WO2021000687A1 - Procédé de préparation d'une forme cristalline de pac-1 - Google Patents

Procédé de préparation d'une forme cristalline de pac-1 Download PDF

Info

Publication number
WO2021000687A1
WO2021000687A1 PCT/CN2020/094138 CN2020094138W WO2021000687A1 WO 2021000687 A1 WO2021000687 A1 WO 2021000687A1 CN 2020094138 W CN2020094138 W CN 2020094138W WO 2021000687 A1 WO2021000687 A1 WO 2021000687A1
Authority
WO
WIPO (PCT)
Prior art keywords
pac
crystal form
solvent
preparing
mixed solvent
Prior art date
Application number
PCT/CN2020/094138
Other languages
English (en)
Chinese (zh)
Inventor
王智民
刘晓谦
郭中原
Original Assignee
北京科佑爱科技有限责任公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京科佑爱科技有限责任公司 filed Critical 北京科佑爱科技有限责任公司
Publication of WO2021000687A1 publication Critical patent/WO2021000687A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and specifically relates to a crystal form of PAC-1 and a preparation method thereof.
  • Cancer is a malignant disease with extremely high morbidity and mortality worldwide and relatively poor treatment effect.
  • anti-tumor drugs have become the largest therapeutic area in the drug market.
  • Currently commonly used anti-tumor drugs include cytotoxic drugs, hormone drugs, molecular targeted therapies, biological response modifiers, tumor differentiation inducers, Tumor angiogenesis inhibitors and drugs for adjuvant treatment of tumors.
  • Chinese Patent Publication CN101184491A and U.S. Patent Publication US2007/0049602A1 disclose to the public the first small molecule compound PAC-1 that directly activates procaspasse-3, and require protection of PAC-1 and PAC-1 derivative library compounds, including those with the ZZ formula, Related compounds of ZZ2, ZZ3, and ZZ4 formulas and their synthesis methods; at the same time, methods for selectively inducing apoptosis in cancer cells, methods for directly screening compounds that can modify procaspasse-3 molecules in vitro and in cells, and identification Or a method for judging the potential sensitivity of cancer cells to treatment with pro-caspase activating compounds, a screening method that can be applied to caspase by identifying elevated levels of pro-caspase in candidate cancer patients The method of the original activator treatment of the candidate is protected.
  • International patent WO2010/091382A1 protects PAC-1, non-neurotoxic compound S-PAC-1 and its analogs.
  • Cipheral Patent Publication CN104910100A discloses an amorphous PAC-1 named ZYS-1, which also mentions a PAC-1 needle crystal in the prior art, and its X-ray powder diffraction (XRPD) pattern is shown in the figure 2 shown.
  • ZYS-1 amorphous PAC-1
  • XRPD X-ray powder diffraction
  • the crystal form refers to the arrangement of molecules in the crystal lattice of a crystalline substance, and the difference between the crystal forms is essentially the difference in the microstructure of the unit cell.
  • Different crystal forms of the same compound may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., which affect the stability, bioavailability and efficacy of the drug. This phenomenon is manifested in oral solid preparations. Especially obvious. Drug polymorphism is one of the important factors affecting the quality and clinical efficacy of drugs, so it is particularly important to pay special attention to the analysis of crystal forms.
  • the purpose of the present invention is to provide a method for preparing PAC-1 crystal form A.
  • a method for preparing PAC-1 crystal form A using an anti-solvent addition method which comprises: dissolving a PAC-1 compound in a normal solvent, and then adding an anti-solvent dropwise, and collecting the obtained solid to obtain PAC-1 crystal Type A.
  • PAC-1 crystal form A is volatilized at room temperature.
  • a method for preparing PAC-1 crystal form A using a suspension stirring method which comprises: adding a solvent to the PAC-1 compound to obtain a suspension, stirring the suspension, and centrifuging the obtained solid to obtain PAC-1 crystal Type A.
