Crystal form of religolil solvate and preparation method thereof

Abstract

The invention belongs to the field of chemical medicines, and particularly relates to a novel crystal form of a rerugolil 2-methyltetrahydrofuran solvate, and the novel crystal form of rerugolil 2-methyltetrahydrofuran is a crystal form alpha. Compared with an existing crystal form, the crystal form has high solubility and excellent powder property, is beneficial to storage and operation in a production process, is low in impurity content, and is beneficial to purification of a rugolix crude product and feeding in a refining step.

Description

Technical Field

[0001] The invention belongs to the field of chemical medicine, and specifically relates to a crystal form of relugolix solvate and a preparation method thereof. Background Art

[0002] On December 18, 2020, the U.S. Food and Drug Administration (FDA) approved Orgovyx (relugolix) for the treatment of adult patients with advanced prostate cancer. Relugolix is ​​an oral non-peptide gonadotropin-releasing hormone (GnRH) receptor blocker, jointly developed by Takeda, ASKA and Myovant, and was approved in Japan in 2018 for the treatment of uterine fibroids. In addition to the already approved uterine fibroids and prostate cancer, this product is also being developed in combination with norgestrel for the treatment of pain (phase) and dysmenorrhea (phase) caused by endometriosis.

[0003] In the process of synthesizing relugolix products, by-products may be introduced, and the obtained products also contain unreacted reaction raw materials. The presence of these impurities affects the quality of relugolix products and brings a large amount of separation costs for the industrial production of relugolix. Among them, US10464945B2 discloses a method for preparing relugolix tetrahydrofuran solvate. The tetrahydrofuran solvate product obtained according to the preparation method has large heat-sensitive impurities, and the obtained product particles are fine powders with large electrostatic properties, which is not conducive to the purification of relugolix crude products and feeding in the refining steps. Summary of the invention

[0004] In order to overcome the defects of the prior art, the inventors of the present application accidentally discovered that the crystalline form α of 2-methyltetrahydrofuran solvate of relugolix provided by the present invention has advantages in physical and chemical properties, powder properties, production and storage, such as advantages in at least one aspect of purification, solubility, hygroscopicity, stability, fluidity, adhesion, etc., especially higher solubility, better stability, better purification effect, better fluidity and non-stickiness, which provides a new and better choice for the industrial production and storage of relugolix, and is of great significance.

[0005] The first aspect of the present invention provides a crystalline form α of a compound of formula I:

[0006]

[0007] X is 1 to 4;

[0008] The X-ray powder diffraction pattern of the crystalline form α has diffraction peaks at 2θ of 7.1°±0.2°, 10.3°±0.2°, 10.9°±0.2°, 14.8°±0.2°, 15.4°±0.2°, 16.6°±0.2°, 19.3°±0.2°, 21.1°±0.2°, 22.8°±0.2° and 23.1°±0.2°.

[0009] Furthermore, the X is selected from 1, 2, 3 or 4.

[0010] In some embodiments, the X-ray powder diffraction pattern of Form α is substantially the same as Figure 1 Consistent.

[0011] In some embodiments, the differential scanning calorimetry pattern of Form α is substantially the same as Figure 2 Consistent.

[0012] In some embodiments, the thermogravimetric analysis pattern of Form α is substantially the same as Figure 3 Consistent.

[0013] The second aspect of the present invention provides a method for preparing the crystalline form α of the compound of formula I, comprising the following steps: the relugolix raw material is first slurried with a water-miscible organic solvent, filtered, the obtained filter cake is then slurried with a halogenated hydrocarbon, and then 2-methyltetrahydrofuran is added, and part of the solvent is removed by reduced pressure distillation, and then 2-methyltetrahydrofuran is added again, the temperature is reduced for crystallization, and filtered to obtain the crystalline form α of the compound of formula I.

[0014] In some embodiments, the water-miscible organic solvent is selected from C 3-5 Ketones, C 1-4 alcohols or acetonitrile; the halogenated hydrocarbon is dichloromethane; further the water-miscible organic solvent is selected from acetone, isopropanol, ethanol, methanol or acetonitrile.

