was continued for 24 hours at room temperature and dried by filtration to give a white solid. Upon examination, the solid obtained in this example was Volasertib crystal form A.

Example 6

Preparation method of Volasertib crystal form A:

8.3 mg of the free base of the compound of the formula (I) was weighed and dissolved in 75 μL of 1,4-dioxane, 2.0 mL of water was added dropwise, and a solid precipitated. Stirring was continued for 24 hours at room temperature and dried by filtration to give a white solid. Upon examination, the solid obtained in this example was Volasertib crystal form A.

Example 7

Preparation method of Volasertib crystal form A:

7.9 mg of the free base of the compound of the formula (I) was weighed and dissolved in 25 μL of methanol, and the solution was added dropwise to 2.0 mL of water to precipitate a solid. Stirring was continued for 24 hours at room temperature and dried by filtration to give a white solid. Upon examination, the solid obtained in this example was Volasertib crystal form A.

Example 8

Preparation method of Volasertib crystal form A:

7.9 mg of the free base of the compound of the formula (I) was weighed and dissolved in 25 μL of ethanol, and the solution was added dropwise to 2.0 mL of water to precipitate a solid. Stirring was continued for 24 hours at room temperature and dried by filtration to give a white solid. Upon examination, the solid obtained in this example was Volasertib crystal form A.

Example 9

Preparation method of Volasertib crystal form A:

7.8 mg of the free base of the compound of the formula (I) was weighed and dissolved in 25 μL of tetrahydrofuran, and the solution was added dropwise to 2.0 mL of water to precipitate a solid. Stirring was continued for 24 hours at room temperature and dried by filtration to give a white solid. Upon examination, the solid obtained in this example was Volasertib crystal form A.

Example 10

Preparation method of Volasertib crystal form A:

8.4 mg of the free base of the compound of the formula (I) was weighed and dissolved in 75 μL of 1,4-dioxane, and the solution was added dropwise to 2.0 mL of water, and a solid precipitated immediately. Stirring was continued for 24 hours at room temperature and dried by filtration to give a white solid. Upon examination, the solid obtained in this example was Volasertib crystal form A.

Example 11

Preparation method of Volasertib trihydrochloride salt form I:

29.4 mg of the free base of the compound of the formula (I) was weighed and dissolved in 1.0 mL of isobutanol, and 15.0 μL of 37% concentrated hydrochloric acid was added dropwise, and the reaction was stirred at room temperature for two hours, and dried by filtration to obtain a white solid. Solid, detected as Volasertib Trihydrochloride Form I.

The trihydrochloride product of the compound of the formula (I) prepared by the above method has a ¹ H NMR chart as shown in Fig. 8, and the ¹ H NMR identification data is as follows: ¹ H NMR (40 () MHz, D ₂ O) δ 7.83 ( d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.40 (dd, J = 6.8, 1.8 Hz, 2H), 4.53 (dd, J = 5.9, 3.2 Hz, 1H), 4.36 (dt, J =13.4, 6.7 Hz, 1H), 4.00-3.33 (m, 13H), 3.25 (s, 3H), 3.18 (d, J = 7.5 Hz, 2H), 2.22 (dd, J = 30.2, 10.7 Hz, 4H) , 2.08-1.85 (m, 2H), 1.72 (dd, J = 21.9, 12.3 Hz, 2H), 1.52 (dd, J = 25.0, 10.5 Hz, 2H), 1.34 (d, J = 6.8 Hz, 6H), 1.17-1.05 (m, 1H), 0.83-0.69 (m, 5H), 0.42 (q, J = 4.8 Hz, 2H).