  • the method for preparing PAC-1 crystal form A wherein the solvent is selected from a mixed solvent of acetone and water, a mixed solvent of tetrahydrofuran and water, n-propanol and water Mixed solvents, mixed solvents of dimethylformamide and water, mixed solvents of ethanol and water, mixed solvents of acetonitrile and water, mixed solvents of methyl isobutyl ketone and n-heptane, dioxane and n-heptane
  • the solvent is selected from a mixed solvent of acetone and water, a mixed solvent of tetrahydrofuran and water, n-propanol and water Mixed solvents, mixed solvents of dimethylformamide and water, mixed solvents of ethanol and water, mixed solvents of acetonitrile and water, mixed solvents of methyl isobutyl ketone and n-heptane, dioxane and n-heptane
  • a method for preparing PAC-1 crystal form A using a gas-liquid permeation method which comprises: dissolving the PAC-1 compound in a positive solvent to make a clear solution, and opening a container containing the clear solution Place it in a sealed container with an anti-solvent and let it stand still, and collect the precipitated solid to obtain PAC-1 crystal form A.
  • a method for preparing PAC-1 crystal form A using a gas-solid permeation method which comprises: placing an open container containing PAC-1 compound in a sealed container containing a positive solvent, standing still, and taking it out The solid obtained PAC-1 crystal form A.
  • a method for preparing PAC-1 crystal form A using a slow cooling method which comprises: dissolving the PAC-1 compound in a solvent, heating at 30-140°C, filtering the solution after it becomes clear, and removing the filtrate from Slowly lower the temperature from 30 ⁇ 140°C to 0 ⁇ 25°C, and keep it at 0 ⁇ 25°C for 0.1 ⁇ 10 days, then transfer the filtrate to -20 ⁇ -5°C for 0.1 ⁇ 10h, collect the obtained solid to obtain PAC-1 Form A.
  • a method for preparing PAC-1 crystal form A using a slow volatilization method which comprises: placing the PAC-1 compound in a container, and adding a solvent to dissolve the PAC-1 compound in the solvent to prepare a clear solution , Then slowly evaporate, and collect the resulting solid to obtain PAC-1 crystal form A.
  • a method for preparing PAC-1 crystal form A by using a polymer induction method which comprises: dissolving the PAC-1 compound in a positive solvent, adding the polymer, stirring and turning to volatilization, and collecting the resultant The solid obtained PAC-1 crystal form A.
  • a method for preparing PAC-1 crystal form A using a humidity induction method which comprises: placing a container containing PAC-1 compound in a desiccator with a humidity of 5-100%, and collecting it after 0.1-10 days The solid obtained PAC-1 crystal form A.
  • the method for preparing PAC-1 crystal form A according to item 32 which comprises: placing a container containing the PAC-1 compound in a desiccator with a humidity of 45% to 100%, and collecting the solid after 7 days PAC-1 crystal form A was obtained.
  • a method for preparing PAC-1 crystal form A by applying a grinding-to-crystal method which comprises: grinding the PAC-1 compound at 5-50° C. for 1 to 80 minutes to obtain PAC-1 crystal form A .
  • the preparation method of the PAC-1 crystal form A provided by the invention is simple, stable, and has strong operability, is suitable for industrial production, and the obtained PAC-1 crystal form A has high stability.
  • PAC-1 refers to a small molecule compound that can directly activate Procaspase-3, and its chemical name is 1-Piperazineacetic acid, 4-(phenylmethyl)-2 -[[2-hydroxy-3-(2-propen-1-yl)phenyl]methylene]((E)-N'-(3-allyl-2-hydroxybenzylidene)-2-(4 -Benzylpiperazin-1-yl)acethydrazine), with the structure shown in formula 1, which is believed to be able to selectively induce tumor cell apoptosis, and thus can be used as an antitumor drug.
  • Thermogravimetric Analysis refers to a thermal analysis technique that measures the relationship between the quality of the sample to be tested and the temperature change under program control temperature, and is used to study the thermal stability and composition of materials. TGA is a commonly used testing method in R&D and quality control. Thermogravimetric analysis is often used in combination with other analysis methods in actual material analysis to conduct comprehensive thermal analysis and analyze materials comprehensively and accurately. The curve recorded by the thermogravimetric analyzer is called the TGA curve.
  • Differential scanning calorimetry under the control of a temperature program, is a technique for measuring the heat flow rate of a sample relative to a reference with temperature or time.
  • the curve recorded by the differential scanning calorimeter is called the DSC curve.
  • W/g or mW/mg that is, the power per gram of sample
  • T or time t the abscissa.
