Crystal form of ALK inhibitor

Abstract

Disclosed is a crystal form of an ALK inhibitor. In particular, the present invention relates to a succinate polymorph of an ALK inhibitor. The prepared crystal form has good thermodynamic stability and chemical stability, and also has proper hygroscopicity and solubility, such that same is suitable for storage as a bulk drug, and is also suitable for being used as an active ingredient of a solid oral preparation.

Description

A crystalline form of an ALK inhibitor

[0001] This application claims the benefit of Chinese Patent Application No. 2023110465004, filed on August 18, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and specifically relates to a crystalline form of an anaplastic lymphoma kinase (ALK) inhibitor, a preparation method thereof, and its use in preparing medicines and treating diseases. Background Art

[0003] Anaplastic lymphoma kinase (ALK) is a receptor protein tyrosine kinase (rPTK) and a member of the insulin receptor superfamily. It was first described in 1994 as an NPM-ALK fusion protein expressed in most anaplastic large cell lymphomas. In recent years, ALK inhibitors have made breakthrough progress in the field of tumor treatment. Preclinical studies have shown that ALK inhibitors have shown strong in vivo anti-tumor activity in positive lung cancer and lymphoma. Many small molecule ALK inhibitors, including crizotinib, ceritinib, and alectinib, are used to treat ALK-positive tumor patients. The U.S. invention patent application publication (publication number US2014 / 0128387A1) discloses many compounds with good ALK inhibitory activity, including a compound having the structure described in the following formula A:

[0004] Drug polymorphism is a significant factor influencing drug safety and efficacy. Different crystalline forms of the same drug can exhibit significant differences in appearance, solubility, melting point, dissolution rate, and bioavailability, thereby impacting drug stability, bioavailability, and efficacy. This phenomenon is particularly pronounced in solid dosage forms and non-true solutions (e.g., tablets, capsules, and oral suspensions). Consequently, research on drug polymorphism has garnered increasing attention and importance in recent years within pharmaceutical R&D and national drug regulatory oversight.

[0005] Summary of the Invention

[0006] Different preparation processes of raw materials may lead to different crystal forms, crystal water, crystallization solvents and impurities, thereby causing changes in physical and chemical parameters such as stability, hygroscopicity, and solubility. One of the main objectives of the present invention is to provide a polymorphic form of the succinate salt of compound A.

[0007] To achieve the above object, the technical solution adopted by the present invention is:

[0008] The present invention provides a succinate salt crystal form I of a compound of formula A, wherein the succinate salt of the compound of formula A has the structure shown below:

[0009] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form I includes characteristic peaks at 2θ of 7.9±0.2, 9.8±0.2, 14.4±0.2, 16.2±0.2, and 22.8±0.2.

[0010] Furthermore, the present invention provides a succinate salt crystalline form I of the compound of formula A as described above. Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I includes characteristic peaks of 2θ of 7.9±0.2, 9.8±0.2, 14.4±0.2, 16.2±0.2, 17.6±0.2, 18.4±0.2, 19.6±0.2, 20.2±0.2, 20.8±0.2, and 22.8±0.2.

[0011] Furthermore, the present invention provides a succinate salt form I of the compound of formula A as described above. Using Cu-Kα radiation, the X-ray powder diffraction pattern of the form I includes characteristic peaks of 2θ of 7.9±0.2, 9.8±0.2, 10.1±0.2, 14.4±0.2, 16.2±0.2, 17.6±0.2, 18.4±0.2, 19.6±0.2, 20.2±0.2, 20.8±0.2, 22.8±0.2, and 25.9±0.2.

[0012] Furthermore, the present invention provides a succinate salt form I of the compound of formula A as described above. Using Cu-Kα radiation, the X-ray powder diffraction pattern of the form I includes characteristic peaks at 2θ of 7.9±0.2, 8.1±0.2, 9.8±0.2, 10.1±0.2, 14.4±0.2, 14.6±0.2, 16.2±0.2, 16.8±0.2, 17.0±0.2, 17.6±0.2, 17.8±0.2, 18.4±0.2, 19.6±0.2, 20.2±0.2, 20.8±0.2, 22.2±0.2, 22.8±0.2, 23.3±0.2, 23.4±0.2, 23.9±0.2, 25.4±0.2, and 25.9±0.2.

[0013] Furthermore, the present invention provides a succinate salt of the compound of formula A as described above, Form I, wherein the X-ray powder diffraction pattern of Form I under Cu-Kα radiation includes characteristic peaks at 2θ values ​​as described in Table 1 below, wherein the error of the 2θ values ​​is ±0.2°:

[0014] Table 1

[0015] Furthermore, the present invention provides a succinate salt crystal form I of the compound of formula A as described above, using Cu-Kα radiation, and the X-ray powder diffraction pattern of the crystal form I includes characteristic peaks of 2θ values ​​basically as shown in Figure 1, wherein the error of the 2θ value is ±0.2°.

[0016] Furthermore, in a specific embodiment of the present invention, the crystal form I exhibits an endothermic peak at around 191°C, which is a melting endothermic peak. The differential scanning calorimetry analysis diagram is substantially as shown in FIG2 .

[0017] Furthermore, in a specific embodiment of the present invention, the thermogravimetric analysis diagram of Form I is substantially as shown in FIG3 .