[0015] In some embodiments, the temperature of the cooling crystallization is 0-10°C.

[0016] In some embodiments, the ratio of the volume of the re-added 2-methyltetrahydrofuran to the mass of the relugolix drug substance is 2 to 5:1.

[0017] Compared with the prior art, the present invention has the following advantages:

[0018] (1) Compared with the tetrahydrofuran solvate of relugolix, the crystalline form α of the compound of formula I of the present invention has higher solubility. In a methanol solution at a temperature of 10°C, the solubility of the crystalline form α is 3.0 times that of the tetrahydrofuran solvate of relugolix; in an ethanol solution at a temperature of 10°C, the solubility of the crystalline form α is 2.5 times that of the tetrahydrofuran solvate of relugolix.

[0019] The increase in solubility will directly reduce the amount of solvent used during crystallization, thereby reducing production costs and the amount of waste generated, which has important production practical significance.

[0020] (2) Compared with the tetrahydrofuran solvate of relugolix, the crystalline form α of the compound of formula I of the present invention has better powder properties. In the fluidity test, the Hausner ratio of the crystalline form α of the compound of formula I is 1.1, indicating that the crystalline form α has good fluidity, while the Hausner ratio of the tetrahydrofuran solvate is 1.8, indicating that the fluidity of the tetrahydrofuran solvate is very poor. In the adhesion test, the PE bag adsorption rate of the crystalline form α of the compound of formula I is 0.0008, while the PE bag adsorption rate of the tetrahydrofuran solvate is 0.0100, indicating that the crystalline form α of the compound of formula I has lower adhesion and is significantly better than the tetrahydrofuran solvate in the adhesion test.

[0021] Good powder properties can effectively improve or avoid the phenomenon of sticking to the wheel and the punch caused by dry granulation and tablet pressing, which is beneficial to improve the product appearance, weight difference, etc. In addition, the better adhesion of the α-crystal can effectively reduce the agglomeration of raw materials, which is beneficial to the dispersion of raw materials and mixing with other excipients, ensuring the mixing uniformity and content uniformity of the preparation.

[0022] (3) The crystal form α of the compound of formula I obtained by the present invention has a good purification effect, and the purity is greatly improved after the raw material is prepared into the crystal form of the present invention. In a specific embodiment, the purity of the raw material used in the present invention is significantly improved after the crystal form α is prepared by primary crystallization, the yield is higher than that of the tetrahydrofuran solvate, and the content of each impurity is reduced.

[0023] The crystal form with good purification effect can show a strong impurity removal ability in the crystallization process, so that a high-purity raw material drug can be obtained through crystallization, which effectively overcomes the shortcomings of low drug stability, poor efficacy, high toxicity and so on caused by low drug purity, and is beneficial to the purification and refining steps of the crude relugolix.

[0024] (4) The crystalline form α provided by the present invention has better stability. The crystalline form α was not significantly degraded when placed under the conditions of 60°C, 92.5% RH and 45°C / 75% RH for 30 days, while the tetrahydrofuran solvate was significantly degraded when placed under the conditions of 60°C, 92.5% RH and 45°C / 75% RH for 30 days, indicating that the crystalline form α of the compound of formula I has better stability under long-term conditions, which is beneficial to the storage of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 , X-ray powder diffraction (XRPD) spectrum of Form α of the compound of Formula I.

[0026] Figure 2, differential scanning calorimetry (DSC) diagram of Form α of the compound of Formula I.

[0027] Figure 3 , thermogravimetric (TGA) diagram of Form α of the compound of Formula I.

[0028] Figure 4 , X-ray powder diffraction (XRPD) pattern of relugolix tetrahydrofuran solvate.

[0029] Figure 5 , Differential scanning calorimetry (DSC) diagram of relugolix tetrahydrofuran solvate.