  • Thermodynamic and kinetic parameters such as specific heat capacity, heat of reaction, heat of transition, phase diagram, reaction rate, crystallization rate, polymer crystallinity, sample purity, etc.
  • the method uses a wide temperature range (-175 ⁇ 725°C), high resolution, and small sample amount. It is suitable for the analysis of inorganic substances, organic compounds and drugs.
  • the PAC-1 crystal form of the present invention is named PAC-1 crystal form A, and its X-ray powder diffraction (XRPD) pattern is shown in FIG. 1.
  • XRPD X-ray powder diffraction
  • the PAC-1 crystal form A produced by the present invention is an amorphous type.
  • an anti-solvent addition method a suspension stirring method, a gas-liquid infiltration method, a gas-solid infiltration method, a slow cooling method, a slow volatilization method, a polymer induction method, a humidity induction method, and a grinding crystal conversion method can be used to prepare PAC-1 Form A.
  • the present invention uses the anti-solvent addition method to prepare PAC-1 crystal form A.
  • the anti-solvent addition method is to combine the positive solvent and the anti-solvent to reduce the solubility of the crystallized substance in the solvent.
  • the dissolved material to be crystallized is mixed with the anti-solvent around the transition temperature. Since the anti-solvent is combined with water, the solubility of the crystallized substance is reduced, so that the crystallized substance is precipitated, and the crystallized substance is obtained by filtration.
  • the method for preparing PAC-1 crystal form A using the anti-solvent addition method includes: dissolving the PAC-1 compound in a normal solvent, then adding the anti-solvent dropwise, and collecting the obtained solid to obtain PAC-1 Crystal form.
  • the anti-solvent addition method is used to prepare PAC-1 crystal form A, and the normal solvent is selected from methanol, acetone, tetrahydrofuran, dioxane, acetonitrile, ethanol, methyl ethyl ketone, and ethyl acetate. , 2-methyltetrahydrofuran, anisole, dichloromethane, toluene, acetone, dimethylacetamide, any one or a combination of any several, the anti-solvent is selected from water, n-heptane, cyclopentane Any one or a combination of any of the methyl ether.
  • the present invention applies the suspension stirring method to prepare PAC-1 crystal form A. Specifically, a solvent is added to the raw material sample to obtain a suspension, and the suspension is placed at room temperature or 25-100° C. and stirred for 0.1-10 days, and the obtained solid is collected by centrifugation to obtain PAC-1 crystal form A.
  • the suspension stirring method is used to prepare PAC-1 crystal form A, a solvent is added to the raw material sample to obtain a suspension, and the solvent is selected from ethanol, isopropanol, ethyl acetate, and methyl tert-butyl.
  • the obtained suspension is stirred at room temperature for 0.1 to 10 days, preferably for 6 days, and the obtained solid is collected by centrifugation to obtain PAC-1 crystal form A.
  • the solvent is a mixed solvent of methanol and water, and the volume ratio of the mixed solvent of methanol and water is methanol: water is 1:1.3 to 1:14; in any other mixed solvent, two solvents The volume ratio
  • the suspension stirring method is used to prepare PAC-1 crystal form A, and a solvent is added to the raw material sample to obtain a suspension.
  • the solvent is selected from a mixed solvent of dioxane and n-heptane, chloroform and n-heptane Alkane mixed solvent, isobutanol, isobutyl acetate, cyclopentyl methyl ether, methyl tert-butyl ether, acetone and n-heptane mixed solvent, isopropanol and n-heptane mixed solvent, acetonitrile and water Any one or a combination of any one of the mixed solvent of dioxane and water, or any combination of several, the suspension is placed at 50°C and stirred for 0.1-10 days, preferably 6 days, the resulting solid is collected by centrifugation and dried , Get PAC-1 crystal form A.
  • the present invention applies the gas-liquid permeation method to prepare PAC-1 crystal form A.
  • the raw material sample is dissolved in a positive solvent to make a clear solution, and the container with the clear solution is placed in a sealed container with an anti-solvent, and it is allowed to stand at room temperature to collect the precipitated solid to obtain PAC-1 crystal form A.