[0018] Furthermore, in a specific embodiment of the present invention, the Form I exhibited slight hygroscopicity, exhibiting a weight gain of 0.6% (w / w) under a 0% RH-80% RH environment. A dynamic moisture sorption profile is shown in Figure 4 . A comparison of X-ray powder diffraction patterns of Form I before and after dynamic moisture sorption testing is shown in Figure 5 , demonstrating that the Form I exhibited no change before and after testing.

[0019] Further, in a specific embodiment of the present invention, the crystallographic data of the crystalline form I are shown in Table 2, comprising a monoclinic space group of P21 and about and unit cell parameters of β = 100.797(2)°.

[0020] Table 2

[0021] The powder X-ray diffraction pattern of the crystalline compound of Form I was simulated based on the single crystal X-ray data, as shown in FIG6 , which is consistent with the pattern obtained in the specific embodiment.

[0022] The present invention also aims to provide a method for preparing the succinate salt crystal form I of the compound of formula A as described above, the preparation method comprising:

[0023] The succinate salt of the compound of formula A is mixed with a single solvent or a mixed solvent to form a suspension, stirred, separated, and dried to obtain the crystalline form I, wherein the solvent is selected from one or more of alcohols, esters, ketones, alkanes, and halogenated alkanes; preferably, the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, acetone, dichloromethane, and chloroform.

[0024] Alternatively, the succinate salt of the compound of formula A is dissolved in a solvent, cooled or filtered and then cooled to form a saturated or supersaturated solution, crystallized, separated, and the obtained solid is dried to obtain the crystalline form I, wherein the solvent is selected from one or a combination of alcohols, esters and ketones, the dissolution temperature is between (15°C lower than the boiling point of the solvent) and the boiling point of the solvent, and the cooling temperature after cooling or filtering is cooled to 0°C to room temperature; preferably, the dissolution temperature is between (10°C lower than the boiling point of the solvent) and the boiling point of the solvent, and the cooling temperature after cooling or filtering is cooled to 0°C to 10°C; more preferably, the solvent is selected from one or a combination of methanol, ethanol, n-propanol, isopropanol, acetone, and tetrahydrofuran.

[0025] Alternatively, dissolving the succinate salt of the compound of formula A in a good solvent, adding a poor solvent until a solid precipitates, separating and drying to obtain the crystalline form I, wherein the good solvent is selected from one or a combination of alcohols, halogenated alkanes, and ketones, and the poor solvent is selected from one or a combination of esters, ethers, alkanes, and nitro-substituted alkanes, the dissolution temperature is between 20 and 60° C., and the crystallization temperature after the addition of the poor solvent is between 0 and 30° C.;

[0026] Preferably, the good solvent is selected from one or a combination of dichloromethane, chloroform, trifluoroethanol, ethanol, and acetone;

[0027] Preferably, the poor solvent is selected from one or a combination of ethyl acetate, methyl tert-butyl ether, n-hexane, petroleum ether, and nitromethane;

[0028] Alternatively, the succinate salt of the compound of formula A is dissolved in a good solvent, slowly added to several times the volume of a poor solvent, stirred for crystallization, separated and dried to obtain the crystalline form I, wherein the good solvent is selected from one or a combination of alcohols, halogenated alkanes and ketones, and the poor solvent is selected from one or a combination of esters, ethers and alkanes, the dissolution temperature is between 40 and 60° C., the temperature of adding to the poor solvent for stirring and crystallization is 20 to 30° C., and the volume ratio of the good solvent to the poor solvent is 1:5 to 10;

[0029] Preferably, the good solvent is selected from one or a combination of dichloromethane, chloroform, trifluoroethanol, ethanol, and acetone;

[0030] Preferably, the poor solvent is selected from one of ethyl acetate, methyl tert-butyl ether, n-hexane, petroleum ether, nitromethane or a combination thereof.

[0031] The present invention provides a crystalline form VI of a succinate salt of a compound of formula A, wherein the succinate salt of the compound has the structure shown below:

[0032] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A includes characteristic peaks at 2θ of 8.0±0.2, 9.1±0.2, 10.5±0.2, 13.8±0.2, 16.7±0.2, and 18.1±0.2.

[0033] Furthermore, the present invention provides a succinate salt form VI of the compound of formula A as described above. Using Cu-Kα radiation, the X-ray powder diffraction pattern of the form I includes characteristic peaks of 2θ of 8.0±0.2, 9.1±0.2, 10.5±0.2, 13.8±0.2, 14.6±0.2, 16.7±0.2, 17.5±0.2, 18.1±0.2, 19.8±0.2, 21.0±0.2, 21.8±0.2, and 25.3±0.2.

[0034] Furthermore, the present invention provides a succinate salt crystalline form VI of the compound of formula A as described above, wherein the X-ray powder diffraction pattern of the crystalline form VI using Cu-Kα radiation includes characteristic peaks at 2θ values ​​as described in Table 3 below, wherein the 2θ value error is ±0.2°:

[0035] Table 3

[0036] Furthermore, the present invention provides a succinate salt crystal form VI of the compound of formula A as described above. Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I includes characteristic peaks at 2θ values ​​substantially as shown in Figure 7, wherein the error of the 2θ value is ±0.2°.

[0037] Furthermore, in a specific embodiment of the present invention, the crystal form VI has an endothermic peak near 125°C, an exothermic peak near 138°C, and an endothermic peak near 190°C; the differential scanning calorimetry analysis diagram is basically as shown in Figure 8.

