CN113754684A

CN113754684A - Serapatinib crystal form and preparation method thereof

Info

Publication number: CN113754684A
Application number: CN202110170309.5A
Authority: CN
Inventors: 申淑匣; 谷宇恒; 张良
Original assignee: 上海希迈医药科技有限公司; 上海创诺医药集团有限公司
Current assignee: Shanghai chuangnao Pharmaceutical Group Co., Ltd; Shanghai Qisheng Heyan Pharmaceutical Technology Co ltd
Priority date: 2021-02-08
Filing date: 2021-02-08
Publication date: 2021-12-07

Abstract

The invention provides a serpatatinib crystal form and a preparation method thereof. Specifically, the invention provides a crystal form of a compound shown as a formula I, wherein the crystal form is a crystal form CM-A, a crystal form CM-B, a crystal form CM-C, a crystal form CM-D, a crystal form CM-E, a crystal form CM-F, a crystal form CM-C, a crystal form CM-G, a crystal form CM-H, a crystal form CM-I, a crystal form CM-J, a crystal form CM-K, a crystal form CM-L and a crystal form CM-M. The crystalline forms of serpatatinib of the present invention have advantages in at least one of flowability, stability, hygroscopicity, and subsequent processing.

Description

Serapatinib crystal form and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, and in particular relates to a crystal form of serpatatinib and a preparation method thereof.

Background

Serpatatinib, the english name selpercatinib, its chemical name is: (6- (2-hydroxy-2-methylpropoxy) -4- (6- (6- (6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Hept 3-yl) pyridin-3-yl) pireno [1, 5-a]Pyridine-3-carbonitrile, having the trade name: RETEVMO, molecular formula: c₂₉H₃₁N7O₃The molecular weight is: 525.6, CAS number: 2152628-33-4, the chemical structural formula is shown in formula (I):

selpercatinib is a potent oral RET kinase inhibitor from loxonocolgy, a gift to pharmaceutical subsidiary, approved by the FDA 5/8/2020. selpercatinib is intended to inhibit natural RET signaling and the expected acquired resistance mechanisms for patients carrying aberrant RET kinases in tumors. In the U.S. regulatory aspect, the FDA has granted selpercatinib breakthrough drug eligibility (BTD) to treat three classes of patients, specifically: (1) metastatic RET fusion-positive NSCLC patients who progress after receiving platinum-containing chemotherapy and one PD-1 or PD-L1 tumor immunotherapy treatment, in need of systemic treatment (systemic treatment); (2) RET mutant Medullary Thyroid Carcinoma (MTC) patients who had progressed on treatment without an acceptable alternative treatment option and who needed systemic treatment; (3) patients with advanced RET fusion-positive thyroid cancer who had progressed after receiving other regimens and had no acceptable alternative treatment regimen, requiring systemic treatment.

WO2019075108 discloses seletracenib Form1 (anhydrate), Form2 (hydrate), Form7 (hydrate) and Form8(IPA solvate). The Form1 crystal Form has relatively good stability, but poor solubility, and is not beneficial to human body absorption. Form2 and Form7 have poor crystal Form stability, and Form1 is converted in the drying process, Form8 is an IPA solvate, has solvent toxicity and is not suitable for medicinal use. In addition, the Form1 has poor stability in solution, and is easy to generate crystal transformation in the subsequent preparation and production processes, which is not beneficial to preparing medicines.

For drug development, the polymorphism of a drug is a crucial research content. Different crystal forms have different solubilities, dissolution speeds and stabilities, and can obviously influence the bioavailability of the medicament, thereby causing different clinical effects. According to FDA data, the Seliptinib is a low-solubility drug, so that a new crystal form with good solubility and good crystal form stability needs to be searched to meet the requirement of pharmaceutical preparation.

Disclosure of Invention

The invention aims to provide a novel crystal form with good solubility and good crystal form stability so as to meet the requirement of medicinal preparation.

In a first aspect of the invention, there is provided a crystalline form of a compound of formula (I):

preferably, the crystalline form is selected from the group consisting of: the crystal form is CM-A, CM-B, CM-C, CM-D, CM-E, CM-F, CM-C, CM-G, CM-H, CM-I, CM-J, CM-K, CM-L, CM-M;

wherein the XRPD pattern of the crystalline form CM-a comprises 3 or more than 3 2 Θ values selected from the group consisting of: 6.2 +/-0.2 DEG, 7.5 +/-0.2 DEG, 9.2 +/-0.2 DEG, 12.0 +/-0.2 DEG, 13.2 +/-0.2 DEG, 17.1 +/-0.2 DEG and 21.0 +/-0.2 DEG;

the XRPD pattern of the crystalline form CM-B comprises 3 or more than 3 2 Θ values selected from the group consisting of: 4.8 +/-0.2 degrees, 9.9 +/-0.2 degrees, 19.5 +/-0.2 degrees and 19.9 +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-C comprises 3 or more than 3 2 Θ values selected from the group consisting of: 5.1 +/-0.2 degrees, 9.8 +/-0.2 degrees, 11.0 +/-0.2 degrees and 15.0 +/-0.2 degrees;

the XRPD pattern of crystalline form CM-D comprises 3 or more than 3 2 Θ values selected from the group consisting of: 5.1 +/-0.2 degrees, 10.9 +/-0.2 degrees, 19.7 +/-0.2 degrees and 22.2 +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-E comprises 3 or more than 3 2 Θ values selected from the group consisting of: 6.0 +/-0.2 degrees, 10.1 +/-0.2 degrees, 19.2 +/-0.2 degrees and 19.6 +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-F comprises 3 or more than 3 2 Θ values selected from the group consisting of: 6.0 +/-0.2 degrees, 10.1 +/-0.2 degrees, 15.7 +/-0.2 degrees and 24.8 +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-G comprises 3 or more than 3 2 Θ values selected from the group consisting of: 4.8 +/-0.2 degrees, 10.3 +/-0.2 degrees, 10.8 +/-0.2 degrees and 19.3 +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-H comprises 3 or more than 3 2 Θ values selected from the group consisting of: 4.8 +/-0.2 degrees, 9.9 +/-0.2 degrees, 19.6 +/-0.2 degrees and 20.0 +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-I comprises 3 or more than 3 2 Θ values selected from the group consisting of: 4.8 +/-0.2 degrees, 9.8 +/-0.2 degrees, 10.2 +/-0.2 degrees and 19.9 +/-0.2 degrees;

the XRPD pattern of crystalline form CM-J comprises 3 or more than 3 2 Θ values selected from the group consisting of: 4.5 +/-0.2 degrees, 10.2 +/-0.2 degrees, 18.1 +/-0.2 degrees and 19.4 +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-K comprises 3 or more than 3 2 Θ values selected from the group consisting of: 4.8 +/-0.2 degrees, 10.1 +/-0.2 degrees, 15.7 +/-0.2 degrees and 19.7 +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-L comprises 3 or more than 3 2 Θ values selected from the group consisting of: 4.7 +/-0.2 degrees, 8.6 +/-0.2 degrees, 10.2 +/-0.2 degrees and 19.1 +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-M comprises 3 or more than 3 2 Θ values selected from the group consisting of: 4.5 +/-0.2 degrees, 4.8 +/-0.2 degrees, 17.9 +/-0.2 degrees and 20.1 +/-0.2 degrees.