  • the gas-liquid permeation method is used to prepare PAC-1 crystal form A
  • the normal solvent is selected from ethanol, methyl ethyl ketone, 2-methyltetrahydrofuran, N-methylpyrrolidone, and n-propanol.
  • the anti-solvent is selected from any one of water and n-heptane.
  • the present invention uses gas-solid infiltration method to prepare PAC-1 crystal form A. Specifically, the container containing the raw material sample is placed in a sealed container containing a positive solvent, and left standing at room temperature, and the solid is taken out to obtain PAC-1 crystal form A.
  • the gas-solid permeation method is used to prepare PAC-1 crystal form A
  • the positive solvent is preferably ethanol and acetone.
  • the present invention uses a slow cooling method to prepare PAC-1 crystal form A.
  • the raw material sample is dissolved in a solvent, heated at 30-140°C, preferably 50°C, the heated solution becomes clear and filtered, and then the filtrate is slowly cooled to 0-25°C, preferably 5°C, and the cooling rate is controlled.
  • a slow cooling method is used to prepare PAC-1 crystal form A, and the solvent is selected from isopropanol, methyl tert-butyl ether, butyl acetate, a mixed solvent of alcohol and water, tetrahydrofuran and water Any one or a combination of any of the mixed solvent of, the mixed solvent of anisole and n-heptane, and the mixed solvent of acetonitrile and n-heptane.
  • the present invention applies the slow volatilization method to prepare PAC-1 crystal form A.
  • the raw material sample is placed in a container, and a solvent is added to dissolve it to prepare a clear solution, which is placed at room temperature to slowly volatilize, and the obtained solid is collected to obtain PAC-1 crystal form A.
  • a sealing film is used to seal the container containing the clear solution, and the sealing film has small holes.
  • a slow volatilization method is used to prepare PAC-1 crystal form A, and the solvent is selected from methanol, ethanol, ethyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, toluene, acetonitrile, and methylene chloride. , Chloroform, methyl tert-butyl ether, acetic acid or any combination of several.
  • the present invention uses a polymer induction method to prepare PAC-1 crystal form A. Specifically, a raw material sample is dissolved in a solvent, and a polymer is added. After stirring at room temperature for 0.1 to 12 hours, preferably after 2 hours, it is converted to volatilization, and the precipitated solid is collected to obtain PAC-1 crystal form A.
  • a polymer induction method is used to prepare PAC-1 crystal form A, and the polymer is selected from polyvinyl chloride, polyvinyl alcohol, polyvinyl acetate, methyl cellulose, and polyvinylpyrrolidone , Hydroxypropyl methylcellulose, etc.; the solvent is selected from any one or a combination of any of methanol, ethanol, acetone, and tetrahydrofuran.
  • the present invention uses the humidity induction method to prepare PAC-1 crystal form A. Specifically, the raw material sample is placed in a desiccator with a humidity of 45%-100%, and after 0.1-10 days, preferably 7 days later, the PAC-1 crystal form A is collected.
  • the humidity induction method is used to prepare PAC-1 crystal form A.
  • the container containing the raw material sample is sealed with a sealing film first, and the sealing film has small holes, and then the raw material sample The container is placed in a desiccator.
  • the present invention applies the grinding and crystal transformation method to prepare PAC-1 crystal form A. Specifically, the raw material sample is ground at 5-50° C. for 1-80 minutes to obtain PAC-1 crystal form A.
  • the anti-solvent addition method suspension stirring method, gas-liquid infiltration method, gas-solid infiltration method, slow cooling method, slow volatilization method, polymer induction method, humidity induction method, grinding and crystal conversion method of the present invention
  • the obtained PAC-1 crystal form A is dried.
  • Anti-solvent addition method Weigh about 20 mg of each sample into a 20-ml vial, dissolve it with a certain amount of positive solvent, add the corresponding anti-solvent in the table below to the clear solution dropwise, and stir while adding dropwise When a solid precipitated, the obtained solid was dried.
  • the solids finally obtained in the examples in Table 1 are respectively labeled as solids 1-1 to 1-14, and the precipitated solids are subjected to XRPD detection, and they are all crystal form A.
  • Suspension stirring method Weigh about 15 mg of each sample into a vial, add 0.3 ml of the solvents listed in the table below, and place the resulting suspension at room temperature and 50°C and stir for 6 days. Centrifuge to collect the solid and dry .