[0038] Furthermore, in a specific embodiment of the present invention, the thermogravimetric analysis diagram of Form VI is shown in FIG9 .

[0039] Furthermore, in a specific embodiment of the present invention, the crystal form VI gains weight by 5.4% (w / w) under a 0% RH-80% RH environment and is hygroscopic. The dynamic moisture adsorption diagram is shown in FIG10 , and the X-ray powder diffraction comparison diagram of the crystal form VI before and after the dynamic moisture adsorption test is shown in FIG11 . The results show that the solid hygroscopic material is amorphous after the test.

[0040] The present invention also aims to provide a method for preparing the succinate salt crystal form VI of the compound of formula A as described above, the preparation method comprising:

[0041] The succinate salt of the compound of formula A is dissolved in a solvent, cooled or filtered to form a saturated or supersaturated solution, crystallized, separated, and dried to obtain the crystalline form VI, wherein the solvent is a mixed solvent of ketones or alcohols and halogenated alkanes, the dissolution temperature is between 55 and 65° C., and the cooling or filtration cooling temperature is cooled to 0 to 25° C. or 0° C. to room temperature;

[0042] Preferably, the ketone solvent is selected from methyl isobutyl ketone, methyl isopropyl ketone, methyl ethyl ketone, acetone or a mixture thereof;

[0043] Preferably, the alcohol solvent is selected from butanol;

[0044] Preferably, the cooling or filtration cooling temperature is 0-10°C.

[0045] Alternatively, the succinate salt of the compound of formula A is dissolved in a good solvent, mixed with several times the volume of a poor solvent, stirred for crystallization, separated, and dried to obtain the crystalline form VI, wherein the volume ratio of the good solvent to the poor solvent is 1:5 to 10 times;

[0046] Preferably, the good solvent is selected from dichloromethane, and the poor solvent is selected from isooctane;

[0047] Preferably, the dissolving temperature is between 20-30°C, and the mixing with the poor solvent and the stirring and crystallization temperature is 0-10°C.

[0048] The succinate salt of the compound of formula A used in the above method of the present invention is selected from any solid form, or the succinate salt of the compound of formula A is obtained by directly reacting the compound of formula A and succinic acid in a stoichiometric ratio of 1:1 in the solvent used.

[0049] Furthermore, the present invention provides a pharmaceutical composition comprising the above-mentioned succinate salt crystal form I of the compound of formula A or the succinate salt crystal form VI of the compound of formula A or a mixture thereof.

[0050] Furthermore, the present invention provides a pharmaceutical composition, wherein the succinate salt crystal form I of the compound of formula A or the succinate salt crystal form VI of the compound of formula A is in a therapeutically and / or preventively effective amount.

[0051] Furthermore, the present invention provides a pharmaceutical composition, which further comprises at least one pharmaceutically acceptable carrier or excipient.

[0052] Furthermore, the present invention provides a method for treating a disease, which comprises administering a therapeutically effective amount of crystalline form I of the succinate salt of the compound of formula A or crystalline form VI of the succinate salt of the compound of formula A or a mixture thereof or the pharmaceutical composition as described above to a human or other animal in need thereof.

[0053] Furthermore, the present invention provides a method for treating a disease, which comprises administering a therapeutically effective amount of a succinate salt crystalline form I of a compound of formula A or a succinate salt crystalline form VI of a compound of formula A or a mixture thereof or a pharmaceutical composition as described above to a human or other animal in need thereof, wherein the disease is selected from a disease caused by anaplastic lymphoma kinase (ALK) disorder.

[0054] Furthermore, the present invention provides a use of the above-described succinate salt crystal form I of the compound of formula A or the succinate salt crystal form VI of the compound of formula A in the preparation of a drug, wherein the drug is used to treat diseases caused by anaplastic lymphoma kinase (ALK) disorder.

[0055] Furthermore, the disease caused by dysregulation of anaplastic lymphoma kinase described in the present invention is selected from tumors and / or neoplastic diseases, and preferably the tumor and / or neoplastic disease is selected from one or more of anaplastic large cell lymphoma, non-Hodgkin's lymphoma, inflammatory myofibroblastic tumor, and neuroblastoma.

[0056] Compared with the prior art, the present invention has the following beneficial effects:

[0057] 1) The present invention provides a succinate salt of the compound of Formula A, Form I, having excellent mechanical stability. The Form I API exhibits no change in crystalline form after dry grinding or wet grinding with ethanol or water. During formulation processing, raw materials often require grinding or dry or wet granulation. Good physical stability can reduce the risk of API crystallinity loss and crystal transformation during processing.

[0058] 2) The present invention provides a thermodynamically more stable Form I of the succinate salt of the compound of Formula A. Form VI and Form I both converted to Form I in competitive experiments, indicating that Form I is more stable.

[0059] 3) The present invention provides a succinate salt of the compound of formula A, Form I, which has lower hygroscopicity, eliminating the need to strictly control humidity during production and storage, thereby reducing costs.