[0030] Figure 6 , Thermogravimetric (TGA) graph of relugolix tetrahydrofuran solvate. DETAILED DESCRIPTION

[0031] Example 1. Crystal form screening

[0032] In the process of studying the purification method of crude relugolix, a variety of solvents were screened, and 2-methyltetrahydrofuran solvate was unexpectedly discovered. Further research found that it has a significant purification effect. The specific screening results are summarized in Table 1 below:

[0033] Table 1

[0034]

[0035]

[0036] Example 2. Preparation of Crystalline Form α of Compound of Formula I

[0037] Weigh 10 g of the crude wet product of relugoli into a reactor, add 20 mL of isopropanol and slurry at room temperature for 1 hour. Filter with suction, add 50 mL of dichloromethane to the filter cake, control the internal temperature to about 5 ° C and slurry for 1 hour. Add 50 mL of 2-methyltetrahydrofuran, control the external temperature to about 30 ° C and distill under reduced pressure until the remaining volume is about half of the original volume. After distillation, add 30 mL of 2-methyltetrahydrofuran, control the internal temperature to about 30 ° C and stir for 1 hour. Cool to about 5 ° C and stir for 1 hour. Filter with suction, and after XRPD detection, the obtained solid is the crystal form α of the present invention.

[0038] Example 3. Preparation of Crystalline Form α of Compound of Formula I

[0039] Weigh 20g of the crude wet product of relugoli into a reactor, add 40mL of isopropanol and slurry at room temperature for 1 hour. Filter with suction, add 100mL of dichloromethane to the filter cake, control the internal temperature to about 5°C and slurry for 1 hour. Add 100mL of 2-methyltetrahydrofuran, control the external temperature to about 30°C and distill under reduced pressure until the remaining volume is about half of the original volume. After distillation, add 60mL of 2-methyltetrahydrofuran and crystal form α seeds, control the internal temperature to about 30°C and stir for 1 hour. Cool to about 10°C and stir for 1 hour. Filter with suction, do not dry. XRPD detection shows that the obtained solid is the crystal form α of the present invention.

[0040] Example 4. Preparation of Crystalline Form α of Compound of Formula I

[0041] Weigh 10 g of the crude wet product of relugoli into a reactor, add 20 mL of acetonitrile and slurry at room temperature for 1 hour. Filter with suction, add 50 mL of dichloromethane to the filter cake, control the internal temperature to about 5 ° C and slurry for 1 hour. Add 50 mL of 2-methyltetrahydrofuran, control the external temperature to about 30 ° C and distill under reduced pressure until the remaining volume is about half of the original volume. After distillation, add 30 mL of 2-methyltetrahydrofuran and crystal form α seeds, control the internal temperature to about 30 ° C and stir for 1 hour. Cool to about 0 ° C and stir for 1 hour. Filter with suction, do not dry. XRPD detection shows that the obtained solid is the crystal form α of the present invention.

[0042] Example 5. Preparation of Crystalline Form α of Compound of Formula I

[0043] Weigh 40g of the crude wet product of relugoli into a reactor, add 80mL of acetone and slurry at room temperature for 1 hour. Filter with suction, add 200mL of dichloromethane to the filter cake, control the internal temperature to about 5°C and slurry for 1 hour. Add 200mL of 2-methyltetrahydrofuran, control the external temperature to about 30°C and distill under reduced pressure until the remaining volume is about half of the original volume. After distillation, add 120mL of 2-methyltetrahydrofuran and crystal form α seeds, control the internal temperature to about 30°C and stir for 1 hour. Cool to about 5°C and stir for 1 hour. Filter with suction, do not dry. XRPD detection shows that the obtained solid is the crystal form α of the present invention.

[0044] Table 2 and Figure 1 Characteristic XRPD peaks and patterns of Form α of the compound of Formula I are shown.

[0045] Table 2

[0046]

[0047]

[0048] Example 6. Preparation of Relugoli Tetrahydrofuran Solvate

[0049] Weigh 10 g of relugolix as the starting material and add it to a 100 mL reactor, add 50 mL of tetrahydrofuran, control the internal temperature at 60±5°C and stir for 1 hour. Cool to 5±5°C, stir for 2 hours, filter, take a sample and send it for XRPD inspection. The obtained solid is relugolix tetrahydrofuran solvate.

