CN115872918A - Indobufen crystal form E and preparation method thereof - Google Patents

Abstract

The invention discloses a crystal form E of indobufen. The crystal form E is an anhydrous substance, and the solubility in three biological media from large to small is FaSSIF>FeSSIF>FaSSGF, and the crystal form E is in three biological media. It can exist stably, does not undergo crystal transformation, and has good crystallinity, good thermal stability, poor hygroscopicity, no solvent in the preparation process, and is environmentally friendly.

Description

Indobufen crystal form E and preparation method thereof

Technical Field

The present invention belongs to the technical field of drug crystal forms, and particularly relates to an indobufen crystal form E and a preparation method thereof.

Background Art

Thromboembolic disease is a type of systemic disease that affects the heart, brain and peripheral blood vessels. It is divided into arterial and venous types. High-risk patients for this type of disease include those with previous ischemic cerebrovascular disease, atrial fibrillation, long-term immobilization, intermittent claudication, etc. Prevention is more important than treatment, and antiplatelet drugs are widely used in preventing such thrombotic events.

Among various antiplatelet drugs, indobufen is an antithrombotic drug that effectively blocks platelet aggregation by reversibly inhibiting cyclooxygenase and reducing the production of thromboxane A2. It can selectively act on circulating platelets, block thrombus formation, inhibit the release of platelet factors and exert antiplatelet aggregation effects without changing plasma parameters or damaging platelet function, and can restore abnormal platelet function to normal.

In 2008, the American College of Chest Physicians (ACCP) guidelines proposed that indobufen is an effective platelet cyclooxygenase-1 (Cox-1) inhibitor, which is comparable to standard-dose aspirin in terms of both biochemical efficacy and clinical effectiveness. Compared with similar drugs, indobufen inhibits platelet factors, and its antiplatelet aggregation effect is 2 to 5 times that of salicylic acid, with a slightly shorter bleeding time. Compared with ticlopidine, there is no significant difference in oral clinical efficacy, but indobufen shows good tolerability.

Chinese invention patent CN106397298B discloses three crystalline forms of indobufen compounds, among which crystal form A is prepared by two methods: a) ultrasonic dissolution of indobufen and a solvent (selected from any proportion of ethanol/water, acetonitrile/water, 1,4-dioxane/water, ethyl acetate, butanone) and volatilization at room temperature to 60°C; b) ultrasonic dissolution of indobufen and a solvent (selected from any one of isopropanol, dimethyl sulfoxide, ethyl acetate) and diffusion in a water vapor atmosphere at room temperature to 40°C. The infrared spectrum of this crystal form has characteristic peaks at 2942, 1682, 1610, 1467, 1446, 1381, 1305, 1269, 1218, 1156, 959, 810 and 730 cm-1, and its dynamic adsorption curve shows that the weight change of the sample at 0% RH to 80% RH is about 0.06%.

Form B is prepared by heating indobufen to 189°C at 10°C/min and then cooling to 20°C at 10°C/min by DSC. The infrared spectrum of the form has characteristic peaks at 2930, 1727, 1649, 1612, 1514, 1439, 1397, 1307, 1263, 1176, 929, 833 and 739 cm-1, and its dynamic adsorption curve shows that the weight change of the sample at 0% RH to 80% RH is about 0.14%.

Form C was obtained by ultrasonically dissolving indobufen and dichloromethane and then rapidly volatilizing under reduced pressure at 40°C. However, when the product was scaled up to 100 mg, Form B was obtained, indicating that Form C and its preparation process are unstable and cannot be scaled up for the time being.

The currently reported crystal forms and disclosed preparation methods are limited to the hundred milligram level. In order to meet the requirements of indobufen solid preparations for drug solubility, expand the raw material forms selected for preparation development, and at the same time meet the reproducibility and controllability of the crystallization process in the industrial production process, the art needs to develop new indobufen crystal forms and corresponding preparation methods suitable for industrial production.