[0060] 4) The present invention provides a succinate salt of the compound of Formula A, Form I, which exhibits excellent physicochemical stability. Form I API exhibited no change in crystalline form after one month of exposure to light, with a slight decrease in chemical purity. However, Form VI and amorphous samples exhibited significant color changes and decreased chemical purity by 0.14% and 7.5% after one month of exposure to light, demonstrating that Form I exhibits more stable photochemical properties. Furthermore, Form I API exhibited no change in crystalline form and maintained chemical purity above 99.86% for at least one month when stored in an open or closed container at 40°C / 75% RH. Form VI and amorphous samples both dissolved in an open container at 40°C / 75% RH, while the amorphous sample transformed into Form I under a sealed container at 40°C / 75% RH. This demonstrates that Form I exhibits superior physicochemical properties compared to other solid-state forms, exhibits unexpected storage stability, and can avoid changes in drug dissolution rate, bioavailability, and toxicity due to changes in crystalline form or impurities, which is of great practical significance for ensuring drug efficacy and safety.

[0061] 5) The present invention provides a simpler preparation of Form I of the succinate salt of the compound of Formula A. Compared to Form VI, which can only be prepared under specific systems and methods, Form I can be directly prepared by cooling crystallization, suspension crystallization, forward or reverse dissolution in most common solvent systems. This simple and easy preparation method is suitable for large-scale chemical industrial production.

[0062] 6) The crystalline form I prepared by the present invention has good pharmacokinetic properties and has good in vivo exposure and bioavailability when administered orally or by gavage.

[0063] 7) The crystalline form I and crystalline form VI prepared by the present invention have improved solubility. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] FIG1 is an XRPD pattern of the succinate salt of the compound of formula A, Form I;

[0065] FIG2 is a DSC diagram of the succinate salt of the compound of formula A, Form I;

[0066] FIG3 is a TGA diagram of the succinate salt crystal form I of the compound of formula A;

[0067] FIG4 is a DVS diagram of the succinate salt of the compound of formula A, Form I;

[0068] FIG5 is a comparison of XRPD images of the succinate salt form I of the compound of Formula A before and after DVS detection (from top to bottom: before DVS detection, after DVS detection);

[0069] Figure 6 is a comparison of single crystal diffraction data simulation and XRPD data of Form I of the succinate salt of the compound of Formula A (from top to bottom: powder testing, single crystal data simulation);

[0070] FIG7 is an XRPD pattern of the succinate salt of the compound of Formula A, Form VI;

[0071] FIG8 is a DSC graph of Form VI of the succinate salt of the compound of Formula A;

[0072] FIG9 is a TGA diagram of the crystalline form VI of the succinate salt of the compound of formula A;

[0073] FIG10 is a DVS diagram of the crystalline form VI of the succinate salt of the compound of formula A;

[0074] FIG11 is a comparison of XRPD images of Form VI of the succinate salt of the compound of Formula A before and after DVS detection (from top to bottom: after DVS detection, before DVS detection);

[0075] FIG12 is an XRPD pattern of the amorphous form of the succinate salt of the compound of formula A. DETAILED DESCRIPTION

[0076] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is further described below in conjunction with specific implementation methods.

[0077] Unless otherwise specified, Form I referred to in the present invention refers to Form I of the succinate salt of the compound of Formula A, Form VI refers to Form VI of the succinate salt of the compound of Formula A, amorphous refers to the amorphous form of the succinate salt of the compound of Formula A, and free form refers to the compound of Formula A that does not form an addition salt with other acids or bases.

[0078] The drying mentioned in the present invention can be carried out by vacuum drying, forced air drying, atmospheric pressure drying, hygroscopic drying, etc. The drying temperature is sufficient to remove low-boiling point substances such as solvents and water adsorbed on the solid without causing changes in the structure and physical and chemical properties of the dried substance.

[0079] The methods for separating solids and liquids mentioned in the present invention include but are not limited to centrifugation, normal pressure filtration, reduced pressure filtration, hot filtration, etc. Those skilled in the art can adopt conventional solid-liquid separation methods according to specific needs.

[0080] The powder X-ray diffraction pattern of the present invention was collected on a Bruker D8 advance powder X-ray diffractometer, and the specific method parameters are as follows:

[0081] X-ray reflection parameters: Cu, Kα

[0082] Voltage: 40 kilovolts (kV)

[0083] Current: 40 milliamperes (mA)

[0084] Scanning range: from 3.0 to 40.0 degrees

[0085] Step size: 0.02 degrees

[0086] Scan rate: 0.2 seconds per step

[0087] Sola slit: 2.5 degrees

[0088] Emission slit: 0.6 mm

[0089] The X-ray single crystal diffraction pattern of the present invention was collected on a Bruker D8 Venture X-ray single crystal diffractometer, and the specific method parameters are as follows:

[0090] X-ray reflection parameters: Cu,

[0091] Detector: CMOS area detector

[0092] Resolution:

[0093] Voltage: 50 kilovolts (kV)

[0094] Current: 1.4 milliamperes (mA)

[0095] Exposure time: 100s

[0096] Distance from surface detector to sample: 40mm

[0097] Test temperature: 170(2)K

[0098] The differential scanning calorimetry (DSC) analysis of the present invention was performed on a Mettler DSC 3+, and the specific method parameters are as follows:

[0099] Measuring temperature range: 30-300℃

[0100] Heating rate: 10℃ / min

[0101] Nitrogen flow rate: 50mL / min

[0102] Protective atmosphere: 100-200mL / min

[0103] The thermogravimetric analysis (TGA) diagrams described in the present invention were collected on a Mettler TGA 2, and the specific method parameters are as follows:

[0104] Measuring temperature range: room temperature-350℃

[0105] Heating rate: 10℃ / min

[0106] Nitrogen flow rate: 50mL / min

[0107] Protective atmosphere: 100-200mL / min

[0108] The dynamic moisture sorption (DVS) graph of the present invention was collected on a dynamic moisture sorption instrument (DVS Intrinsic) produced by SMS. The specific method parameters are as follows:

[0109] Test range: 40%-0%-95%-0%-40% relative humidity, dm / dt less than 0.002% / min, crystal form detection is performed after the test.

