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WO2022166680A1 - 奥德昔巴特的晶型及其制备方法和用途 - Google Patents

奥德昔巴特的晶型及其制备方法和用途 Download PDF

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Publication number
WO2022166680A1
WO2022166680A1 PCT/CN2022/073757 CN2022073757W WO2022166680A1 WO 2022166680 A1 WO2022166680 A1 WO 2022166680A1 CN 2022073757 W CN2022073757 W CN 2022073757W WO 2022166680 A1 WO2022166680 A1 WO 2022166680A1
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compound
crystal form
crystal
preparation
drug
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PCT/CN2022/073757
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English (en)
French (fr)
Inventor
陈敏华
施文睿
张婧
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苏州科睿思制药有限公司
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Priority to CN202280045359.3A priority Critical patent/CN118382619A/zh
Publication of WO2022166680A1 publication Critical patent/WO2022166680A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/36—Seven-membered rings

Definitions

  • the present invention relates to the field of crystal chemistry. Specifically, it relates to the crystalline form of odexibat and its preparation method and use.
  • PFIC Progressive familial intrahepatic cholestasis
  • Biliary atresia is a rare pediatric liver disease whose symptoms usually appear around 2 to 8 weeks after birth. Damage or absence of extrahepatic bile ducts results in the retention of bile and bile acids in the liver, which can rapidly lead to cirrhosis and even liver failure.
  • Alagille syndrome is a rare multisystem genetic disorder that can affect the liver, heart, bones, central nervous system, kidneys, eyes or face, among others.
  • Odevixibat is the first drug approved in the United States for the treatment of pruritus in patients with progressive familial intrahepatic cholestasis (PFIC) of 3 months and older.
  • Odexobacter is an ileal bile acid transporter (IBAT) inhibitor that inhibits the spontaneous reabsorption of bile acids from the ileum into the hepatic portal circulation. Bile acids that are not reabsorbed from the ileum are secreted into the feces, and bile acids are removed from the intestine. Complete removal of the hepatic circulation results in a decrease in serum and liver bile acid levels.
  • Odesibate is also used in the treatment of BA and ALGS with positive results in the clinical stage.
  • Compound I 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N- ⁇ (R)- ⁇ -[N- ((S)-1-Carboxypropyl)carbamoyl]-4-hydroxybenzyl ⁇ carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothio Heterodiazepine (hereinafter referred to as "Compound I”), its structural formula is as follows:
  • a crystal is a solid in which the molecules of a compound are arranged in a three-dimensional order in a microstructure to form a crystal lattice.
  • Polymorphism is the phenomenon in which a compound exists in more than one crystal form. Compounds may exist in one or more crystalline forms, but their existence and identity cannot be specifically expected. APIs with different crystal forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. Especially for some insoluble oral solid or semi-solid preparations, the crystal form is very important to the product performance. In addition to this, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.
  • WO2019245448A1 discloses that the crude product obtained by repeating the last step of preparing Compound I in Example 29 in WO2003022286A1 is amorphous, and the amorphous shape of multiple batches of Compound I contains solvent residues, such as formic acid, and the solvent residues are far more than The acceptable range for medicinal use does not meet the medicinal standard.
  • Crystal modification 2 can contain both organic solvent and water, and different organic solvents (such as methanol, ethanol, 2-propanol, acetone, acetonitrile, 1,4-dioxane, N,N-dimethyl
  • organic solvents such as methanol, ethanol, 2-propanol, acetone, acetonitrile, 1,4-dioxane, N,N-dimethyl
  • the presence of formamide and dimethyl sulfoxide caused only a small change in the unit cell volume of the crystal unit and did not lead to any significant deformation of the crystal structure of crystalline modification 2, so the XRPD patterns of the different mixed solvates were essentially the same.
  • the specification also discloses that Crystal Modification 2 is unstable in air and mostly becomes amorphous after drying. In conclusion, the modified crystal 2 contains organic solvents and is unstable, which does not meet the pharmaceutical standards.
  • Crystal Modification 1 is a pipeline hydrate, and its crystal water content will change, and its XRPD pattern will shift with the change of relative humidity.
  • Crystal Modification 1 contains a void volume that, depending on the relative humidity, such that each mole of Compound 1 contains up to about 2 moles of water of crystallisation.
  • An additional 1.5% (w/w) of water was absorbed when the relative humidity was increased to 95%, forming an over-hydrated crystalline modification 1 .
  • Pipe hydrates contain a variable number of water molecules in the lattice, which is disordered due to weak hydrogen bonds that bind water molecules to compound molecules. Therefore, it is easier for water to diffuse out of these pipes.
  • the water molecule content of pipe hydrates is highly dependent on environmental conditions, which makes quality control of pipe hydrates particularly difficult during formulation processing and drug storage because of the need to ensure that they contain predictable water molecules composition. Changes in water content may also have an impact on key parameters such as drug stability and solubility, resulting in changes in drug quality, bioavailability, and toxic side effects.
  • WO2019245448A1 it is disclosed in the specification of WO2019245448A1 that although the crystalline modification 1 is a pipeline hydrate, it cannot be obtained directly through water crystallization, and the crystalline modification 2 needs to be separated and dried to obtain the crystalline modification 1 indirectly. This makes the crystal modification 1 easy to have solvent residues, thereby affecting the safety of the drug.
  • the inventors of the present application repeated the preparation method of the modified crystal 1 disclosed in WO2019245448A1, and the obtained modified crystal 1 contained about 5500 ppm of acetonitrile. According to the guidelines of ICH HARMONISED GUIDELINE Q3C (R8) on residual solvents, acetonitrile belongs to the second-class solvent, and its residual concentration limit is 410ppm.
  • Compound I is a BCS class IV drug, that is, a drug with low solubility and low permeability, which is unfavorable for absorption in the human body and has low bioavailability.
  • WO2019245449A1 discloses that the solid solubility of Compound I is very low, and due to the poor solubility, it is easy to agglomerate during the wet granulation process, which subsequently affects the uniformity of drug capsule particles, thereby ultimately affecting the quality of the drug.
  • the present invention provides a new crystal form of compound I, a preparation method and use thereof, and a pharmaceutical composition comprising the new crystal form.
  • the present invention provides the anhydrate of compound I.
  • the anhydrate is crystalline form CSI (hereinafter referred to as "crystalline form CSI").
  • the X-ray powder diffraction pattern of the crystalline form CSI has diffraction angle 2 ⁇ values of 3.0° ⁇ 0.2°, 5.2° ⁇ 0.2°, 5.9° ⁇ 0.2°, 7.9° ⁇ 0.2° There are characteristic peaks at any 1, 2, or 3, or 4 positions.
  • the X-ray powder diffraction pattern of the crystalline form CSI has diffraction angle 2 ⁇ values of 3.0° ⁇ 0.2°, 5.2° ⁇ 0.2°, 5.9° ⁇ 0.2°, 7.9° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2° any one, or two, or three, or four, or five, or six characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSI is substantially as shown in FIG. 1 .
  • thermogravimetric analysis diagram is basically shown in FIG. 2 .
  • the differential scanning calorimetry analysis diagram of the crystal form CSI is basically as shown in FIG. 3 .
  • the present invention also provides a preparation method of the crystal form CSI, the preparation method comprising:
  • the solid compound I was stirred in a mixed solvent of nitromethane, nitromethane/ketones, or nitromethane/halogenated hydrocarbon to obtain crystal form CSI.
  • volume ratio (v/v) of the nitromethane/ketones is preferably 30:1; the volume ratio (v/v) of the nitromethane/halogenated hydrocarbon is preferably 9:1; the stirring The temperature is preferably 20°C to 50°C.
  • ketones are preferably butanone; the halogenated hydrocarbons are preferably chloroform.