Summary of the invention

Among the existing reported crystal forms, the inventors of the present application repeated the preparation of crystal forms A and B according to the methods provided in Examples 9, 10, 13, and 14 of patent CN106397298B, and found that the reproducibility of crystal forms A and B was poor, and the corresponding crystal forms could not be obtained when the specification was 200 mg, and the solubility in the three biological media had no obvious advantage. Therefore, the present invention provides an indobufen crystal form E, which has a stable structure, a simple preparation method, is easy to scale up, and has improved crystal solubility.

The present invention provides an indobufen crystal form E, wherein the powder X-ray diffraction pattern of the crystal form E has a characteristic diffraction angle 2θ, a crystal plane spacing d and a relative intensity %, and a 2θ error of ±0.2 degrees; the X-ray powder diffraction pattern has diffraction peaks at least at one or more of 2θ angles of 6.346, 15.047, 22.976, 24.598, and 26.085.

Preferably, the characteristic diffraction angle 2θ includes 6.346, 13.479, 14.824, 15.047, 17.125, 20.060, 22.045, 22.976, 24.598, and 26.085.

More preferably, the crystalline form E has an X-ray powder diffraction pattern substantially as shown in FIG1 , having characteristic peaks and their relative intensities at the following diffraction angles 2θ:

As a further preference, the TGA spectrum is shown in Figure 3: Form E has only a 0.2±0.2% weight loss from room temperature to 100°C, and decomposes at around 250°C.

As a further preference, the DSC spectrum is shown in Figure 3: Form E has obvious endothermic peaks at peaks of 167±2°C and 182±2°C, respectively. According to the results of thermal analysis, Form E is an anhydrous substance.

As a further preference, the DVS spectrum is shown in Figure 4: Form E gained 0.10% weight at 95% RH and lost 0.04% weight at 0% RH, indicating that Form E has very poor hygroscopicity. The XRPD results showed that the sample after DVS test did not undergo crystal form change.

Furthermore, the preparation method of the crystal form E of the present invention comprises the following steps:

The indobufen amorphous form is heated to 110-150° C. and then cooled to obtain Form E.

Further, preferably, the heating rate is 10-30°C/min; preferably, the heating process is to heat to 130°C.

Furthermore, preferably, the cooling is natural cooling.

Furthermore, preferably, the preparation method of the amorphous indobufen includes spray drying, rotary evaporation, rapid precipitation, thermal crystallization and the like.

As a specific embodiment, the method for preparing the amorphous indobufen is as follows: heating indobufen to 200-240° C., and then cooling to -5-5° C. to obtain the amorphous indobufen.

Further, preferably, the heating rate is 10-30°C/min; preferably, the temperature of the heating process rises to 230°C,

Furthermore, preferably, during the cooling process, the cooling rate is 20-50°C/min, down to 0°C.

The present invention also discloses a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and an effective amount of indobufen crystal form E.

Furthermore, the indobufen crystal form E is used in the preparation of a drug for preventing and/or treating antiplatelet diseases, wherein the disease is ischemic cardiovascular disease, ischemic cerebrovascular disease, venous thrombosis caused by arteriosclerosis, or for preventing thrombosis during hemodialysis.

Compared with the existing disclosed crystal forms, the advantages of the crystal forms described in the present invention are:

1. By comparing the XRPD with the disclosed indobufen crystal forms, the crystal form E of the present invention is a new crystal form with high purity (see the attached Figure 2 NMR), low hygroscopicity, good crystallinity and regular morphology.

2. Form E can be prepared in multiple batches in small trials, indicating that the crystallization process has good reproducibility, stability and controllability; and the crystallization process is solvent-free and environmentally friendly.

3. Crystal form E is a blocky crystal with good fluidity.

4. The solubility test results show that the solubility of Form E in the three biological media is FaSSIF>FeSSIF>FaSSGF from high to low. Form E can exist stably in the three biological media without crystal transformation, which is of great significance for in vitro dissolution evaluation during the development of formulations.