[0110] High performance liquid chromatography (HPLC) purity and content detection method:

[0111] Chromatographic conditions: octadecylsilane bonded silica gel as the filler of the chromatographic column; phosphate buffer-methanol (95:5) as the mobile phase A, acetonitrile as the mobile phase B, and gradient elution.

[0112] Preparation Example 1: Preparation of the free base of compound A

[0113] The compound of formula A was prepared according to the method described in Example 10 of US invention patent US2014 / 0128387A1.

[0114] Example I-1: Preparation of Succinate Salt of Formula A

[0115] Add 50.0 g of the compound of formula A and 600 ml of ethyl acetate to a reaction flask, stir, heat to 65°C to dissolve, filter, add 11.5 g of succinic acid, stir thoroughly, cool to room temperature and hold for 3 hours, slowly precipitate a solid, filter, and dry under reduced pressure to obtain 53.2 g of a succinate salt of the compound of formula A; the HPLC purity (normalized method) is not less than 98%.

[0116] Example I-2: Preparation of Form I of the Succinate Salt of Formula A

[0117] 50 mg of the succinate solid of the compound of formula A was suspended in 0.4 mL of ethanol, suspended at room temperature for 2 weeks, centrifuged, and dried at room temperature to obtain a white solid. Powder X-ray diffraction analysis showed that it was Form I. Its X-ray powder diffraction spectrum is shown in Figure 1, its DSC spectrum is shown in Figure 2, and its TGA spectrum is shown in Figure 3.

[0118] Example I-3: Preparation of Form I of the Succinate Salt of Formula A

[0119] 50 mg of the solid succinate salt of the compound of Formula A was dissolved in 1.0 mL of ethanol at 60°C to form a supersaturated solution, which was then filtered. The resulting supersaturated solution was rapidly cooled in an ice-water bath and stirred at approximately 0°C for 1 hour. A large amount of white solid precipitated, which was then centrifuged and dried at room temperature to obtain a white solid, which was confirmed to be Form I by powder X-ray diffraction.

[0120] Example I-4: Preparation of Form I of the Succinate Salt of Formula A

[0121] 50 mg of the solid succinate of compound A was dissolved in 0.3 mL of dichloromethane at room temperature, filtered, and 1.8 mL of methyl tert-butyl ether was slowly added dropwise to precipitate a large amount of white solid. The mixture was stirred at room temperature for 21 hours, then centrifuged and dried at room temperature to obtain a white solid, which was found to be Form I by powder X-ray diffraction.

[0122] Example I-5: Preparation of Form I of the Succinate Salt of Formula A

[0123] Dissolve 50 mg of the solid succinate salt of the compound of Formula A in 0.3 mL of dichloromethane at room temperature and filter. Slowly add the clear filtrate dropwise to 1.5 mL of methyl isobutyl ketone (MIBK) pre-cooled in an ice-water bath. Stir at approximately 0°C for 2 hours, then centrifuge and dry at room temperature to obtain a white solid, which was confirmed to be Form I by powder X-ray diffraction.

[0124] Example I-6: Preparation of Single Crystal of Form I of Succinate Salt of Formula A

[0125] 10 mg of the solid succinate salt of the compound of Formula A was dissolved in 1 mL of acetonitrile at 60°C and filtered. The mixture was allowed to evaporate slowly at room temperature. The resulting single crystal particles were analyzed by X-ray single crystal diffractometer, and their crystallographic data are shown in Table 2. The single crystal X-ray data simulated the X-ray diffraction pattern of the Form I crystalline compound powder, as shown in Figure 6.

[0126] Example II-1: Preparation of Form VI of the Succinate Salt of Formula A

[0127] 5 g of the succinate salt of Compound A was heated to reflux in 90 ml of methyl isobutyl ketone / dichloromethane (1 / 2, v / v). A large amount of white solid remained undissolved. 40 mL of dichloromethane was added and refluxed until the solution cleared. The solution was filtered and rapidly stirred in an ice-water bath for approximately 1 hour. A large amount of white solid precipitated. The suspension was allowed to stand at -20°C to grow crystals, filtered, and the wet product was collected and dried in a vacuum oven at 40°C for approximately 24 hours to obtain 3.85 g of a white solid.

[0128] After testing, the obtained solid crystal is the crystal form VI described in the present invention. Its X-ray powder diffraction spectrum is shown in Figure 7, its DSC spectrum is shown in Figure 8, its TGA spectrum is shown in Figure 9, and its X-ray powder diffraction data are shown in Table 3.

[0129] Example II-2: Preparation of Form VI of the Succinate Salt of Formula A

[0130] 1 g of the solid succinate of compound A was dissolved in 5 mL of dichloromethane at room temperature, filtered, and slowly added dropwise to 30 mL of isooctane pre-cooled in an ice-water bath. A large amount of white solid precipitated. The solid was placed in an ice-water bath and stirred for 2 hours, then filtered and collected. After vacuum drying at 30°C, 0.93 g of a white solid was obtained, which was confirmed to be Form VI by powder X-ray diffraction.

