WO2021244323A1 - Forme cristalline d'upadacitinib, son procédé de préparation et son utilisation - Google Patents

Forme cristalline d'upadacitinib, son procédé de préparation et son utilisation Download PDF

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WO2021244323A1
WO2021244323A1 PCT/CN2021/095103 CN2021095103W WO2021244323A1 WO 2021244323 A1 WO2021244323 A1 WO 2021244323A1 CN 2021095103 W CN2021095103 W CN 2021095103W WO 2021244323 A1 WO2021244323 A1 WO 2021244323A1
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crystalline
csv
crystal form
csiv
ray powder
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PCT/CN2021/095103
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Chinese (zh)
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陈敏华
张婧
史佳明
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苏州科睿思制药有限公司
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Priority to CN202180004686.XA priority Critical patent/CN114206877B/zh
Publication of WO2021244323A1 publication Critical patent/WO2021244323A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the invention relates to the field of crystal chemistry. Specifically, it relates to the crystal form of upatinib and its preparation method and use.
  • Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of joints and other parts of the body, and leads to permanent joint destruction and deformity. If the disease is left untreated, it can cause substantial disability and pain due to loss of joint function, and ultimately shorten life expectancy.
  • Crohn's disease (Crohn's disease) is an inflammatory bowel disease. Symptoms usually include: abdominal pain, diarrhea, fever, and weight loss. People with this disease have a greater risk of bowel cancer. Ulcerative colitis is a chronic disease that causes inflammation and ulcers in the colon and rectum. The main symptoms of the attack include abdominal pain and diarrhea accompanied by blood in the stool. The symptoms usually occur slowly and vary in severity.
  • Psoriatic arthritis is an inflammatory joint disease associated with psoriasis, with a psoriatic rash accompanied by pain, swelling, tenderness, stiffness, and movement disorders in the joints and surrounding soft tissues.
  • JAK1 is a target of immune-inflammatory diseases, and its inhibitors are beneficial for the treatment of immune inflammatory disorders such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis and psoriatic arthritis.
  • Upatinib is a second-generation oral JAK1 inhibitor developed by AbbVie, which shows high selectivity for inhibiting JAK1.
  • the chemical name of the drug is: (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N -(2,2,2-Trifluoroethyl)pyrrolidine-1-carboxamide, its structural formula is as follows:
  • the crystal form is a solid in which the compound molecules are arranged in a three-dimensional order in the microstructure to form a crystal lattice.
  • the phenomenon of drug polymorphism refers to the existence of two or more different crystal forms of the drug. Because of the different physical and chemical properties, different crystal forms of the drug may have different dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent. Especially for poorly soluble solid drugs, the crystal form will have a greater impact. Therefore, the crystal form of a drug must be an important content of drug research and an important content of drug quality control.
  • the molecules in the amorphous solid are disorderly arranged and the stability is poor, so amorphous drugs are prone to crystalline transformation during the production and storage process.
  • the poor stability of the amorphous form may lead to changes in the bioavailability and dissolution of the drug, leading to changes in the clinical efficacy of the drug.
  • drug co-crystal consists of two or more different molecules (one of which is the active pharmaceutical ingredient (API)) in the same lattice through non-ionic bonds and non-co-polymers at a certain stoichiometric ratio.
  • Drug co-crystals provide an opportunity to design solid forms on the basis of traditional bulk drug solid forms (such as salts and polymorphs). Drug co-crystals can be used to improve the bioavailability and stability of drugs, and to improve the processing performance of bulk drugs during drug production. Another advantage of drug co-crystals is that for some APIs that are difficult to salt due to lack of ionizable functional groups, drug co-crystals can provide more solid forms for them.
  • WO2017066775A1 discloses the free form crystal form A, crystal form B, crystal form C, crystal form D and amorphous form of upatinib and its salts.
