Enpatoran crystal form as well as preparation method and application thereof

Abstract

The invention relates to a novel crystal form of Enpatoran (hereinafter referred to as' Compound I ') and a preparation method thereof, a pharmaceutical composition containing the crystal form, and application of the crystal form in preparation of TLR7 / 8 inhibitor drugs and drugs for treating skin type lupus erythematosus and systemic lupus erythematosus. # imgabs0 #

Description

Enpatoran crystal form, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of crystal chemistry, and more particularly to a crystal form of Enpatoran, a preparation method thereof, and uses thereof. Background Art

[0002] Toll-like receptors (TLRs) are a group of pattern recognition receptors in the innate immune system that can recognize conserved microbial RNA structures such as lipopolysaccharide, flagellin, and viruses. TLR7 and TLR8 can recognize microbial single-stranded RNA, purine analogs, and imidazoquinolines, causing the body to produce inflammatory cytokines and immune responses to protect the host. Abnormal activation of TLR7 / 8 is potentially pathogenic and is associated with the progression of autoimmune diseases such as lupus. Lupus can cause joint pain, fever, rash, and organ damage. There are several different types of lupus. Systemic lupus erythematosus (SLE) is the most common, affecting 70% of lupus patients. Other types of lupus include cutaneous lupus erythematosus (CLE), drug-induced lupus, and neonatal lupus. The global number of newly diagnosed SLE patients is estimated to be 400,000 per year, and there is still an urgent need to develop Toll-like receptor inhibitors for the treatment of lupus.

[0003] Enpatoran is a Toll-like receptor 7 / 8 (TLR7 / 8) inhibitor developed by Merck that blocks the activation of Toll-like receptors TLR7 and TLR8, and has achieved positive results in the clinical stage for the treatment of cutaneous lupus erythematosus and systemic lupus erythematosus. The chemical name of Enpatoran is 5-((3R, 5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile) (hereinafter referred to as "Compound I"). WO2017106607A1 discloses the structure of Compound I, but does not disclose any solid form of Compound I, and the amorphous form of Compound I is obtained by Example 31 of WO2017106607A1. The structural formula of Compound I is as follows:

[0004] In small molecule drug development, drug polymorphism is a common phenomenon and a significant factor affecting drug quality. Crystals are solids whose compound molecules are arranged in an orderly three-dimensional microstructure, forming a lattice. Polymorphism refers to the phenomenon of a single compound existing in multiple crystalline forms. A compound may exist in one or more crystalline forms, but their existence and properties cannot be precisely predicted.

[0005] Different solid forms of active pharmaceutical ingredients (APIs) have different physicochemical properties, including chemical stability, thermal stability, solubility, and hygroscopicity. This can lead to varying dissolution and absorption of the drug in the body, thereby impacting the drug's clinical efficacy to a certain extent. Furthermore, different solid forms of active pharmaceutical ingredients (APIs) have different manufacturability characteristics, including yield, purification, filtration, drying, milling, and stability to pressure during tableting, which can affect the processing of the active pharmaceutical ingredient during production. Therefore, different solid forms of active pharmaceutical ingredients may have different properties, providing opportunities to improve drug performance.

[0006] In order to find a new solid form that can improve the performance of drugs, the inventors of the present application accidentally discovered that the crystalline solid of Compound I provided by the present invention has advantages in at least one aspect of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and bioavailability. In particular, it has good physicochemical stability, low hygroscopicity, good purification effect and high purity, and has good stability in the drug preparation process, is more suitable for drug preparation development, and is of great significance to the development of drugs containing Compound I.

[0007] Summary of the Invention

[0008] The present invention provides a crystalline solid of Compound I, a method for preparing the same, and a pharmaceutical composition comprising the crystalline solid.

[0009] According to the object of the present invention, the present invention provides a crystalline solid of Compound I.

[0010] According to the purpose of the present invention, the present invention provides an anhydrate of Compound I.

[0011] According to the purpose of the present invention, the present invention provides a hydrate of compound I.

[0012] According to the purpose of the present invention, the present invention provides a crystalline form CSI of Compound I (hereinafter referred to as "crystalline form CSI").

[0013] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 8.8°±0.2°, 13.5°±0.2°, and 11.4°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 8.8°±0.2°, 13.5°±0.2°, and 11.4°±0.2°.

[0014] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 9.8°±0.2°, 18.5°±0.2°, and 21.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 9.8°±0.2°, 18.5°±0.2°, and 21.9°±0.2°.

[0015] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one or two of the diffraction angles 2θ of 14.2°±0.2° and 23.5°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 14.2°±0.2° and 23.5°±0.2°.

[0016] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, or two, or three, or four, or five, or six, or seven, or eight, or nine of the diffraction angles 2θ of 8.8°±0.2°, 13.5°±0.2°, 11.4°±0.2°, 9.8°±0.2°, 18.5°±0.2°, 21.9°±0.2°, 14.2°±0.2°, 23.5°±0.2°, 15.3°±0.2°, 20.6°±0.2°, and 25.1°±0.2°.