[0050] Example 7. Comparison of Purification Effects of Form α of Compound of Formula I and Relugolix Tetrahydrofuran Solvate

[0051] The crystal form α of the compound of formula I and the tetrahydrofuran solvate of relugolix were tested. The results are shown in Table 3. The crystal form α had a good impurity removal effect and yield of relugolix, while the tetrahydrofuran solvate had a poor impurity removal effect of relugolix and a lower yield than the crystal form α.

[0052] Table 3

[0053]

[0054] Example 8 Physical / chemical stability study of the crystalline form α of the compound of formula I and relugolix tetrahydrofuran solvate

[0055] The crystal form α of the compound of formula I and the tetrahydrofuran solvate of relugolix were placed under 60°C, 92.5%RH, light and 45°C / 75%RH conditions respectively. The samples were taken before and after placement and the crystal form was determined by XRPD. The results are shown in Table 4. The results show that the crystal form α was not significantly degraded after being placed under 60°C, 92.5%RH and 45°C / 75%RH conditions for 30 days, and the crystal form was stable. The tetrahydrofuran solvate was significantly degraded after being placed under 60°C, 92.5%RH and 45°C / 75%RH conditions for 30 days, and some of the crystals were transformed. Therefore, the stability of the crystal form α placed under 60°C, 92.5%RH, light and 45°C / 75%RH conditions is significantly better than that of the tetrahydrofuran solvate.

[0056] Table 4

[0057]

[0058]

[0059] Example 9. Solubility Study of Crystalline Form α of Compound of Formula I and Relugolix Tetrahydrofuran Solvate

[0060] At different temperatures, the crystalline form α of the compound of formula I and the tetrahydrofuran solvate of relugolix were prepared into saturated solutions with methanol, ethanol and dimethyl sulfoxide, respectively, and the results were recorded. As shown in Table 5, the solubility of the crystalline form α in methanol, ethanol and dimethyl sulfoxide at different temperatures was significantly higher than that of the tetrahydrofuran solvate.

[0061] Table 5

[0062]

[0063] Example 10. Hygroscopicity of the crystalline form α of the compound of formula I and relugolix tetrahydrofuran solvate

[0064] The hygroscopicity of each crystal form was investigated at room temperature and 80% RH humidity by taking samples of the crystal form α of the compound of formula I of the present invention and relugolix tetrahydrofuran solvate. The test results are shown in Table 6. The negative value of the hygroscopicity of the relugolix tetrahydrofuran solvate indicates that the tetrahydrofuran is partially removed and the crystal form is unstable. In terms of hygroscopicity, the crystal form α of the compound of formula I is more reliable than the relugolix tetrahydrofuran solvate, and has certain advantages in crystal stability.

[0065] Table 6

[0066] Crystal form Weight gain after moisture absorption (%) Crystal form α 0 Tetrahydrofuran Solvate -0.1

[0067] Example 11. Fluidity of the crystalline form α of the compound of formula I and relugolix tetrahydrofuran solvate

[0068] The powder properties of the API will affect its fluidity. The Carr coefficient and Hausner ratio tests were performed on the crystalline form α of the compound of Formula I and the tetrahydrofuran solvate of relugolix to compare their fluidity. The fluidity evaluation results are shown in Table 7. The fluidity of the crystalline form α is better than that of the tetrahydrofuran solvate.

[0069] Testing methods for bulk density and tap density:

[0070] This experiment uses a vibrator and is measured according to the fixed volume method. The specific operation is as follows: put the weighed powder into a 50mL measuring cylinder and fix the measuring cylinder on a support. Set the vibration to 55±5 times per minute for 6-8 minutes. Measure the volume change of the powder in the measuring cup. The ratio of the powder mass to the volume of the material before vibration (50mL) is the bulk density of the powder, and the ratio of the powder mass to the volume of the material after vibration is the tap density of the powder.

