Crystal Form II of Eroviquine and Method for Preparing the Same

Abstract

The crystalline form II of erobicixibat. The X-ray powder diffraction pattern of crystalline form II has specific peaks at 2θ values of 9.4±0.2° and 7.8±0.2°, and has one or more of the following characteristic peaks: 3.9±0.2°, 11.7±0.2°, 16.1±0.2°, 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.9±0.2°, 22.1±0.2°, and 25.8±0.2°. Crystalline form II is stable, has low hygroscopicity, and when exposed to a high humidity environment of 25°C / 92.5%RH, the chemical purity of crystalline form II does not change significantly, and the X-ray powder diffraction pattern of the crystalline form also does not change accordingly. Furthermore, crystalline form II is accompanied by a simple and convenient preparation method, has low requirements for the preparation process and storage conditions, and has high medical value.

Description

Technical Field

[0001] The present invention relates to the crystalline forms of elobixibat, which belongs to the fields of pharmaceuticals and chemical technology.

Background Art

[0002] Elobixibat is a drug (trade name: Goofice) developed by Albireo AB and is the world's first approved ileal bile acid transporter inhibitor. Elobixibat was approved by PMDA for the treatment of chronic constipation in 2018. Compared with conventional intestinal secretion promoters and intestinal motility promoters, elobixibat effectively reduces the hardness of feces, increases the frequency of bowel movements, improves the ease of defecation, and reduces abdominal cramps or pain. The structural formula of this compound is as shown in formula (1).

Chem.

[0003] Patent Document 1 discloses the compound of formula (1) together with its preparation method and pharmaceutical composition.

[0004] Patent Document 2 discloses the monohydrate crystal IV of elobixibat, and its X-ray powder diffraction pattern has specific peaks at 2θ of 6.3±0.2°, 19.4±0.2°, 10.2±0.2°, 10.5±0.2°, 9.4±0.2°, and 9.5±0.2°. This patent also discloses the crystal modifications EtOH-1, MeOH-1, 1-PrOH-1, and 2-PrOH-1 of elobixibat.

[0005] Patent Document 3 (Patent Document 4) discloses anhydrous crystal form C, dihydrate crystal form E, anhydrous crystal form F, anhydrous crystal form L, and dihydrate crystal form N. Anhydrous crystal form C and anhydrous crystal form L have strong hygroscopicity and transfer to hydrated crystals at 30% - 70% RH. Therefore, in the actual manufacturing or preparation process, it is necessary to strictly control moisture and environmental humidity. Patent Document 3 also discloses a method for preparing anhydrous crystal form F involving solid - solid transition of solvates. Specifically, this process requires first preparing MIBK solvate G or EA solvate H and then vacuum - drying at a high temperature of 100°C to obtain the desired product. This preparation process is very demanding and difficult to implement in actual production. Also, the preparation process of anhydrous crystal form F by high - temperature drying often causes problems due to sample inconsistency, making in - process control impossible, leading to the risk of mixed crystallization and a decrease in reproducibility.

[0006] According to previous reports on crystal forms, the eriboxibat compound is likely to form solvates, and these solvates have low drug - discovery potential due to the problem of solvent residues. On the other hand, the hydrate form and anhydrous form of eriboxibat always tend to be hygroscopic or require strict preparation conditions. Only anhydrous crystal form F has barely acceptable hygroscopicity and relatively good stability. However, as shown in its preparation process, this crystal form is obtained by vacuum - drying from the corresponding MIBK solvate G and EA solvate H at a high temperature of 100°C, which is not useful for industrial production and quality control.

[0007] The present invention provides a new crystal form of eriboxibat and a method for preparing the same. This crystal form has stable physical and chemical properties and can meet the requirement of low hygroscopicity for medical purposes. The preparation method of this crystal form is simple to operate and useful for achieving industrial production.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

[0009] Based on the above technical background, the present invention provides an anhydrous crystal form II of elobixibat (hereinafter also referred to as "crystal form II") having good stability and a method for preparing the same.

[0010] The present invention provides a crystal form II of elobixibat, and the X-ray diffraction pattern of crystal form II has peaks characteristic of 2θ values of 9.4 ± 0.2° and 7.8 ± 0.2°.