[0017] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSI is substantially as shown in FIG1 .

[0018] Without limitation, the thermogravimetric analysis of Form CSI is substantially as shown in FIG. 2 , with a mass loss of approximately 0.08% when heated to approximately 150° C.

[0019] Without limitation, the differential scanning calorimetry chart of Form CSI comprises two endothermic peaks, the peak temperature of the first endothermic peak being about 143°C, and the peak temperature of the second endothermic peak being about 164°C.

[0020] Without limitation, the differential scanning calorimetry analysis diagram of Form CSI is substantially as shown in FIG3 .

[0021] Without limitation, the crystalline form CSI is an anhydrate.

[0022] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSI, the preparation method comprising:

[0023] The solid compound I is placed in a mixed solvent of alcohol and water and stirred, and the crystalline form CSI is separated.

[0024] Furthermore, the alcohol is preferably methanol; and the volume ratio of the alcohol to water in the mixed solvent is preferably 1:5.

[0025] The crystalline CSI provided by the present invention has the following unexpected technical effects:

[0026] (1) Crystalline CSI has lower hygroscopicity.

[0027] The crystalline form CSI has a hygroscopic weight gain of 0.36% at 0%-80% RH, while the amorphous form has a hygroscopic weight gain of 7.45% at 0%-80% RH. Crystalline CSI has low hygroscopicity, making it less demanding on drug production and storage, reducing drug production, storage, and quality control costs, and possessing strong economic value.

[0028] (2) Crystalline CSI is more suitable for the preparation of pharmaceutical preparations.

[0029] Crystalline CSI maintains its solid form after grinding in ethanol and remains stable before and after the formulation process. The solid form of the amorphous form changes after grinding in ethanol. Wet granulation is commonly used in the production of solid dosage forms. Wet granulation often requires mixing the active pharmaceutical ingredient with a wetting agent such as water or ethanol and applying mechanical force. Crystalline CSI exhibits good physical stability and low hygroscopicity in alcoholic solvents, which can reduce the risk of decreased crystallinity and solid form transformation of the active pharmaceutical ingredient during wet granulation.

[0030] (3) Crystalline CSI has better purification effect.

[0031] After the raw materials are prepared into crystalline CSI, the purity is significantly improved. In a specific embodiment, using raw materials with a purity of 97.09%, after the crystalline CSI is prepared, the purity is increased to 99.00%, and the purity is increased by 1.91%. However, when the same raw materials are prepared into an amorphous form, the purity is reduced by 0.23%. Crystalline CSI has a good purification effect and has a strong ability to remove impurities. Through crystallization, a higher purity raw material can be obtained, which effectively overcomes the shortcomings of low drug purity such as poor drug stability, poor efficacy, and high toxicity.

[0032] (4) Crystalline CSI has better stability.

[0033] Crystalline CSI has better humidity stability. After the two amorphous forms were subjected to humidity changes from 0% RH to 95% RH and then to 0% RH, the solid form of crystalline CSI remained unchanged, while the solid form of the amorphous form changed. This indicates that crystalline CSI has better humidity stability than the amorphous form.

[0034] Crystalline CSI exhibits superior physicochemical stability. When stored at 40°C / 75% RH, the solid form of the crystalline CSI remained unchanged for at least six months, with essentially unchanged purity. When stored at 60°C / 75% RH, the solid form remained unchanged for at least three months, with essentially unchanged purity. The amorphous form undergoes a solid form change after one week at 60°C / 75% RH.

[0035] Crystalline CSI formulations exhibit excellent stability. When mixed with excipients to form pharmaceutical preparations, the solid form of crystalline CSI remained unchanged for at least one month at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH, and the purity remained essentially unchanged during storage.

[0036] High humidity conditions caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs. The excellent stability of crystalline CSI and formulations helps prevent the effects of solid form changes on drug quality during storage, transportation, and production, thereby ensuring consistent and controllable API quality and minimizing changes in drug quality, bioavailability, and toxic side effects caused by solid form changes.

[0037] According to the purpose of the present invention, the present invention provides a crystalline form CSII of Compound I (hereinafter referred to as "crystalline form CSII").

[0038] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 8.5°±0.2°, 13.1°±0.2°, and 10.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2θ of 8.5°±0.2°, 13.1°±0.2°, and 10.9°±0.2°.

[0039] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 17.6°±0.2°, 18.9°±0.2°, and 21.6°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2θ of 17.6°±0.2°, 18.9°±0.2°, and 21.6°±0.2°.

[0040] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 18.1°±0.2°, 23.4°±0.2°, and 24.5°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2θ of 18.1°±0.2°, 23.4°±0.2°, and 24.5°±0.2°.