  • the patent text discloses that crystal form A and crystal form B have poor crystallinity and are unstable, and are easily dehydrated into amorphous; crystal form D can only be obtained at low water activity, and the crystallization is slow, and the repeatability is poor. Under water activity, it will transform into crystal form C; compared with other free forms of upatinib disclosed in WO2017066775A1, crystal form C has better properties, but crystal form C has the disadvantages of poor repeatability and difficulty in crystallizing from solution .
  • WO2020063939A1 discloses acetate solvate Form CSI
  • WO2020115213A1 discloses a two acetate solvate Form AHOA C and Form BHOA C, wherein the Form AHOA C isomorphic CSI.
  • the inventor of the present application found that the stability of the acetic acid solvate is poor and does not meet the requirements of pharmaceutical development.
  • the art still needs to develop a crystal form with good stability, good repeatability, easy to crystallize from solution, and other properties that meet the needs of medicinal use, for use in drugs containing upatinib Development.
  • the inventor of the present application unexpectedly discovered that the crystal form CSV and crystal form CSV of upatinib provided by the present invention have stability, melting point, solubility, dissolution in vivo and in vitro, hygroscopicity, bioavailability, adhesion, and compressibility.
  • Fluidity, processing performance, purification, formulation development, etc. have advantages in at least one aspect, especially good solubility and stability, simple preparation process, and solve the problems existing in the crystal form of the prior art.
  • the drug development of tinib is of great significance.
  • the main purpose of the present invention is to provide a new crystal form of upatinib and its preparation method and application.
  • the present invention provides a sebacic acid co-crystal of upatinib (hereinafter referred to as "crystalline form CSIV").
  • the X-ray powder diffraction of the crystal form CSIV has a diffraction angle 2 ⁇ value of 5.8° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.7° ⁇ 0.2° at 1 or 2 , Or three characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSIV has characteristic peaks at the diffraction angle 2 ⁇ values of 5.8° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CSIV has a diffraction angle of 4.6° ⁇ 0.2°, 14.1° ⁇ 0.2°, 15.9° ⁇ 0.2°, or 2 positions , Or three characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSIV has characteristic peaks at diffraction angle 2 ⁇ values of 4.6° ⁇ 0.2°, 14.1° ⁇ 0.2°, 15.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CSIV has a diffraction angle 2 ⁇ value of 10.6° ⁇ 0.2°, 10.9° ⁇ 0.2°, 14.9° ⁇ 0.2° at 1 or 2 , Or three characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSIV has characteristic peaks at diffraction angle 2 ⁇ values of 10.6° ⁇ 0.2°, 10.9° ⁇ 0.2°, and 14.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CSIV has diffraction angle 2 ⁇ values of 5.8° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.7° ⁇ 0.2°, 4.6° ⁇ 0.2°, Any of 14.1° ⁇ 0.2°, 15.9° ⁇ 0.2°, 10.6° ⁇ 0.2°, 10.9° ⁇ 0.2°, 14.9° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.2° ⁇ 0.2°, 20.2° ⁇ 0.2° 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12 characteristic peaks.
  • the X-ray powder diffraction pattern of the crystal form CSIV is shown in FIG. 1.
  • thermogravimetric analysis chart of the crystalline CSIV is shown in FIG. 2, which has a weight loss of about 0.2% when heated to 150°C.
  • the differential scanning calorimetry chart of the crystalline CSIV is shown in FIG. 5, an endothermic peak begins to appear around 110° C., and the endothermic peak is a melting endothermic peak.
  • the molar ratio of sebacic acid to upatinib in the crystal form CSIV is 0.2:1-0.6:1, and further, the molar ratio of sebacic acid to upatinib in the crystal form CSIV is preferably 0.3: 1-0.5:1.
  • the present invention also provides a method for preparing the crystal form CSIV, which includes: placing upatinib and sebacic acid in a mixed solvent of esters and ethers and stirring to obtain a solid, The obtained solid is placed in a nitrile solvent and stirred to obtain the crystal form CSIV; or
  • ester solvent is preferably ethyl acetate, isopropyl acetate or ethyl propionate
  • ether solvent is preferably methyl tert-butyl ether
  • nitrile solvent is preferably acetonitrile
  • volume ratio of the esters and ethers is preferably 1:1 to 1:2.