[0011] The present invention provides a crystal form II of elobixibat, and the X-ray diffraction pattern of crystal form II has peaks characteristic of 2θ values of 9.4 ± 0.2° and 7.8 ± 0.2°, and has one or more of the following characteristic peaks: 3.9 ± 0.2°, 11.7 ± 0.2°, 16.1 ± 0.2°, 17.6 ± 0.2°, 18.3 ± 0.2°, 19.6 ± 0.2°, 20.9 ± 0.2°, 22.1 ± 0.2°, and 25.8 ± 0.2°.

[0012] Furthermore, the X-ray diffraction pattern of elobixibat crystal form II provided by the present invention also has peaks characteristic of 2θ values of 3.9 ± 0.2°, 8.8 ± 0.2° and 19.6 ± 0.2°.

[0013] The present invention provides a crystalline form II of erovixibat, and the X-ray diffraction pattern of the crystalline form II has peaks characteristic of 2θ values of 3.9 ± 0.2°, 7.8 ± 0.2°, 9.4 ± 0.2°, 11.7 ± 0.2°, 16.1 ± 0.2°, 17.6 ± 0.2°, 18.3 ± 0.2°, 19.6 ± 0.2°, 20.9 ± 0.2°, 22.1 ± 0.2° and 25.8 ± 0.2°, and has one or more of the following characteristic peaks: 8.5 ± 0.2°, 8.8 ± 0.2°, 10.4 ± 0.2°, 11.1 ± 0.2°, 13.0 ± 0.2°, 14.0 ± 0.2°, 14.5 ± 0.2°, 15.1 ± 0.2°, 17.1 ± 0.2°, 19.0 ± 0.2°, 20.6 ± 0.2°, 21.3 ± 0.2°, 22.6 ± 0.2°, 23.7 ± 0.2°, 24.5 ± 0.2°, 24.7 ± 0.2°, 26.6 ± 0.2°, 27.2 ± 0.2°, 27.5 ± 0.2°, 28.4 ± 0.2°, 28.6 ± 0.2°, 29.9 ± 0.2°, 30.5 ± 0.2°, 31.6 ± 0.2°, 32.5 ± 0.2°, 33.5 ± 0.2°, 34.5 ± 0.2°, 35.4 ± 0.2°, 37.1 ± 0.2°, and 38.1 ± 0.2°.

[0014] More preferably, the present invention provides a crystalline form II of the compound of formula I, and the XPRD pattern of the crystalline form II is consistent with FIG. 1 or FIG. 2.

[0015] In another aspect, the present invention relates to a method for preparing the crystalline form II, and the method is one selected from the group consisting of the following:

[0016] Method 1: a) Dissolve the raw material erovixibat in a mixed solvent of a ketone or a ketone and a liquid alkane, b) Stir and cool until crystallization, then filter and collect the precipitated crystals, and dry the crystals to obtain the crystalline form II.

[0017] Method 2: a) Suspend the raw material erovixibat in a mixed solvent of a ketone or a ketone and a liquid alkane at an appropriate temperature (for example, 10 °C to 40 °C, preferably room temperature) to obtain a suspension, b) Stir and cool by continuously stirring for a certain period of time (for example, 12 hours or more, preferably 24 to 48 hours) until the crystals are completely precipitated (for example, at 0°C to 8°C, preferably about 5°C), filter and collect the precipitated crystals, and dry the crystals to obtain Crystal Form II.

[0018] Furthermore, the raw material erovixibat used in Method 1 or Method 2 is an amorphous erovixibat or another crystal form of erovixibat. In a preferred embodiment, the raw material erovixibat is the monohydrate crystal form IV of erovixibat reported in Patent Document 2. Furthermore, other solvates of erovixibat (for example, those reported in Patent Document 2 or Patent Document 3 (Patent Document 4), or crystal forms prepared by other conventional crystallization methods), or even other raw material erovixibats such as the amorphous form of erovixibat can also be used.

[0019] In some embodiments, the mass-to-volume ratio (g:mL) of erovixibat to the ketone or the mixed solvent of ketone and liquid alkane in Method 1 or Method 2 is 1:5 to 100, preferably 1:15 to 30.