[0041] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, or two, or three, or four, or five, or six, or seven, or eight, or nine of the diffraction angles 2θ of 8.5°±0.2°, 13.1°±0.2°, 10.9°±0.2°, 17.6°±0.2°, 18.9°±0.2°, 21.6°±0.2°, 18.1°±0.2°, 23.4°±0.2°, 24.5°±0.2°, 21.1°±0.2°, and 25.5°±0.2°.

[0042] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSII is substantially as shown in FIG. 14 .

[0043] Without limitation, the thermogravimetric analysis of Form CSII is substantially as shown in FIG15 , and there is substantially no mass loss when heated to about 150° C.

[0044] Without limitation, the differential scanning calorimetry analysis chart of Form CSII has one endothermic peak with an onset temperature of about 163°C.

[0045] Without limitation, the differential scanning calorimetry analysis diagram of Form CSII is substantially as shown in FIG16 .

[0046] Without limitation, Form CSII is an anhydrate.

[0047] According to the purpose of the present invention, the present invention also provides a preparation method of the crystal form CSII, which comprises: heating the solid compound I to 150°C-165°C, and then cooling to room temperature to obtain the crystal form CSII.

[0048] The crystal form CSII provided by the present invention has the following unexpected technical effects:

[0049] (1) Crystal form CSII has lower hygroscopicity.

[0050] The crystalline form CSII has a hygroscopic weight gain of 0.34% at 0%-80% RH, while the amorphous form has a hygroscopic weight gain of 7.45% at 0%-80% RH. The low hygroscopicity of the crystalline form CSII makes it less demanding on drug production and storage, reducing production, storage, and quality control costs, thus offering significant economic value.

[0051] (2) Crystal form CSII is more suitable for the preparation of pharmaceutical preparations.

[0052] Crystalline Form CSII maintains its solid form after grinding in ethanol and remains stable before and after the formulation process. The solid form of the amorphous form changes after grinding in ethanol. Wet granulation is commonly used in the production of solid dosage forms. Wet granulation often requires mixing the active pharmaceutical ingredient with a wetting agent such as water or ethanol and applying mechanical force. Crystalline Form CSI exhibits good physical stability and low hygroscopicity in alcoholic solvents, which can reduce the risk of decreased crystallinity and solid form transformation of the active pharmaceutical ingredient during wet granulation.

[0053] (3) Crystal form CSII has better purification effect.

[0054] After the raw materials are prepared into crystalline Form CSII, the purity is improved. In a specific embodiment, using raw materials with a purity of 97.09%, the purity of crystalline Form CSII increased to 97.70%, a purity increase of 0.61%. However, when the same raw materials are prepared into an amorphous form, the purity actually decreases by 0.23%. Crystal Form CSII has a good purification effect, and a higher purity API can be obtained through crystallization, effectively overcoming the shortcomings of low-purity drugs such as poor drug stability, poor efficacy, and high toxicity.

[0055] (4) Crystal form CSII has better stability.

[0056] Crystalline Form CSII has better humidity stability. After both crystalline Form CSII and the amorphous form were subjected to humidity fluctuations from 0% RH to 95% RH and then to 0% RH, the solid form of crystalline Form CSII remained unchanged, while the solid form of the amorphous form changed. This indicates that crystalline Form CSII has better humidity stability than the amorphous form.

[0057] Crystalline Form CSII exhibits superior physicochemical stability. Crystalline Form CSII maintained its solid form unchanged for at least six months at 40°C / 75% RH, with essentially unchanged purity. When stored at 60°C / 75% RH, it maintained its solid form unchanged for at least three months, with essentially unchanged purity. The amorphous form undergoes a solid phase transition after one week at 60°C / 75% RH.

[0058] Crystalline CSII preparations exhibit excellent stability. When mixed with excipients to form pharmaceutical preparations, the solid form of CSII remained unchanged for at least one month at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH, and the purity remained essentially unchanged during storage.

[0059] High humidity conditions caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs. The excellent stability of Form CSII and its formulations helps prevent the effects of solid form changes on drug quality during storage, transportation, and production, thereby ensuring consistent and controllable API quality and minimizing changes in drug quality, bioavailability, and toxic side effects caused by solid form changes.

[0060] According to the purpose of the present invention, the present invention provides a crystalline form CSIII of Compound I (hereinafter referred to as "crystalline form CSIII").

[0061] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 7.1°±0.2°, 10.6°±0.2°, and 13.3°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 7.1°±0.2°, 10.6°±0.2°, and 13.3°±0.2°.

[0062] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 6.0°±0.2°, 12.2°±0.2°, and 17.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 6.0°±0.2°, 12.2°±0.2°, and 17.9°±0.2°.

[0063] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 20.6°±0.2°, 21.5°±0.2°, and 24.8°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 20.6°±0.2°, 21.5°±0.2°, and 24.8°±0.2°.

