Crystal form of isoquinoline compound and preparation method and application thereof

Abstract

The present application relates to the chemical medicine technical field, especially to the crystal form of isoquinoline compound and preparation method and application, the present application provides the crystal form B and crystal form F of formula (I) compound, at least one of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, biological effectiveness and processing performance, purification effect, preparation, safety and so on in aspect, there is superiority, provides new and better choice for the preparation of drug preparation containing formula (I) compound, has very important significance for drug development.

Description

Technical Field

[0001] This invention relates to the field of chemical and pharmaceutical technology, and in particular to the crystal forms, preparation methods, and applications of isoquinoline compounds. Background Technology

[0002] Phosphodiesterases (PDEs) are a class of hydrolases that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), playing an important regulatory role in cellular activity. PDEs are widely distributed in the human body, and their physiological functions involve multiple research areas, attracting widespread attention from scholars and becoming a new research hotspot.

[0003] Currently, there are 11 known PDE families, among which: PDE3 is mainly distributed in smooth muscle cells and participates in regulating cardiac contractility and vascular smooth muscle. Inhibition of PDE3 will produce the effect of relaxing smooth muscle and bronchodilating. PDE4 is mainly distributed in various immune cells, airway epithelial cells and fibroblasts. Inhibition of PDE4 can cause an increase in cAMP levels in inflammatory cells and immune regulatory cells, thereby inhibiting the function of inflammatory cells and relaxing airway smooth muscle.

[0004] Chronic obstructive pulmonary disease (COPD) and asthma are common complex inflammatory diseases of the respiratory tract, characterized primarily by airway obstruction.

[0005] Currently, the marketed PDE inhibitors include roflumilast and ensifentrine (RPL554), which have been approved for marketing.

[0006] CN118955496A (application number 202310775924.8) discloses the 60th compound of a PDE3 / PDE4 dual-target inhibitor, chemically named 9-ethoxy-2-((3-hydroxypropyl)(tolyl)amino)-10-methoxy-6,7-dihydro-4H-pyrrolo[6,1-a]isoquinoline-4-one, which exhibits good inhibitory activity against PDE3A and PDE4B1. Its structural formula is shown below:

[0007]

[0008] The compound in formula (1) above is a drug for treating chronic obstructive pulmonary disease (COPD) and asthma. It has poor stability below 150°C and is not suitable for subsequent formulation development. Summary of the Invention

[0009] In view of this, the technical problem to be solved by the present invention is to provide a crystal form of isoquinoline compounds, a preparation method and an application thereof, wherein the prepared isoquinoline compounds have high stability.

[0010] To achieve the above objectives, the present invention provides crystal form B of the isoquinoline compound shown in formula (I), which, when irradiated with Cu-Kα, exhibits a characteristic peak at a diffraction angle of 2θ in its X-ray powder diffraction pattern, wherein 2θ includes: 9.6±0.2°, 11.1±0.2°, 15.8±0.2°, 18.9±0.2°, and 23.2±0.2°;

[0011] .

[0012] Preferably, the 2θ further includes one or more characteristic peaks selected from 8.5±0.2°, 14.2±0.2°, 16.8±0.2°, 21.6±0.2°, and 25.5±0.2°.

[0013] Preferably, the crystal form B has one or more characteristic peaks at the 2θ angle in X-ray powder diffraction: 8.5±0.2°, 14.2±0.2°, 16.8±0.2°, 21.6±0.2° or 25.5±0.2°.

[0014] Further preferably, the crystal form B has characteristic peaks at an X-ray powder diffraction angle of 2θ: 8.5±0.2°, 14.2±0.2°, 16.8±0.2°, 21.6±0.2° and 25.5±0.2°.

[0015] Ideally, the crystal form B has characteristic peaks in its X-ray powder diffraction at an angle of 2θ: 8.5±0.2°, 9.6±0.2°, 11.1±0.2°, 14.2±0.2°, 15.8±0.2°, 16.8±0.2°, 18.9±0.2°, 21.6±0.2°, 23.2±0.2°, and 25.5±0.2°.

[0016] The crystal form B is an anhydrous form.

[0017] This invention also provides a method for preparing crystal form B of the above-mentioned isoquinoline compounds, comprising the following steps:

[0018] The compound of formula (I) was dissolved in anhydrous ethanol, and purified water was added dropwise until a solid precipitated to obtain crystal form A;

[0019] Crystal form A is dried at high temperature to obtain crystal form B;

[0020] Alternatively, crystal form A can be obtained by cyclic stirring in chloroform / methyl tert-butyl ether at a certain temperature to obtain crystal form B.