[0020] In some embodiments, the ketone in Method 1 or Method 2 is preferably selected from acetone, and the liquid alkane is preferably at least one selected from the group consisting of pentane, n-hexane or n-heptane, and more preferably at least one selected from the group consisting of n-hexane or n-heptane.

[0021] In some embodiments, the volume ratio of the ketone to the liquid alkane in Method 1 or Method 2 is 2:1 to 1:15, preferably the ketone is acetone, the liquid alkane is n-hexane or n-heptane, and the volume ratio of acetone to n-hexane or the volume ratio of acetone to n-heptane is 2:1 to 1:15, preferably 1:3 to 1:10.

[0022] In some embodiments, the drying in Method 1 or Method 2 is vacuum drying or blowing drying. Preferably, the drying time is from 1 hour to 24 hours.

[0023] In some embodiments, step a) of Method 1 of dissolving the raw material eribixibat in a solvent of a ketone or a mixed solvent of a ketone and a liquid alkane may include heating the solution to dissolve the material. In the method of the present invention, it is preferably heated to a temperature of 50°C to 60°C. The heating and cooling rates do not have a decisive influence on the formation of Crystal Form II. However, considering various aspects such as industrialization, it is recommended to heat at a rate of 5°C to 30°C / min, for example, specifically at a rate of 5°C to 15°C / min.

[0024] In some embodiments, in step b) of Method 1, it is recommended to cool at a rate of 1°C to 15°C / min, preferably to cool naturally to room temperature.

[0025] The Crystal Form II of eribixibat provided by the present invention has a DSC thermogram with an endothermic peak at 169.5 ± 0.5°C.

[0026] Furthermore, the Crystal Form II of eribixibat provided by the present invention has a DSC thermogram with the same endothermic peak position as shown in Figure 4.

[0027] Without limitation, in a specific embodiment of the present invention, when the above-mentioned Crystal Form II of eribixibat provided by the present invention is subjected to thermogravimetric analysis (TGA) at a heating rate of 10°C / min from room temperature to 300°C, it shows a weight loss of 2% or less, preferably 1.2% or less, by 150°C. Crystal Form II is an anhydrous crystal form. The anhydrous crystal form has no risk of losing the solvent and thus has no risk of crystallizing under reduced pressure and high temperature. Therefore, it is only necessary to remove the solvent from the surface. Preferably, the solid is dried at room temperature under a vacuum environment.

[0028] Although not limited, in a particular embodiment of the present invention, the crystalline form II of elovibibat provided by the present invention exhibits a stable physical form in a room temperature environment. The crystalline form II does not absorb water molecules to form a hydrate crystal form IV or any other hydrate crystal form even when exposed to moisture in the air.

[0029] Although not limited, in a particular embodiment of the present invention, the crystalline form II of elovibibat provided by the present invention exhibits stable chemical purity in a room temperature environment. The chemical purity of the crystalline form II does not change significantly even when exposed to a high humidity environment of 40 °C / 75%RH or 25 °C / 92.5%RH.

[0030] Although not limited, in a particular embodiment of the present invention, the crystalline form II of elovibibat provided by the present invention is slightly hygroscopic when exposed to an environment of 25 °C and 0% - 90%RH, and the XRPD pattern shows no signs of crystallographic transition.

[0031] The DVS isotherm plot of the crystalline form II provided by the present invention shows no signs of a significant change in moisture content (Figure 8 shows that the water absorption is 1.1%, which is significantly lower than the 5.0% (0% - 90%RH) of the crystalline form C reported in Patent Document 3 (Patent Document 4)). The XRPD pattern of the sample is consistent before and after the hygroscopicity test, indicating that there is no risk of crystal transition during the adsorption - desorption process. The crystalline form II provided by the present invention is more suitable for industrial production. Compared with Figure 10, the crystalline form II provided by the present invention shows significant differences from all the crystalline forms reported in Patent Document 3 and can be identified as a different crystalline form.

[0032] The present invention also provides a therapeutic agent for constipation containing an active ingredient, and the active ingredient contains crystal form II of the above-described elobixibat crystal. This medicament contains an excipient in addition to the active ingredient. The selection of the excipient and the preparation of the medicament are conventional options. For example, pharmaceutical excipients can be selected from microcrystalline cellulose, D-mannitol, hydroxypropylmethylcellulose, croscarmellose sodium, light anhydrous silicic acid, magnesium stearate, polyethylene glycol 6000, titanium oxide, yellow iron oxide, carnauba wax, and the like.