  • crystal form CSII crystal form CSII
  • the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angle 2 ⁇ values of 3.7° ⁇ 0.2° and 10.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSII is at any one of the diffraction angle 2 ⁇ values of 6.4° ⁇ 0.2°, 6.8° ⁇ 0.2°, 7.7° ⁇ 0.2°, or There are characteristic peaks at 2 or 3 locations; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has features at diffraction angle 2 ⁇ values of 6.4° ⁇ 0.2°, 6.8° ⁇ 0.2°, 7.7° ⁇ 0.2° peak.
  • the X-ray powder diffraction pattern of the crystalline form CSII has diffraction angle 2 ⁇ values of 3.7° ⁇ 0.2°, 10.1° ⁇ 0.2°, 6.4° ⁇ 0.2°, 6.8° ⁇ 0.2° , 7.7° ⁇ 0.2° in any 2 places, or 3 places, or 4 places, or 5 places have characteristic peaks.
  • the X-ray powder diffraction pattern of crystalline form CSII is substantially as shown in FIG. 7 .
  • thermogravimetric analysis diagram of the crystalline form CSII is substantially as shown in FIG. 8 , with a mass loss of about 0.9% when heated to 100°C.
  • differential scanning calorimetry analysis diagram of the crystalline form CSII is substantially as shown in FIG. 9 .
  • the present invention also provides a preparation method of the crystal form CSII, the preparation method comprising:
  • the solid compound I was dissolved in formic acid, evaporated and dried to obtain the crystal form CSII.
  • volatilization temperature is preferably 10-50°C, more preferably 20-30°C; the drying temperature is preferably 25-100°C, more preferably 40-60°C.
  • the present invention provides the use of the anhydrate of compound I for preparing other crystal forms or co-crystals or salts of compound I.
  • the present invention provides the use of crystal form CSI or crystal form CSII for preparing other crystal forms or co-crystals or salts of compound I.
  • the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of anhydrous compound I and pharmaceutically acceptable excipients.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of crystal form CSI, crystal form CSII or any mixture of the above crystal forms and pharmaceutically acceptable auxiliary materials.
  • the present invention provides the use of the anhydrate of compound I in the preparation of IBAT inhibitor medicine.
  • the present invention provides the use of crystal form CSI or crystal form CSII in the preparation of IBAT inhibitor medicine.
  • the present invention provides the use of the anhydrate of compound I in the preparation of a medicament for the treatment of progressive familial intrahepatic cholestasis, biliary atresia and Alagille syndrome.
  • the present invention provides the use of crystalline form CSI or crystalline form CSII in the preparation of a medicament for the treatment of progressive familial intrahepatic cholestasis, biliary atresia and Alagille syndrome.
  • the crystalline form CSI provided by the present invention has no solvent residue. Residual solvents not only affect the safety of the drug, but also have an impact on the quality and stability of the drug. Residual solvents may lead to drug transcrystallization or degradation during production and storage, resulting in changes in drug bioavailability and toxic side effects.
  • the crystal form CSI provided by the invention has no solvent residue, and effectively overcomes the disadvantages of low drug stability, poor curative effect and high toxicity caused by drug degradation or high solvent residue.
  • the crystalline form CSI provided by the present invention has higher solubility.
  • the solubility of crystalline form CSI was 4.8 times that of the prior art WO2019245448A1 crystalline modification 1; in simulated fed state intestinal fluid (FeSSIF), the solubility of crystalline form CSI was The solubility is 3.4 times that of the prior art WO2019245448A1 crystal modification 1.
  • Compound I is a poorly water soluble drug and belongs to BCS class IV.
  • the crystal form CSI provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
  • Crystalline CSI is anhydrous and does not contain crystal water, so the content of crystal water will not change when the external humidity changes.
  • the specification of WO2019245448A1 discloses that the crystal modification 1 in the prior art is a pipeline hydrate, and as the relative humidity changes, each mole of the crystal of the compound I can contain about 2 moles of water.
  • the specification further discloses that when the relative humidity is increased to 95%, an additional 1.5% (w/w) of water is absorbed, the additional water can be adsorbed on the surface, or can be further filled in the pipes of the crystal structure, which can lead to The crystal structure changes accordingly.
  • Crystal form of CSI is anhydrous, which can effectively avoid changes in crystal structure and drug quality caused by changes in water content; and is conducive to quality control during preparation processing and drug storage.
  • the crystal form CSI provided by the present invention has better high temperature stability.
  • the TGA diagram of the crystalline form CSI shows that there is only about 0.3% mass loss when heated to 100 °C, corresponding to the removal of surface adsorbed water.
  • the TGA diagram of the prior art crystalline modification 1 of WO2019245448A1 shows that in the process of heating from 25°C to 100°C, water is always removed, and the mass loss is as high as about 3.5%. After the hydrate is dehydrated, the crystal structure may change. It can be seen that the crystalline form CSI has better high temperature stability. In the process of storage, transportation and production of APIs, they will encounter high temperature conditions caused by seasonal differences, climate differences in different regions, and weather factors.
  • the crystal form CSI Compared with the crystal modification 1 in the prior art, the crystal form CSI has better stability under harsh conditions, which is beneficial to avoid the influence of deviation from the storage conditions on the label on the quality of the drug. Minimize drug quality changes, bioavailability changes, and even drug side effects caused by changes in crystal form.
  • the crystal form CSI API provided by the present invention has good physical and chemical stability. Crystalline CSI APIs, placed under the conditions of 25°C/60%RH, did not change the crystal form for at least 3 months, and the purity remained basically unchanged during storage. It shows that the crystalline CSI API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystal form of CSI API has not changed after being placed at 40°C/75%RH for at least 3 months, and the crystal form has not changed at 60°C/75%RH for at least 1 month, and the storage process has not changed. Purity remains largely unchanged. It shows that the crystalline form CSI API has better stability under accelerated conditions and more severe conditions.
  • Crystalline CSI has good physical and chemical stability, ensuring consistent and controllable quality of APIs, and can reduce drug quality changes, bioavailability changes and toxic and side effects caused by changes in crystal form or impurities.
  • the crystal form CSI provided by the present invention has better humidity stability. After the crystal form CSI was cycled once under the conditions of 0%RH-95%RH-0%RH, the crystal form did not change. Seasonal differences, climate differences in different regions and environmental factors bring about high humidity conditions that will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under more severe conditions is crucial for the drug.
  • the crystalline form of CSI API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • the crystal form CSII provided by the present invention has no solvent residue. Residual solvents not only affect the safety of the drug, but also have an impact on the quality and stability of the drug. Residual solvents may lead to drug transcrystallization or degradation during manufacturing and storage, resulting in changes in drug bioavailability and toxic side effects.
  • the crystal form CSII provided by the invention has no solvent residue, and effectively overcomes the disadvantages of low drug stability, poor curative effect and high toxicity caused by drug degradation or high solvent residue.
  • the crystal form CSII provided by the present invention has higher solubility. Especially at 4 hours, the solubility of crystalline form CSII in both FaSSIF and FeSSIF is twice that of the prior art WO2019245448A1 crystal modification 1.
  • Compound I is a poorly water soluble drug and belongs to BCS class IV.
  • the crystal form CSII provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
  • Crystalline CSII is anhydrous and does not contain crystal water, so when the external humidity changes, the content of crystal water will not change accordingly, so that the structure of the crystal will not be affected.
  • the specification of WO2019245448A1 discloses that the crystal modification 1 in the prior art is a pipeline hydrate, and as the relative humidity changes, each mole of the crystal of the compound I can contain about 2 moles of water.
  • the specification further discloses that when the relative humidity is increased to 95%, an additional 1.5% (w/w) of water is absorbed, the additional water can be adsorbed on the surface, or can be further filled in the pipes of the crystal structure, which can lead to The crystal structure changes accordingly. Changes in water content may also have an impact on key parameters such as drug stability and solubility, resulting in changes in drug quality, bioavailability, and toxic side effects.
  • the crystal form CSII is anhydrous, which can effectively avoid the change of crystal structure caused by the change of water content, and the change of drug quality; and it is beneficial to the quality control during preparation processing and drug storage.