[0064] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 7.1°±0.2°, 10.6°±0.2°, 13.3°±0.2°, 6.0°±0.2°, 12.2°±0.2°, 17.9°±0.2°, 20.6°±0.2°, 21.5°±0.2°, 24.8°±0.2°, 24.0°±0.2° or 27.9°±0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9.

[0065] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSIII is substantially as shown in FIG. 23 .

[0066] Without limitation, the thermogravimetric analysis of Form CSIII is substantially as shown in FIG. 24 , whereby heating to approximately 100° C. results in a weight loss of approximately 2.5%.

[0067] Without limitation, Form CSIII is a hydrate.

[0068] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSIII, which comprises: dissolving compound I in a mixed solvent of nitriles and water, adding water and stirring to obtain the crystalline form CSIII.

[0069] Furthermore, the nitrile solvent is preferably acetonitrile; the volume ratio of acetonitrile to water in the mixed solvent is preferably 3:1; the stirring temperature is preferably 5-15°C, more preferably 5°C; the stirring time is preferably 2-24 hours, more preferably 4-8 hours, and even more preferably 6 hours.

[0070] The crystal form CSIII provided by the present invention has the following unexpected technical effects:

[0071] (1) Crystal form CSIII has lower hygroscopicity.

[0072] The crystalline form CSIII has a hygroscopic weight gain of 0.83% at 40%-80% RH, while the amorphous form has a hygroscopic weight gain of 5.43% at 40%-80% RH. The low hygroscopicity of the crystalline form CSIII reduces the production and storage requirements of the drug, reduces the costs of drug production, storage, and quality control, and has strong economic value.

[0073] (2) Crystal form CSIII has better purification effect.

[0074] After the raw materials are prepared into crystalline Form CSIII, the purity is improved. In a specific embodiment, using raw materials with a purity of 97.09%, the purity of crystalline Form CSIII increased to 97.51%, a purity increase of 0.42%. However, when the amorphous form is prepared from the same raw materials, the purity actually decreases by 0.23%. Crystal Form CSIII has a good purification effect, and a high-purity API can be obtained through crystallization, effectively overcoming the shortcomings of low drug purity such as low drug stability, poor efficacy, and high toxicity.

[0075] According to the purpose of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline solid of Compound I and a pharmaceutically acceptable excipient.

[0076] Furthermore, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline form CSI, crystalline form CSII or crystalline form CSIII and pharmaceutically acceptable excipients.

[0077] According to the purpose of the present invention, the present invention provides the use of the crystalline solid of Compound I in the preparation of TLR7 / 8 inhibitor drugs.

[0078] Furthermore, the present invention provides use of the crystalline form CSI, crystalline form CSII or crystalline form CSIII in the preparation of TLR7 / 8 inhibitor drugs.

[0079] According to the purpose of the present invention, the present invention provides use of a crystalline solid of Compound I in the preparation of a medicament for treating cutaneous lupus erythematosus and systemic lupus erythematosus.

[0080] Furthermore, the present invention provides the use of the crystal form CSI, the crystal form CSII or the crystal form CSIII in the preparation of drugs for treating cutaneous lupus erythematosus and systemic lupus erythematosus. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Figure 1 is the XRPD pattern of crystal form CSI

[0082] Figure 2 is the TGA diagram of crystal form CSI

[0083] Figure 3 is the DSC diagram of crystal form CSI

[0084] Figure 4 is the XRPD pattern of amorphous

[0085] Figure 5 is the DVS adsorption curve of crystalline CSI

[0086] Figure 6 shows the DVS adsorption curve of amorphous

[0087] Figure 7 is a comparison of XRPD images of the crystal form CSI before and after DVS testing (from top to bottom: before DVS, after DVS)

[0088] Figure 8 is a comparison of XRPD images of amorphous before and after DVS testing (from top to bottom: before DVS, after DVS)

[0089] Figure 9 is a comparison of XRPD images of the crystal form CSI before and after grinding (from top to bottom: before grinding, after grinding)

[0090] Figure 10 is a comparison of XRPD images of amorphous before and after grinding (from top to bottom: before grinding, after grinding)

[0091] Figure 11 is a comparison of XRPD images of Form CSI placed under different conditions (from top to bottom: before placement, after 6 months at 40°C / 75% RH, and after 3 months at 60°C / 75% RH)

[0092] Figure 12 is a comparison of XRPD images of the crystalline form CSI before and after the formulation process (from top to bottom: blank mixed powder, crystalline form CSI after the formulation process, crystalline form CSI)

[0093] Figure 13 is a comparison of XRPD patterns of crystalline CSI preparations placed under different conditions (from top to bottom: before placement, after 1 month at 25°C / 60% RH, after 1 month at 40°C / 75% RH, and after 1 month at 60°C / 75% RH)