[0033] The active ingredient of the medicament provided by the present invention may contain only crystal form II of elobixibat, and in that case, crystal form II of elobixibat is present in an effective amount. The medicament provided by the present invention has a significantly improved solubility of crystal form II compared with existing medicaments containing elobixibat crystal form (monohydrate), and thus has a more flexible excipient selection and enhanced pharmaceutical safety.

[0034] The new anhydrous crystal form II of elobixibat provided by the present invention has good stability and low hygroscopicity compared with the prior art, satisfies pharmaceutical requirements, and also exhibits significantly improved solubility. This is expected to be an ideal option for pharmaceutical formulations, having better bioavailability and contributing to enhanced drug efficacy and reduced dosage.

[0035] This crystal form has milder drying conditions than crystal form IV, and crystal form II provided by the present invention can be vacuum-dried at 30°C to 60°C without the risk of losing moisture and causing crystal transition.

Brief Description of the Drawings

[0036]

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Figure 8

Figure 9

Figure 10

Embodiments for Carrying Out the Invention

[0037] In order to further illustrate the present invention, the following specific embodiments are provided. It should be understood that the following detailed description of the technical solutions in these embodiments only helps to further understand the advantages and effects of the technical solutions of the present invention, and does not limit the scope of the present invention. The protection scope of the invention is defined by the scope of the patent claims.

[0038] Experimental methods not specifically described in the embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0039] Unless otherwise specified, the raw materials or reagents used in the embodiments are commercially available.

[0040] Unless otherwise specified, the reagents mentioned are used as they are without purification. All solvents are purchased from commercial suppliers and used without further treatment.

[0041] The XPRD pattern was collected using a Bruker D8 ADVANCE diffractometer. The parameters of the X-ray powder diffraction method were as follows: X-ray reflection parameter: Cu, Kα Tube voltage: 40 kilovolts (kV) Tube current: 40 milliamperes (mA) Slit: No. 2 Scattering slit: 1°, No. 3 Anti-scattering slit: 1°, No. 4 Receiving slit: 0.3 mm Scan mode: Step-and-scan Step angle: 0.02° Sampling time: 0.2 seconds Scan range: 3.0° to 40.0°

[0042] Dynamic vapor sorption (DVS) Weigh approximately 5 mg to 16 mg of the sample, place it in a metal container, and put the metal container into an Intrinsic DVS Advantage device. The sample undergoes two consecutive adsorption-desorption cycles each performed at relative humidities (%RH) of 0% to 90% to 0%. Each cycle consists of 10 steps, and each of these steps varies by 10% RH between 0% and 90% RH. At each stage, the following equilibrium criterion is used: dm / dt < 0.002% in 5 minutes (dm is the mass change and dt is the time change, and the minimum and maximum times for each phase are 10 minutes and 360 minutes respectively).

[0043] Comparative example Weighed out 111 mg of the monohydrate form IV of elobixibat (prepared according to the method of Example 6 of Patent Document 2), placed it in a 10 mL test tube, and added a magnetic stir bar and 2.0 mL of a 50:50% (v / v) acetone / water mixed solution. The observed phenomenon was as follows: A gel-like substance was formed, and it needed to be stirred manually and shaken vigorously for several minutes. The test tube was closed and magnetically stirred at 20 °C to 30 °C.

[0044] The contents of the test tube were filtered, poured into a crystallization bowl, and then dried in vacuo at 60 °C for 2 hours. Analysis of the sample by XRPD showed that the solid form was the anhydrous form C. By comparison of the XRPD patterns, it was confirmed that it was the same crystal form as the anhydrous crystal form C disclosed in Patent Document 3 (Patent Document 4).