Preferably, the crystalline form CM-a has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-a comprises 6 or more 2 Θ values selected from the group consisting of: 6.2 +/-0.2 °, 7.5 +/-0.2 °, 9.2 +/-0.2 °, 10.9 +/-0.2 °, 12.0 +/-0.2 °, 13.2 +/-0.2 °, 17.1 +/-0.2 °, 17.6 +/-0.2 °, 18.1 +/-0.2 °, 19.6 +/-0.2 °, 19.8 +/-0.2 °, 21.1 +/-0.2 °, 22.5 +/-0.2 °, 25.0 +/-0.2 °, 29.2 +/-0.2 ° and 30.0 +/-0.2 °;

2) the crystalline form CM-A has an XRPD pattern substantially as shown in figure 1;

3) the crystalline form CM-a has a TGA profile substantially as shown in figure 2;

4) said crystalline form CM-A having a DSC profile substantially as shown in figure 3;

5) the crystalline form CM-a has a 1H NMR spectrum substantially as shown in figure 4.

6) Said crystalline form CM-A having a DVS profile substantially as shown in figure 5

Preferably, the crystalline form CM-B has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-B comprises 6 or more 2 Θ values selected from the group consisting of: the 2 theta values are 4.8 +/-0.2 degrees, 8.6 +/-0.2 degrees, 9.9 +/-0.2 degrees, 15.5 +/-0.2 degrees, 17.3 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.5 +/-0.2 degrees, 19.9 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.0 +/-0.2 degrees, 25.3 +/-0.2 degrees and 26.1 +/-0.2 degrees.

2) The crystalline form CM-B has an XRPD pattern substantially as shown in figure 6;

3) the crystalline form CM-B has a TGA profile substantially as shown in figure 7;

4) the crystalline form CM-B has a DSC profile substantially as shown in figure 8.

5) The crystalline form CM-B has a 1H NMR spectrum substantially as shown in figure 9.

Preferably, the crystalline form CM-C has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-C comprises 6 or more 2 Θ values selected from the group consisting of: the 2 theta values are 5.1 +/-0.2 degrees, 6.3 +/-0.2 degrees, 8.2 +/-0.2 degrees, 9.8 +/-0.2 degrees, 10.4 +/-0.2 degrees, 11.0 +/-0.2 degrees, 12.1 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.6 +/-0.2 degrees, 16.6 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.0 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.0 +/-0.2 degrees, 22.1 +/-0.2 degrees, 22.4 +/-0.2 degrees and 24.2 +/-0.2 degrees.

2) The crystalline form CM-C has an XRPD pattern substantially as shown in figure 10;

3) the crystalline form CM-C has a TGA profile substantially as shown in figure 11;

4) the crystalline form CM-C has a DSC profile substantially as shown in figure 12.

5) The crystalline form CM-C has a 1H NMR spectrum substantially as shown in figure 13;

6) the crystalline form CM-C has a DVS profile substantially as shown in figure 14;

preferably, the crystalline form CM-D has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of crystalline form CM-D comprises 6 or more than 62 Θ values selected from the group consisting of: the values of 2 theta are 5.1 +/-0.2 degrees, 10.3 +/-0.2 degrees, 10.5 +/-0.2 degrees, 10.9 +/-0.2 degrees, 11.1 +/-0.2 degrees, 18.4 +/-0.2 degrees, 19.7 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.2 +/-0.2 degrees, 22.5 +/-0.2 degrees, 23.8 +/-0.2 degrees and 24.3 +/-0.2 degrees.

2) The crystalline form CM-D has an XRPD pattern substantially as shown in figure 15;

preferably, the crystalline form CM-E has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-E comprises 6 or more 2 Θ values selected from the group consisting of: the 2 theta values are 4.6 +/-0.2 degrees, 10.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.5 +/-0.2 degrees, 16.5 +/-0.2 degrees, 18.0 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.2 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.5 +/-0.2 degrees, 22.0 +/-0.2 degrees, 24.1 +/-0.2 degrees and 25.4 +/-0.2 degrees.

2) The crystalline form CM-E has an XRPD pattern substantially as shown in figure 16;

preferably, the crystalline form CM-F has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-F comprises 6 or more 2 Θ values selected from the group consisting of: the values of 2 theta are 4.8 +/-0.2 degrees, 6.0 +/-0.2 degrees, 6.8 +/-0.2 degrees, 10.1 +/-0.2 degrees, 15.7 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.5 +/-0.2 degrees, 21.7 +/-0.2 degrees, 23.2 +/-0.2 degrees, 24.8 +/-0.2 degrees and 31.1 +/-0.2 degrees.

2) The crystalline form CM-F has an XRPD pattern substantially as shown in figure 17;

preferably, the crystalline form CM-G has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-G comprises 6 or more 2 Θ values selected from the group consisting of: the 2 theta values are 4.8 +/-0.2 degrees, 6.2 +/-0.2 degrees, 10.3 +/-0.2 degrees, 10.8 +/-0.2 degrees, 15.2 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.8 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.6 +/-0.2 degrees and 24.1 +/-0.2 degrees.

2) The crystalline form CM-G has an XRPD pattern substantially as shown in figure 18;

preferably, the crystalline form CM-H has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-H comprises 6 or more than 62 Θ values selected from the group consisting of: the 2 theta values are 4.8 +/-0.2 degrees, 8.6 +/-0.2 degrees, 9.9 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.3 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.9 +/-0.2 degrees, 23.4 +/-0.2 degrees, 24.6 +/-0.2 degrees, 25.7 +/-0.2 degrees and 26.1 +/-0.2 degrees.