[0131] Example III: Preparation of amorphous succinate salt of compound A

[0132] 5 g of the solid succinate of compound A was dissolved in 100 mL of dichloromethane at room temperature, filtered, and concentrated under reduced pressure to complete dryness. After vacuum drying at 50° C. for 19 hours, 4.2 g of a white solid was obtained. Powder X-ray diffraction analysis showed that the solid was amorphous, as shown in FIG12 .

[0133] Test Example 1: Mechanical stability test

[0134] The Form I, Form VI, and amorphous succinate samples prepared according to the present invention were manually ground or 1-2 drops of solvent were added, and then fully moistened and manually ground for 5 minutes. The stability of the crystal forms during dry granulation and wet granulation was simulated and investigated. The test results are shown in Table 4.

[0135] Table 4 Grinding stability data

[0136] Experimental results: The crystallinity of Form I did not change significantly after grinding under the above conditions, but the crystallinity of Form VI was significantly weakened after grinding. In addition, Form VI and the amorphous sample showed materialization during solvent-assisted grinding, indicating that Form I has good mechanical stability.

[0137] Test Example 2: Suspension competition experiment between Form I and Form VI

[0138] 3 mg of Form I prepared in the present invention and 3 mg of Form VI prepared in the present invention were weighed and prepared into a suspension in 0.2 mL of a saturated solution of the succinate salt of the compound of Formula A. The suspension was stirred at a specific temperature for 6 days and then sampled and tested. The results are shown in Table 5.

[0139] Table 5 Suspension competition experiment of Form I and Form VI

[0140] Experimental results: At different system temperatures, Form VI converts to Form I, indicating that Form I is a thermodynamically more stable form.

[0141] Test Example 3: Solid-State Stability

[0142] Approximately 30-40 mg of the Form I, Form VI, and amorphous sample prepared by the present invention were weighed and spread flat in glass bottles, either open or sealed, and placed under 60°C, 92.5% RH, 30°C / 65% RH, and 40°C / 75% RH conditions, respectively. The physicochemical stability at different time points was investigated. The results are shown in Table 6.

[0143] Table 6 Stability data

[0144] Experimental results: The Form VI sample is highly hygroscopic and has already undergone chemical transformation under open conditions of 40°C / 75% RH. In addition, the Form VI has poor photochemical stability. Under light conditions, it can be clearly observed that the sample turns off-white and the purity decreases by 1.24%.

[0145] The amorphous sample is highly hygroscopic and has poor crystal stability. It undergoes chemical transformation under open conditions at 40°C / 75% RH, but transforms to Form I under sealed conditions and high temperature. The amorphous sample also exhibits poor chemical stability. Even under sealed conditions at 30°C / 65% RH, the chemical purity decreased by 0.14%. Even worse, under light conditions, the sample clearly turns yellow, and the purity decreases by 7.5%.

[0146] Therefore, compared with other crystal forms, crystal form I has good stability in physical and chemical properties.

[0147] Test Example 4: Moisture absorption test

[0148] Appropriate amounts of Form I and Form VI prepared according to the present invention were tested for hygroscopicity using DVS. The experimental results are shown in Table 7. The DVS spectra of Form I and Form VI are shown in Figures 4 and 10, respectively. The XRPD overlays before and after DVS are shown in Figures 5 and 11, respectively.

[0149] Table 7 Hygroscopicity data

[0150] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2015 edition General Chapter 9103 Guiding Principles for Hygroscopicity Test of Drugs, experimental conditions: 25℃±1℃, 80%RH):

[0151] Deliquescence: Absorbs enough water to become liquid

[0152] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%

[0153] Hygroscopic: Weight gain due to moisture absorption is less than 15% but not less than 2%

[0154] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%

[0155] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%

[0156] Experimental results: The weight gain of Form I due to moisture absorption at 80% RH was about 0.6%, and the crystal form did not change before and after the test, indicating that it was slightly hygroscopic. The weight gain of Form VI due to moisture absorption at 80% RH was about 5.4%, and the solid was amorphous after the test, presumably due to excessive hygroscopicity, which caused hygroscopic material to decompose during the test process.

[0157] Test Example 4: Solubility Test

[0158] Approximately 40 mg or 80 mg of Form I or Form VI prepared according to the present invention were weighed into 10 mL of FaSSIF (fasting state simulated intestinal fluid) or SGF (simulated gastric fluid), respectively, to prepare suspensions at an initial concentration of 4 mg / mL or 8 mg / mL. Three replicates of each medium were prepared for each sampling time point. The suspensions were stirred continuously at 37°C. Samples were taken after 1 hour and 4 hours, incubated at 37°C, and centrifuged at 10,000 rpm for 5 minutes. The filtrates were then subjected to HPLC analysis to determine the content and pH. The results are shown in Table 8.

[0159] Table 8 Solubility data

[0160] Experimental results show that Forms I and VI of the present invention exhibit good solubility in SGF and FaSSIF within 4 hours. This excellent solubility ensures the smooth dissolution of the crystalline forms in the formulation, facilitating effective absorption of the active ingredients in the formulation, and achieving optimal drug bioavailability and efficacy.

[0161] Test Example 5: Pharmacokinetic Experiment

[0162] The crystalline form I powder of the succinate salt of the compound of formula A prepared in the present invention was weighed, and 5 times the mass volume (mg-ml) of 0.5% methyl cellulose was added to prepare a suspension, which was then orally administered to rats.