[0021] In the above methods:

[0022] The specific preparation method of the crystal form A is as follows: weigh an appropriate amount of solid compound of formula (I), add anhydrous ethanol to dissolve it, cool to room temperature, add 1-5 times the volume of water of anhydrous ethanol, filter after the solid precipitates, and obtain the solid, which is crystal form A.

[0023] The preferred temperature for high-temperature drying is 140~180℃, and for example, it can be 140, 150, 160, 170 or 180℃.

[0024] The preferred high-temperature drying time is 4 to 16 hours, and for example, it can be 4, 8, 10, 12, 14 or 16 hours.

[0025] In some specific embodiments, the conditions for circulating stirring of crystal form A in chloroform / methyl tert-butyl ether to obtain crystal form B are: starting stirring at 50°C and slowly decreasing the temperature to 5°C at a rate of 0.1°C / min (50°C~5°C, 0.1°C / min).

[0026] The volume ratio of chloroform to methyl tert-butyl ether is preferably 1:(6~12), more preferably 1:(8~10), and for example, it can be 1:6, 1:8, 1:9, 1:10 or 1:12.

[0027] Based on this, the present invention also provides a crystal form A of the isoquinoline compound shown in formula (I), which, when irradiated with Cu-Kα, has a characteristic peak at a diffraction angle of 2θ in its X-ray powder diffraction pattern, wherein 2θ includes 19.2 ± 0.2°.

[0028] The present invention also provides a crystal form F of the isoquinoline compound shown in formula (I), which, when irradiated with Cu-Kα, has a characteristic peak at a diffraction angle of 2θ in its X-ray powder diffraction pattern, wherein the 2θ includes: 12.5±0.2°, 13.8±0.2°, 19.7±0.2° and 24.9±0.2°;

[0029] .

[0030] Preferably, the 2θ further includes one or more characteristic peaks selected from 14.8±0.2°, 16.5±0.2°, 17.6±0.2°, and 27.3±0.2°.

[0031] Preferably, the X-ray powder diffraction of the crystal form F has one or more characteristic peaks at the 2θ angle, namely: 14.8±0.2°, 16.5±0.2°, 17.6±0.2° or 27.3±0.2°.

[0032] Further preferably, the X-ray powder diffraction of the crystal form F has diffraction peaks at an angle of 2θ: 14.8±0.2°, 16.5±0.2°, 17.6±0.2° and 27.3±0.2°.

[0033] Ideally, the X-ray powder diffraction of the crystal form F has characteristic peaks at the 2θ angle: 12.5±0.2°, 13.8±0.2°, 14.8±0.2°, 16.5±0.2°, 17.6±0.2°, 19.7±0.2°, 24.9±0.2° and 27.3±0.2°.

[0034] The crystal form F is an anhydrous substance.

[0035] This invention provides a method for preparing crystal form F of the above-mentioned isoquinoline compounds, comprising the following steps:

[0036] The compound of formula (I) was dissolved in anhydrous ethanol, purified water was added dropwise until a solid precipitated to obtain crystal form A. Crystal form A was suspended and stirred in an organic solvent to obtain crystal form F of the compound of formula (1).

[0037] The organic solvent is methanol / methyl tert-butyl ether, isopropyl acetate, isopropanol aqueous solution, or methanol / n-hexane.

[0038] The volume ratio of methanol to methyl tert-butyl ether is preferably 1:(1~15), more preferably 1:(3~15), and for example, it can be 1:6, 1:8, 1:9, 1:10 or 1:12.

[0039] In some specific embodiments, crystal form A is placed in a methanol / methyl tert-butyl ether mixture, heated to 30~80°C, more preferably to 50°C, stirred for 24~96 hours, more preferably for 48 hours, cooled to room temperature, and filtered to obtain crystal form F.

[0040] In some specific embodiments, crystal form A is placed in isopropyl acetate and suspended and stirred at 30~80°C, more preferably 50°C, for 2~5 days, more preferably for 4 days.

[0041] In the isopropanol aqueous solution, the volume ratio of isopropanol to water is preferably 1:(1~10), more preferably 1:(1~9), and for example, it can be 1:1, 1:3, 1:5, 1:7 or 1:9.

[0042] In some specific implementations, crystal form A is placed in an aqueous isopropanol solution and suspended and stirred at room temperature for 2 to 5 days, more preferably for 3 days.

[0043] The volume ratio of methanol to n-hexane is preferably 1:(1~15), more preferably 1:(3~15), and for example, it can be 1:3, 1:5, 1:7, 1:9, 1:11, 1:13 or 1:15.