5. The solubility test results show that the solubility of Form E in the three biological media is better than that of the disclosed Forms A/B/I, and Form B undergoes crystal transformation during the test, while Form A undergoes melting crystal transformation at high temperature. Therefore, in terms of crystal stability, Form E is relatively stable among the currently disclosed crystals, and in terms of solubility in the three biological media, Form E is relatively superior among the currently disclosed crystals.

6. Crystal form E has good stability under high temperature, high humidity and light conditions, and no crystal transformation occurs within 15 days, making it easy to store and transport for a long time.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a powder X-ray diffraction pattern of Form E;

FIG2 is a TGA spectrum and a DSC spectrum of Form E;

FIG3 is a DVS diagram of Form E;

FIG4 is a powder X-ray diffraction pattern of Form E before and after DVS testing;

FIG5 is a PLM diagram of Form E;

FIG6 is a DSC graph of different stages in the preparation process of Form E in Example 2;

FIG7 is a DSC graph of different stages in the preparation process of Form B in Example 4;

FIG8 is a powder X-ray diffraction pattern of Form B in Example 4;

FIG9 is a powder X-ray diffraction pattern of the stability study of Form E in Example 5;

FIG10 is a powder X-ray diffraction pattern of the solid remaining after the crystal form E in Example 6 was shaken in a medium for 24 hours.

DETAILED DESCRIPTION

The present invention will be further described below with reference to the accompanying drawings and in combination with specific embodiments. The embodiments are provided to better illustrate the content of the present invention, but the content of the present invention is not limited to the embodiments. Therefore, those skilled in the art may make non-essential improvements and adjustments to the implementation scheme according to the above invention content, which still fall within the protection scope of the present invention.

Example

Testing instruments and methods:

1. Nuclear magnetic resonance analysis ( ¹ H NMR)

Several milligrams of solid sample were dissolved in dimethyl sulfoxide- ^d6 solvent and subjected to NMR analysis on Bruker AVANCE-III (Bruker, GER).

2. X-ray powder diffraction (XRPD)

The solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2θ scanning angle was from 3° to 45°, the scanning step was 0.02°, and the exposure time was 0.12 seconds. When testing the samples, the tube voltage and current were 40 kV and 40 mA respectively, and the sample pan was a zero background sample pan.

3. Thermogravimetric analysis (TGA)

The model of the thermogravimetric analyzer is TA Discovery 55 (TA, US). 2-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C/min, and the nitrogen purge rate at the sample was 60 mL/min and the nitrogen purge rate at the balance was 40 mL/min.

4. Differential Scanning Calorimetry (DSC)

The model of the differential scanning calorimeter was TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a DSC Tzero sample pan with holes, and heated to the final temperature at a rate of 10°C/min, with a nitrogen purge rate of 50 mL/min in the furnace.

5. Dynamic moisture adsorption and desorption analysis (DVS)

Dynamic moisture adsorption and desorption analysis was performed using DVS Intrinsic (SMS, UK). The test used a gradient mode, with humidity changes of 50%-95%-0%-50%, and the humidity change of each gradient in the range of 0% to 90% was 10%. The gradient endpoint was determined using the dm/dt method, with dm/dt less than 0.002% and maintained for 10 minutes as the gradient endpoint. After the test was completed, the sample was subjected to XRPD analysis to confirm whether the solid morphology had changed.

6. Polarized light microscopy (PLM)

The polarizing microscope model is Nikon Ci-POL (Nikon, Japan). Place a small amount of sample on a glass slide and select a suitable lens to observe the sample morphology.

7. High Performance Liquid Chromatography (HPLC)

The HPLC model was Waters Acquity Arc (Waters, US), and the test conditions were shown in Table 1.