[0094] Figure 14 is the XRPD pattern of Form CSII

[0095] Figure 15 is a TGA diagram of crystal form CSII

[0096] Figure 16 is a DSC diagram of Form CSII

[0097] Figure 17 is the DVS adsorption curve of crystalline form CSII

[0098] Figure 18 is a comparison of XRPD images of Form CSII before and after DVS testing (from top to bottom: before DVS, after DVS)

[0099] Figure 19 is a comparison of XRPD images of Form CSII before and after grinding (from top to bottom: before grinding, after grinding)

[0100] FIG20 is a comparison of XRPD patterns of Form CSII placed under different conditions (from top to bottom: before placement, after 6 months at 40°C / 75% RH, and after 3 months at 60°C / 75% RH)

[0101] Figure 21 is a comparison of XRPD images of Form CSII before and after the formulation process (from top to bottom: blank mixed powder, Form CSII after the formulation process, Form CSII)

[0102] FIG22 is a comparison of XRPD patterns of crystalline CSII preparations placed under different conditions (from top to bottom: before placement, after 1 month at 25°C / 60% RH, after 1 month at 40°C / 75% RH, and after 1 month at 60°C / 75% RH)

[0103] Figure 23 is the XRPD pattern of Form CSIII

[0104] Figure 24 is a TGA diagram of Form CSIII DETAILED DESCRIPTION

[0105] The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many variations in both materials and methods may be made without departing from the scope of the present invention.

[0106] The abbreviations used in the present invention are explained as follows:

[0107] RH: relative humidity

[0108] TGA: Thermogravimetric analysis

[0109] DSC: Differential Scanning Calorimetry

[0110] DVS: Dynamic Water Sorption

[0111] RRT: relative retention time

[0112] 1 H NMR: liquid hydrogen nuclear magnetic spectroscopy

[0113] HPLC: High Performance Liquid Chromatography

[0114] XRPD: X-ray powder diffraction

[0115] Instruments and methods used to collect data:

[0116] The X-ray powder diffraction pattern of the present invention was collected on a Bruker X-ray powder diffractometer. The method parameters of the X-ray powder diffraction of the present invention are as follows:

[0117] X-ray source: Cu, Kα

[0118] Kα1 :1.5406;Kα2 :1.5444

[0119] Kα2 / Kα1 intensity ratio: 0.50

[0120] Voltage: 40 kilovolts (kV)

[0121] Current: 40 milliamperes (mA)

[0122] Scanning range: from 3.0 to 40.0 degrees or from 4.0 to 40.0 degrees

[0123] The thermogravimetric analysis (TGA) graphs of the present invention were collected on a TA Q500. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

[0124] Scan rate: 10℃ / min

[0125] Shielding gas: N2

[0126] The differential scanning calorimetry (DSC) graphs of the present invention were collected on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

[0127] Scan rate: 10℃ / min

[0128] Shielding gas: N2

[0129] The nuclear magnetic resonance hydrogen spectrum data of the present invention ( 1 H NMR spectra were obtained on a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated chloroform to prepare a 2-10 mg / mL solution.

[0130] The purity detection method of the present invention is shown in Table 1.

[0131] Table 1

[0132] In the present invention, the "crystalline solid" refers to a solid substance with different molecular arrangements and / or conformations in the crystal lattice.

[0133] The "anhydrous substance" refers to a solid substance that does not contain crystal water or crystallization solvent.

[0134] The "hydrate" refers to a solid substance containing water of crystallization.

[0135] The "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm and the mechanical stirring is preferably 100-300 rpm.

[0136] The separation is accomplished by conventional methods in the art, such as centrifugation or filtration. The centrifugation operation is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all solids settle to the bottom of the centrifuge tube.

[0137] The "room temperature" is not a specific temperature value, but refers to the temperature range of 10-30°C.

[0138] The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Kα radiation, the peak position can usually have an error of ±0.2°.

[0139] In the present invention, "crystals" or "crystal forms" can be characterized by X-ray powder diffraction. Those skilled in the art will appreciate that X-ray powder diffraction patterns can vary depending on instrument conditions, sample preparation, and sample purity. The relative intensities of diffraction peaks in an X-ray powder diffraction pattern may also vary with experimental conditions, so the diffraction peak intensities cannot be the sole or decisive factor in determining a crystal form. In fact, the relative intensities of diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal. The diffraction peak intensities shown herein are illustrative and not intended for absolute comparison. Therefore, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the crystal forms claimed by the present invention do not necessarily have to be identical to those in the Examples described herein; any crystal form having an X-ray powder diffraction pattern with characteristic peaks identical or similar to those in these patterns falls within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction patterns listed herein with those of an unknown crystal form to determine whether the two patterns reflect the same or different crystal forms.