[0045] Example 1: Crystal Form II of Elobixibat Example 1.1 Added 30 mg of crude elobixibat to 0.5 mL of an acetone / n-hexane mixed solvent (volume ratio 1:1) and heated it to 50 °C to 55 °C. Stirring was continued while cooling the mixture at a rate of 5 °C / min until the temperature reached 25 °C, and then the mixture was maintained at this temperature for 24 hours while stirring. Vacuum filtration was carried out, and the filter cake was dried in vacuo at 50 °C to 60 °C for 16 hours. Then, a sample was taken for testing.

[0046] The X-ray powder diffraction pattern of the solid product obtained after the test is as shown in Figure 1. The X-ray diffraction pattern of the obtained crystal form II has characteristic peaks at 2θ values of 3.9±0.2°, 7.8±0.2°, 9.4±0.2°, 11.7±0.2°, 16.1±0.2°, 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.9±0.2°, 22.1±0.2° and 25.8±0.2°, and has one or more of the following characteristic peaks: 8.5±0.2°, 8.8±0.2°, 10.4±0.2°, 11.1±0.2°, 13.0±0.2°, 14.0±0.2°, 14.5±0.2°, 15.1±0.2°, 17.1±0.2°, 19.0±0.2°, 20.6±0.2°, 21.3±0.2°, 22.6±0.2°, 23.7±0.2°, 24.5±0.2°, 24.7±0.2°, 26.6±0.2°, 27.2±0.2°, 27.5±0.2°, 28.4±0.2°, 28.6±0.2°, 29.9±0.2°, 30.5±0.2°, 31.6±0.2°, 32.5±0.2°, 33.5±0.2°, 34.5±0.2°, 35.4±0.2°, 37.1±0.2°, and 38.1±0.2°.

[0047] The TGA thermogram of the obtained crystal form II is shown in Figure 3. The TGA data shows that the crystal form has a weight loss of approximately 1.02% in the heating range of 0°C to 150°C.

[0048] As shown in Figure 4, the DSC thermogram of the obtained crystal form II shows that crystal form II has a single melting endothermic peak at 164°C to 200°C. Specifically, crystal form II has a single absorption peak at 169.5±0.5°C.

[0049] Example 1.2 30 mg of crude elobixibat was added to 0.6 mL of acetone and stirred at 50°C to 60°C. Stirring was continued while cooling the mixture until the temperature reached 25°C, and then the mixture was maintained at this temperature for 24 hours. Vacuum filtration was performed, and the filter cake was vacuum dried at 40°C for 16 hours. Then, a sample was taken for testing to obtain crystal form II.

[0050] After the test, the X-ray powder diffraction pattern of the obtained solid product is as shown in Figure 2. The X-ray powder diffraction pattern measured using the Cu-Kα line of the obtained crystal is consistent with that of Example 1.1.

[0051] Example 1.3 30 mg of crude elobixibat was added to 0.5 mL of an acetone / n-hexane mixed solvent (volume ratio 1:3), and the mixture was stirred at 55 °C to 60 °C. Stirring was continued while cooling the mixture until the temperature reached 25 °C, and then the mixture was maintained at this temperature for 24 hours. Vacuum filtration was performed, and the filter cake was vacuum dried at 40 °C for 16 hours. Then, a sample was taken for testing, and crystalline form II was obtained.

[0052] The X-ray powder diffraction pattern measured using the Cu-Kα line of the obtained crystal is consistent with that of Example 1.1.

[0053] Example 1.4 30 mg of crude elobixibat was added to 0.6 mL of an acetone / n-hexane mixed solvent (volume ratio 1:5), and the mixture was stirred at 20 °C to 30 °C to obtain a suspension. Stirring was continued while cooling the mixture until the temperature reached 5 °C, and then the mixture was maintained at this temperature for 48 hours. Vacuum filtration was performed, and the filter cake was vacuum dried at 30 °C for 16 hours. Then, a sample was taken for testing, and crystalline form II was obtained.

[0054] The X-ray powder diffraction pattern measured using the Cu-Kα line of the obtained crystal is consistent with that of Example 1.1.

[0055] Example 1.5 30 mg of crude elobixibat was added to 0.5 mL of an acetone / n-hexane mixed solvent (volume ratio 1:9), and the mixture was stirred at 50 °C to 55 °C. Stirring was continued while cooling the mixture until the temperature reached 25 °C, and then the mixture was maintained at this temperature for 24 hours. Vacuum filtration was performed, and the filter cake was vacuum dried at 30 °C for 16 hours. Then, a sample was taken for testing, and crystalline form II was obtained.