  • the crystal form CSII provided by the present invention has better high temperature stability.
  • the TGA diagram of crystalline form CSII shows that there is only about 0.9% mass loss when heated to 100 °C, which corresponds to the removal of surface adsorbed water.
  • the TGA diagram of the prior art crystalline modification 1 of WO2019245448A1 shows that in the process of heating from 25°C to 100°C, water is always removed, and the mass loss is as high as about 3.5%. After the hydrate is dehydrated, the crystal structure may change. It can be seen that the crystalline form CSII has better high temperature stability.
  • the crystal form CSII In the process of storage, transportation and production of APIs, they will encounter high temperature conditions caused by seasonal differences, climate differences in different regions, and weather factors. Compared with the crystal modification 1 in the prior art, the crystal form CSII has better stability under harsh conditions, which is beneficial to avoid the influence of deviation from the storage conditions on the label on the quality of the drug. Minimize drug quality changes, bioavailability changes, and even drug side effects caused by changes in crystal form.
  • the crystal form CSII bulk drug provided by the present invention has better physical and chemical stability.
  • Crystal form CSII API placed under the condition of 40°C/75%RH for at least 3 months, the crystal form did not change, and the purity remained basically unchanged during storage. It shows that the crystalline form CSII API has better stability under accelerated conditions.
  • the good physical and chemical stability of the crystalline form of the bulk drug can ensure that the drug will not be crystallized during the production and storage process, and basically no impurities will be generated.
  • the crystal form CSII has good physical and chemical stability, which ensures the consistent and controllable quality of the API, and reduces drug quality changes, bioavailability changes and toxic and side effects caused by crystal form changes or impurities.
  • the crystal form CSII provided by the present invention has better humidity stability. After the crystal form CSII was cycled once under the conditions of 60%RH-0%RH-95%RH-0%RH, the crystal form did not change. Seasonal differences, climate differences in different regions and environmental factors bring about high humidity conditions that will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under more severe conditions is crucial for the drug.
  • the crystalline form CSII API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • Figure 1 shows the XRPD pattern of crystalline form CSI
  • Figure 2 is the TGA diagram of the crystal form CSI
  • Figure 3 is the DSC chart of the crystal form CSI
  • Figure 4 is the XRPD comparison chart of crystal form CSI before and after DVS test (top: before DVS, bottom: after DVS)
  • Figure 5 is the XRPD comparison chart of crystal form CSI before and after being placed under different conditions (from top to bottom: before placing, placed at 25°C/60%RH for 3 months (sealed package), placed at 25°C/60%RH for 3 months month (open packaging), 3 months at 40°C/75%RH (sealed packaging), 3 months at 40°C/75%RH (open packaging))
  • Figure 6 is the XRPD comparison chart of the crystal form CSI before and after being placed under the condition of 60°C/75%RH (from top to bottom: before placing, placed at 60°C/75%RH for 1 month (sealed packaging))
  • Figure 7 is the XRPD pattern of the crystalline form CSII
  • Figure 8 is a TGA diagram of crystal form CSII
  • Fig. 9 is the DSC chart of crystal form CSII
  • Figure 10 is the XRPD comparison chart of crystal form CSII before and after DVS test (top: before DVS, bottom: after DVS)
  • Figure 11 is the XRPD comparison chart of crystal form CSII before and after being placed under different conditions (from top to bottom: before placing, placed at 25°C/60%RH for 3 months (sealed package), placed at 25°C/60%RH for 3 months month (open package), 3 months at 40°C/75%RH (sealed package)
  • the X-ray powder diffraction patterns described in the examples of the present invention were collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of the described X-ray powder diffraction are as follows:
  • thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Q500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • DSC Differential Scanning Calorimetry
  • the hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) of the present invention was collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL.
  • the dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS company (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the described dynamic moisture adsorption instrument are as follows:
  • Relative humidity range 0%RH-95%RH
  • test parameters of the related substance detection of the present invention are shown in Table 2:
  • the "anhydrous" refers to a crystal formed only by strictly periodic arrangement of drug molecules in three-dimensional space.
  • the “stirring” is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring speed is preferably 300-900 rev/min, and the mechanical stirring speed is preferably 100-100 rpm. 300 rpm.
  • the “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the operation of "centrifugation” is: put the sample to be separated into a centrifuge tube, and centrifuge at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.
  • the "volatilization” is accomplished by conventional methods in the art, such as slow volatilization or rapid volatilization.
  • the slow volatilization can be by sealing the container with a sealing film, puncturing the holes, and standing to volatilize; the fast volatilization can be by leaving the container open to volatilize.
  • Drying is accomplished by conventional methods in the art, such as vacuum drying, blast drying or natural air drying. Drying is performed in a fume hood, blast oven or vacuum oven.
  • the "sealed packaging" is accomplished by conventional methods in the art, such as placing the sample in a glass vial, screwing the bottle cap tightly, and finally sealing it in an aluminum foil bag; or placing the sample in a glass vial, Tighten the bottle cap, then seal it in an aluminum foil bag together with 1 g of silica gel desiccant; or place the sample in a glass vial, cover the bottle with a layer of aluminum foil paper and make a hole in the aluminum foil paper, then mix with 1 g of silica gel desiccant Sealed together in an aluminum foil bag.
  • the "open packaging" is accomplished by conventional methods in the art, such as placing the sample in a glass vial, covering the bottle opening with a layer of aluminum foil and opening holes in the aluminum foil.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern will vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the intensity of the diffraction peaks cannot be used as the only or decisive factor for determining the crystal form.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with the characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • the crystalline forms CSI and CSII of the present invention are pure and substantially not mixed with any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% (by weight) of other crystal forms, especially less than 10% (by weight) of other crystal forms, and even less More than 5% (weight) of other crystal forms, more refers to less than 1% (weight) of other crystal forms.
  • the compound I and/or its salts as raw materials include, but are not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I and/or its salts as starting materials are in solid form.
  • Compound I and/or its salts used in the following examples may be solids/crystal forms disclosed in the prior art, such as those disclosed in WO2019245448A1.
  • Embodiment 1 The preparation method of crystal form CSI
  • the obtained crystalline solid is the crystal form CSI of the present invention, its X-ray powder diffraction pattern is shown in Figure 1, and the X-ray powder diffraction data is shown in Table 3.
  • Embodiment 2 The preparation method of crystal form CSI
  • the TGA of the sample 1 of the present invention is shown in FIG. 2 , when heated to 100° C., it has a mass loss of about 0.3%.
  • Table 5 shows the X-ray powder diffraction data of the sample 1 of the present invention.
  • Table 6 shows the X-ray powder diffraction data of the sample 2 of the present invention.
  • prior art crystal modification 1 was prepared: 20.2 mg of compound I solid was weighed into a 4 mL glass bottle, 1.5 mL of acetonitrile was added to it, and 2.5 mL of water was added to obtain a suspension , continue to suspend and stir the obtained suspension at room temperature for 20 minutes, then centrifuge to separate the solid, and vacuum dry the obtained solid at 25° C. for about 17 hours to obtain the prior art crystal modification 1.
  • the residual solvent in the prior art crystal modification 1 was detected by 1 H NMR.
  • the peak detected at 2.07 ppm is that of acetonitrile, with about 0.10 molar equivalents
  • the crystalline form CSI has higher solubility in both FeSSIF and FaSSIF. Especially at 4 hours, the solubility of crystalline form CSI in FeSSIF is 3.4 times that of prior art crystalline modification 1; in FaSSIF, the solubility of crystalline form CSI is 4.8 times that of prior art crystalline modification 1.
  • the TGA of the crystal form CSI of the present invention is shown in FIG. 2 , when heated to 100° C., there is only about 0.3% mass loss, which corresponds to the removal of surface adsorbed water.
  • FIG. 13 As shown in the TGA diagram of the prior art crystalline modification 1 in WO2019245448A1 (Fig. 13), in the process of heating from 25°C to 100°C, the crystallization water is continuously removed, and the prior art crystalline modification 1 has Mass loss is as high as around 3.5%.