  • the stirring temperature in the ester and ether mixed solvent is preferably 0°C-40°C, and the stirring time is preferably more than 12 hours.
  • the crystal form CSIV provided by the present invention has higher solubility.
  • the crystal form CSIV has higher solubility in both FaSSIF (artificial intestinal fluid under fasting state) and FeSSIF (artificial intestinal fluid under fed state), and the solubility is 2-3 times that of the prior art WO2017066775A1 crystal form C .
  • Higher solubility is conducive to improving the absorption of drugs in the human body, improving bioavailability, and making the drugs play a better therapeutic effect; in addition, higher solubility can reduce the dose of drugs while ensuring the efficacy of drugs, thereby reducing drugs Side effects and improve the safety of medicines.
  • the crystalline CSIV bulk drug provided by the present invention has good stability.
  • the crystal form CSIV bulk drug is placed under the condition of 25°C/60%RH (relative humidity), the crystal form has not changed for at least 6 months, and the chemical purity is above 99.7%, and the purity remains basically unchanged during storage. It shows that the crystalline CSIV bulk drug has good stability under long-term conditions, which is conducive to the storage of the drug.
  • the crystal form of the CSIV API has been placed at 40°C/75%RH (closed mouth + desiccant) for at least 6 months without any change in crystal form, and at least 1 under 60°C/75% RH (closed mouth + desiccant) conditions
  • the monthly crystal form has not changed, and the chemical purity is above 99.6%, and the purity remains basically unchanged during storage.
  • the stability of the drug substance under accelerated conditions and more severe conditions is very important for the drug. Seasonal differences, climate differences in different regions and weather factors brought high temperature and high humidity conditions will affect the storage, transportation, and production of APIs.
  • the crystalline CSIV bulk drugs and preparations have better stability under harsh conditions, which is beneficial to avoid the impact of deviation from the storage conditions on the label on the quality of the drugs.
  • the transformation of the crystal form will cause changes in the absorption of the drug, affect the bioavailability, and even cause the toxic and side effects of the drug.
  • Good chemical stability can ensure that there are basically no impurities generated during storage.
  • the crystal form CSIV has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and minimizing changes in drug quality, bioavailability, and even toxic side effects caused by changes in crystal form or impurities.
  • the present invention provides upatinib glutaric acid co-crystal CSV (hereinafter referred to as "crystal CSV").
  • the X-ray powder diffraction of the crystalline CSV has a diffraction angle 2 ⁇ value of 6.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, 22.5° ⁇ 0.2° at 1 or 2 positions , Or three characteristic peaks; preferably, the X-ray powder diffraction of the crystalline CSV has characteristic peaks at diffraction angle 2 ⁇ values of 6.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, 22.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline CSV has a diffraction angle of 4.7° ⁇ 0.2°, 15.6° ⁇ 0.2°, 21.2° ⁇ 0.2°, or 2 , Or three characteristic peaks; preferably, the X-ray powder diffraction of the crystalline CSV has characteristic peaks at the diffraction angle 2 ⁇ values of 4.7° ⁇ 0.2°, 15.6° ⁇ 0.2°, 21.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline CSV has characteristic peaks at 1 or 2 of the diffraction angle 2 ⁇ values of 16.9° ⁇ 0.2°, 18.7° ⁇ 0.2°; preferably The X-ray powder diffraction of the crystalline CSV has characteristic peaks at diffraction angle 2 ⁇ values of 16.9° ⁇ 0.2° and 18.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline CSV has diffraction angle 2 ⁇ values of 6.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, 22.5° ⁇ 0.2°, 4.7° ⁇ 0.2°, 15.6° ⁇ 0.2°, 21.2° ⁇ 0.2°, 16.9° ⁇ 0.2°, 18.7° ⁇ 0.2°, 12.5° ⁇ 0.2°, 12.9° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.1° Any 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13 characteristic peaks within ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystalline CSV is shown in FIG. 7.