[0044] In some specific embodiments, crystal form A is placed in a methanol / n-hexane mixture, heated to 30~80°C, more preferably to 50°C, stirred for 24~96 hours, more preferably for 48 hours, cooled to room temperature, and filtered to obtain crystal form F.

[0045] In some specific implementation schemes, the above preparation method is as follows:

[0046] Add 5-15 times the weight of methanol / methyl tert-butyl ether to crystal form A, heat and stir for 12-48 hours, cool to room temperature, filter, and obtain crystal form F.

[0047] Or, more specifically: crystal form A is placed in isopropyl acetate in a volume of 5-20 times its weight, heated and stirred, and filtered to obtain crystal form F.

[0048] Or, more specifically: crystal form A is placed in a system of isopropanol / water at 10-20 times its weight, suspended and stirred at room temperature for 1-5 days, then filtered to obtain crystal form F.

[0049] Or, more specifically: Place crystal form A into methanol / n-hexane (1:1~1:15, v / v) at a volume of 5-15 times the weight of crystal form A, heat, stir for 12-96 hours, cool to room temperature, filter, and obtain crystal form F.

[0050] In the above preparation method, the units of weight and volume are as follows: the weight unit is g, the volume unit is ml, or multiples of the above units, such as 0.01, 0.1, 10, 100, 1000, etc.

[0051] Differential scanning calorimetry (DSC) results show that:

[0052] The weight loss of crystal form A sample was 2.87% when heated to 150℃ and 4.27% when heated to 200℃. DSC data showed that the melting temperature of crystal form A was about 165.4℃ (initial temperature) and there was an endothermic peak at 203.1℃.

[0053] The weight loss of the crystal form B sample was 1.53% when heated to 150℃. DSC data showed that the melting temperature of crystal form B was approximately 203.6℃ (initial temperature).

[0054] The weight loss of the F crystal sample was 0.92% when heated to 150℃. DSC data showed that the melting temperature of F crystal was approximately 183.5℃ (initial temperature).

[0055] Dynamic water adsorption (DVS) experiment results show that:

[0056] Crystal form F has a moisture adsorption rate of 0.2209% at 25℃ / 80%RH, indicating slight hygroscopicity, and the crystal form of the sample did not change after DVS testing.

[0057] The results of solid stability experiments show that:

[0058] Crystal form F showed no significant change in purity after being placed at 165℃ for 2 hours and at 25℃ / 60%RH and 40℃ / 75%RH for 1 week.

[0059] It is evident that the crystal form B and crystal form F provided by this invention have excellent stability and are suitable for subsequent preparation of drug dosage forms.

[0060] The present invention also provides a pharmaceutical composition comprising crystal form B or crystal form F of the above-mentioned isoquinoline compound, and a pharmaceutically acceptable excipient.

[0061] The dosage form of the composition is not specifically limited in this invention and can be any dosage form known to those skilled in the art, including but not limited to powder for injection, inhalation, tablets, capsules, etc.

[0062] The present invention does not impose any special limitation on the type of excipients, and those skilled in the art can select them according to the dosage form.

[0063] The present invention also provides the use of crystal form B of the above-mentioned isoquinoline compound or crystal form F of the above-mentioned isoquinoline compound or the above-mentioned pharmaceutical composition in the preparation of medicaments for the prevention, treatment and / or relief of inflammation, bronchiectasis, chronic obstructive pulmonary disease and / or asthma.

[0064] According to the present invention, the compound of formula (I) used as a raw material refers to its solid (crystalline or amorphous), semi-solid, wax, or oil form. Preferably, the compound of formula (I) used as a raw material is in solid powder form.

[0065] The "stirring" is performed using conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm. Magnetic stirring is preferably performed at 300-900 rpm, and mechanical stirring is preferably performed at 100-300 rpm.

[0066] In this invention, "crystal" refers to that confirmed by the X-ray diffraction pattern shown. Those skilled in the art will understand that the physicochemical properties discussed herein can be characterized, and the experimental errors therein depend on the instrument conditions, sample preparation, and sample purity.

[0067] In particular, it is well known to those skilled in the art that X-ray diffraction patterns typically change depending on instrument conditions. It is especially important to note that the relative intensities of X-ray diffraction patterns can also vary with experimental conditions, therefore the order of peak intensities cannot be considered the sole or decisive factor.

[0068] In fact, the relative intensity of diffraction peaks in X-ray diffraction patterns is related to the preferred orientation of the crystal. The peak intensities shown in this article are for illustrative purposes rather than for absolute comparison.

[0069] In addition, experimental errors in peak angles are typically 5% or less, and these angle errors should also be taken into account, generally allowing for ±0.2°. Furthermore, experimental factors such as sample thickness can cause overall peak angle shifts, which are also generally permissible.