[0056] The X-ray powder diffraction pattern measured using the Cu-Kα ray of the obtained crystal is consistent with that of Example 1.1.

[0057] Example 1.6 30 mg of crude elobixibat was added to 0.5 mL of an acetone / n-hexane mixed solvent (volume ratio 1:3), and the mixture was stirred at 50 °C to 55 °C. Stirring was continued while cooling the mixture until the temperature reached 25 °C, and then the mixture was maintained at this temperature for 24 hours. Vacuum filtration was performed, and the filter cake was vacuum dried at 30 °C for 12 hours. Then, a sample was taken for testing, and crystalline form II was obtained.

[0058] The X-ray powder diffraction pattern measured using the Cu-Kα ray of the obtained crystal is consistent with that of Example 1.1.

[0059] Example 1.7 30 mg of crude elobixibat was added to 0.5 mL of an acetone / n-hexane mixed solvent (volume ratio 1:7), and the mixture was stirred at 20 °C to 30 °C to obtain a suspension. Stirring was continued while cooling the mixture until the temperature reached 5 °C, and then the mixture was maintained at this temperature for 48 hours. Vacuum filtration was performed, and the filter cake was vacuum dried at 30 °C for 16 hours. Then, a sample was taken for testing, and crystalline form II was obtained.

[0060] The X-ray powder diffraction pattern measured using the Cu-Kα ray of the obtained crystal is consistent with that of Example 1.1.

[0061] Example 1.8 30 mg of crude elobixibat was added to 3 mL of an acetone / n-hexane mixed solvent (volume ratio 1:15), and the mixture was stirred at 50 °C to 55 °C. Stirring was continued while cooling the mixture until the temperature reached 25 °C, and then the mixture was maintained at this temperature for 24 hours. Vacuum filtration was performed, and the filter cake was vacuum dried at 30 °C for 16 hours. Then, a sample was taken for testing, and crystalline form II was obtained.

[0062] The X-ray powder diffraction pattern measured using the Cu-Kα ray of the obtained crystal is consistent with that of Example 1.1.

[0063] Example 1.9 30 mg of crude elobixibat was added to 0.15 mL of an acetone / n-hexane mixed solvent (volume ratio 2:1), and the mixture was stirred at 50 °C to 55 °C. Stirring was continued while cooling the mixture until the temperature reached 25 °C, and then the mixture was maintained at this temperature for 24 hours. Vacuum filtration was performed, and the filter cake was dried in vacuo at 30 °C for 16 hours. Then, a sample was taken for testing to obtain Crystal Form II.

[0064] The X-ray powder diffraction pattern measured using the Cu-Kα line of the obtained crystals is consistent with that of Example 1.1.

[0065] Example 2 Stability Test Crystal Form II obtained in Example 1.1, Crystal Form IV prepared according to the method of Patent Document 2, and Crystal Form C obtained in the Comparative Example were exposed to different temperature and humidity conditions for 3 days or 1 week. Samples were taken from each group for XRPD determination to compare the crystal forms, and the purity was measured by HPLC to compare the chemical purity. The results are shown in Table 1.

[0066] [Table 1]

[0067] As can be seen from the data in Table 1, the results show that Crystal Form II of elobixibat provided by the present invention and Crystal Form IV prepared according to the method of Patent Document 2 have similar stability.

[0068] As shown in FIGS. 5 and 7, the X-ray powder diffraction patterns of crystalline form II provided by the present invention and crystalline form IV prepared according to the method of Patent Document 2 show no significant changes when stored for one week under five different humidity and temperature conditions (25°C / 60%RH, 40°C / 75%RH, 25°C / 92.5%RH, room temperature environment (28°C / 66%RH) or (25°C / 10%RH)) shown in Table 1, indicating that these crystalline forms can be stored in the above-mentioned environment for at least one week.

[0069] As shown in FIG. 6, when crystalline form C was stored for 3 days under five different humidity and temperature conditions (25°C / 60%RH, 40°C / 75%RH, 25°C / 92.5%RH, room temperature environment (28°C / 66%RH)) shown in Table 1, it transformed into crystalline form E disclosed in Patent Document 3.