2) The crystalline form CM-H has an XRPD pattern substantially as shown in figure 19;

preferably, the crystalline form CM-I has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-I comprises 6 or more than 62 Θ values selected from the group consisting of: the 2 theta values are 4.8 +/-0.2 degrees, 6.1 +/-0.2 degrees, 9.8 +/-0.2 degrees, 10.2 +/-0.2 degrees, 14.8 +/-0.2 degrees, 15.7 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.9 +/-0.2 degrees and 24.8 +/-0.2 degrees.

2) The crystalline form CM-I has an XRPD pattern substantially as shown in figure 20;

preferably, the crystalline form CM-J has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of crystalline form CM-J comprises 6 or more than 62 Θ values selected from the group consisting of: the 2 theta values are 4.5 +/-0.2 degrees, 8.5 +/-0.2 degrees, 9.5 +/-0.2 degrees, 10.2 +/-0.2 degrees, 14.7 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.4 +/-0.2 degrees, 16.3 +/-0.2 degrees, 17.7 +/-0.2 degrees, 18.1 +/-0.2 degrees, 18.5 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.1 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.5 +/-0.2 degrees and 28.1 +/-0.2 degrees.

2) The crystalline form CM-J has an XRPD pattern substantially as shown in figure 21;

preferably, the crystalline form CM-K has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-K comprises 6 or more 2 Θ values selected from the group consisting of: the 2 theta values are 4.8 +/-0.2 degrees, 6.0 +/-0.2 degrees, 9.7 +/-0.2 degrees, 10.1 +/-0.2 degrees, 14.8 +/-0.2 degrees, 15.7 +/-0.2 degrees, 16.7 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.9 +/-0.2 degrees, 23.2 +/-0.2 degrees, 24.8 +/-0.2 degrees and 26.0 +/-0.2 degrees.

2) The crystalline form CM-K has an XRPD pattern substantially as shown in figure 22;

preferably, the crystalline form CM-L has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-L comprises 6 or more 2 Θ values selected from the group consisting of: the value of 2 theta is 4.7 +/-0.2 degrees, 8.6 +/-0.2 degrees, 9.5 +/-0.2 degrees, 10.2 +/-0.2 degrees, 14.9 +/-0.2 degrees, 15.2 +/-0.2 degrees, 15.6 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.3 +/-0.2 degrees, 19.1 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.4 +/-0.2 degrees, 21.1 +/-0.2 degrees, 22.0 +/-0.2 degrees, 23.8 +/-0.2 degrees and 25.2 +/-0.2 degrees.

2) The crystalline form CM-L has an XRPD pattern substantially as shown in figure 23;

preferably, the crystalline form CM-M has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-M comprises 6 or more 2 Θ values selected from the group consisting of: the value of 2 theta is 4.5 +/-0.2 degrees, 4.8 +/-0.2 degrees, 8.9 +/-0.2 degrees, 9.9 +/-0.2 degrees, 11.4 +/-0.2 degrees, 13.1 +/-0.2 degrees, 15.5 +/-0.2 degrees, 16.7 +/-0.2 degrees, 16.9 +/-0.2 degrees, 17.3 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.6 +/-0.2 degrees, 20.1 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.3 +/-0.2 degrees, 23.0 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.2 +/-0.2 degrees and 27.0 +/-0.2 degrees.

2) The crystalline form CM-M has an XRPD pattern substantially as shown in figure 24;

in another aspect of the present invention, there is provided a method for preparing the crystalline form as described above, characterized in that,

the method comprises the following steps: a) providing a solution of a Selpatinib raw material in a first solvent, adding a second solvent into the solution for crystallization, and collecting precipitated solids to obtain the crystal form.

Alternatively, the first and second electrodes may be,

the method comprises the following steps: b) providing a solution of a Selpatinib raw material in a first solvent, adding the solution into a second solvent for crystallization, and collecting precipitated solids to obtain the crystal form.

Alternatively, the first and second electrodes may be,

the method comprises the following steps: c) providing a mixture of a Selipatinib raw material and a first solvent, treating the solution to obtain a solid, and collecting the obtained solid to obtain the crystal form; wherein the treatment comprises stirring, pulping, volatilizing, cooling and the like.

Preferably, said step a), after providing the solution of the starting material of serpatatinib in the first solvent, comprises the steps of: filtering the solution and adding seed crystals, wherein the seed crystals are in a crystalline form of serpatatinib;

preferably, in the step a), the adding of the second solvent to the solution is performed under the condition of temperature rise and/or stirring.

Preferably, said step b), after providing the solution of the starting material of serpatatinib in the first solvent, comprises the steps of: filtering the solution;

preferably, the filtration is filtration using a filtration membrane;

preferably, the first solvent comprises water, an alcohol solvent, a hydrocarbon solvent, an ether solvent, or a combination thereof;

the alcohol solvent is selected from the group consisting of: methanol, ethanol;

the hydrocarbon solvent is selected from the group consisting of: dichloromethane, nitromethane;

the ether solvent is selected from the following group: tetrahydrofuran, 1, 4-dioxane.

Preferably, the first solvent is a mixed solvent comprising two or more components selected from the group consisting of: water, methanol, ethanol, dichloromethane, 1, 4-dioxane, nitromethane and tetrahydrofuran.

Preferably, the second solvent comprises an alcohol, a ketone solvent, a hydrocarbon solvent, an ether solvent, an ester solvent, or a combination thereof;

the alcohol solvent is selected from the group consisting of: isopropanol, n-pentanol, sec-butanol;

the ketone solvent is selected from the group consisting of: acetone, cyclohexanone, 4-methyl-2-pentanone, pinacolone;

the hydrocarbon solvent is selected from the group consisting of: n-heptane;

the ether solvent is selected from the following group: 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, petroleum ether, isopropyl ether;

the ester solvent is selected from the group consisting of: ethyl formate, methyl acetate.

The crystallization process comprises one or more of solution crystallization, volatilization crystallization, diffusion crystallization, cooling crystallization and volatilization crystallization.

The standing is carried out in a closed environment.

The celecoxib raw material is any crystalline form, amorphous form or any combination thereof of the celecoxib.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

Figure 1 is an XRPD spectrum of crystalline form CM-a of celecoxib according to the invention.

Figure 2 is a TGA profile of crystalline form CM-a of serpatatinib according to the present invention.

Figure 3 is a DSC profile of crystalline form CM-a of celecoxib according to the invention.

FIG. 4 is a crystalline form CM-A of serpatatinib according to the invention¹H-NMR spectrum.

Figure 5 is a DVS spectrum of crystalline form CM-a of serpatatinib according to the present invention.