  • Placement conditions packing condition put time Crystal form purity start —— —— Form CSI 99.33% 25°C/60%RH seal 3 months Form CSI 99.46% 25°C/60%RH exposure 3 months Form CSI 99.51% 40°C/75%RH seal 3 months Form CSI 99.48% 40°C/75%RH exposure 3 months Form CSI 99.34%
  • Placement conditions packing condition put time Crystal form purity start —— —— Form CSI 99.45% 60°C/75%RH seal 1 month Form CSI 99.38%
  • the crystalline form CSI can be stable for at least 3 months under the conditions of 25°C/60%RH and 40°C/75%RH; it can be seen that the crystalline form CSI can maintain good stability under both long-term and accelerated conditions. Crystalline CSI is stable for at least 1 month at 60°C/75%RH, and it can be seen that the stability is also very good under more severe conditions.
  • Embodiment 9 The preparation method of crystal form CSII
  • the obtained crystalline solid is the crystal form CSII of the present invention, its X-ray powder diffraction pattern is shown in Figure 7, and the X-ray powder diffraction data is shown in Table 11. Confirmed by 1 H NMR data, the structure of crystalline form CSII is consistent with compound I.
  • TGA results are shown in Figure 8, with a mass loss of about 0.9% when heated to 100°C.
  • DSC results are shown in Figure 9, which has an endothermic peak, which begins to appear around 133°C.
  • the solvent residue comparison table is shown in Table 12.
  • Table 12 The results show that there is no organic solvent residue in the crystal form CSII of the present invention, while the prior art crystal modification 1 prepared repeatedly by the method disclosed in the prior art contains about 5500 ppm of acetonitrile residue.
  • ICH HARMONISED GUIDELINE Q3C (R8) on residual solvents acetonitrile belongs to the second-class solvent, and its residual concentration limit is 410ppm, so the residual amount of acetonitrile in the prior art crystal modification 1 even exceeds its solubility limit by 10 times. many.
  • the TGA of the crystal form CSII of the present invention is shown in FIG. 8 .
  • When heated to 100° C. there is only a mass loss of about 0.9%, which corresponds to the removal of surface adsorbed water.
  • the TGA diagram of the prior art crystalline modification 1 in WO2019245448A1 Fig. 13
  • Mass loss is as high as around 3.5%.
  • Placement conditions packing condition put time Crystal form purity start —— ——— Form CSII 98.74% 25°C/60%RH seal 3 months Form CSII 98.85% 25°C/60%RH exposure 3 months Form CSII 98.72% 40°C/75%RH seal 3 months Form CSII 98.73%

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Abstract

提供奥德昔巴特(称为"化合物I")的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备IBAT抑制剂药物和治疗进行性家族性肝内胆汁淤积症、胆道闭锁和Alagille综合征药物中的用途。提供的化合物I的新晶型比现有技术具有一种或多种改进的性质，解决了现有技术存在的问题，对含化合物I药物的优化和开发具有重要价值。

Description

奥德昔巴特的晶型及其制备方法和用途 技术领域
本发明涉及晶体化学领域。具体而言，涉及奥德昔巴特的晶型及其制备方法和用途。
背景技术
进行性家族性肝内胆汁淤积症(PFIC)是幼儿中一种罕见且威胁生命的疾病，会导致进行性的、危及生命的肝病。在许多病例中，PFIC会在患者10岁前造成肝硬化及肝功能衰竭。PFIC最突出的持续表现是瘙痒或剧烈瘙痒，这通常会导致生活质量严重下降。
胆道闭锁(BA)是一种罕见的儿科肝脏疾病，其症状通常在出生后约2至8周出现。肝外胆管受损或缺失会导致胆汁和胆汁酸滞留在肝内，迅速导致肝硬化甚至肝功能衰竭。
Alagille综合征(ALGS)是一种罕见的多系统遗传疾病，可影响肝脏、心脏、骨骼、中枢神经系统、肾脏、眼睛或面部等。
奥德昔巴特(Odevixibat)，是首个在美国获批用于治疗3个月及以上进行性家族性肝内胆汁淤积症(PFIC)患者瘙痒症的药物。奥德昔巴特是一种回肠胆汁酸转运体(IBAT)抑制剂，抑制胆汁酸从回肠自发再吸收进入肝门静脉循环中，未从回肠再吸收的胆汁酸会分泌至粪便中，胆汁酸自肠肝循环全部移除导致血清及肝脏中的胆汁酸水平降低。奥德昔巴特还可用于治疗BA和ALGS，并在临床阶段取得了积极效果。
奥德昔巴特的化学名称为1，1-二氧代-3，3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2，3，4，5-四氢-1，2，5-苯并硫杂二氮杂
Figure PCTCN2022073757-appb-000001
(以下称为“化合物I”)，其结构式如下：
Figure PCTCN2022073757-appb-000002
晶体是化合物分子在微观结构中三维有序排列而形成晶格的固体。多晶型是指一种化合物存在多种晶体形式的现象。化合物可能以一种或多种晶型存在，但是无法具体预期其存在与特性。不同晶型的原料药有不同的理化性质，可能导致药物在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效。特别是一些难溶性口服固体或半固体制剂，晶型对产品性能至关重要。除此之外，晶型的理化性质对生产过程至关重要。因此，多晶型是药物研究和药物质量控制的重要内容。
WO2019245448A1说明书中公开：通过重复WO2003022286A1中实施例29制备化合物I的最后一个步骤得到的粗产品为无定形，且多批次的化合物I的无定形均含有溶剂残留，例如甲酸，并且溶剂残留远超过药用可接受的范围，不符合药用标准。