[0070] Crystalline form II and crystalline form IV have good stability even under high temperature and high humidity conditions. In particular, crystalline form II of erovibibat shows particularly excellent stability because no change in the purity of crystalline form II of erovibibat is observed under the conditions of 40°C / 75%RH and 25°C / 92.5%RH.

[0071] Example 3 Hygroscopicity test A moisture adsorption / desorption test of about 15 mg of crystalline form II prepared in Example 1.1 under the conditions of 0% - 90% - 0%RH was measured, and its hygroscopicity was measured using a dynamic vapor sorption (DVS) apparatus.

[0072] The experimental results are shown in Table 2.

[0073]

Table 2

[0074] The DVS pattern of the hygroscopicity test of crystalline form II is as shown in FIG. 8, and the comparative diagram of XPRD before and after the test is as shown in FIG. 9.

[0075] The results showed that the crystalline form II of the present application had a weight increase of approximately 1.14% after reaching equilibrium at 90% humidity and was classified as slightly hygroscopic. This demonstrates that the crystalline form II of the present application maintains stability under different humidity conditions and exhibits good low hygroscopicity.

[0076] Patent Document 3 (Patent Document 4) discloses the DVS of anhydrous crystalline form C and crystalline form E. Crystalline form C undergoes a transition to the hydrated form E at 30% - 70% RH and absorbs approximately 5% water at 90% humidity. In actual manufacturing processes or formulation processes, strict control of moisture and environmental humidity is required.

[0077] Patent Document 2 discloses the DVS of monohydrate crystalline form IV, which absorbs approximately 2.45% water between 0% RH and 10% RH and absorbs more than 3% water at 90% humidity. Similarly, moisture and environmental humidity must be controlled during manufacturing and formulation to prevent polymorphic transitions.

[0078] Therefore, the crystalline form II in the present application demonstrates better low hygroscopicity compared to the anhydrous crystalline form C disclosed in Patent Document 3 (Patent Document 4) and the monohydrate crystalline form IV disclosed in Patent Document 2. In the manufacturing process and storage process of pharmaceuticals, crystalline form II can maintain a stable state without the need for strict humidity control, so the requirements for the drug preparation process and storage conditions are not so strict.

[0079] Example 4 Under room temperature conditions (approximately 35°C), samples of crystalline form C prepared in the comparative example, crystalline form II prepared in Example 1.1, and crystalline form IV prepared according to the method of Patent Document 2 were each added to a phosphate buffer solution pH 6.8 (simulated artificial intestinal fluid). The content of eribulin in the solution was measured by high-performance liquid chromatography (HPLC) after 2 hours, 6 hours, and 24 hours respectively. The experimental results are shown in Table 3.

[0080]

Table 3

[0081] The results showed that the crystalline form II of the present application had significantly higher solubility and dissolution rate in phosphate buffer (pH 6.8) than the crystalline form IV obtained according to the method of Patent Document 2.

Industrial Applicability

[0082] The present invention provides a crystalline form II of eriboxibat and a method for preparing the same. This crystalline form has stable physical properties and chemical characteristics and can meet the requirement of low hygroscopicity for medical purposes. The method for preparing this crystalline form is simple to operate and is useful for achieving industrial production.