  • thermogravimetric analysis chart of the crystalline CSV is shown in FIG. 10, and it has a weight loss of about 1.1% when heated to 100°C.
  • the molar ratio of glutaric acid to upatinib in the crystalline CSV is preferably 0.5:1 to 1:1, and further, the molar ratio of glutaric acid to upatinib in the crystalline CSV is preferably 0.6: 1-1:1.
  • the present invention also provides a preparation method of the crystalline CSV, and the preparation method includes:
  • the upatinib and glutaric acid are placed in an ester solvent or a mixed solvent of esters and ethers and stirred to obtain the crystal form CSV.
  • ester solvent is preferably isopropyl acetate
  • ether is preferably methyl tert-butyl ether.
  • the molar feed ratio of upatinib and glutaric acid is preferably 1:1-1:3, and the volume ratio of ester to ether in the mixed solvent of esters and ethers is preferably 1:1-1: 3.
  • the crystal form CSV of the present invention has higher solubility.
  • the crystal form CSV has higher solubility in both FaSSIF and FeSSIF, and the solubility is 2-5 times that of the prior art WO2017066775A1 crystal form C.
  • Higher solubility is conducive to improving the absorption of drugs in the human body, improving bioavailability, and making the drugs play a better therapeutic effect; in addition, higher solubility can reduce the dose of drugs while ensuring the efficacy of drugs, thereby reducing drugs Side effects and improve the safety of medicines.
  • the crystalline CSV bulk drug provided by the present invention has good stability.
  • the crystalline CSV bulk drug is placed under the condition of 25°C/60%RH, the crystalline form has not changed for at least 6 months, and the chemical purity is above 99.7%, and the purity remains basically unchanged during storage. It shows that the crystalline CSV bulk drug has good stability under long-term conditions, which is conducive to the storage of the drug.
  • the crystal form of the CSV bulk drug has not changed after being placed under the closed condition of 40°C/75%RH for at least 3 months, and the chemical purity is above 99.7%, and the purity remains basically unchanged during storage.
  • the stability of the drug substance under accelerated conditions and more severe conditions is very important for the drug. Seasonal differences, climate differences in different regions and weather factors brought high temperature and high humidity conditions will affect the storage, transportation, and production of APIs. Crystalline CSV bulk drugs and preparations have better stability under harsh conditions, which is beneficial to avoid the impact of deviation from the storage conditions on the label on the quality of the drug.
  • the crystalline CSV has good mechanical stability.
  • the crystal form of the crystalline CSV bulk drug did not change before and after grinding, and it has good physical stability.
  • the preparation process often requires the grinding and pulverization of the drug substance, and good physical stability can reduce the risk of crystallinity change and crystal transformation of the drug substance in the preparation process.
  • Crystalline CSV has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and minimizing changes in drug quality, bioavailability, and even toxic side effects caused by changes in crystal form or impurities.
  • the present invention also provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline CSV, crystalline CSV and pharmaceutically acceptable excipients.
  • the present invention provides the use of crystal form CSV and crystal form CSV in the preparation of JAK1 inhibitor pharmaceutical preparations.
  • the present invention provides the use of crystal form CSV and crystal form CSV in the preparation of pharmaceutical preparations for the treatment of rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis and psoriatic arthritis.
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, at a stirring speed of 50-1800 revolutions per minute, wherein the magnetic stirring is preferably 300-900 revolutions per minute, and mechanical stirring It is preferably 100-300 revolutions per minute.
  • the "drying” can be performed at room temperature or higher.
  • the drying temperature is from room temperature to about 60°C, or to 50°C, or to 40°C.
  • the drying time can be 2-48 hours, or overnight. Drying is carried out in a fume hood, blast oven or vacuum oven.
  • the “characteristic peak” refers to a representative diffraction peak used to distinguish crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • the "saturated sebacic acid solution” is prepared by conventional methods in the art. For example, the excess sebacic acid is mixed with the corresponding solvent to prepare a suspension and then the supernatant is taken.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern is affected by 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 intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystals.