WO2019245448A1还公开了多种混合溶剂合物的结晶修饰物2A、2B、及2C，统称为 结晶修饰物2。结晶修饰物2可以同时含有有机溶剂与水两种溶剂，并且不同有机溶剂(例如甲醇，乙醇，2-丙醇，丙酮，乙腈，1,4-二氧六环，N,N-二甲基甲酰胺和二甲基亚砜)的存在仅造成晶体单元晶胞体积的微小变化，不会导致结晶修饰物2的晶体结构的任何显著变形，因此不同混合溶剂合物的XRPD图基本相同。其说明书还披露结晶修饰物2在空气中不稳定且大部分在干燥后变成无定形。综上，结晶修饰物2含有有机溶剂且不稳定，不符合药用标准。
WO2019245448A1说明书中披露结晶修饰物1为管道水合物，其结晶水含量会发生变化，且其XRPD图会随着相对湿度的变化发生偏移。结晶修饰物1含有空隙体积，所述空隙体积视相对湿度而定，使得每摩尔化合物I含有至多约2摩尔结晶水。当相对湿度增加至95％时还可额外吸收1.5％(w/w)的水，形成过度水合结晶修饰物1。过度水合结晶修饰物1相比于结晶修饰物1的XRPD图会有偏移，该偏移在XRPD图的2θ范围为5-13°及18-25°中最明显。管道水合物在晶格中包含的水分子数量是可变的，由于水分子与化合物分子结合的氢键较弱，水分子是无序的。因此，水更容易从这些管道中扩散出来。此外，管道水合物的水分子含量在很大程度上取决于环境条件，这导致管道水合物在制剂加工和药物储存过程中的质量控制变的尤为困难，因为需要确保它们包含可预测的水分子组成。水含量的变化还可能对药物稳定性和溶解度等关键参数产生影响，从而引起药物质量变化，生物利用度变化和毒副作用。
此外，WO2019245448A1说明书中公开结晶修饰物1虽为管道水合物，但不能直接经由水结晶获得，需分离及干燥结晶修饰物2间接获得结晶修饰物1。这使得结晶修饰物1容易有溶剂残留，从而影响药物的安全性。本申请发明人重复了WO2019245448A1公开的结晶修饰物1的制备方法，得到的结晶修饰物1含有约5500ppm的乙腈。根据ICH HARMONISED GUIDELINE Q3C(R8)关于残留溶剂的指导原则，乙腈属于二类溶剂，其残留浓度限度在410ppm，结晶修饰物1含有的溶剂残留远超过药用可接受范围。
化合物I为BCS IV类药物，即为低溶解度低渗透性的药物，此类药物不利于人体内的吸收，且生物利用度低。此外，WO2019245449A1公开了化合物I的固体溶解度很低，由于溶解性差导致在湿法制粒的过程中容易团聚，随之影响药品胶囊颗粒的均匀度，从而最终影响药品的质量。
为了克服现有技术固体湿度稳定性差、水含量容易发生变化，有溶残，溶解度低等问题，仍然需要一种符合药用标准的新晶型，以用于含化合物I药物的开发。
此外经本申请发明人研究发现，化合物I容易以无定形形式存在。本申请发明人采用了多种实验方法，开展了约200个实验均得到了无定形。在付出大量的创造性劳动后，本申请发明人终于创造性地发现了本发明提供的化合物I晶型，其在溶残、溶解度，引湿性，提纯效果，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势，特别是没有溶残，溶解度高，高温稳定性好解决了现有技术存在的问题，对含化 合物I的药物开发具有非常重要的意义。
发明内容
本发明提供化合物I的新晶型及其制备方法和用途以及包含该新晶型的药物组合物。
根据本发明的目的，本发明提供化合物I的无水物。
非限制性地，该无水物为晶型CSI(以下称作“晶型CSI”)。
一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为3.0°±0.2°、5.2°±0.2°、5.9°±0.2°、7.9°±0.2°中的任意1处、或2处、或3处、或4处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为3.0°±0.2°、5.2°±0.2°、5.9°±0.2°、7.9°±0.2°、12.0°±0.2°、13.0°±0.2°中的任意1处、或2处、或3处、或4处、或5处、或6处有特征峰。
非限制性地，晶型CSI的X射线粉末衍射图基本如图1所示。
非限制性地，晶型CSI加热至100℃时，具有约0.3％的质量损失，热重分析图基本如图2所示。
非限制性地，晶型CSI的差示扫描量热分析图基本如图3所示。
根据本发明的目的，本发明还提供所述晶型CSI的制备方法，所述制备方法包括：
将化合物I固体置于硝基甲烷，硝基甲烷/酮类，或硝基甲烷/卤代烃的混合溶剂中搅拌，得到晶型CSI。
进一步地，所述硝基甲烷/酮类的体积比(v/v)优选30:1；所述硝基甲烷/卤代烃的体积比(v/v)优选9:1；所述搅拌的温度优选20℃-50℃。
更进一步地，所述酮类优选丁酮；所述卤代烃优选氯仿。
非限制性地，该无水物为晶型CSII(以下称作“晶型CSII”)。
一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为3.7°±0.2°、10.1°±0.2°处具有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为6.4°±0.2°、6.8°±0.2°、7.7°±0.2°中的任意1处、或2处、或3处具有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为6.4°±0.2°、6.8°±0.2°、7.7°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为3.7°±0.2°、10.1°±0.2°、6.4°±0.2°、6.8°±0.2°、7.7°±0.2°中的任意2处、或3处、或4处、或5处有特征峰。
非限制性地，使用Cu-Kα辐射，晶型CSII的X射线粉末衍射图基本如图7所示。
非限制性地，晶型CSII的热重分析图基本如图8所示，加热至100℃时，具有约0.9％的质量损失。
非限制性地，晶型CSII的差示扫描量热分析图基本如图9所示。
根据本发明的目的，本发明还提供所述晶型CSII的制备方法，所述制备方法包括：
将化合物I固体溶于甲酸中，挥发，干燥得到晶型CSII。
进一步地，所述挥发温度优选10-50℃，更优选20-30℃；所述干燥温度优选25-100℃，更优选40-60℃。
根据本发明的目的，本发明提供化合物I的无水物用于制备化合物I其他晶型或共晶或盐的用途。
进一步地，根据本发明的目的，本发明提供晶型CSI或晶型CSII用于制备化合物I其他晶型或共晶或盐的用途。
根据本发明的目的，本发明提供一种药物组合物，所述药物组合物包含有效治疗量的化合物I的无水物及药学上可接受的辅料。
进一步地，本发明提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSI、晶型CSII或以上晶型的任意混合及药学上可接受的辅料。
根据本发明的目的，本发明提供化合物I的无水物在制备IBAT抑制剂药物中的用途。
进一步地，本发明提供晶型CSI或晶型CSII在制备IBAT抑制剂药物中的用途。
根据本发明的目的，本发明提供化合物I的无水物在制备治疗进行性家族性肝内胆汁淤积症、胆道闭锁和Alagille综合征药物中的用途。
更进一步地，本发明提供晶型CSI或晶型CSII在制备治疗进行性家族性肝内胆汁淤积症、胆道闭锁和Alagille综合征药物中的用途。
有益效果
本发明提供的晶型CSI具有以下优势：
(1)与现有技术相比，本发明提供的晶型CSI无溶剂残留。残留溶剂不仅会影响药物的安全性，还会对药物质量和稳定性产生影响。残留溶剂可能会导致药物在生产和储存的过程中发生转晶或者降解，从而引起药物生物利用度变化和毒副作用。本发明提供的晶型CSI无溶剂残留，有效地克服了药物降解或溶剂残留高带来的药物稳定性低、疗效差、毒性高等缺点。
(2)与现有技术相比，本发明提供的晶型CSI具有更高的溶解度。特别是在4小时时，在模拟禁食状态肠液(FaSSIF)中，晶型CSI的溶解度是现有技术WO2019245448A1结晶修饰物1的4.8倍；在模拟进食状态肠液(FeSSIF)中，晶型CSI的溶解度是现有技术WO2019245448A1结晶修饰物1的3.4倍。化合物I是水溶性差的药物，且属于BCS IV类。本发明提供的晶型CSI有更高的溶解度，有利于提高药物在人体内的吸收，提高生物利用度；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
(3)与现有技术相比，本发明提供的晶型CSI的结晶水含量不发生变化。晶型CSI为 无水物不含结晶水，因此在外界湿度变化时，其结晶水的含量不会随之发生变化。而WO2019245448A1说明书公开现有技术结晶修饰物1为管道水合物，随着相对湿度的变化，每摩尔化合物I的晶体可以包含约2摩尔的水。说明书进一步公开，当相对湿度增加到95％时，会额外吸收1.5％(w/w)的水，额外的水可以被吸附在表面上，或者可以进一步填充在晶体结构的管道中，这会导致晶体结构随之变化。水含量的变化还可能对药物稳定性和溶解度等关键参数产生影响，从而引起药物质量变化，生物利用度变化和毒副作用。晶型CSI为无水物，可以有效地避免因为水含量变化而引起的晶体结构和药物质量的变化；并且利于制剂加工和药物储存过程中的质量控制。