Table 1 HPLC test conditions

Example 1

Weigh indobufen sample (305.4 mg) and place it in a weighing bottle, heat it to 230°C in a blast drying oven, increase the temperature by 10°C/min, keep the temperature constant until the sample is completely melted, quickly take out the weighing bottle, place it at 0°C for 3 minutes, cool it down by 50°C/min, then place the weighing bottle in a 100°C blast drying oven, heat it to 130°C, increase the temperature by 10°C/min, keep the temperature constant for 10 minutes, and then naturally cool it to room temperature to obtain Form E, which is a solid with good crystallinity. Its powder X-ray diffraction pattern is shown in Figure 1;

The TGA spectrum is shown in Figure 2: Form E has only a 0.2% weight loss from room temperature to 100°C, and may decompose at temperatures above 250°C.

The DSC spectrum is shown in Figure 2: Form E has a melting endothermic peak at 167°C, followed by an exothermic signal corresponding to recrystallization at 171°C, and then a melting endothermic peak of the recrystallized solid appears at 182°C. According to the thermal analysis results, Form E is anhydrous.

The DVS spectrum is shown in Figure 3: Form E gained 0.10% weight at 95% RH and lost 0.04% weight at 0% RH, indicating that Form E has very poor hygroscopicity; XRPD results showed that no crystal transformation occurred during the test (see Figure 4).

The PLM image is shown in Figure 5: The PLM image shows that Form E is a block crystal, and the size is generally less than 10μm.

Example 2

Weigh an indobufen sample (85.6 mg) and place it in a weighing bottle. Heat it to 200°C using DSC at a heating rate of 10°C/min. Maintain the temperature until the sample is completely melted. Then cool it to 0°C at a cooling rate of 50°C/min. Then heat it to 125°C at a heating rate of 10°C/min. Maintain the temperature for 10 min. Then naturally cool it to room temperature to obtain Form E.

The crystal form E was subjected to a heating-cooling (50°C/min)-reheating treatment using a DSC analyzer (see attached Figure 6). There was no obvious heat flow signal during the cooling process from 50°C/min to 0°C; during the heating process from 50°C/min to 125°C, a glass transition occurred at around 44°C, and there was a recrystallization exothermic peak at around 100°C.

Example 3

Weigh an indobufen sample (95.3 mg) and place it in a weighing bottle. Heat it to 200°C on a hot plate at a heating rate of 10°C/min. Keep the temperature constant until the sample is completely melted. Then cool it to 0°C at a cooling rate of 50°C/min. Then heat it to 125°C at a heating rate of 10°C/min. Keep the temperature constant for 10 min. Then cool it naturally to room temperature to obtain Form E.

Example 4 - Comparative Example

Weigh an indobufen sample (77.3 mg) and place it in a weighing bottle. Heat it to 200°C on a hot plate at a heating rate of 10°C/min. Keep the temperature constant until the sample is completely melted. Then cool it to 0°C at a cooling rate of 10°C/min. Then heat it to 115°C at a heating rate of 10°C/min. Keep the temperature constant for 10 min. Then cool it naturally to room temperature. Most of the solid obtained is form B, containing a few diffraction peaks of other forms.

Example 5 - Stability Test

About 10 mg of sample was weighed and placed in a weighing bottle, and placed under high temperature (60°C), high humidity (25°C/92.5% RH), light (25°C/4500Lux), and accelerated (40°C/75% RH), and samples were taken for XRPD characterization at 7 days and 15 days. The results are shown in Table 2. The XRPD results show (see Figure 9) that Form E was stable under high temperature, high humidity, light, and accelerated conditions for 15 days, and no crystal transformation occurred.