Figure 6 is an XRPD spectrum of crystalline form CM-B of serpatatinib according to the present invention.

Figure 7 is a TGA profile of crystalline form CM-B of serpatatinib according to the present invention.

Figure 8 is a DSC profile of crystalline form CM-B of celecoxib according to the invention.

FIG. 9 is a crystalline form CM-B of serpatatinib according to the invention¹H-NMR spectrum.

Figure 10 is an XRPD spectrum of crystalline form CM-C of serpatatinib according to the present invention.

Figure 11 is a TGA profile of crystalline form CM-C of serpatatinib according to the present invention.

Figure 12 is a DSC profile of crystalline form CM-C of seletracenib according to the present invention.

FIG. 13 is a crystalline form CM-C of serpatatinib according to the invention¹H-NMR spectrum.

Figure 14 is a DVS spectrum of crystalline form CM-C of serpatatinib according to the present invention.

Figure 15 is an XRPD spectrum of crystalline form CM-D of serpatatinib according to the present invention.

Figure 16 is an XRPD spectrum of crystalline form CM-E of serpatatinib according to the present invention.

Figure 17 is an XRPD spectrum of crystalline form CM-F of serpatatinib according to the present invention.

Figure 18 is an XRPD pattern of crystalline form CM-G of serpatatinib according to the present invention.

Figure 19 is an XRPD spectrum of crystalline form CM-H of serpatatinib according to the present invention.

Figure 20 is an XRPD pattern of crystalline form CM-I of serpatatinib according to the present invention.

Figure 21 is an XRPD spectrum of crystalline form CM-J of serpatatinib according to the present invention.

Figure 22 is an XRPD spectrum of crystalline form CM-K of serpatatinib according to the present invention.

Figure 23 is an XRPD pattern of crystalline form CM-L of serpatatinib according to the present invention.

Figure 24 is an XRPD pattern of crystalline form CM-M of serpatatinib according to the present invention.

Figure 25 is an XRPD spectrum of Form1 prepared according to the method of WO 2019075108.

Detailed Description

Term(s) for

In this context, each abbreviation is used in the conventional sense understood by those skilled in the art, unless otherwise specified.

As used herein, unless otherwise specified, the term "celecoxib starting material" refers to various solid forms of a compound of the formula celecoxib (including the various crystalline forms referred to herein or amorphous forms referred to in various documents or patents, published or unpublished).

Preferably, the raw material of the serpatatinib adopted by the invention is the serpatatinib prepared according to the preparation method provided in the embodiment of the invention.

Preferably, the starting material of the material employed in the present invention is prepared according to the preparation method described in patent WO 2018071447.

As used herein, "crystalline form of the invention" refers to the crystalline form of celecoxib CM-A, CM-B, CM-C, CM-D, CM-E, CM-F, CM-G, CM-H, CM-I, CM-J, CM-K, CM-L and/or CM-M as described herein.

As used herein, the manner of "slow addition" includes, but is not limited to: dropwise adding, and slowly adding along the wall of the container;

the invention will be further elucidated with reference to the specific embodiments and the accompanying drawings. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.

General procedure

All test methods of the invention are general methods, and the test parameters are as follows:

XRPD pattern determination method:

x-ray powder diffraction instrument: bruker D2 Phaser X-ray powder diffractometer; radiation source Cu

Generator (Generator) kv: 30 kv; generator (Generator) mA: 10 mA; initial 2 θ: 2.0 °, scan range: 2.0 to 35.0 degrees.

TGA profiling method:

thermogravimetric analysis (TGA) instrument: TGA55 model of TA, USA, with a heating rate of 10 ℃/min and a nitrogen flow rate of 40ml/min within a temperature range of 20-300 ℃.

DSC spectrum measuring method:

differential Scanning Calorimetry (DSC) instrument: TAQ2000 type of TA of America, with a heating rate of 10 ℃/min and a nitrogen flow rate of 50ml/min within a temperature range of 25-300 ℃.

Method for determining 1H-NMR spectra:

hydrogen nuclear magnetic resonance (1H-NMR) instrument Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer; frequency: 400 MHz; solvent: deuterated DMSO.

A method for measuring a DVS spectrogram;

TAQ5000 SA from TA, USA; temperature: 25 ℃; nitrogen flow rate: 50 mL/min; change in mass per unit time: 0.002%/min; relative humidity range: 0% RH to 90% RH.

Technical effects

Compared with the prior art, the crystal form CM-A has the following remarkable beneficial effects:

(1) the crystal form CM-A of the invention is an anhydrate crystal form, and avoids solvent toxicity.

(2) The crystal form CM-A of the invention has good crystal form stability and chemical stability, especially has good crystal form stability in a solvent, is more beneficial to the crystal form stability in the subsequent preparation production process and the preparation product storage process, and avoids the dissolution difference risk caused by crystal transformation. .

(3) The crystal form CM-A has good fluidity and good compressibility, and is suitable for producing solid preparations.

(4) The crystal form CM-A has low hygroscopicity and no static electricity, and is favorable for the stability of bulk drugs and preparations in the storage process.

(5) The preparation process of the crystal form CM-A is simple, strong in operability, high in yield, stable in quality, short in production period and easy to realize large-scale production.

(6) The crystal form CM-A of the invention has better crystal form stability in the solvent, is more beneficial to the crystal form stability of the subsequent preparation production process and the storage process of the preparation product, and avoids the risk of dissolution difference caused by crystal transformation.

Example 1

Preparation of Serapatinib crystal form CM-A

Examples 1 to 1

0.2mg of the celecoxib compound is weighed out at room temperature in 1ml of methanol: the mixture is dissolved in dichloromethane (1:1, v: v) and then filtered by a filter membrane. And (3) adding a small amount of CM-A crystal seeds into the filtrate in a small bottle of 20ml, dropwise adding 10ml of MIBK solvent at room temperature, and magnetically stirring at room temperature for 24 hours to separate out a solid, wherein the obtained solid is the crystal form CM-A of the Seliptinib compound. The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 1, and the XRPD pattern of which is shown in fig. 1; TGA testing was performed on the resulting solid, the spectrum of which is shown in figure 2; subjecting the obtained solid to DSC test, wherein the spectrum is shown in figure 3; subjecting the obtained solid to¹H NMR measurement, spectrum thereofAs shown in fig. 4; the obtained solid was subjected to DVS detection, and the spectrum is shown in fig. 5.

As can be seen from fig. 2, the TGA profile of the crystalline form CM-a has no significant weight loss step, and the crystalline form is known to be an anhydrate.