(4)与现有技术相比，本发明提供的晶型CSI具有更好的高温稳定性。晶型CSI的TGA图显示，加热至100℃时仅有0.3％左右的质量损失，对应于表面吸附水的脱去。而WO2019245448A1现有技术结晶修饰物1的TGA图显示，从25℃升温至100℃的过程中，一直有水在脱去，且质量损失高达3.5％左右。水合物脱去结晶水后，可能会导致晶体结构发生变化。可见，晶型CSI具有更好的高温稳定性。原料药在储存、运输、生产过程中会遇到季节差异、不同地区气候差异和天气因素等带来的高温条件。晶型CSI相比于现有技术结晶修饰物1，在苛刻的条件下具有更好的稳定性，有利于避免偏离标签上的贮藏条件对药物质量的影响。最大程度地减少药物由于晶型改变引起的药物质量变化，生物利用度改变，甚至引起药物的毒副作用。
(5)本发明提供的晶型CSI原料药有较好的物理化学稳定性。晶型CSI原料药，在25℃/60％RH条件下放置，至少3个月晶型未发生变化，且储存过程中纯度基本保持不变。说明晶型CSI原料药在长期条件下具有较好的稳定性，有利于药物的储存。
晶型CSI原料药，在40℃/75％RH条件下放置至少3个月晶型未发生变化，在60℃/75％RH条件下放置至少1个月晶型未发生变化，且储存过程中纯度基本保持不变。说明晶型CSI原料药在加速条件及更严苛的条件下，具有较好的稳定性。
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSI具有良好的物理化学稳定性，保证原料药质量一致可控，可减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化和毒副作用。
(6)本发明提供的晶型CSI具有较好的湿度稳定性。晶型CSI在0％RH-95％RH-0％RH的条件下循环一次后，晶型未发生变化。季节差异、不同地区气候差异和环境因素等带来高湿条件会影响原料药的储存、运输、生产。因此，原料药在更严苛的条件下的稳定性对于药物至关重要。晶型CSI原料药在苛刻的条件下具有更好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
本发明提供的晶型CSII具有以下优势：
(1)与现有技术相比，本发明提供的晶型CSII无溶剂残留。残留溶剂不仅会影响药物的安全性，还会对药物质量和稳定性产生影响。残留溶剂可能会导致药物在生产和储存的过 程中发生转晶或者降解，从而引起药物生物利用度变化和毒副作用。本发明提供的晶型CSII无溶剂残留，有效地克服了药物降解或溶剂残留高带来的药物稳定性低、疗效差、毒性高等缺点。
(2)与现有技术相比，本发明提供的晶型CSII具有更高的溶解度。特别是4小时时，在FaSSIF和FeSSIF中，晶型CSII的溶解度均是现有技术WO2019245448A1结晶修饰物1的2倍。化合物I是水溶性差的药物，且属于BCS IV类。本发明提供的晶型CSII有更高的溶解度，有利于提高药物在人体内的吸收，提高生物利用度；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
(3)与现有技术相比，本发明提供的晶型CSII的结晶水含量不发生变化。晶型CSII为无水物不含结晶水，因此在外界湿度变化时，其结晶水的含量不会随之发生变化，从而不会影响晶体的结构。而WO2019245448A1说明书公开现有技术结晶修饰物1为管道水合物，随着相对湿度的变化，每摩尔化合物I的晶体可以包含约2摩尔的水。说明书进一步公开，当相对湿度增加到95％时，会额外吸收1.5％(w/w)的水，额外的水可以被吸附在表面上，或者可以进一步填充在晶体结构的管道中，这会导致晶体结构随之变化。水含量的变化还可能对药物稳定性和溶解度等关键参数产生影响，从而引起药物质量变化，生物利用度变化和毒副作用。晶型CSII为无水物，可以有效地避免因为水含量变化而引起的晶体结构的变化，和药物质量的变化；并且利于制剂加工和药物储存过程中的质量控制。
(4)与现有技术相比，本发明提供的晶型CSII具有更好的高温稳定性。晶型CSII的TGA图显示，加热至100℃时仅有0.9％左右的质量损失，对应于表面吸附水的脱去。而WO2019245448A1现有技术结晶修饰物1的TGA图显示，从25℃升温至100℃的过程中，一直有水在脱去，且质量损失高达3.5％左右。水合物脱去结晶水后，可能会导致晶体结构发生变化。可见，晶型CSII具有更好的高温稳定性。原料药在储存、运输、生产过程中会遇到季节差异、不同地区气候差异和天气因素等带来的高温条件。晶型CSII相比于现有技术结晶修饰物1，在苛刻的条件下具有更好的稳定性，有利于避免偏离标签上的贮藏条件对药物质量的影响。最大程度地减少药物由于晶型改变引起的药物质量变化，生物利用度改变，甚至引起药物的毒副作用。
(5)本发明提供的晶型CSII原料药有较好的物理化学稳定性。晶型CSII原料药，在25℃/60％RH条件下放置，至少3个月晶型未发生变化，且储存过程中纯度基本保持不变。说明晶型CSII原料药在长期条件下具有较好的稳定性，有利于药物的储存。
晶型CSII原料药，在40℃/75％RH条件下放置至少3个月晶型未发生变化，且储存过程中纯度基本保持不变。说明晶型CSII原料药在加速条件下，具有较好的稳定性。
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSII具有良好的物理化学稳定性，保证原料药质量一致可控，减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化和毒副作用。
(6)本发明提供的晶型CSII具有较好的湿度稳定性。晶型CSII在60％RH-0％RH-95％RH-0％RH的条件下循环一次后，晶型未发生变化。季节差异、不同地区气候差异和环境因素等带来高湿条件会影响原料药的储存、运输、生产。因此，原料药在更严苛的条件下的稳定性对于药物至关重要。晶型CSII原料药在苛刻的条件下具有更好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
附图说明
图1为晶型CSI的XRPD图
图2为晶型CSI的TGA图
图3为晶型CSI的DSC图
图4为晶型CSI在DVS测试前后的XRPD对比图(上：DVS前，下：DVS后)
图5为晶型CSI在不同条件下放置前后的XRPD对比图(从上至下依次为：放置前，25℃/60％RH放置3个月(密封包装)，25℃/60％RH放置3个月(敞口包装)，40℃/75％RH放置3个月(密封包装)，40℃/75％RH放置3个月(敞口包装))
图6为晶型CSI在60℃/75％RH条件下放置前后的XRPD对比图(从上至下依次为：放置前，60℃/75％RH放置1个月(密封包装))
图7为晶型CSII的XRPD图
图8为晶型CSII的TGA图
图9为晶型CSII的DSC图
图10为晶型CSII在DVS测试前后的XRPD对比图(上：DVS前，下：DVS后)
图11为晶型CSII在不同条件下放置前后的XRPD对比图(从上至下依次为：放置前，25℃/60％RH放置3个月(密封包装)，25℃/60％RH放置3个月(敞口包装)，40℃/75％RH放置3个月(密封包装))
具体实施方式
结合以下实施例对本发明做详细说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
1H NMR：液态核磁氢谱
RH：相对湿度
BCS：生物药剂学分类系统
HPLC：高效液相色谱
采集数据所用的仪器及方法：
本发明实施例所述的X射线粉末衍射图在Bruker D2 PHASER X射线粉末衍射仪上采集。所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Kα1
Figure PCTCN2022073757-appb-000003
1.54060；Kα2
Figure PCTCN2022073757-appb-000004
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围(2θ)：自3.0至40.0度
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：N 2
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：N 2
本发明所述的核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲基亚砜溶解，配成2-10mg/mL的溶液。
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200mL/min
相对湿度范围：0％RH-95％RH
本发明所述动态溶解度测试参数如表1所示：
表1
Figure PCTCN2022073757-appb-000005
Figure PCTCN2022073757-appb-000006
本发明所述有关物质检测的测试参数如表2所示：
表2
Figure PCTCN2022073757-appb-000007
本发明中，所述“无水物”是指仅由药物分子在三维空间内严格周期性排列形成的晶体。
所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌速度优选300-900转/分钟，机械搅拌速度优选100-300转/ 分钟。
所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。