  • the intensity of the diffraction peaks shown in the present invention is illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the protected crystal form of the present invention does not have to be exactly the same as the X-ray powder diffraction pattern in the embodiment referred to here, and any characteristic peaks in these patterns.
  • the crystal forms of the same or similar X-ray powder diffraction patterns 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 the 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 crystal form CSV and crystal form CSV of the present invention are pure, and there is basically no mixing of any other crystal forms.
  • substantially no when used to refer to a new crystal form means that this 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. Other crystal forms that are less than 5% by weight, and even other crystal forms that are less than 1% by weight.
  • Figure 1 is an XRPD diagram of the crystal form CSIV obtained according to Example 1
  • Figure 2 is a TGA diagram of the crystal form CSIV obtained according to Example 1
  • Figure 3 is an XRPD diagram of the crystal form CSIV obtained according to Example 2.
  • Figure 4 is an XRPD diagram of the crystal form CSIV obtained according to Example 3.
  • Figure 5 is a DSC chart of the crystal form CSIV obtained according to Example 3.
  • Figure 6 XRPD overlays before and after placement of crystal form CSIV (from top to bottom: before placement, after placement at 25°C/60%RH (closed with desiccant) for 6 months, 25°C/60%RH open placement 6 Months later, after placing it at 40°C/75%RH (closed mouth with desiccant) for 6 months, after placing it at 60°C/75%RH (closed mouth with desiccant) for 1 month)
  • Figure 7 is an XRPD diagram of the crystalline CSV obtained according to Example 6
  • Figure 8 is an XRPD diagram of the crystalline CSV obtained according to Example 7
  • Figure 9 is an XRPD diagram of the crystalline CSV obtained according to Example 9
  • Figure 10 is a TGA diagram of the crystalline CSV obtained according to Example 9
  • Figure 11 XRPD comparison diagrams before and after placement of the crystalline CSV (from top to bottom: before placement, after storage at 25°C/60%RH closed for 6 months, after storage at 25°C/60%RH open for 6 months, After putting it in the closed mouth at 40°C/75%RH for 3 months)
  • Figure 12 XRPD comparison diagram of crystal form CSV before and after grinding (from top to bottom: crystal form CSV after grinding, crystal form CSV before grinding)
  • the X-ray powder diffraction pattern of the present invention is collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the parameters of the X-ray powder diffraction method of the present invention are as follows:
  • thermogravimetric analysis (TGA) chart of the present invention is collected on TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:
  • the differential scanning calorimetry (DSC) chart of the present invention was collected on TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:
  • the proton nuclear magnetic resonance spectrum data ( 1 H NMR) was collected from the 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 make a 2-10 mg/mL solution.
  • test parameters of the dynamic solubility and related substance detection method in the present invention are as follows:
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the upatinib and/or its salt as a raw material includes, but is not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • upatinib and/or its salt as a raw material is in solid form.
  • upatinib and/or its salt (corresponding to the starting materials in the examples) used in the following examples can be prepared according to the prior art, for example, according to the method described in the WO2017066775A1 document.
  • the obtained crystalline solid is the crystal form CSIV of the present invention.
  • the XRPD pattern is shown in FIG. 4, and the XRPD data is shown in Table 3.
  • the DSC shown in Figure 5 has an endothermic peak, which begins to appear around 110°C.
  • the crystalline CSIV can be stable for at least 6 months under the conditions of 25°C/60%RH (closed mouth + desiccant), 25°C/60% RH (open) and 40°C/75% RH (closed mouth + desiccant). It can be seen that the crystalline CSIV can maintain good stability under long-term and accelerated conditions. It can be stable for at least 1 month under the condition of 60°C/75%RH (closed mouth + desiccant). It can be seen that the crystal form CSIV is also very stable under more severe conditions.
  • WO2017066775A1 discloses the solubility of crystal form C. The same method is used to test the solubility of crystal form CSIV in pH5.0FeSSIF and pH6.5FaSSIF. After 48 hours of equilibrium, the content of upatinib in the saturated solution is determined by HPLC. The result As shown in Table 5.