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 3. The XRPD diagram is shown in Fig. 4. The DSC diagram is shown in Fig. 5. The TGA diagram is shown in Fig. 6. The infrared spectrum is shown in Fig. 7.

table 3

2theta	d interval	strength%
7.59	11.65	77.10
10.11	8.75	100.00
11.23	7.88	30.64

12.55	7.05	8.95
13.49	6.57	16.36
14.24	6.22	15.32
14.92	5.94	15.80
15.39	5.76	23.18
17.47	5.08	9.91
18.99	4.67	18.52
20.07	4.42	11.53
21.61	4.11	38.82
22.95	3.88	75.18
23.36	3.81	30.35
24.32	3.66	46.63
24.89	3.58	17.54
26.91	3.31	30.37
28.26	3.16	13.41
28.80	3.10	14.66
29.80	3.00	10.62
31.27	2.86	13.91

Example 12

Preparation method of Volasertib trihydrochloride salt form I:

100.1 mg of the free base of the compound of the formula (I) was weighed and dissolved in 4.0 mL of isobutanol, 50.0 μL of 37% concentrated hydrochloric acid was added dropwise, and the reaction was stirred at room temperature for three hours, and dried by filtration to give a white solid. The solid was collected and tested as Volasertib Trihydrochloride Form I.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 4.

Table 4

2theta	d interval	strength%
7.60	11.63	100.00
10.05	8.80	47.76
11.22	7.89	20.50
13.36	6.63	15.03
14.26	6.21	17.25
14.93	5.93	24.01
15.34	5.78	33.31
17.66	5.02	5.17
19.03	4.66	21.17
20.08	4.42	20.17
21.67	4.10	29.47

23.00	3.87	70.76
23.35	3.81	50.03
24.35	3.66	51.54
26.91	3.31	27.41
28.81	3.10	15.09
29.86	2.99	11.71
31.26	2.86	17.20

Example 13

Preparation method of Volasertib trihydrochloride salt form II:

Weigh 4.8 mg of the compound (I) compound trihydrochloride trihydrate in 0.5 mL of a methanol/chloroform (V:V = 1:2) mixed solvent, and slowly evaporate at room temperature to obtain a white solid. Volasertib Trihydrochloride Form II.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 5. The XRPD pattern is shown in Figure 9, and the infrared spectrum is shown in Figure 10.

table 5

2theta	d interval	strength%
7.47	11.83	43.68
7.72	11.45	100.00
8.42	10.51	18.76
10.78	8.21	11.93
11.64	7.60	18.38
12.29	7.20	15.90
13.36	6.63	54.26
13.80	6.42	8.33
15.32	5.78	14.31
16.09	5.51	14.71
16.40	5.40	10.95
17.88	4.96	20.14
18.99	4.67	7.95
19.48	4.56	7.16
20.33	4.37	6.06
21.99	4.04	6.08
22.53	3.95	20.49
23.25	3.83	33.74
23.89	3.72	19.60
25.13	3.54	23.58
25.76	3.46	12.80
26.96	3.31	9.28

Example 14

Preparation method of Volasertib trihydrochloride salt form II:

Weigh 5.1 mg of the compound (I) compound trihydrochloride trihydrate dissolved in 0.5 mL of methanol / toluene (V: V = 1: 2) mixed solvent, slowly evaporate at room temperature to obtain a white solid, collect solids, after testing It is Volasertib Trihydrochloride Form II.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 6.

Table 6

2theta	d interval	strength%
7.46	11.85	47.05
7.71	11.46	100.00
8.42	10.50	25.13
10.78	8.21	17.07
11.69	7.57	20.72
12.27	7.21	22.90
13.35	6.63	40.96
13.82	6.41	6.25
15.33	5.78	13.40
16.06	5.52	17.21
16.42	5.40	10.78
16.85	5.26	3.19
17.87	4.96	33.15
18.52	4.79	10.11
18.94	4.68	9.46
19.52	4.55	9.09
20.29	4.38	10.98
21.96	4.05	6.48
22.51	3.95	26.69
22.86	3.89	9.38
23.22	3.83	23.05
23.66	3.76	10.02
23.87	3.73	14.84
25.13	3.54	13.90
25.75	3.46	25.68
26.95	3.31	14.53
27.73	3.22	9.21
28.64	3.12	7.54
30.05	2.97	2.99
33.22	2.70	5.60

35.05

2.56

2.03

Example 15

Volasertib crystal form A, Volasertib trihydrochloride form I and Volasertib trihydrochloride form II of the present invention, Volasertib crystal form reported in WO2009019205A1 (hereinafter referred to as the existing Volasertib crystal form) and crystal form reported by CN101379064 B (below) The polarized microscope (PLM) test was performed on the existing Volasertib trisalate crystal form, and the polarized light microscope data was collected at room temperature by an Axio Lab. A1 upright microscope. The results are shown in Figures 11-15.