[0071] The method for converting the Hausner ratio and compression is as follows. The description of the Hausner ratio and fluidity is shown in Table 8:

[0072] Material Hausner ratio = tap density / bulk density

[0073] Material compression degree = (tapped density - bulk density) / tapped density

[0074] Table 7

[0075]

[0076] Table 8

[0077] Hausnaby Liquidity Description 1.00-1.11 Very good liquidity 1.12-1.18 Good liquidity 1.19-1.25 Good or medium fluidity 1.26-1.34 Liquidity is OK 1.35-1.45 Poor liquidity 1.46-1.59 Very poor liquidity

[0078] Example 12 Adhesion of the Compound of Formula I Crystalline Form α and Relugolix Tetrahydrofuran Solvate

[0079] The crystalline form α of the compound of formula I of the present invention and relugolix tetrahydrofuran solvate were put into a ziplock bag of fixed size, the seal was sealed, and the bag was flipped at a speed of 5 rpm for 10 minutes. After changing the direction and continuing to flip at a fixed speed for 10 minutes, the raw materials in the bag were poured out, the remaining raw material mass was accurately weighed, and the adsorption rate was calculated.

[0080] The adsorption rate is calculated as follows:

[0081] Adsorption rate = (initial material mass - remaining material mass) / contact surface area

[0082] The adhesion results of the crystalline form α and the tetrahydrofuran solvate of the compound of formula I are shown in Table 9. From the results, it can be seen that the PE bag adsorption rate of the crystalline form α is better than that of the tetrahydrofuran solvate.

[0083] Table 9

[0084] Solid state crystal <![CDATA[PE bag adsorption rate (g / cm 2 )]]> Crystal form α 0.0008 Tetrahydrofuran Solvate 0.0100

Claims

1. Crystalline Form α of the compound of Formula I: It is characterized in that X is 1 to 4; The X-ray powder diffraction pattern of the crystalline form α has diffraction peaks at 2θ of 7.1°±0.2°, 10.3°±0.2°, 10.9°±0.2°, 14.8°±0.2°, 15.4°±0.2°, 16.6°±0.2°, 19.3°±0.2°, 21.1°±0.2°, 22.8°±0.2° and 23.1°±0.2°.

2. The crystalline form α of the compound of formula I according to claim 1, characterized in that: The X is selected from 1, 2, 3 or 4.

3. The crystalline form α of the compound of formula I according to claim 1, characterized in that: Its X-ray powder diffraction pattern is basically consistent with that in FIG1 .

4. The crystalline form α of the compound of formula I according to claim 1, characterized in that: Its differential scanning calorimetry diagram is basically consistent with that in FIG2 .

5. The crystalline form α of the compound of formula I according to claim 1, characterized in that: Its thermogravimetric analysis diagram is basically consistent with that in FIG3 .

6. A method for preparing the crystalline form α of the compound of formula I according to any one of claims 1 to 5, characterized in that: The relugolix raw material is first slurried with a water-miscible organic solvent and filtered with suction. The resulting filter cake is then slurried with a halogenated hydrocarbon, and then 2-methyltetrahydrofuran is added. Part of the solvent is distilled off under reduced pressure, and then 2-methyltetrahydrofuran is added again. The temperature is lowered for crystallization, and suction is filtered to obtain the crystalline form α of the compound of formula I.

7. The method for preparing the crystalline form α of the compound of formula I according to claim 6, characterized in that: The water-miscible organic solvent is selected from C 3-5 Ketones, C 1-4 alcohols or acetonitrile; the halogenated hydrocarbon is dichloromethane.

8. The method for preparing the crystalline form α of the compound of formula I according to claim 7, characterized in that: The water-miscible organic solvent is selected from acetone, isopropanol, ethanol, methanol or acetonitrile.

9. The method for preparing the crystalline form α of the compound of formula I according to claim 6, characterized in that: The temperature of the cooling crystallization is 0-10°C.

10. The method for preparing the crystalline form α of the compound of formula I according to claim 6, characterized in that: The ratio of the volume of the 2-methyltetrahydrofuran added again to the mass of the relugolix raw material drug is 2 to 5:1.

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