  • the TGA shown in Figure 10 has a mass loss of approximately 1.1% when it is heated to 100°C.
  • 1 H NMR detected 0.83 molar equivalent of glutaric acid in the crystalline CSV.
  • the crystalline CSV can be stable for at least 6 months under the conditions of 25°C/60%RH. It can be seen that the crystalline CSV can maintain good stability under long-term stability conditions. It can be stable for at least 3 months under the condition of 40°C/75%RH. It can be seen that the crystal form CSV can also maintain good stability under more severe conditions.
  • the crystalline CSV of the present invention was placed in a mortar, and was manually ground for about 5 minutes.
  • the XRPD test was performed before and after the grinding.
  • the test result is shown in FIG. 12. The results show that the crystal form of the crystal form CSV of the present invention does not change after grinding, and the crystallinity is basically unchanged.
  • WO2017066775A1 discloses the solubility of crystal form C.
  • 25 mg of crystal form CSV prepared by the present invention was dispersed in 2.0 mL of pH 5.0 FeSSIF and pH 6.5 FaSSIF, respectively, to prepare a saturated solution. After equilibrating for 48 hours, the content of upatinib in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 10.

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Abstract

La présente invention concerne une nouvelle forme cristalline d'upadacitinib, son procédé de préparation, une composition pharmaceutique contenant la forme cristalline, et l'utilisation de la forme cristalline dans la préparation de médicaments inhibiteurs de JAK et de médicaments pour le traitement de la polyarthrite rhumatoïde, de la maladie de Crohn, de la rectocolite hémorragique, de la dermatite atopique et de l'arthrite psoriasique. Par comparaison avec l'état de la technique, la forme cristalline d'upadacitinib selon la présente invention a une ou plusieurs caractéristiques améliorées, et est d'une grande valeur pour l'optimisation et le développement de ce médicament à l'avenir.
PCT/CN2021/095103 2020-06-05 2021-05-21 Forme cristalline d'upadacitinib, son procédé de préparation et son utilisation WO2021244323A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN114380837A (zh) * 2021-12-27 2022-04-22 上海邈金医药科技有限公司 一种具有Janus激酶抑制活性的化合物、包括该化合物的组合物及其应用
US11572365B2 (en) 2020-07-08 2023-02-07 Crystal Pharmaceutical (Suzhou) Co., Ltd. Crystal form of upadacitinib, preparation method therefor, and use thereof
CN117447481A (zh) * 2023-12-23 2024-01-26 潍坊医学院 一种乌帕替尼-焦谷氨酸盐的无定形物及其制备方法与应用
JP7436057B2 (ja) 2019-05-09 2024-02-21 スーチョウ ポンシュイ ファーマテック カンパニー、リミテッド ウパダシチニブのジ－ｐ－トルオイル－Ｌ－タートレートの結晶形

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CN108368121A (zh) * 2015-10-16 2018-08-03 艾伯维公司 制备(3S，4R)-3-乙基-4-(3H-咪唑并[1，2-a]吡咯并[2，3-e]吡嗪-8-基)-N-(2，2，2-三氟乙基)吡咯烷-1-甲酰胺及其固态形式的方法
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JP7436057B2 (ja) 2019-05-09 2024-02-21 スーチョウ ポンシュイ ファーマテック カンパニー、リミテッド ウパダシチニブのジ－ｐ－トルオイル－Ｌ－タートレートの結晶形
US11572365B2 (en) 2020-07-08 2023-02-07 Crystal Pharmaceutical (Suzhou) Co., Ltd. Crystal form of upadacitinib, preparation method therefor, and use thereof
CN114380837A (zh) * 2021-12-27 2022-04-22 上海邈金医药科技有限公司 一种具有Janus激酶抑制活性的化合物、包括该化合物的组合物及其应用
CN117447481A (zh) * 2023-12-23 2024-01-26 潍坊医学院 一种乌帕替尼-焦谷氨酸盐的无定形物及其制备方法与应用

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