所述“挥发”，采用本领域的常规方法完成，例如慢速挥发或快速挥发。慢速挥发可以是将容器封上封口膜，扎孔，静置挥发；快速挥发可以是将容器敞口放置挥发。
所述“干燥”，采用本领域的常规方法完成，例如真空干燥，鼓风干燥或自然晾干。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
所述“密封包装”，采用本领域的常规方法完成，例如将样品置于玻璃小瓶中，瓶口用瓶盖旋紧，最后密封于铝箔袋中；或将样品置于玻璃小瓶中，瓶口用瓶盖旋紧，随后与1g硅胶干燥剂一同密封于铝箔袋中；或将样品置于玻璃小瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开孔，随后与1g硅胶干燥剂一同密封于铝箔袋中。
所述“敞口包装”，采用本领域的常规方法完成，例如将样品置于玻璃小瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开孔。
所述“室温”不是特定的温度值，是指10-30℃温度范围。
所述“特征峰”是指用于甄别晶体的有代表性的衍射峰，使用Cu-Kα辐射测试时，峰位置通常可以有±0.2°的误差。
本发明中，“晶体”或“晶型”可以用X射线粉末衍射表征。本领域技术人员能够理解，X射线粉末衍射图受仪器的条件、样品的准备和样品纯度的影响而有所改变。X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度不能作为判定晶型的唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本发明所示的衍射峰强度为说明性而非用于绝对比较。因而，本领域技术人员可以理解的是，本发明所保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CSI和CSII是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
除非特殊说明，以下实施例均在室温条件下操作。
根据本发明，作为原料的所述化合物I和/或其盐包括但不限于固体形式(结晶或无定 形)、油状、液体形式和溶液。优选地，作为原料的化合物I和/或其盐为固体形式。
以下实施例中所使用的化合物I和/或其盐可以是现有技术公开的固体/晶型，例如WO2019245448A1公开的固体。
实施例1 晶型CSI的制备方法
称量303.7mg化合物I固体于玻璃瓶中，加入5mL硝基甲烷/丁酮(v/v，30:1)混合溶剂，再加入8.9mg晶型CSI作为晶种，50℃悬浮搅拌5天后，分离得到结晶固体。
经检测，所得结晶固体为本发明晶型CSI，其X射线粉末衍射图如图1所示，X射线粉末衍射数据如表3所示。
表3
衍射角2θ d值 强度％
2.98 29.61 63.73
5.16 17.11 100.00
5.95 14.86 30.42
7.88 11.21 26.85
11.99 7.38 3.12
13.02 6.80 2.07
实施例2 晶型CSI的制备方法
根据表4所示，称取一定质量的化合物I固体置于一定体积的溶剂中，50℃悬浮搅拌，离心收集固体，并于50℃干燥得到结晶固体。将得到的结晶固体分别标记为样品1和样品2。经检测，所得样品1和样品2均为本发明晶型CSI。
经 1H NMR数据确认，晶型CSI的结构与化合物I相符。
本发明所述样品1的TGA如图2所示，加热至100℃时，具有约0.3％的质量损失。
本发明所述样品1的X射线粉末衍射数据如表5所示。
本发明所述样品2的X射线粉末衍射数据如表6所示。
表4
Figure PCTCN2022073757-appb-000008
表5
Figure PCTCN2022073757-appb-000009
Figure PCTCN2022073757-appb-000010
表6
Figure PCTCN2022073757-appb-000011
实施例3 晶型CSI的DSC测试
取少量晶型CSI进行DSC测试，结果如图3所示，其有一个吸热峰，在144℃附近开始出现这个吸热峰。
实施例4 晶型CSI和现有技术的残留溶剂测试
称量200.0mg化合物I固体到20mL玻璃瓶中，向其中加入2mL硝基甲烷形成悬浊液，50℃下悬浮搅拌约46小时后，分离得到固体。将所得固体在室温放置一段时间后再于50℃真空干燥约22小时，得到结晶固体CSI。通过 1H NMR检测晶型CSI中残留溶剂。核磁数据为： 1H NMR(400MHz,DMSO)δ12.64(s,1H),9.38(s,1H),8.60(d,J＝8.0Hz,1H),8.37(d,J＝7.9Hz,1H),7.36–7.17(m,6H),7.11(d,2H),6.96(t,J＝6.7Hz,1H),6.70(d,J＝8.6Hz,2H),6.58(s,1H),5.53(d,J＝8.0Hz,1H),4.69(dd,J＝35.4,14.6Hz,2H),4.22–3.98(m,1H),3.86(brs,2H),2.12(s,3H),1.79–1.31(m,7H),1.17–0.88(m,7H),0.79–0.65(m,9H)。核磁结果表明没有任何有机溶剂残留。
根据现有技术WO2019245448A1实施例7公开的方法，制备现有技术结晶修饰物1：称量20.2mg化合物I固体到4mL玻璃瓶中，向其中加入1.5mL乙腈，再加入2.5mL水得到悬浊液，将所得悬浊液继续在室温下悬浮搅拌20分钟后离心分离固体，将所得固体在25℃真空干燥约17小时后得到现有技术晶型结晶修饰物1。通过 1H NMR检测现有技术结晶修饰物1中的残留溶剂。核磁数据如下 1H NMR(400MHz,DMSO)δ12.63(s,1H),9.38(s,1H),8.58(d,J＝7.9Hz,1H),8.37(d,J＝7.9Hz,1H),7.36–7.18(m,6H),7.11(d,2H),6.95(t,1H),6.70(d,J＝8.5Hz,2H),6.58(s,1H),5.53(d,J＝8.0Hz,1H),4.69(dd,J＝20.5Hz,2H),4.21–4.03(m,J＝4.8Hz,1H),3.83(brs,2H),2.12(s,3H),2.07(s,0.29H),1.76–1.32(m,7H),1.17–0.89(m,7H),0.82–0.64(m,9H)。在2.07ppm处检测到的峰为乙腈的峰，约有0.10摩尔当量的乙腈残留，对应约5500ppm。
溶剂残留对比如表7所示。结果表明，本发明晶型CSI中没有任何有机溶剂残留，而采用现有技术公开的方法重复制备得到的现有技术结晶修饰物1中，含有约5500ppm的乙腈残留。根据ICH HARMONISED GUIDELINE Q3C(R8)关于残留溶剂的指导原则，乙腈属于二类溶剂，其残留浓度限度在410ppm，故现有技术结晶修饰物1中残留的乙腈量甚至超出其溶残限度10倍之多。
表7
Figure PCTCN2022073757-appb-000012
实施例5 晶型CSI和现有技术的动态溶解度
取本发明晶型CSI及现有技术结晶修饰物1各约20mg分别分散在2mL的FeSSIF和FaSSIF中，配制成悬浊液，在37℃平衡1小时和4小时后用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表8示。
表8
Figure PCTCN2022073757-appb-000013
结果表明，晶型CSI在FeSSIF和FaSSIF中均具有更高的溶解度。特别是在4小时时，在FeSSIF中，晶型CSI的溶解度是现有技术结晶修饰物1的3.4倍；在FaSSIF中，晶型CSI的溶解度是现有技术结晶修饰物1的4.8倍。
实施例6 晶型CSI的高温稳定性
本发明晶型CSI的TGA如图2所示，加热至100℃时，仅有约0.3％的质量损失，对应于表面吸附水的脱去。然而，如WO2019245448A1中现有技术结晶修饰物1的TGA图(附图13)所示，从25℃加热至100℃的过程中，结晶水在不断脱去，且现有技术结晶修饰物1的质量损失高达3.5％左右。
结果表明晶型CSI有更好的高温稳定性。
实施例7 晶型CSI的湿度稳定性
取适量本发明晶型CSI，采用动态水分吸附仪(DVS)评估其湿度稳定性。25℃下，在0％RH-95％RH-0％RH条件下循环一次，并在DVS测试前后，用XRPD测试晶型。DVS前后的XRPD对比图如图4所示。结果表明，DVS测试前后，晶型CSI未发生变化，有较好的湿度稳定性。
实施例8 晶型CSI的稳定性
取适量本发明晶型CSI采用一定的方式包装后，分别放置在25℃/60％RH、40℃/75％RH或60℃/75％RH条件下，采用HPLC和XRPD测定纯度与晶型。结果如表9，表10所示，XRPD对比图如图5，图6。
表9
放置条件 包装条件 放置时间 晶型 纯度
起始 —— —— 晶型CSI 99.33％
25℃/60％RH 密封 3个月 晶型CSI 99.46％
25℃/60％RH 敞口 3个月 晶型CSI 99.51％
40℃/75％RH 密封 3个月 晶型CSI 99.48％
40℃/75％RH 敞口 3个月 晶型CSI 99.34％
表10
放置条件 包装条件 放置时间 晶型 纯度
起始 —— —— 晶型CSI 99.45％
60℃/75％RH 密封 1个月 晶型CSI 99.38％