[0070] Therefore, those skilled in the art will understand that the X-ray diffraction pattern of a crystal form in this invention need not be completely identical to the X-ray diffraction pattern in the examples referred to herein. The phrase "same X-ray diffraction pattern" does not mean absolutely identical; the positions of the same peaks may differ by ±0.2°, and the peak intensities are allowed to have some variability. Any crystal form with a pattern having the same or similar characteristic peaks as those in these spectra falls within the scope of this invention. Those skilled in the art can compare the spectra listed in this invention with a spectra of an unknown crystal form to verify whether the two sets of spectra reflect the same or different crystal forms.

[0071] In some embodiments, the crystal form B or F of the present invention is pure and singular, substantially free of any other crystal form. In the present invention, "substantially free" when used to refer to a new crystal form means that the crystal form contains less than 20% (by weight) of other crystal forms, particularly less than 10% (by weight) of other crystal forms, more specifically less than 5% (by weight) of other crystal forms, and even more specifically less than 1% (by weight) of other crystal forms.

[0072] It should be noted that the numerical values ​​and ranges mentioned in this invention should not be narrowly interpreted as numerical values ​​or ranges themselves. Those skilled in the art should understand that they may fluctuate around specific numerical values ​​depending on the specific technical environment, without departing from the spirit and principles of this invention. In this invention, such fluctuation ranges that are foreseeable by those skilled in the art are often expressed by the term "about".

[0073] The crystal forms B and F of the compound of formula (I) provided by this invention have advantages in at least one aspect of solubility, melting point, stability, dissolution rate, hygroscopicity, adhesion, flowability, bioavailability, processing performance, purification effect, formulation production, and safety. They provide new and better options for the preparation of pharmaceutical formulations containing compound (I) and are of great significance for drug development. Attached Figure Description

[0074] Figure 1 Example 1: XRPD image of crystal form C;

[0075] Figure 2 Example 2: XRPD image of crystal form A;

[0076] Figure 3 Example 3: XRPD image of crystal form B;

[0077] Figure 4 Example 4: XRPD image of crystal form F;

[0078] Figure 5 Example 1: TGA / DSC image of crystal form C;

[0079] Figure 6 Example 2: TGA / DSC image of crystal form A;

[0080] Figure 7 Example 3: TGA / DSC image of crystal form B;

[0081] Figure 8 Example 4: TGA / DSC image of crystal form F;

[0082] Figure 9 Example 1: 1H NMR spectrum of crystal form C;

[0083] Figure 10 Example 2: 1H NMR spectrum of crystal form A;

[0084] Figure 11 Example 3 Crystal form B 1 H NMR spectrum;

[0085] Figure 12 Example 4 Crystal form F 1 H NMR spectrum;

[0086] Figure 13 Example 1: PLM diagram of crystal form C;

[0087] Figure 14 Example 2: PLM diagram of crystal form A;

[0088] Figure 15 Example 3: PLM diagram of crystal form B;

[0089] Figure 16 Example 4: PLM diagram of crystal form F;

[0090] Figure 17 Example 4: DVS diagram of crystal form F;

[0091] Figure 18Example 4: XRD comparison images of crystal form F before and after DVS detection;

[0092] Figure 19 Example 4: XRPC overlay diagram for evaluating the stability of solid crystal form F.

[0093] In the image, the sample name is: 829157-01-A ( Figure 2 , 6 14) is crystal form A of Example 2, 829157-12-A10 ( Figure 3 , 7 15) is crystal form B of Example 3, 829157-11-A2 ( Figure 8 , 16 , 18) is the crystal form F, 829157-10-A6 of Example 4 ( Figure 1 , 5 13) is crystal form C of Example 1. Detailed Implementation

[0094] To further illustrate the present invention, a detailed description is provided below with reference to embodiments. However, it should be understood that these descriptions are merely for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims.

[0095] There are no particular restrictions on the source of any raw materials used in this invention; they can be purchased from the market or prepared using conventional methods known to those skilled in the art.

[0096] Unless otherwise specified, "room temperature" in this invention usually refers to 25°C.

[0097] The abbreviations used in this invention are explained as follows:

[0098] XRPD: X-ray powder diffraction;

[0099] DSC: Differential Scanning Calorimetry;

[0100] TGA: Thermogravimetric analysis;

[0101] 1 HNMR: Proton nuclear magnetic resonance spectrum;

[0102] PLM: Polarizing Microscopy;

[0103] DVS: Dynamic Moisture Adsorption;

[0104] HPLC: High Performance Liquid Chromatography.