[0140] In some embodiments, the crystalline form CSI, crystalline form CSII, or crystalline form CSIII of the present invention is pure and substantially free of any other crystalline form. As used herein, "substantially free" when referring to a new crystalline form means that the crystalline form contains less than 20% (by weight) of any other crystalline form, particularly less than 10% (by weight) of any other crystalline form, more particularly less than 5% (by weight) of any other crystalline form, and even more particularly less than 1% (by weight) of any other crystalline form.

[0141] The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0142] Unless otherwise specified, the following examples were all performed at room temperature.

[0143] According to the present invention, the compound I as a raw material includes but is not limited to solid form (crystalline or amorphous), oily, liquid form and solution. Preferably, the compound I as a raw material is in solid form.

[0144] Compound I used in the following examples can be prepared according to existing technologies, for example, according to the method described in WO2017106607A1.

[0145] Example 1 Preparation method of crystal form CSI

[0146] 15.6 mg of Compound I solid was weighed into a glass bottle, and 0.3 mL of a mixed solvent of methanol and water (1:5, v / v) was added. The mixture was then stirred at room temperature for 5 days, the solid was separated by centrifugation, and vacuum dried at 30° C. for 1.5 hours to obtain a dry solid.

[0147] The obtained dry solid was tested to be the crystalline form CSI of the present invention. Its X-ray powder diffraction data is shown in Table 2, and its X-ray powder diffraction pattern is shown in FIG1 .

[0148] As shown in the TGA graph in FIG2 , when heated to about 150° C., the material has a mass loss of about 0.08%.

[0149] The DSC graph is shown in FIG3 , which has two endothermic peaks. The peak temperature of the first endothermic peak is about 143° C., and the peak temperature of the second endothermic peak is about 164° C.

[0150] Table 2

[0151] Example 2 Hygroscopicity and humidity stability of crystalline form CSI

[0152] About 10 mg of each of the crystalline form CSI and the amorphous form (the amorphous form was obtained by the method of Example 31 of WO2017106607A1, and its XRPD pattern is shown in Figure 4) was weighed and tested for its hygroscopicity using a dynamic moisture sorption (DVS) instrument. The relative humidity was cycled once at 0%-95%-0%, and the mass change at each humidity was recorded. The crystal form of the sample before and after the DVS test was tested by XRPD. The experimental results are shown in Table 3. The DVS adsorption curves of the crystalline form CSI and the amorphous form are shown in Figures 5 and 6, respectively. The XRPD comparison diagrams of the crystalline form CSI and the amorphous form before and after the DVS test are shown in Figures 7 and 8, respectively.

[0153] Experimental results showed that the crystalline CSI exhibited a 0.36% weight gain upon humidity exposure from 0% to 80% RH, and the solid morphology remained unchanged after humidity cycling from 0% to 95% to 0% RH. The amorphous form exhibited a 7.45% weight gain upon humidity exposure from 0% to 80% RH, and the amorphous solid morphology transitioned after humidity cycling from 0% to 95% to 0% RH. This suggests that the crystalline CSI exhibits lower hygroscopicity and better humidity stability.

[0154] Table 3

[0155] Example 3 Purification effect of crystal form CSI

[0156] Crystalline CSI and amorphous forms were prepared from the same starting materials. The chemical purity of the starting materials, crystalline CSI, and amorphous forms was determined by HPLC, and the test results are shown in Table 4. The results show that crystalline CSI, prepared from the same starting materials, has higher purity and exhibits superior purification of impurities at RRT = 0.30 and RRT = 1.57.

[0157] Table 4

[0158] ND: Not Detected

[0159] Example 4 Stability of Crystalline Form CSI under Mechanical Force

[0160] Approximately 10 mg of crystalline CSI and amorphous CSI were placed in a centrifuge tube, added with zirconium beads and 5 μL of ethanol, and ball-milled at 500 rpm for 5 minutes. XRPD analysis was performed before and after milling, as shown in Figures 9 and 10, respectively. The results show that the solid morphology of the crystalline CSI remains unchanged after ball milling, while the solid morphology of the amorphous CSI changes after ball milling, indicating that the crystalline CSI exhibits better stability under mechanical forces.

[0161] Example 5 Physicochemical Stability of Crystalline Form CSI

[0162] An appropriate amount of crystalline CSI was sealed and packaged with a desiccant, then placed at 40°C / 75% RH and 60°C / 75% RH. HPLC and XRPD were used to determine the purity and solid form. The results are shown in Table 5, and the XRPD comparison diagram is shown in Figure 11. The results show that crystalline CSI is stable for at least 6 months at 40°C / 75% RH and for at least 3 months at 60°C / 75% RH, indicating that it maintains good stability under accelerated and harsh conditions. The amorphous form undergoes a solid phase transition after being placed at 60°C / 75% RH for one week, indicating poor physical stability under harsh conditions.