Claims

**Claim 1** The crystalline form II of erovixibat, wherein the crystalline form II has peaks characteristic of diffraction angles 2θ of 9.4 ± 0.2° and 7.8 ± 0.2° in the X-ray powder diffraction pattern, and the following characteristic peaks: one or more of 3.9 ± 0.2°, 11.7 ± 0.2°, 16.1 ± 0.2°, 17.6 ± 0.2°, 18.3 ± 0.2°, 19.6 ± 0.2°, 20.9 ± 0.2°, 22.1 ± 0.2°, and 25.8 ± 0.2°. The crystalline form II of erovixibat. **Claim 2** The crystalline form II of erovixibat according to claim 1, wherein the crystalline form II has peaks characteristic of diffraction angles 2θ of 3.9 ± 0.2°, 8.8 ± 0.2°, and 19.6 ± 0.2° in the X-ray powder diffraction pattern. **Claim 3** The crystalline form II of erovixibat according to claim 1, wherein the crystalline form II has peaks characteristic of diffraction angles 2θ of 3.9 ± 0.2°, 7.8 ± 0.2°, 9.4 ± 0.2°, 11.7 ± 0.2°, 16.1 ± 0.2°, 17.6 ± 0.2°, 18.3 ± 0.2°, 19.6 ± 0.2°, 20.9 ± 0.2°, 22.1 ± 0.2°, and 25.8 ± 0.2°, and the following characteristic peaks: one or more of 8.5 ± 0.2°, 8.8 ± 0.2°, 10.4 ± 0.2°, 11.1 ± 0.2°, 13.0 ± 0.2°, 14.0 ± 0.2°, 14.5 ± 0.2°, 15.1 ± 0.2°, 17.1 ± 0.2°, 19.0 ± 0.2°, 20.6 ± 0.2°, 21.3 ± 0.2°, 22.6 ± 0.2°, 23.7 ± 0.2°, 24.5 ± 0.2°, 24.7 ± 0.2°, 26.6 ± 0.2°, 27.2 ± 0.2°, 27.5 ± 0.2°, 28.4 ± 0.2°, 28.6 ± 0.2°, 29.9 ± 0.2°, 30.5 ± 0.2°, 31.6 ± 0.2°, 32.5 ± 0.2°, 33.5 ± 0.2°, 34.5 ± 0.2°, 35.4 ± 0.2°, 37.1 ± 0.2°, and 38.1 ± 0.2°. **Claim 4** The crystalline form II of erovixibat according to claim 1, wherein the crystalline form II has an X-ray powder diffraction pattern that matches Figure 1 or Figure 2. **Claim 5** The crystalline form II of erovixibat according to claim 1, wherein the crystalline form II has a DSC pattern with an endothermic peak at 169.5 ± 0.5°C. **Claim 6** The crystalline form II according to claim 1 of the elobixibat, having a TGA pattern showing a weight loss of 2% or less, preferably 1.2% or less, between 0 °C and 150 °C.

7. A method for preparing the crystalline form II of elobixibat according to any one of claims 1 to 6, wherein the method is as follows: Method 1: a) Dissolve the raw material elobixibat in a ketone or a mixed solvent of a ketone and a liquid alkane. b) Stir and cool until crystallization, filter and collect the precipitated crystals, and dry the crystals to obtain the crystalline form II. Method 2: a) Suspend the raw material elobixibat in a ketone or a mixed solvent of a ketone and a liquid alkane at 10 °C to 40 °C to obtain a suspension. b) Stir continuously for 12 hours or more, preferably 24 hours to 48 hours, until the crystals are completely precipitated, while stirring and cooling to 0 °C to 8 °C, filter and collect the precipitated crystals, and dry the crystals to obtain the crystalline form II. The preparation method is one selected from the group consisting of.

8. The preparation method according to claim 7, wherein the raw material elobixibat used in Method 1 or Method 2 is amorphous elobixibat or another crystalline form of elobixibat, preferably the monohydrate crystalline form IV of elobixibat.

9. The preparation method according to claim 7 or 8, wherein the mass-to-volume ratio (g: mL) of the elobixibat to the ketone or the mixed solvent of the ketone and the liquid alkane in Method 1 or Method 2 is 1: (5 to 100), preferably 1: (15 to 30).

10. In Method 1 or Method 2, the ketone is acetone, and the liquid alkane is at least one selected from the group consisting of pentane, n-hexane or n-heptane, and more preferably at least one selected from the group consisting of n-hexane or n-heptane. The preparation method according to claim 7 or 8.

11. In Method 1 or Method 2, the volume ratio of the ketone to the liquid alkane is preferably 2:1 to 1:15, preferably the ketone is acetone, and the liquid alkane is n-hexane or n-heptane. The preparation method according to claim 7 or 8.

12. The preparation method according to claim 7 or 8, wherein step a) of Method 1 involves dissolving the raw material erovixibat in the mixed solvent of the ketone or the ketone and the liquid alkane by heating the solution, preferably to a temperature of 50°C to 60°C.

13. A pharmaceutical composition comprising the crystalline form II of erovixibat according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

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