[0163] Four groups of rats were enrolled, each receiving a single oral gavage (IG) dose of 1, 2, and 4 mg / kg (calculated as free base, the same applies below) and an intravenous (IV) dose of 1 mg / kg. Six rats were included in each group, half male and half female. Blood (0.2 mL) was collected from the retroorbital venous plexus before dosing and at 5 minutes, 0.25, 0.5, 1.0, 2.0, 3.0, 5.0, 7.0, 11, 15, 24, and 48 hours after dosing. Pharmacokinetic parameters were calculated based on the drug concentration-time curves (Table 9).

[0164] Table 9

[0165] AUC 0-tThe average value was calculated, and the absolute bioavailability of rats after a single oral administration of 1 mg / kg of succinate-form I was approximately 69.0%.

[0166] The basic principles, main features and advantages of the present invention are shown and described above. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention, and such changes and modifications fall within the scope of the invention as claimed.

Claims

1. A succinate salt crystal form I of a compound of formula A, wherein the succinate salt of the compound of formula A has a structure as shown in the following formula (1): It is characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I includes characteristic peaks at 2θ of 7.9±0.2, 9.8±0.2, 14.4±0.2, 16.2±0.2, and 22.8±0.

2.

2. The succinate salt form I of the compound of formula A according to claim 1, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the form I includes characteristic peaks at 2θ of 7.9±0.2, 9.8±0.2, 14.4±0.2, 16.2±0.2, 17.6±0.2, 18.4±0.2, 19.6±0.2, 20.2±0.2, 20.8±0.2, and 22.8±0.

2.

3. The succinate salt crystal form I of the compound of formula A according to claim 1, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the form I includes characteristic peaks at 2θ of 7.9±0.2, 9.8±0.2, 10.1±0.2, 14.4±0.2, 16.2±0.2, 17.6±0.2, 18.4±0.2, 19.6±0.2, 20.2±0.2, 20.8±0.2, 22.8±0.2, and 25.9±0.

2.

4. The succinate salt crystal form I of the compound of formula A according to claim 1, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I includes characteristic peaks at 2θ of 7.9±0.2, 8.1±0.2, 9.8±0.2, 10.1±0.2, 14.4±0.2, 14.6±0.2, 16.2±0.2, 16.8±0.2, 17.0±0.2, 17.6±0.2, 17.8±0.2, 18.4±0.2, 19.6±0.2, 20.2±0.2, 20.8±0.2, 22.2±0.2, 22.8±0.2, 23.3±0.2, 23.4±0.2, 23.9±0.2, 25.4±0.2, and 25.9±0.

2.

5. The succinate salt form I of the compound of formula A according to claim 1, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form I includes characteristic peaks with 2θ values ​​substantially as shown in FIG1 , wherein the 2θ value error is ±0.2°.

6. A succinate salt crystal form I of a compound of formula A, wherein the succinate salt of the compound of formula A has a structure as shown in the following formula (1): It is characterized in that The crystallographic data of Form I include a monoclinic space group of P21 and approximately and unit cell parameters of β = 100.797(2)°.

7. A method for preparing the succinate salt form I of the compound of formula A according to any one of claims 1 to 5, characterized in that The preparation method comprises: The succinate salt of the compound of formula A is mixed with a single solvent or a mixed solvent to form a suspension, stirred, separated, and dried to obtain the crystalline form I, wherein the solvent is selected from one or more of alcohols, esters, ketones, alkanes, and halogenated alkanes; Preferably, the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, acetone, dichloromethane and chloroform.

8. A method for preparing the succinate salt form I of the compound of formula A according to any one of claims 1 to 5, characterized in that The preparation method comprises: The succinate of the compound of formula A is dissolved in a solvent, cooled or filtered and then cooled to form a saturated or supersaturated solution, crystallized, separated, and the obtained solid is dried to obtain the crystalline form I, wherein the solvent is selected from one or a combination of alcohols, esters and ketones, the dissolving temperature is between (15°C lower than the boiling point of the solvent) and the boiling point of the solvent, and the cooling or cooling after filtering is cooled to 0°C to room temperature; Preferably, the dissolving temperature is between (10°C lower than the boiling point of the solvent) and the boiling point of the solvent, and the cooling or cooling after filtering is cooled to 0°C to 10°C; More preferably, the solvent is selected from one of methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran or a combination thereof.

9. A method for preparing the succinate salt form I of the compound of formula A according to any one of claims 1 to 5, characterized in that The preparation method comprises: The succinate of the compound of formula A is dissolved in a good solvent, a poor solvent is added until a solid is precipitated, and the crystalline form I is obtained after separation and drying, wherein the good solvent is selected from one or a combination of alcohols, halogenated alkanes and ketones, and the poor solvent is selected from one or a combination of esters, ethers, alkanes, and nitro-substituted alkanes, the dissolving temperature is between 20 and 60° C., and the poor solvent is added and the crystallization temperature is between 0 and 30° C.; Preferably, the good solvent is selected from one or a combination of dichloromethane, chloroform, trifluoroethanol, ethanol, and acetone; Preferably, the poor solvent is selected from one of ethyl acetate, methyl tert-butyl ether, n-hexane, petroleum ether, nitromethane or a combination thereof.