As can be seen in FIG. 3, DSC of crystalline form CM-A shows a 1 st endothermic peak at 197.08 ℃ and a 2 nd endothermic peak at 209.84 ℃.

As can be seen from the DVS test results in fig. 5, the crystalline form CM-a has almost no hygroscopicity.

TABLE 1

2θ/°	Relative strength	2θ/°	Relative strength	2θ/°	Relative strength
						6.2±0.2	3.0％	15.8±0.2	1.2％	24.2±0.2	2.1％
7.5±0.2	18.5％	16.2±0.2	5.9％	24.6±0.2	8.3％
						9.2±0.2	4.7％	17.1±0.2	26.3％	25.0±0.2	7.5％
10.2±0.2	3.1％	17.6±0.2	13.0％	26.7±0.2	2.2％
						10.9±0.2	3.2％	18.1±0.2	6.2％	27.6±0.2	1.9％
12.0±0.2	12.8％	19.6±0.2	5.2％	29.2±0.2	8.2％
						13.2±0.2	14.9％	19.8±0.2	24.9％	30.0±0.2	7.5％
14.3±0.2	2.2％	21.1±0.2	100.0％	33.3±0.2	3.2％
						15.0±0.2	2.8％	22.5±0.2	6.8％

Examples 1 to 2

10mg of the celecoxib compound was dissolved in 0.2ml of methanol: methylene chloride (1:1, v: v), rapidly cleared at 50 ℃ and then filtered through a filter membrane, and the filtrate was placed in a 5ml centrifuge tube. And (3) dropwise adding 2ml of pinacolone solvent at room temperature, and magnetically stirring at room temperature for 24h to obtain the solid of the Selipatinib compound crystal form CM-A.

Examples 1 to 3

10mg of the celecoxib compound was dissolved in 0.2ml of methanol: 1, 4-dioxane (1:1, v: v), rapidly dissolving at 50 deg.C, filtering with filter membrane, and placing the filtrate in 5ml centrifuge tube. And dropwise adding 2ml of MIBK solvent at 40 ℃, and magnetically stirring at room temperature for 24h to obtain a solid which is the crystal form CM-A of the Selipatinib compound.

Examples 1 to 4

10mg of the celecoxib compound was dissolved in 0.2ml of methanol: 1, 4-dioxane (1:1, v: v), rapidly dissolving at 50 deg.C, filtering with filter membrane, and placing the filtrate in 5ml centrifuge tube. And (3) dripping the filtrate into 2ml of MIBK solvent at the temperature of 50 ℃, and continuing to stir for 2h by magnetic force to obtain a solid which is the crystal form CM-A of the Seliptinib compound.

Example 2

Preparation of crystalline form CM-B

Example 2-1

10mg of the celecoxib compound was dissolved in 0.2ml ethanol: dichloromethane (1:2, v: v), quickly dissolving at 50 ℃, then filtering with a filter membrane, putting the filtrate into a 5ml centrifuge tube, dropwise adding 2ml of n-amyl alcohol solvent at room temperature, and magnetically stirring at room temperature for 24h to obtain the solid which is the Selipatinib compound crystal form CM-B. The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 2, and the XRPD pattern of which is shown in fig. 6; TGA testing was performed on the resulting solid, the spectrum of which is shown in figure 7; the obtained solid is subjected to DSC test, and the spectrum is shown in figure 8; subjecting the obtained solid to¹H NMR measurement, spectrum as shown in fig. 9; .

As can be seen from fig. 7, the TGA profile of crystalline form CM-B has no significant weight loss step, indicating that the crystalline form is an anhydrate.

FIG. 8DSC shows that it has the 1 st endotherm at 148.76 deg.C and the 2 nd and 3 rd endotherms at 206.61 deg.C and 211.83 deg.C.

TABLE 2

2θ/°	Relative strength	2θ/°	Relative strength
				4.8±0.2	100.0％	19.5±0.2	14.5％
8.6±0.2	4.4％	19.9±0.2	37.4％
				9.9±0.2	43.7％	21.5±0.2	4.8％
14.9±0.2	1.6％	22.0±0.2	5.4％
				15.5±0.2	10.4％	24.5±0.2	2.7％
17.3±0.2	9.8％	25.3±0.2	3.2％
				18.2±0.2	9.9％	26.1±0.2	3.3％

Examples 2 to 2

10mg of the celecoxib compound was dissolved in 0.2ml tetrahydrofuran: and (3) adding the mixture into a water (9:1, v: v) mixed solvent, filtering by using a filter membrane, adding the filtrate into a 5ml centrifuge tube, dropwise adding 2ml of n-pentanol solvent at room temperature, and magnetically stirring for 4 hours at room temperature to obtain a solid, namely the Seliptinib compound crystal form CM-B.

Examples 2 to 3

10mg of the celecoxib compound was dissolved in 0.2ml tetrahydrofuran: water (9:1, v: v) mixed solvent, then filter membrane filtration, filtrate in 5ml centrifuge tube. And dropwise adding the filtrate into 2ml of n-amyl alcohol solvent at 35 ℃, and magnetically stirring for 1h at room temperature to obtain a solid which is the crystal form CM-B of the Seliparitinib compound.

Example 3

Preparation of Serapatinib crystal form CM-C

Example 3-1

10mg of the celecoxib compound was dissolved in 0.2ml of methanol: dissolving nitromethane (1:1, v: v) at 50 ℃ quickly, filtering with a filter membrane, putting the filtrate into a 5ml centrifuge tube, dropwise adding 2ml of a toluene solvent, and magnetically stirring at room temperature to separate out a solid, wherein the obtained solid is the crystal form CM-C of the Selipatinib compound. The resulting solid was subjected to XRPD testing, with X-ray powder diffraction data as shown in table 3 and an XRPD pattern as shown in figure 10; TGA testing was performed on the resulting solid, the spectrum of which is shown in figure 11; the obtained solid is subjected to DSC test, and the spectrum is shown in figure 12; subjecting the obtained solid to¹H NMR measurement, spectrum as shown in fig. 13; the obtained solid was subjected to DVS detection, and the pattern is shown in fig. 14.

Crystalline form CM-C is a solvate, combining TGA and nuclear magnetic data.