[0163] Table 5

[0164] Example 6 Preparation of Crystalline CSI Preparation

[0165] Crystalline CSI formulations and blank powder mix formulations were prepared using the formulation formulations shown in Tables 6 and 7 and the formulation process shown in Table 8. XRPD results of the blank powder mix and formulation samples before and after formulation were shown in Figure 12. The results demonstrate that the solid form of crystalline CSI remains stable before and after the formulation process.

[0166] Table 6

[0167] Table 7

[0168] Table 8

[0169] Example 7 Stability of Crystalline CSI Formulation

[0170] Appropriate amounts of crystalline CSI preparation samples were sealed and packaged with desiccant and antioxidants. They were then placed under 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH. The purity and solid form were determined using HPLC and XRPD. The results are shown in Table 9 and Figure 13. These results demonstrate that the crystalline CSI preparation was stable at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH for at least one month, with no significant change in purity. This indicates that the crystalline CSI preparation exhibits excellent stability under conventional, accelerated, and harsh conditions.

[0171] Table 9

[0172] Example 8 Preparation Method of Crystal Form CSII

[0173] The solid of Compound I was heated to 155° C. at a rate of 10° C. / min under nitrogen protection, kept at 155° C. for 5 minutes, and returned to room temperature to obtain a dry solid.

[0174] The obtained dry solid was tested to be the crystalline form CSII of the present invention. Its X-ray powder diffraction data are shown in Table 10, and its X-ray powder diffraction pattern is shown in FIG14 .

[0175] The TGA graph is shown in FIG15 , and there is essentially no mass loss when heated to approximately 150° C.

[0176] The DSC graph is shown in FIG16 , where a melting endothermic peak begins to appear at approximately 163°C.

[0177] Table 10

[0178] Example 9 Hygroscopicity and Humidity Stability of Crystalline Form CSII

[0179] Approximately 10 mg of each of crystalline Form CSII and amorphous form were weighed and tested for hygroscopicity using a dynamic moisture sorption (DVS) instrument. The samples were cycled through a relative humidity range of 0%-95%-0%, and the mass change at each humidity level was recorded. The solid morphology of the samples before and after the DVS test was also analyzed using XRPD. The experimental results are shown in Table 11. The DVS adsorption curve of Form CSII is shown in Figure 17. A comparison of the XRPD images of Form CSII before and after the DVS test is shown in Figure 18.

[0180] Experimental results showed that Form CSII exhibited a 0.34% weight gain from humidity exposure (0% to 80% RH) and maintained its crystalline form after humidity cycling from 0% to 95% to 0% RH. The amorphous form exhibited a 7.45% weight gain from humidity exposure (0% to 80% RH) and underwent a 0% to 95% to 0% RH humidity cycling, resulting in a transition to an amorphous solid state. This suggests Form CSII exhibits lower hygroscopicity and improved humidity stability.

[0181] Table 11

[0182] Example 10 Purification Effect of Crystal Form CSII

[0183] Crystalline Form CSII and an amorphous form were prepared from the same starting materials. The chemical purity of the starting materials, crystalline Form CSII, and amorphous form was determined by HPLC, and the test results are shown in Table 12. The results show that crystalline Form CSII, prepared from the same starting materials, has higher purity and exhibits superior purification of impurities at RRT = 0.30 and RRT = 1.57.

[0184] Table 12

[0185] Example 11 Stability of Form CSII under Mechanical Force

[0186] Approximately 10 mg of crystalline Form CSII and amorphous form were placed in a centrifuge tube, added with zirconium beads and 5 μL of ethanol, and ball-milled at 500 rpm for 5 minutes. XRPD analysis was performed before and after milling, and the test results are shown in Figures 19 and 10, respectively. The results show that the solid state of crystalline Form CSII remains unchanged after ball milling, while the solid state of the amorphous form undergoes a transformation after ball milling, indicating that crystalline Form CSII has better stability under mechanical forces.

[0187] Example 12 Physicochemical Stability of Form CSII

[0188] An appropriate amount of Form CSII was sealed and packaged with a desiccant, then placed at 40°C / 75% RH and 60°C / 75% RH. HPLC and XRPD were used to determine the purity and solid form. The results are shown in Table 13, and the XRPD comparison diagram is shown in Figure 20. The results show that Form CSII is stable for at least 6 months at 40°C / 75% RH and for at least 3 months at 60°C / 75% RH, demonstrating its good stability under accelerated and harsh conditions. The amorphous form undergoes a solid phase transition after one week at 60°C / 75% RH, indicating poor physical stability under harsh conditions.

[0189] Table 13

[0190] Example 13 Preparation of Crystalline Form CSII

[0191] Formulations of crystalline Form CSII and blank powder mixes were prepared using the formulation formulas shown in Tables 6 and 7 and the formulation process shown in Table 8. XRPD analysis of the blank powder mix and the formulation samples before and after formulation is performed is shown in Figure 21. The results demonstrate that the solid form of Form CSII remains stable before and after the formulation process.