10. The method for preparing the succinate salt form I of the compound of formula A according to claim 1-5, characterized in that The preparation method comprises: The succinate of the compound of formula A is dissolved in a good solvent, slowly added to a several times volume of a poor solvent, stirred for crystallization, separated and dried to obtain the crystalline form I, wherein the good solvent is selected from one or a combination of alcohols, halogenated alkanes and ketones, the poor solvent is selected from one or a combination of esters, ethers and alkanes, the dissolving temperature is between 40 and 60° C., the temperature of adding to the poor solvent for stirring and crystallization is 20 to 30° C., and the volume ratio of the good solvent to the poor solvent is 1:5 to 10; Preferably, the good solvent is selected from one or a combination of dichloromethane, chloroform, trifluoroethanol, ethanol, and acetone; Preferably, the poor solvent is selected from one of ethyl acetate, methyl tert-butyl ether, n-hexane, petroleum ether, nitromethane or a combination thereof.

11. A method for preparing the succinate salt form I of the compound of formula A according to any one of claims 7 to 10, characterized in that The succinate salt of the compound of formula A used to prepare the crystalline form I is selected from any solid state, or the succinate salt of the compound of formula A is obtained by directly reacting the compound of formula A and succinic acid in the solvent used.

12. A succinate salt crystal form VI of a compound of formula A, wherein the succinate salt of the compound of formula A has a structure as shown in the following formula (1): It is characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the form VI includes characteristic peaks at 2θ of 8.0±0.2, 9.1±0.2, 10.5±0.2, 13.8±0.2, 16.7±0.2, and 18.1±0.

2.

13. The succinate salt form VI of the compound of formula A according to claim 12, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the form VI includes characteristic peaks at 2θ of 8.0±0.2, 9.1±0.2, 10.5±0.2, 13.8±0.2, 14.6±0.2, 16.7±0.2, 17.5±0.2, 18.1±0.2, 19.8±0.2, 21.0±0.2, 21.8±0.2, and 25.3±0.

2.

14. The succinate salt crystal form VI of the compound of formula A according to claim 12, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form VI includes characteristic peaks with 2θ values ​​substantially as shown in FIG7 , wherein the 2θ value error is ±0.2°.

15. A method for preparing the succinate salt form VI of the compound of formula A according to any one of claims 12 to 14, characterized in that The method includes: The succinate of the compound of formula A is dissolved in a solvent, cooled or filtered to form a saturated or supersaturated solution, stirred for crystallization, separated, and dried to obtain the crystal form VI, wherein the solvent is a mixed solvent of ketones or alcohols and halogenated alkanes, the dissolving temperature is between 55 and 65° C., and the cooling or filtering cooling temperature is cooled to 0 to 25° C. or 0° C. to room temperature; Preferably, the ketone solvent is selected from methyl isobutyl ketone, methyl isopropyl ketone, methyl ethyl ketone, acetone or a mixture thereof; Preferably, the alcohol solvent is selected from butanol; Preferably, the cooling temperature of the cooling or filtration cooling is 0-10°C.

16. A method for preparing the succinate salt form VI of the compound of formula A according to any one of claims 12 to 14, characterized in that The method includes: The succinate salt of the compound of formula A is dissolved in a good solvent, mixed with several times the volume of a poor solvent, stirred for crystallization, separated, and dried to obtain the crystal form VI, wherein the volume ratio of the good solvent to the poor solvent is 1:5 to 10 times; Preferably, the good solvent is selected from dichloromethane, and the poor solvent is selected from isooctane; Preferably, the dissolving temperature is between 20-30°C, and the mixing with the poor solvent and the stirring and crystallization temperature is between 0-10°C.

17. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the succinate salt crystal form I of the compound of formula A according to any one of claims 1-6 or the succinate salt crystal form VI of the compound of formula A according to any one of claims 12-14, or a mixture thereof.

18. The pharmaceutical composition according to claim 17, characterized in that The succinate salt crystal form I of the compound of formula A or the succinate salt crystal form VI of the compound of formula A or a mixture thereof is a therapeutically and / or preventively effective amount.

19. The pharmaceutical composition according to any one of claims 17 or 18, characterized in that The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier or excipient.

20. A method for treating a disease, characterized in that The method comprises administering to a human or other animal in need thereof a therapeutically effective amount of a succinate salt crystalline form I of the compound of formula A as described in any one of claims 1-6 or a succinate salt crystalline form VI of the compound of formula A as described in any one of claims 12-14 or a mixture thereof or a pharmaceutical composition as described in any one of claims 17-19.

21. The method for treating a disease according to claim 20, characterized in that The disease is selected from diseases caused by anaplastic lymphoma kinase (ALK) disorder; Preferably, the disease is selected from a tumor or a neoplastic disease, and preferably the tumor or neoplastic disease is selected from one or more of anaplastic large cell lymphoma, non-Hodgkin's lymphoma, inflammatory myofibroblastic tumor, and neuroblastoma.

22. Use of the succinate salt crystal form I of the compound of formula A according to any one of claims 1 to 6, or the succinate salt crystal form VI of the compound of formula A according to any one of claims 12 to 14, or a mixture thereof, or the pharmaceutical composition according to any one of claims 17 to 19 in the preparation of a drug, wherein the drug is used to treat a disease caused by anaplastic lymphoma kinase (ALK) disorder; Preferably, the disease is selected from a tumor or a neoplastic disease, and preferably the tumor or neoplastic disease is selected from one or more of anaplastic large cell lymphoma, non-Hodgkin's lymphoma, inflammatory myofibroblastic tumor, and neuroblastoma.

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