As can be seen from Figures 11-15, the Volasertib crystal form A, Volasertib trihydrochloride form I and Volasertib trihydrochloride form II of the present invention are all in the form of a block, while the existing Volasertib crystal form and Volasertib trihydrochloride crystal form. The types are all needle-shaped, in contrast, the crystal form of the present invention has good fluidity and is advantageous for industrial production.

Example 16

The accelerated stabilization experiments were carried out on Volasertib crystal form A, Volasertib trihydrochloride form I and Volasertib trihydrochloride form II of the present invention, respectively.

(1) Accelerated stability experiment on Volasertib crystal form A

The crystal form A obtained by the present invention was placed at 25 ° C, relative humidity of 60%, 40 ° C, and relative humidity of 75% for 3 months, and samples were taken at the end of 0.5, 1 and 3, respectively, for purity measurement and The XRPD test, the purity determination results are shown in Table 7, and the results of the XRPD test at the beginning and end of March are shown in Fig. 16. The uppermost spectrum is the initial test, and the middle map is 25 °C / 60% RH. The test was obtained after 3 months, and the lowermost spectrum was tested after being placed at 40 ° C / 75% RH for 3 months. The test results show that Volasertib Form A has good stability under the test conditions.

Table 7

(2) Accelerated stability experiment on Volasertib trihydrochloride crystal form I

The crystal form I prepared by the present invention was placed at 25 ° C, relative humidity of 60%, 40 ° C, and relative humidity of 75% for 3 months, and samples were taken at the end of 0.5, 1 and 3, respectively, for purity measurement and The XRPD test, the purity determination results are shown in Table 8, and the XRPD test results at the beginning and end of March are shown in Fig. 17, wherein the topmost spectrum is obtained at the initial test, and the middle map is placed at 25 ° C / 60% RH. The test was obtained after 3 months, and the lowermost spectrum was tested after being placed at 40 ° C / 75% RH for 3 months. The test results show that Volasertib trihydrochloride Form I has good stability under the test conditions.

Table 8

(3) Accelerated stability experiment on Volasertib trihydrochloride crystal form II

The crystal form II prepared by the present invention was placed under the condition of 25 ° C and 60% relative humidity for 3 months, and samples were taken at the end of 0.5, 1 and 3, respectively, for purity measurement and XRPD test, and the purity measurement results are shown in Table 9. As shown, the results of the XRPD test at the beginning and end of March are shown in Fig. 18. The upper spectrum is the test at the beginning, and the lower spectrum is the test after 25 months at 25 ° C / 60% RH.

Table 9

In addition, the crystal form II prepared by the present invention was sealed in an aluminum plastic bag and placed at 40 ° C and a relative humidity of 75% for half a month for purity measurement and XRPD test. The results are shown in Table 10 and Figure 19, respectively. (The upper graph is measured at the beginning, and the lower graph is measured after half a month.) The results show that the crystal form II of the present invention has good stability under the test conditions.

Table 10

Example 17

The existing Volasertib crystal form was placed in water together with the Volasertib crystal form A of the present invention, and stirred at room temperature. After 1 day, samples were taken for XRPD detection, and it was found that the existing Volasertib crystal form was converted into the crystal form A of the present invention. It is demonstrated that the crystalline form A of the present invention is more stable than the existing Volasertib crystal form.

The existing Volasertib trihydrochloride crystal form was placed in a different solvent system together with the Volasertib trihydrochloride salt form II of the present invention, and stirred at room temperature. After 4 days, samples were taken for XRPD detection, and the results are shown in Table 11. The results show that the crystalline form II of the present invention is more stable than the existing crystal form of Volasertib trihydrochloride, and the existing crystal form of Volasertib trihydrochloride is converted into the crystalline form II of the present invention.