[0105] Example 1: Preparation of compound (1) (i.e., compound 60)

[0106] (Prepared using the method of Example 57 of CN118955496A)

[0107]

[0108] Step 1: Synthesis of Compound 60A

[0109] IM-02 (1.0 g) was dissolved in toluene (20 mL), followed by the addition of 3-(tert-butyldimethylsiloxane)propanol (0.71 g) and cyanomethylenetri-n-butylphosphine (1.81 g). The mixture was heated to 120 °C under a nitrogen atmosphere and stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by Flash reversed-phase chromatography to obtain 60A.

[0110] Step 2, Synthesis of Compound 60

[0111] 60A (600 mg) was dissolved in dichloromethane (10 mL), and a hydrogen fluoride-pyridine solution (617 mg) was slowly added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, it was quenched with saturated sodium bicarbonate (2 mL) and extracted with dichloromethane (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by Flash reversed-phase chromatography to give compound 60 (sample number 829157-10-A6).

[0112] Mass spectrometry and proton NMR spectroscopy revealed that its structure is identical to that of the compound disclosed in CN118955496A.

[0113] Example 2: Preparation of crystal form A

[0114] Preparation method: At room temperature, weigh 10.00 g of compound (I) solid (prepared in Example 1), add 5 vol of anhydrous ethanol, heat to 50 °C, stir until dissolved, slowly add 3 times the amount of water relative to the amount of anhydrous ethanol, slowly cool to room temperature, filter after the solid precipitates, and obtain 7.75 g of off-white solid, which is crystal form A (sample number 829157-01-A).

[0115] Mass spectrometry and proton NMR spectroscopy showed that its structure was identical to that of CN118955496A.

[0116] Example 3: Preparation of crystal form B

[0117] Preparation method 1:

[0118] After drying the crystal form A1 prepared in Example 2 at 40°C for 4 hours, crystal form B was obtained.

[0119] Preparation method 2:

[0120] Crystal form A was subjected to temperature-cycle stirring (50~5℃, 0.1℃ / min) in chloroform / methyl tert-butyl ether (1:9, v / v) to obtain crystal form B.

[0121] The crystal form prepared in Example 3 was tested, and the obtained crystal form was the same. The sample number was set as 829157-12-A10.

[0122] Example 4: Preparation method of crystal form F

[0123] Preparation method 1: 100g of crystal form A was placed in 1000ml of methanol / methyl tert-butyl ether (1:9, v / v), heated to 50℃, stirred for 48 hours, cooled to room temperature, and filtered to obtain crystal form F.

[0124] Preparation method 2: 100g of crystal form A is placed in 10 times the volume of isopropyl acetate by weight of crystal form A, suspended and stirred at 50℃ for 4 days, filtered, and crystal form F is obtained.

[0125] Preparation method 3: Crystal form A is placed in a system of isopropanol / water (1:5, v / v) with a weight of 15 times the volume of crystal form A, suspended and stirred at room temperature for 3 days, filtered, and crystal form F is obtained.

[0126] Preparation method 4: Add 10 times the weight of crystal form A to methanol / n-hexane (1:9; v / v), heat to 50°C, stir for 48 hours, cool to room temperature, filter, and obtain crystal form F.

[0127] The crystal form prepared in Example 4 was tested, and the obtained crystal form was the same. The sample number was set as 829157-11-A2.

[0128] Experimental Example 1: X-ray Powder Diffraction Pattern (XRPD)

[0129] 1. Tested samples: Example 1 (crystal form C, sample number 829157-10-A6), Example 2 (crystal form A, sample number 829157-01-A), Example 3 (crystal form B, sample number 829157-12-A10), Example 4 (crystal form F, sample number 829157-11-A2).

[0130] 2. Detection method: Data were collected using an X-ray powder diffractometer from Panalytical. Relevant parameters: X-ray source: Cu, Kα; Kα1 1.540598; Kα2 1.544426; Kα2 / Kα1 intensity ratio: 0.50; voltage: 45 kV; current: 40 mA; scanning range: from 3 to 40 degrees (2θ angle).

[0131] 3. Test Results:

[0132] 3.1 The XRPD pattern of sample (crystal form C) in Example 1 is shown below. Figure 1As shown, the sample has characteristic peaks at approximately 13.0±0.2° and 23.8±0.2° at a 2θ angle.

[0133] 3.2 The XRPD pattern of sample (crystal form A) in Example 2 is shown below. Figure 2 As shown, the sample has a characteristic peak at an angle of approximately 19.2 ± 0.2° at 2θ.