[0192] Example 14 Stability of Crystalline Form CSII Preparation

[0193] An appropriate amount of crystalline CSII preparation sample was sealed and packaged with a desiccant and antioxidant, and placed under 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH. The purity and solid form were determined by HPLC and XRPD. The results are shown in Table 14 and Figure 22. The results show that crystalline CSII can be stable at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH for at least one month without significant change in purity. It can be seen that the crystalline CSII preparation has good stability under conventional, accelerated, and harsh conditions.

[0194] Table 14

[0195] Example 15 Preparation Method of Crystalline Form CSIII

[0196] Weigh 10.4 mg of Compound I solid into a glass bottle, add 0.05 mL of a mixed solvent of acetonitrile and water (3:1, v / v), heat at 50 ° C for about 1.5 hours, transfer to 5 ° C and let stand for 1 day, then transfer to -20 ° C and let stand for 3 days, and then stir at -20 ° C for 7 days, transfer to 5 ° C while adding 1 mL of water while stirring, continue stirring for 6 hours, let stand at 5 ° C overnight, centrifuge to separate the solid, and leave it open at room temperature overnight to obtain a dry solid.

[0197] After testing, the obtained dry solid was the crystalline form CSIII of the present invention. Its X-ray powder diffraction data is shown in Table 15, and the X-ray powder diffraction pattern is shown in Figure 23.

[0198] Table 15

[0199] Example 16 TGA of Form CSIII

[0200] The TGA graph of Form CSIII is shown in FIG24 , which shows a 2.5% weight loss upon heating to approximately 100° C.

[0201] Example 17 Hygroscopicity and humidity stability of Form CSIII

[0202] Approximately 10 mg of each of crystalline Form CSIII and amorphous form were weighed and tested for hygroscopicity using a dynamic moisture sorption (DVS) instrument. The hygroscopicity was cycled through 40%-95%-0% relative humidity, and the mass change at each humidity level was recorded. The experimental results showed that the crystalline Form CSIII experienced a 0.83% weight gain from 40% to 80% RH. The amorphous form experienced a 5.43% weight gain from 40% to 80% RH. This indicates that the crystalline Form CSIII exhibits lower hygroscopicity.

[0203] Example 18 Purification Effect of Form CSIII

[0204] Crystalline Form CSIII and an amorphous form were prepared from the same starting materials. The chemical purity of the starting materials, crystalline Form CSIII, and amorphous form was determined by HPLC, and the test results are shown in Table 16. The results show that crystalline Form CSIII and amorphous form prepared from the same starting materials have higher purity and exhibit better purification effects for impurities at RRT = 0.30 and RRT = 1.57.

[0205] Table 16

[0206] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. A crystalline solid of Compound I, 2. The crystalline solid of compound I according to claim 1, characterized in that It is anhydrous.

3. The crystalline solid of Compound I according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.8°±0.2°, 13.5°±0.2°, and 11.4°±0.2°.

4. The crystalline solid of Compound 1 according to claim 3, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 9.8°±0.2°, 18.5°±0.2°, and 21.9°±0.2°.

5. The crystalline solid of Compound 1 according to claim 4, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 14.2°±0.2° and 23.5°±0.2°.

6. The crystalline solid of Compound 1 according to claim 3, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 1.

7. The crystalline solid of Compound 1 according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.5°±0.2°, 13.1°±0.2°, and 10.9°±0.2°.

8. The crystalline solid of Compound 1 according to claim 7, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 17.6°±0.2°, 18.9°±0.2°, and 21.6°±0.2°.

9. The crystalline solid of Compound 1 according to claim 8, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 18.1°±0.2°, 23.4°±0.2°, and 24.5°±0.2°.

10. The crystalline solid of Compound 1 according to claim 7, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in FIG14 .

11. The crystalline solid of Compound 1 according to claim 1, characterized in that It is a hydrate.

12. The crystalline solid of Compound 1 according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.1°±0.2°, 10.6°±0.2°, and 13.3°±0.2°.

13. The crystalline solid of Compound 1 according to claim 12, characterized in that Using Cu—Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 6.0°±0.2°, 12.2°±0.2°, and 17.9°±0.2°.

14. The crystalline solid of Compound 1 according to claim 13, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 20.6°±0.2°, 21.5°±0.2°, and 24.8°±0.2°.

15. The crystalline solid of Compound 1 according to claim 12, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in FIG. 23 .

16. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline solid of Compound I according to claim 1 and a pharmaceutically acceptable excipient.

17. Use of the crystalline solid of Compound I according to claim 1 in the preparation of TLR7 / 8 inhibitor drugs.

18. Use of the crystalline solid of Compound I according to claim 1 in the preparation of a medicament for treating cutaneous lupus erythematosus and systemic lupus erythematosus.

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