WO2022166680A1 - Forme cristalline d'odévixibat, procédé de préparation et utilisation associés - Google Patents

Forme cristalline d'odévixibat, procédé de préparation et utilisation associés Download PDF

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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)
Chinese (zh)
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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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    • 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

L'invention concerne une nouvelle forme cristalline d'odévixibat (appelée "composé I"), un procédé de préparation associé, une composition pharmaceutique contenant ladite forme cristalline, et une utilisation de ladite forme cristalline dans la préparation d'un médicament inhibiteur d'IBAT et d'un médicament pour le traitement de la cholestase intrahépatique familiale progressive, de l'atrésie biliaire et du syndrome d'Alagille. La forme cristalline du composé I fournie par la présente invention présente une ou plusieurs propriétés améliorées par rapport à l'état de la technique, résout un problème existant dans l'état de la technique, et a une grande valeur pour l'optimisation et le développement futur d'un médicament contenant le composé I.
PCT/CN2022/073757 2021-06-25 2022-01-25 Forme cristalline d'odévixibat, procédé de préparation et utilisation associés WO2022166680A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003022286A1 (fr) * 2001-09-08 2003-03-20 Astrazeneca Ab Derives de benzothiazepine et de benzothiadiazepine presentant une activite inhibitrice du transport des acides biliaires ileaux (ibat), destines au traitement de l'hyperlipidemie
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
CN103221051A (zh) * 2010-11-08 2013-07-24 阿尔比里奥公司 用于治疗代谢障碍和相关病症的ibat抑制剂
CN103260625A (zh) * 2010-11-08 2013-08-21 阿尔比里奥公司 用于治疗肝脏疾病的ibat抑制剂
CN112262130A (zh) * 2018-06-20 2021-01-22 阿尔比里奥公司 奥德昔巴特的结晶修饰物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003022286A1 (fr) * 2001-09-08 2003-03-20 Astrazeneca Ab Derives de benzothiazepine et de benzothiadiazepine presentant une activite inhibitrice du transport des acides biliaires ileaux (ibat), destines au traitement de l'hyperlipidemie
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
CN103221051A (zh) * 2010-11-08 2013-07-24 阿尔比里奥公司 用于治疗代谢障碍和相关病症的ibat抑制剂
CN103260625A (zh) * 2010-11-08 2013-08-21 阿尔比里奥公司 用于治疗肝脏疾病的ibat抑制剂
CN112262130A (zh) * 2018-06-20 2021-01-22 阿尔比里奥公司 奥德昔巴特的结晶修饰物
CN112312893A (zh) * 2018-06-20 2021-02-02 阿尔比里奥公司 奥德昔巴特的药物制剂

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