TABLE 3

2θ/°	Relative strength	2θ/°	Relative strength	2θ/°	Relative strength
						5.1±0.2	100.0％	16.6±0.2	8.0％	23.7±0.2	3.3％
6.3±0.2	1.5％	16.9±0.2	14.3％	24.2±0.2	10.1％
						8.2±0.2	1.7％	18.0±0.2	10.8％	25.2±0.2	3.3％
9.8±0.2	13.2％	18.5±0.2	6.1％	25.6±0.2	4.0％
						10.4±0.2	2.1％	19.0±0.2	8.8％	26.2±0.2	2.5％
11.0±0.2	12.1％	20.3±0.2	4.3％	27.2±0.2	1.9％
						12.1±0.2	1.0％	21.1±0.2	3.9％	27.6±0.2	1.8％
12.8±0.2	0.9％	22.1±0.2	10.5％	28.4±0.2	2.5％
						13.6±0.2	0.9％	22.4±0.2	15.0％	29.6±0.2	2.4％
15.0±0.2	13.2％	22.7±0.2	3.8％	30.2±0.2	1.3％
						15.6±0.2	7.0％	23.0±0.2	1.9％	31.6±0.2	2.0％

Example 4

Preparation of Serapatinib crystal form CM-D

Example 4-1

Beating 10mg of Seliparitinib compound in 1.5ml sec-butanol at room temperature, magnetically stirring for 24h at room temperature, and collecting the solid to obtain the Seliparitinib compound in the crystal form CM-D. The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 4, and the XRPD pattern of which is shown in fig. 15; TGA testing was performed on the resulting solid, the spectrum of which is shown in figure 16; the obtained solid is subjected to DSC test, and the spectrum is shown in figure 17; subjecting the obtained solid to¹H NMR measurement, the spectrum is shown in FIG. 18.

Crystalline form CM-D is a 0.5 molecule sec-butanol solvate, combining TGA and nuclear magnetic data.

TABLE 4

2θ/°	Relative strength	2θ/°	Relative strength	2θ/°	Relative strength
						5.1±0.2	100.0％	16.1±0.2	0.8％	22.2±0.2	4.3％
6.4±0.2	1.3％	16.6±0.2	0.5％	22.5±0.2	0.8％
						10.3±0.2	1.6％	17.3±0.2	1.0％	23.8±0.2	1.1％
10.5±0.2	2.0％	18.1±0.2	0.6％	24.3±0.2	0.9％
						10.9±0.2	4.7％	18.4±0.2	1.6％	24.6±0.2	0.6％
11.1±0.2	2.5％	19.7±0.2	4.1％	26.5±0.2	0.6％
						15.4±0.2	0.5％	20.5±0.2	0.5％	27.3±0.2	0.5％
15.7±0.2	0.8％	21.7±0.2	1.9％	29.3±0.2	0.7％

Example 5

Preparation of Selpatinib crystal form CM-E

Example 5-1

Dissolving 10mg of Selipatinib compound in 0.2ml of dimethyl sulfoxide, rapidly dissolving at 50 deg.C, and filteringAnd (3) performing membrane filtration, putting the filtrate into a 5ml centrifuge tube, then dropwise adding 2ml of isopropanol solvent, and magnetically stirring at room temperature to obtain a solid which is the crystal form CM-E of the Seliptinib compound. The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 5, and the XRPD pattern of which is shown in fig. 19; TGA testing was performed on the resulting solid, the spectrum of which is shown in figure 20; subjecting the obtained solid to DSC test, and its spectrum is shown in figure 21; subjecting the obtained solid to¹And H NMR measurement, wherein the spectrum is shown in FIG. 22.

Crystalline form CM-E is a solvate, combining TGA and nuclear magnetic data.

TABLE 5

2θ/°	Relative strength	2θ/°	Relative strength	2θ/°	Relative strength
						4.6±0.2	100.0％	16.5±0.2	1.2％	21.2±0.2	0.7％
8.5±0.2	0.8％	18.0±0.2	1.3％	22.0±0.2	1.1％
						10.1±0.2	5.6％	18.1±0.2	2.3％	23.3±0.2	0.8％
14.3±0.2	1.1％	19.2±0.2	5.1％	24.1±0.2	1.4％
						15.1±0.2	1.8％	19.6±0.2	2.2％	25.4±0.2	1.0％
15.5±0.2	1.1％	20.5±0.2	1.7％	26.1±0.2	0.8％

Examples 5 and 2

10mg of the celecoxib compound was dissolved in 0.2ml of methanol: dissolving nitromethane (1:1, v: v) at 50 ℃ quickly, filtering with a filter membrane, putting the filtrate into a 5ml centrifuge tube, dropwise adding 2ml of isopropanol solvent, and magnetically stirring at room temperature to obtain a solid of a Selipatinib compound crystal form CM-E.

Example 6

Preparation of Selpatinib crystal form CM-F

Example 6-1

10mg of the celecoxib compound was dissolved in 0.2ml of methanol: dissolving nitromethane (1:1, v: v) at 50 ℃ quickly, filtering with a filter membrane, dropping the filtrate into 2ml of ethyl formate in a 5ml centrifuge tube, and magnetically stirring at room temperature to obtain a solid which is the crystal form CM-F of the Selipatinib compound. The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 6, and the XRPD pattern of which is shown in fig. 23; TGA testing was performed on the resulting solid, the spectrum of which is shown in figure 24; the obtained solid was subjected to DSC measurement, and its spectrum is shown in FIG. 25.

As can be seen from fig. 24, the TGA profile of crystalline form CM-F has no significant weight loss step, indicating that the crystalline form is an anhydrate.

FIG. 25DSC shows that it has a 1 st endothermic peak at 199.40 ℃ followed by an exothermic peak.

TABLE 6

Example 6 to 2

Dissolving 10mg of the Seldipitinib compound in 0.2ml of DMSO, quickly dissolving and clearing at 50 ℃, filtering with a filter membrane, placing the filtrate in a 5ml glass bottle, slowly dripping 2ml of MIBK along the wall surface, covering a cover, standing at room temperature, waiting for the solid to be separated out, wherein the obtained solid is the Seldipitinib compound crystal form CM-F.

Example 7

Preparation of Selpatinib crystal form CM-G

Example 7-1

10mg of the celecoxib compound was dissolved in 0.2ml of methanol: methylene chloride (1:2, v: v), rapidly cleared at 50 ℃, then filtered through a filter membrane, and the filtrate was placed in a 2ml glass vial; adding 3ml of ethyl formate solvent into a 20ml glass bottle, placing a 2ml small bottle into the 20ml glass bottle, sealing at room temperature, and separating out a solid, wherein the obtained solid is the crystal form CM-G of the Seliptinib compound. The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 7; TGA testing of the resulting solid; performing DSC test on the obtained solid; subjecting the obtained solid to¹H NMR measurement.