[0134] 3.3 The XRPD pattern of sample (crystal form B) in Example 3 is shown below. Figure 3 As shown, the sample has characteristic peaks at angles of approximately 8.5±0.2°, 9.6±0.2°, 11.1±0.2°, 14.2±0.2°, 15.8±0.2°, 16.8±0.2°, 18.9±0.2°, 21.6±0.2°, 23.2±0.2°, and 25.5±0.2° at 2θ.

[0135] 3.4 The XRPD pattern of sample (crystal form F) in Example 4 is shown below. Figure 4 As shown, the sample has characteristic peaks at angles of approximately 12.5±0.2°, 13.8±0.2°, 14.8±0.2°, 16.5±0.2°, 17.6±0.2°, 19.7±0.2°, 24.9±0.2°, and 27.3±0.2° at 2θ.

[0136] Experimental Example 2: Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis Charts

[0137] 1. Tested samples: Example 1 (crystal form C, sample number 829157-10-A6), Example 2 (crystal form A, sample number 829157-01-A), Example 3 (crystal form B, sample number 829157-12-A10), Example 4 (crystal form F, sample number 829157-11-A2).

[0138] 2. Detection method:

[0139] 2.1 Differential scanning calorimetry: Data were collected on a Discovery TA5500 / TA550 thermogravimetric analyzer with the following parameters: scan rate: 10℃ / min; protective gas: nitrogen.

[0140] 2.2 Thermogravimetric analysis chart: Data were collected on a Discovery TA2500 / TA250 differential scanning calorimeter with the following parameters: scan rate: 10℃ / min; protective gas: nitrogen.

[0141] 3. Test Results:

[0142] 3.1 The TGA / DSC chart of Example 1 (Crystal Form C) is shown below. Figure 5As shown; TGA data shows that heating the crystalline C sample to 150℃ resulted in a weight loss of 5.79%, with three endothermic peaks at 125.5, 157.8, and 205.2℃;

[0143] 3.2 The TGA / DSC chart of Example 2 (Crystal Form A) is shown below. Figure 6 As shown; TGA data shows that the weight loss of crystal form A sample was 2.87% when heated to 150℃ and 4.27% when heated to 200℃. DSC data shows that the melting temperature of crystal form A is about 165.4℃ (initial temperature) and there is an endothermic peak at 203.1℃.

[0144] 3.3 The TGA / DSC chart of Example 3 (Crystal Form B) is shown below. Figure 7 As shown: TGA data shows that the weight loss of crystal form B sample was 1.53% when heated to 150℃, and DSC data shows that the melting temperature of crystal form B was approximately 203.6℃ (initial temperature).

[0145] 3.4 The TGA / DSC chart of Example 4 (Crystal Form F) is shown below. Figure 8 As shown, TGA data shows that the weight loss of crystal form F sample was 0.92% when heated to 150℃, and DSC data shows that the melting temperature of crystal form F is approximately 183.5℃ (initial temperature).

[0146] The experimental results above show that crystal form C and crystal form A have poor stability below 150℃ and are not suitable for subsequent inhalation formulations.

[0147] Experimental Example 3: 1 H NMR spectrum

[0148] 1. Tested samples: Example 1 (crystal form C, sample number 829157-10-A6), Example 2 (crystal form A, sample number 829157-01-A), Example 3 (crystal form B, sample number 829157-12-A10), Example 4 (crystal form F, sample number 829157-11-A2).

[0149] 2. Detection method: Data were collected on a Bruker 400M NMR spectrometer, with DMSO-d6 and MeOD as solvents.

[0150] 3. Test Results:

[0151] 3.1 Example 1 (Crystal Form C) 1 H NMR spectrum as shown Figure 9 As shown in the figure; the spectrum shows that the sample contains acetonitrile, and the molar ratio of acetonitrile remaining in the sample is 0.8 (6.3 wt%), which is presumed to be an acetonitrile compound.

[0152] 3.2 Example 2 (Crystal Form A) 1H NMR spectrum as shown Figure 10 As shown in the figure; the spectrum shows that the molar ratio of residual dichloromethane to the sample is 0.1 (1.8 wt%), and the molar ratio of residual ethanol to the sample is 0.2 (2.3 wt%). Based on the TGA / DSC spectrum of crystal form A, it is inferred that crystal form A is a hydrate.

[0153] 3.3 Example 3 (Crystal Form B) 1 H NMR spectrum as shown Figure 11 As shown in the figure; the spectrum shows that there is no solvent residue in the sample. Combined with the TGA / DSC spectrum of crystal form B, it is inferred that crystal form B is amorphous.