Table 2 Form E stability study results

Example 6 - Solubility Test

Dynamic solubility determination was performed on Form E in three biological solvents (FaSSIF, FeSSIF and FaSSGF), FaSSIF (Fasted State Simulated Intestinal Fluid, simulating the intestinal fluid in the small intestine of humans in a hungry state before a meal), FeSSIF (Fed State Simulated Intestinal Fluid, simulating the intestinal fluid in the small intestine of humans in a full state after a meal), and FaSSGF (Fasted State Simulated Gastric Fluid, simulating the gastric fluid when the stomach is empty when humans are hungry). The test method is to add about 30 mg of the sample to 4.0 mL of the biological medium and shake it at a constant temperature of 37°C for 24 hours, take samples at 0.5h, 2h and 24h, filter the sampled solution with a 0.22μm water filter membrane, appropriately dilute some samples with higher concentrations with a diluent, measure the signal peak area of the solution with HPLC, and finally calculate the concentration of the compound in the solution based on the peak area, the HPLC standard curve of the raw material and the dilution factor. In addition, the pH value of the supernatant after 24 h was tested, and the remaining solid was subjected to XRPD test. The specific results are shown in Table 3.

The results show that the 24h solubility of Form E in biological media is FaSSIF>FeSSIF>FaSSGF, and all the remaining solids have not undergone crystal transformation (see Figure 10). At the same time, compared with the published crystal forms, the 24h solubility of Form E in the three biological media has obvious advantages.

Table 3 Dynamic solubility test in biological media

The configuration process of the biological medium is shown in Table 4.

Table 4 Preparation process of biological medium

Claims (14)

1. An indobufen crystal form E, characterized in that: the powder X-ray diffraction pattern of the crystal form E has a characteristic diffraction angle 2θ, interplanar spacing d and relative intensity %, and a 2θ error of ±0.2 degrees; the X-ray powder diffraction pattern has diffraction peaks at least at one or more of 2θ angles of 6.346, 15.047, 22.976, 24.598, and 26.085. 2. The indobufen crystal form E according to claim 1, characterized in that: the powder X-ray diffraction pattern of the crystal form E has a characteristic diffraction angle 2θ, interplanar spacing d and relative intensity %, and the 2θ error is ±0.2 degrees; the characteristic diffraction angle 2θ includes 6.346, 13.479, 14.824, 15.047, 17.125, 20.060, 22.045, 22.976, 24.598, and 26.085. 3. The crystalline form E according to claim 1, characterized in that it has an XRPD pattern substantially the same as Figure 1 of the accompanying drawings of the specification. 4. A method for preparing the crystalline form E according to any one of claims 1 to 3, characterized in that the method comprises the following steps: The indobufen amorphous form is heated to 110-150° C. and then cooled to obtain Form E. 5. The preparation method according to claim 4, characterized in that: the heating rate is 10-30°C/min; preferably, the heating process is to heat to 130°C. 6. The preparation method according to claim 4, characterized in that: the cooling is natural cooling. 7. The preparation method according to claim 4, characterized in that: the preparation method of the amorphous indobufen comprises: The indobufen is heated to 200-240°C and then cooled to -5-5°C to obtain an amorphous form. 8. The preparation method according to claim 6, characterized in that: the heating rate is 10-30°C/min; preferably, the heating process is to raise the temperature to 230°C. 9. The preparation method according to claim 6, characterized in that: during the cooling process, the cooling rate is 20-50°C/min, down to 0°C. 10. The crystal form E according to any one of claims 1 to 3, characterized in that: the crystal form E has a weight loss of 0.2±0.2% from room temperature to 100°C and begins to decompose at about 250°C. 11. The crystal form E according to any one of claims 1 to 3, characterized in that the DSC spectrum of the crystal form E has obvious endothermic peaks at peak values of 167±2°C and 182±2°C respectively. 12. The crystalline form E according to any one of claims 1 to 3, characterized in that the crystalline form E has a DSC-TGA spectrum substantially consistent with that of FIG. 3. 13. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and an effective amount of the indobufen crystalline form E according to any one of claims 1 to 3. 14. Use of the indobufen crystal form E according to any one of claims 1 to 3 in the preparation of a medicament for preventing and/or treating an antiplatelet disease, wherein the disease is ischemic cardiovascular disease, ischemic cerebrovascular disease, venous thrombosis caused by arteriosclerosis, or for preventing thrombosis during hemodialysis.

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