Crystalline form CM-G is a ethyl formate solvate, combining TGA and nuclear magnetic data.

TABLE 7

Example 8

Preparation of Serapatinib crystal form CM-H

Example 8-1

10mg of Seliparitinib compound are dissolved in 0.2ml of methanol: 1, 4-dioxane (1:1, v: v), rapidly dissolving at 50 deg.C, filtering with filter membrane, and placing the filtrate in 2ml glass vial; adding 3ml of isopropanol solvent into a 20ml glass bottle, placing a 2ml small bottle into the 20ml glass bottle, sealing at room temperature, and separating out a solid, wherein the obtained solid is the crystal form CM-H of the Seliptinib compound. The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 8; TGA testing of the resulting solid; performing DSC test on the obtained solid; subjecting the obtained solid to¹H NMR measurement.

Combining TGA and nuclear magnetic data, crystalline form CM-H is a 1, 4-dioxane solvate.

TABLE 8

2θ/°	Relative strength	2θ/°	Relative strength	2θ/°	Relative strength
						4.8±0.2	100.0％	17.3±0.2	2.0％	25.7±0.2	2.4％
8.6±0.2	1.6％	18.1±0.2	5.9％	26.1±0.2	1.8％
						9.9±0.2	9.6％	19.6±0.2	15.1％	27.1±0.2	0.9％
11.6±0.2	0.7％	20.0±0.2	9.7％	27.6±0.2	0.9％
						13.6±0.2	0.5％	21.3±0.2	0.8％	28.7±0.2	1.0％
14.9±0.2	0.8％	21.9±0.2	4.5％	29.6±0.2	1.9％
						15.6±0.2	3.0％	22.4±0.2	1.4％	33.6±0.2	0.6％
15.8±0.2	2.2％	23.4±0.2	1.5％
						16.6±0.2	2.9％	24.6±0.2	3.4％

Example 9

Preparation of Serapatinib crystal form CM-I

Example 9-1

10mg of Seliparitinib compound are dissolved in 0.2ml of methanol: 1, 4-dioxane (1:1, v: v), rapidly dissolving at 50 deg.C, filtering with filter membrane, and placing the filtrate in 2ml glass vial; 3ml of MTBE solvent is added into a 20ml glass bottle, a 2ml small bottle is placed into the 20ml glass bottle and sealed at room temperature, solid is separated out, and the obtained solid is the crystal form CM-I of the Selipatinib compound. The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 9; TGA testing of the resulting solid; the resulting solid was subjected to DSC testing.

Crystalline form CM-I is a solvate, combining TGA and nuclear magnetic data.

TABLE 9

2θ/°	Relative strength
		4.8±0.2	100.0％
6.1±0.2	2.7％
		9.8±0.2	3.8％
10.2±0.2	3.2％
		14.8±0.2	1.4％
15.7±0.2	3.5％
		16.3±0.2	0.8％
18.1±0.2	1.9％
		19.9±0.2	6.0％
23.2±0.2	1.0％
		24.8±0.2	1.6％
29.9±0.2	0.9％

Example 10

Preparation of Serapatinib crystal form CM-J

Example 10-1

Dissolving 10mg of Seliparitinib compound in 4ml of cyclohexanone, quickly dissolving and clearing at 50 ℃, then filtering by a filter membrane, and putting the filtrate in a 20ml glass bottle; adding 16ml of n-heptane solvent into a 20ml glass bottle, and magnetically stirring at room temperature to separate out a solid, wherein the obtained solid is the crystal form CM-J of the Seliptinib compound. The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 10; TGA testing was performed on the resulting solid.

Watch 10

Example 11

Preparation of Serapatinib crystal form CM-K

Example 11-1

10mg of the celecoxib compound was dissolved in 0.2ml of methanol: nitromethane (1:1, v: v), rapidly dissolved at 50 ℃ and then filtered through a filter membrane, and the filtrate is put into a 2ml glass vial; adding 3ml of MIBK solvent into a 20ml glass bottle, placing a 2ml small bottle into the 20ml glass bottle, sealing at room temperature, and separating out a solid, wherein the obtained solid is the crystal form CM-K of the Selipatinib compound. The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 11; TGA testing was performed on the resulting solid.

TABLE 11

2θ/°	Relative strength	2θ/°	Relative strength
				4.8±0.2	100.0％	18.9±0.2	0.9％
6.0±0.2	9.1％	19.7±0.2	4.2％
				8.1±0.2	0.5％	20.9±0.2	1.0％
9.7±0.2	2.9％	22.6±0.2	0.7％
				10.1±0.2	14.2％	23.2±0.2	1.5％
14.8±0.2	5.1％	24.8±0.2	3.1％
				15.7±0.2	5.3％	26.0±0.2	1.1％
16.7±0.2	1.7％	29.8±0.2	1.0％
				18.5±0.2	1.0％

Example 12

Preparation of Serapatinib crystal form CM-L

Example 12-1

Dissolving 10mg of Seliparitinib compound in 1ml of chloroform, quickly dissolving at 50 ℃, filtering by a filter membrane, and putting the filtrate in a 5ml glass vial; sealing a sealing film, poking a plurality of small holes, slowly volatilizing at room temperature to obtain a solid which is the crystal form CM-L of the Selipatinib compound. The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 12; TGA testing of the resulting solid; the resulting solid was subjected to DSC testing.

TABLE 12

2θ/°	Relative strength	2θ/°	Relative strength
				3.0±0.2	7.4％	18.3±0.2	27.3％
4.7±0.2	100.0％	19.1±0.2	35.8％
				8.6±0.2	8.7％	19.4±0.2	17.6％
9.5±0.2	9.6％	20.4±0.2	13.8％
				10.2±0.2	25.1％	21.1±0.2	10.0％
14.9±0.2	9.3％	22.0±0.2	26.8％
				15.2±0.2	6.6％	23.8±0.2	15.0％
15.6±0.2	11.6％	25.2±0.2	7.6％
				16.6±0.2	9.9％	31.0±0.2	5.4％
17.9±0.2	6.0％

Example 13

Preparation of Serapatinib crystal form CM-M

Example 13-1

Dissolving 10mg of Seliparitinib compound in 2ml of acetone, quickly dissolving at 50 ℃, filtering by a filter membrane, and putting the filtrate in a 5ml glass vial; and covering a cover, sealing a sealing film, slowly cooling to 5 ℃ at 50 ℃, and obtaining the solid which is the crystal form CM-M of the Selipatinib compound. The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 13; TGA testing of the resulting solid; the resulting solid was subjected to DSC testing.