[0154] 3.4 Example 4 (Crystal Form F) 1 H NMR spectrum as shown Figure 12 As shown in the figure; the spectrum shows that there is no solvent residue in the sample. Combined with the TGA / DSC spectrum of crystal form F, it is inferred that crystal form F is an amorphous form.

[0155] The experimental results above show that crystal form C is a solvent compound, and solvents are not very friendly to the human body.

[0156] Experiment Example 4: PLM Diagram

[0157] 1. Tested samples: Example 1 (crystal form C, sample number 829157-10-A6), Example 2 (crystal form A, sample number 829157-01-A), Example 3 (crystal form B, sample number 829157-12-A10), Example 4 (crystal form F, sample number 829157-11-A2).

[0158] 2. Detection method: Data were collected at room temperature using a Carl Zeiss Axio Lab. A1 upright microscope.

[0159] 3. Test Results:

[0160] 3.1 The PLM spectrum of Example 1 (Crystal Form C) is as follows Figure 13 As shown in the figure; the spectrum shows that the sample particle size is less than 50 micrometers.

[0161] 3.2 The PLM spectrum of Example 2 (Crystal Form A) is as follows Figure 14 As shown in the figure; the spectrum shows that the sample is in the form of irregular blocks, with a particle size of less than 50 micrometers and exhibiting agglomeration.

[0162] 3.3 The PLM spectrum of Example 3 (Crystal Form B) is as follows: Figure 15 As shown in the figure; the spectrum shows that the sample particle size is less than 50 micrometers and there is agglomeration.

[0163] 3.4 The PLM spectrum of Example 4 (crystal form F) is as follows Figure 16As shown in the figure; the spectrum shows that the sample particle size is less than 50 micrometers.

[0164] The experimental results above show that both crystal form A and crystal form B exhibit aggregation, which is not conducive to subsequent formulation development. Therefore, crystal form F is preferred as the target crystal form.

[0165] Experiment Example 5: Dynamic Water Adsorption (DVS) Experiment

[0166] 1. Test sample: Example 4 (crystal form F).

[0167] 2. Experimental method: Starting with 0% relative humidity (0%RH), the percentage change in sample mass was collected under constant temperature of 25℃ as humidity changed (0%RH-95%RH-0%RH).

[0168] 3. Detection method: Data was collected using DVS Intrinsic Plus of SMS (Surface Measurement Systems). Temperature: 25℃, Sample volume: 10-20 mg, Nitrogen protection, Gas flow rate: 200 ml / min. Minimum equilibration time: 10 min, RH range: 0%RH~95%RH.

[0169] 3. Test Results:

[0170] 3.4 The DVS spectrum of Example 4 (crystal form F) is shown below. Figure 17 and 18 As shown, the water adsorption of crystal form F at 25ºC / 80%RH is 0.2209%, indicating slight hygroscopicity, and the crystal form of the sample did not change after DVS testing.

[0171] Experiment Example 6: Solid Stability Experiment

[0172] 1. Test samples: Example 3 (crystal form B), Example 4 (crystal form F).

[0173] 2. Experimental methods:

[0174] The physical and chemical stability of the sample was determined by XRPD and HPLC after being placed at 165℃ for 2 hours and at 25℃ / 60%RH and 40℃ / 75%RH for 1 week.

[0175] 3. Detection method:

[0176] 3.1 High Performance Liquid Chromatography (HPLC): The chromatographic test was performed using a Thermo Vanquish Core HPLC system. The chromatographic column was an Xbridge C18, 4.6 mm × 150 mm, 5 μm. The mobile phase was A (10 mM KH2PO4 in H2O) and B (ACN). The run time was 15.0 min, the mobile phase flow rate was 1.0 ml / min, the detection wavelength was UV at 335 nm, the column temperature was 40 °C, the injector temperature was room temperature, and the diluent was acetonitrile / water = 1 / 1 (v / v).

[0177] 3.2 X-ray powder diffraction pattern (XRPD): Acquired using an X-ray powder diffractometer from Panalytical. Relevant parameters: X-ray source: Cu, Kα; Kα1 1.540598; Kα2 1.544426; Kα2 / Kα1 intensity ratio: 0.50; Voltage: 45 kV; Current: 40 mA; Scan range: from 3 to 40 degrees (2θ angle).

[0178] 4. Test Results:

[0179] 4.1 Stability assessment of solids with crystalline forms F and B by HPLC is shown in Table 1.

[0180] Table 1: HPLC comparison of the stability assessment of crystalline form F solids

[0181] #Peak RRT Starting point (area %) 165℃ / 2 hours (area %) 25℃ / 60%RH / 1 week (area %) 40℃ / 75%RH / 1 week (area %) 1 1.00 99.89 99.87 99.89 99.84 2 1.05 0.05 0.06 0.06 0.06 3 1.39 - - - 0.05 4 1.62 0.06 0.07 0.05 0.06

[0182] Note: RRT is the relative retention time of the peak position in HPLC.