结果表明，晶型CSI在25℃/60％RH和40℃/75％RH条件下可至少稳定3个月；可见，晶型CSI在长期和加速条件下均可保持良好的稳定性。晶型CSI在60℃/75％RH条件下至少可稳定1月，可见在更严苛的条件下稳定性也很好。
实施例9 晶型CSII的制备方法
称量120.2mg化合物I固体于玻璃瓶中，加入1.0mL甲酸溶解固体，所得溶液过滤并大致均分至4个玻璃瓶中，取2份装有滤液的玻璃瓶分别放入预先装有约5mL甲基叔丁基醚的20mL玻璃瓶中，在室温下快速挥发约3天得到2份样品，随后转移至25℃真空干燥约2.5小时，将2份样品混合均匀后转移至50℃真空干燥约33.5小时，得到结晶固体。
经检测，所得结晶固体为本发明晶型CSII，其X射线粉末衍射图如图7，X射线粉末衍射数据如表11所示。经 1H NMR数据确认，晶型CSII的结构与化合物I相符。
表11
Figure PCTCN2022073757-appb-000014
实施例10 晶型CSII的TGA和DSC测试
取少量晶型CSII进行TGA和DSC测试。TGA结果如图8所示，将其加热至100℃时，具有约0.9％的质量损失。DSC结果如图9所示，其有一个吸热峰，在133℃附近开始出现这个吸热峰。
实施例11 晶型CSII的残留溶剂测试
通过 1H NMR检测实施例9制备得到的晶型CSII中的残留溶剂。核磁数据为： 1H NMR(400MHz,DMSO)δ9.37(s,1H),8.57(d,J＝8.0Hz,1H),8.35(d,J＝7.9Hz,1H),7.33–7.17(m,6H),7.12(d,2H),6.95(t,J＝7.1Hz,1H),6.70(d,J＝8.6Hz,2H),6.58(s,1H),5.53(d,J＝8.0Hz,1H),4.69(dd,J＝35.1,14.6Hz,2H),4.22–3.99(m,J＝4.8Hz,1H),3.85(brs,2H),2.12(s,3H),1.77–1.31(m,J＝62.0,24.1,10.5Hz,7H),1.16–0.89(m,J＝23.0Hz,7H),0.81–0.62(m,9H).其中化合物I中有1个活泼氢未检测到。核磁结果表明没有任何有机溶剂残留。
溶剂残留对比表如表12所示。结果表明，本发明晶型CSII中没有任何有机溶剂残留，而采用现有技术公开的方法重复制备得到的现有技术结晶修饰物1中，含有约5500ppm的乙腈残留。根据ICH HARMONISED GUIDELINE Q3C(R8)关于残留溶剂的指导原则，乙腈属于二类溶剂，其残留浓度限度在410ppm，故现有技术结晶修饰物1中残留的乙腈量甚至超出其溶残限度10倍之多。
表12
Figure PCTCN2022073757-appb-000015
实施例12 晶型CSII和现有技术的动态溶解度
取本发明晶型CSII及现有技术结晶修饰物1各约20mg分别分散在2mL的FeSSIF和FaSSIF中，配制成悬浊液，在37℃平衡1小时和4小时后用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表13所示。
表13
Figure PCTCN2022073757-appb-000016
结果表明，晶型CSII在FeSSIF和FaSSIF中均具有更高的溶解度。特别是在4小时时，在FeSSIF和FaSSIF中，晶型CSII的溶解度是现有技术结晶修饰物1的2倍。
实施例13 晶型CSII的热稳定性
本发明晶型CSII的TGA如图8所示，加热至100℃时，仅有约0.9％的质量损失，对应于表面吸附水的脱去。然而，如WO2019245448A1中现有技术结晶修饰物1的TGA图(附图13)所示，从25℃加热至100℃的过程中，结晶水在不断脱去，且现有技术结晶修饰物1的质量损失高达3.5％左右。
结果表明晶型CSII有更好的热稳定性。
实施例14 晶型CSII的湿度稳定性
取适量本发明晶型CSII，采用动态水分吸附仪(DVS)评估其湿度稳定性。25℃下， 在60％RH-0％RH-95％RH-0％RH条件下循环一次，并在DVS测试前后，用XRPD测试晶型。DVS前后的XRPD对比图如图10所示。结果表明，DVS测试前后，晶型CSII未发生变化。
实施例15 晶型CSII的稳定性
取适量本发明晶型CSII采用一定的方式包装后，分别放置在25℃/60％RH和40℃/75％RH条件下，采用HPLC和XRPD测定纯度与晶型。结果如表14所示，XRPD对比图如图11。
表14
放置条件 包装条件 放置时间 晶型 纯度
起始 —— —— 晶型CSII 98.74％
25℃/60％RH 密封 3个月 晶型CSII 98.85％
25℃/60％RH 敞口 3个月 晶型CSII 98.72％
40℃/75％RH 密封 3个月 晶型CSII 98.73％
结果表明，晶型CSII在25℃/60％RH和40℃/75％RH条件下可至少稳定3个月；可见，晶型CSII在长期和加速条件下均可保持良好的稳定性。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (14)

  1. 化合物I的晶型，其特征在于，所述晶型为无水物，
    Figure PCTCN2022073757-appb-100001
  2. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为3.0°±0.2°、5.2°±0.2°、5.9°±0.2°、7.9°±0.2°中的至少一处具有特征峰。
  3. 根据权利要求2所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图1所示。
  4. 一种权利要求2所述的化合物I的晶型的制备方法，其特征在于，制备方法包括：将化合物I固体置于硝基甲烷，硝基甲烷/酮类，或硝基甲烷/卤代烃的混合溶剂中搅拌，得到化合物I的晶型。
  5. 根据权利要求4所述的化合物I晶型的制备方法，其特征在于，所述硝基甲烷/酮类的体积比为30:1；所述硝基甲烷/卤代烃的体积比为9:1；所述搅拌的温度为20℃-50℃。
  6. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为3.7°±0.2°、10.1°±0.2°处具有特征峰。
  7. 根据权利要求6所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为6.4°±0.2°、6.8°±0.2°、7.7°±0.2°中的至少一处具有特征峰。
  8. 根据权利要求6所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图7所示。
  9. 一种权利要求6所述的化合物I的晶型的制备方法，其特征在于，制备方法包括：将化合物I固体溶于甲酸中，挥发，干燥得到化合物I的晶型。
  10. 根据权利要求9所述的制备方法，其特征在于，所述挥发的温度为10℃-50℃；所述干燥的温度为25℃-100℃。
  11. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1所述的化合物I的晶型及药学上可接受的辅料。
  12. 权利要求1中所述的化合物I的晶型在制备化合物I的其他晶型或共晶或盐的用途。
  13. 权利要求1中所述的化合物I的晶型在制备IBAT抑制剂药物中的用途。
  14. 权利要求1中所述的化合物I的晶型在制备治疗进行性家族性肝内胆汁淤积症、胆 道闭锁和Alagille综合征药物中的用途。
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WO2003022286A1 (en) * 2001-09-08 2003-03-20 Astrazeneca Ab Benzothiazepine and benzothiadiazepine derivatives with ileal bile acid transport (ibat) inhibitory activity for the treatment hyperlipidaemia
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CN103260625A (zh) * 2010-11-04 2013-08-21 阿尔比里奥公司 用于治疗肝脏疾病的ibat抑制剂
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WO2003022286A1 (en) * 2001-09-08 2003-03-20 Astrazeneca Ab Benzothiazepine and benzothiadiazepine derivatives with ileal bile acid transport (ibat) inhibitory activity for the treatment hyperlipidaemia
CN1771027A (zh) * 2003-04-05 2006-05-10 阿斯特拉曾尼卡有限公司 Ibat抑制剂在治疗或预防便秘中的应用
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