In combination with TGA and DSC, crystalline form CM-M is presumed to be an acetone solvate.

Watch 13

Comparative example 1: preparation of Form 1(WO2019075108)

Form1 was prepared according to the method of WO 2019075108.

500mg of the free base of the compound was weighed into a 20ml vial, 4ml of ethyl acetate was added to the vial and the resulting slurry was temperature cycled between 40 ℃ and room temperature for 72 hours, the sample was filtered and the collected material was vacuum dried at 40 ℃ overnight and the resulting solid was the crude serpatanib compound in Form 1. The resulting solid was subjected to XRPD testing.

Effects of the embodiment

1. Stability of crystal form

Samples of Selipatinib Form 1(WO2019075108) and the crystal Form CM-A (example 1-1) were left open at 60 ℃ and 92.5% RH, and 10% RH (in a desiccator filled with phosphorus pentoxide), respectively, for 30 days; the samples after standing were sampled separately and tested for XRPD and HPLC, and the stability of the crystal forms is shown in table 14.

TABLE 14 stability of the different crystalline forms

Crystal form	High temperature of 60 DEG C	High humidity 92.5%	Low humidity 10%	60℃&92.5％
					Form 1(WO2019075108)	Form 1	Form 1	Form 1	Form 1
Crystal form CM-A (example 1-1)	CM-A	CM-A	CM-A	CM-A

Note: '-' represents no detection.

TABLE 15 chemical stability of different crystalline forms

Crystal form	Original purity	High temperature of 60 DEG C	High humidity 92.5%	Low humidity 10%	60℃&92.5％
						Form 1(WO2019075108)	99.72％	99.67％	99.70％	99.71％	99.63％
Crystal form CM-A (example 1-1)	99.83％	99.81％	99.82％	99.82％	99.80％

From the above examples, it can be found that the crystal forms CM-A and Form1 of the present invention have good crystal Form stability and chemical stability under various conditions, and meet the requirement of pharmaceutical use, and the chemical stability of the crystal Form CM-A is better than that of Form 1.

2. Stability of crystal form in solution

1 part (10 mg each) of Seldapatinib Form 1(WO2019075108) and a crystal Form CM-A (example 1-1) and 7 parts of a mixture sample of Form1 and the crystal Form CM-A (5 mg each of Form1 and the crystal Form CM-A in each part and 10mg in total) are respectively weighed, 1ml of purified water with the temperature of 40 ℃, 1ml of ethanol, 1ml of tert-butyl acetate, 1ml of acetone, 1ml of ethyl acetate, 1ml of methanol and 1ml of dichloromethane are respectively added into the samples according to the table below, the temperature is kept and the samples are pulped for 24h, and the change situation of the crystal Form is examined, and the results are shown in the table 16.

TABLE 16 Crystal form stability of different crystal form samples in different solvents

From the above examples, it can be found that Form1 and the crystal Form CM-A of the present invention have good crystal Form stability after being beaten for 24 hours in water. But the Form1 and the CM-A of the invention are mixed in equal proportion and are changed into the CM-A of the invention after being pulped in water, ethanol, tert-butyl acetate, acetone, ethyl acetate, methanol and dichloromethane, and the CM-A of the invention is kept unchanged in different solvents. The daA show that the crystal Form CM-A of the invention has better stability than Form1, the crystal Form CM-A is easy to obtain in a solvent, and the preparation process is more suitable for industrial production.

On the other hand, the crystal form stability of the crystal form CM-A in the solvent is better, which is more beneficial to the subsequent preparation production process (for example, wet granulation is carried out by water or organic solvent) and the crystal form stability of the preparation product storage process, and avoids the dissolution difference risk caused by crystal transformation.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A crystalline form of a compound of formula (I):

2. the crystalline form of claim 1, wherein the crystalline form is selected from the group consisting of: crystalline form CM-A, CM-B, CM-C;

wherein the XRPD pattern of the crystalline form CM-a comprises 3 or more than 3 2 Θ values selected from the group consisting of: 6.2 +/-0.2 DEG, 7.5 +/-0.2 DEG, 9.2 +/-0.2 DEG, 12.0 +/-0.2 DEG, 13.2 +/-0.2 DEG, 17.1 +/-0.2 DEG and 21.0 +/-0.2 DEG; the XRPD pattern of the crystalline form CM-B comprises 3 or more than 3 2 Θ values selected from the group consisting of: 4.8 +/-0.2 degrees, 9.9 +/-0.2 degrees, 19.5 +/-0.2 degrees and 19.9 +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-C comprises 3 or more than 3 2 Θ values selected from the group consisting of: 5.1 +/-0.2 degrees, 9.8 +/-0.2 degrees, 11.0 +/-0.2 degrees and 15.0 +/-0.2 degrees.

3. The crystalline form of claim 1, wherein the crystalline form CM-a has one or more characteristics selected from the group consisting of:

6) The crystalline form CM-A has a DVS profile substantially as shown in figure 5.

4. The crystalline form of claim 1, wherein the crystalline form CM-B has one or more characteristics selected from the group consisting of:

5. The crystalline form of claim 1, wherein the crystalline form CM-C has one or more characteristics selected from the group consisting of:

6) the crystalline form CM-C has a DVS profile substantially as shown in figure 14.

6. The crystalline form of claim 1, wherein the crystalline form is selected from the group consisting of: crystal form CM-D, CM-E, CM-F, CM-G, CM-H, CM-I, CM-J, CM-K, CM-L, CM-M

Wherein the XRPD pattern of crystalline form CM-D comprises 3 or more than 3 2 Θ values selected from the group consisting of: 5.1 +/-0.2 degrees, 10.9 +/-0.2 degrees, 19.7 +/-0.2 degrees and 22.2 +/-0.2 degrees;

7. A process for the preparation of the crystalline form as claimed in any of claims 1 to 6,

Alternatively, the first and second electrodes may be,

8. A pharmaceutical composition, comprising:

(i) a crystalline form according to claim 1 and/or serpatatinib prepared according to the process of claim 7;

and (ii) a pharmaceutically acceptable carrier and/or excipient.

9. Use of the crystalline form according to claim 1 for (i) the preparation of serpatatinib,

and/or (ii) for the manufacture of a medicament for the treatment and/or prophylaxis of patients for whom an abnormal RET kinase is carried in a tumour.

10. Use of a composition according to claim 7 for the preparation of a medicament for the treatment and/or prevention of patients carrying abnormal RET kinases in tumors.