[0183] Table 2: HPLC comparison of the stability assessment of solids with crystal form B

[0184] #Peak RRT Starting point (area %) 165℃ / 2 hours (area %) 25℃ / 60%RH / 1 week (area %) 40℃ / 75%RH / 1 week (area %) 1 0.63 Not detected 0.15 Not detected Not detected 2 1.00 98.84 98.75 98.83 98.84 3 1.07 0.16 0.16 0.18 0.16 4 1.28 0.03 0.03 0.02 0.03 5 1.69 0.18 0.18 0.17 0.18 6 2.19 0.34 0.32 0.36 0.34 7 2.32 0.16 0.15 0.16 0.15

[0185] The results in Tables 1 and 2 show that: Crystal form F showed no significant change in purity after being placed at 165℃ for 2 hours, at 25℃ / 60%RH for 1 week, and at 40℃ / 75%RH for 1 week. Crystal form B showed a 0.15% impurity at the 0.63 relative retention time position after being placed at 165℃ for 2 hours; however, no significant impurities appeared after being placed at 25℃ / 60%RH for 1 week and at 40℃ / 75%RH for 1 week.

[0186] 4.2 Example 4: Stability evaluation of solid crystal form F (XRPD overlay diagram shown) Figure 19 The results showed that its crystal form did not change.

[0187] The superposition diagram of crystal form B is the same as that of crystal form F, and there is no change.

[0188] The above test results show that the solid properties of crystal form B and crystal form F are stable.

[0189] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A crystal form B of an isoquinoline compound of formula (I), characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form B has characteristic peaks at a diffraction angle of 2θ, where 2θ includes: 9.6±0.2°, 11.1±0.2°, 15.8±0.2°, 18.9±0.2° and 23.2±0.2°; 。 2. The crystal form B of the isoquinoline compound of formula (I) according to claim 1, characterized in that, The 2θ also includes one or more characteristic peaks from the following: 8.5±0.2°, 14.2±0.2°, 16.8±0.2°, 21.6±0.2°, and 25.5±0.2°.

3. The crystal form B of the isoquinoline compound of formula (I) according to claim 1, characterized in that, The crystal form B is an anhydrous form.

4. A method for preparing crystal form B of the isoquinoline compound according to any one of claims 1 to 3, comprising the following steps: The compound of formula (I) was dissolved in anhydrous ethanol, and purified water was added dropwise until a solid precipitated to obtain crystal form A; Crystal form A is dried at high temperature to obtain crystal form B; Alternatively, crystal form A can be obtained by cyclic stirring in chloroform / methyl tert-butyl ether at a certain temperature to obtain crystal form B.

5. The preparation method according to claim 4, characterized in that, The high-temperature drying temperature is 140~180℃, and the time is 4~16h; The temperature-cycle stirring specifically involves starting stirring at 50°C and slowly decreasing the temperature to 5°C at a rate of 0.1°C / minute. The volume ratio of chloroform to methyl tert-butyl ether is 1:(6~12).

6. A crystal form F of an isoquinoline compound of formula (I), characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form F has characteristic peaks at diffraction angles of 2θ, including 12.5±0.2°, 13.8±0.2°, 19.7±0.2° and 24.9±0.2°. 。 7. The crystal form F of the isoquinoline compound according to claim 6, characterized in that, The 2θ also includes one or more characteristic peaks from the ranges of 14.8±0.2°, 16.5±0.2°, 17.6±0.2°, and 27.3±0.2°.

8. The crystal form F of the isoquinoline compound according to claim 6, characterized in that, The crystal form F is an anhydrous substance.

9. A method for preparing crystal form F of the isoquinoline compound according to any one of claims 6 to 8, comprising the following steps: The compound of formula (I) was dissolved in anhydrous ethanol, purified water was added dropwise until a solid precipitated to obtain crystal form A. Crystal form A was suspended and stirred in an organic solvent to obtain crystal form F of the compound of formula (1). The organic solvent is methanol / methyl tert-butyl ether, isopropyl acetate, isopropanol aqueous solution, or methanol / n-hexane.

10. The use of crystal form B of the isoquinoline compound according to any one of claims 1 to 3 or crystal form F of the isoquinoline compound according to any one of claims 6 to 8 in the preparation of medicaments for the prevention, treatment and / or relief of inflammation, bronchiectasis, chronic obstructive pulmonary disease and / or asthma.

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