Table 11

Claims (17)

1. a crystal form A of a compound of formula (I),

   

   It is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 4.9 ° ± 0.2 °, 8.6 ° ± 0.2 °, and 9.2 ° ± 0.2 °.
2. The crystal form A according to claim 1, wherein the X-ray powder diffraction pattern is further at a 2theta value of 6.7 ° ± 0.2 °, 14.1 ° ± 0.2 °, 16.9 ° ± 0.2 °; and / or 2theta The values have characteristic peaks at 5.2 ° ± 0.2 °, 10.4 ° ± 0.2 °, and 20.9 ° ± 0.2 °.
3. Crystal Form A according to Claim 1 wherein the X-ray powder diffraction pattern is substantially identical to that of Figure 1.
4. A method for preparing a crystalline form A of a compound of the formula (I), characterized in that the crystalline form A is obtained by adding a compound of the formula (I) to a mixed solvent of an alcohol and water and stirring; or a compound of the formula (I) It is dissolved in an alcohol and/or a cyclic ether solvent and mixed with water to obtain a mixture.
5. The preparation method according to claim 4, wherein the alcohol solvent comprises methanol or ethanol; and the cyclic ether solvent comprises tetrahydrofuran or 1,4-dioxane.
6. a trihydrochloride salt form I of a compound of formula (I),

   

   It is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 10.1°±0.2°, 22.9°±0.2°, and 24.4°±0.2°.
7. The Form I of claim 6 further characterized by an X-ray powder diffraction pattern at a 2theta value of 7.6 ° ± 0.2 °, 11.2 ° ± 0.2 °, 21.7 ° ± 0.2 °; and / or 13.5 Characteristic peaks are found at °±0.2°, 19.0°±0.2°, and 26.9°±0.2°.
8. Crystal Form I according to claim 6, characterized in that its X-ray powder diffraction pattern is substantially identical to that of Figure 4.
9. A method for preparing a trihydrochloride salt form I of a compound of the formula (I), characterized in that the crystal form I is a formula (I) The compound and hydrochloric acid are dissolved in an alcohol solvent to obtain a stirring reaction.
10. The process according to claim 9, wherein the alcohol solvent is isobutanol.
11. a trihydrochloride salt form II of a compound of formula (I),

    

    It is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 7.5 ° ± 0.2 °, 7.7 ° ± 0.2 °, and 22.5 ° ± 0.2 °.
12. The crystal form II according to claim 11, wherein the X-ray powder diffraction pattern is further at a 2theta value of 13.3 ° ± 0.2 °, 17.9 ° ± 0.2 °, 25.8 ° ± 0.2 °; and / or 8.4 Characteristic peaks are found at °±0.2°, 12.3°±0.2°, and 23.2°±0.2°.
13. Crystal Form II according to claim 11 wherein the X-ray powder diffraction pattern is substantially identical to that of Figure 9.
14. Process for the preparation of a trihydrochloride salt form II of a compound of the formula (I), characterized in that the form II is a solution of the trihydrochloride salt trihydrate of the compound of the formula (I) in an alcohol and a halogenated hydrocarbon It is obtained by crystallization of a mixed solvent or a mixed solvent of an alcohol and an aromatic hydrocarbon.
15. The preparation method according to claim 14, wherein the mixed solvent of the alcohol solvent and the halogenated hydrocarbon is a mixed solvent of methanol and chloroform; and the mixed solvent of the alcohol and the aromatic hydrocarbon is a mixed solvent of methanol and toluene.
16. A pharmaceutical composition comprising an effective amount of the crystalline form A of the compound of formula (I) according to any one of claims 1 to 3; and/or, in claims 6 to 8. The trihydrochloride salt form I of the compound of the formula (I) according to any one of the inventions and/or the trihydrochloride salt form of the compound of the formula (I) according to any one of claims 11 to 13 II; and a pharmaceutically acceptable excipient.
17. The crystalline form A of the compound of the formula (I) according to any one of claims 1 to 3; and/or the trihydrochloride of the compound of the formula (I) according to any one of claims 6 to 8. Salt crystal form I; and/or use of the trihydrochloride salt form II of the compound of formula (I) according to any one of claims 11 to 13 for the preparation of a pharmaceutical preparation for the treatment of acute myeloid leukemia.

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