  • the solids finally obtained in the examples in Table 2 are marked as solids 2-1 to 2-27, and the obtained solids are subjected to XRPD detection, and they are all crystal form A.
  • Gas-liquid permeation method Weigh approximately 20 mg of each sample and dissolve it in a certain amount of solvent, place it in a 3 ml vial, take another 20 ml vial and add about 3 ml of anti-solvent to it, and open the 3 ml vial. The mouth is placed in a 20 ml vial, sealed and allowed to stand at room temperature, and the obtained solid is dried after the solid has separated out.
  • the solids finally obtained in the examples in Table 3 are marked as solids 3-1 to 3-12, and XRPD detection is performed, and they are all crystal form A.
  • Slow cooling method Weigh approximately 20 mg of each sample into a 3 ml vial, add 0.8 ml of the solvent in the table below, and place the sample in an oven at 50°C for 1 hour. If it becomes clear after heating and dissolving, then filter. The clear solution was cooled from 50°C to 5°C at a rate of 0.1°C/min, and kept at 5°C for 5 days, then the clear sample was transferred to -20°C, placed for 1 hour, and the obtained solid was collected and dried. The solids finally obtained in this example in Table 4 are marked as solids 4-1 to 4-7, and tested, and they are all crystal form A.
  • Polymer induction method Weigh about 20 mg of each sample into a vial, add about 2 mg of the polymer in the table below and 0.5 ml of solvent, stir at room temperature for 2 hours and then turn to volatilization, and collect after volatilization at room temperature A solid precipitated and dried.
  • the solids finally obtained in this example in Table 6 are marked as solids 6-1 to 6-6, and tested, and they are all crystal form A.
  • Humidity induction method Weigh 15 mg of sample into a vial, then seal 4 small holes with parafilm and place it in a desiccator corresponding to humidity. Collect the solid after 7 days and dry it. The solids finally obtained in this example in Table 7 are marked as solids 7-1 to 7-4, respectively, and tested, and crystal form A is obtained.
  • the X-ray powder diffraction pattern of PAC-1 crystal form A expressed by 2 ⁇ diffraction angles is 5.46 ⁇ 0.2°, 8.92 ⁇ 0.2°, 10.14 ⁇ 0.2°, 15.76 ⁇ 0.2°, 17.14 ⁇ 0.2°, 17.82 ⁇ 0.2° , 18.27 ⁇ 0.2°, 18.90 ⁇ 0.2°, 19.43 ⁇ 0.2°, 20.37 ⁇ 0.2°, 21.48 ⁇ 0.2°, 21.80 ⁇ 0.2° and 26.06 ⁇ 0.2° show characteristic peaks.
  • the X-ray powder diffraction pattern of PAC-1 crystal form A expressed in 2 ⁇ diffraction angles is 5.46 ⁇ 0.2°, 8.92 ⁇ 0.2°, 10.14 ⁇ 0.2°, 11.24 ⁇ 0.2°, 11.91 ⁇ 0.2°, 14.04 ⁇ 0.2° ⁇ 14.53 ⁇ 0.2° ⁇ 16.34 ⁇ 0.2° ⁇ 15.76 ⁇ 0.2° ⁇ 17.14 ⁇ 0.2° ⁇ 17.82 ⁇ 0.2° ⁇ 18.27 ⁇ 0.2° ⁇ 18.90 ⁇ 0.2° ⁇ 19.43 ⁇ 0.2° ⁇ 20.37 ⁇ 0.2° ⁇ 20.96 ⁇ 0.2° , 21.48 ⁇ 0.2°, 21.80 ⁇ 0.2°, 22.52 ⁇ 0.2°, 22.94 ⁇ 0.2°, 23.47 ⁇ 0.2°, 24.00 ⁇ 0.2°, 25.62 ⁇ 0.2°, 26.06 ⁇ 0.2°, 26.84 ⁇ 0.2°, 27.16 ⁇ 0.2° , 27.60 ⁇ 0.2°, 27.90 ⁇ 0.2°, 28.99 ⁇ 0.2°, 29.31 ⁇ 0.2°, 29.98 ⁇ 0.2°, 30.66 ⁇ 0.2°, 32.09 ⁇ 0.2°,
  • the measurement accuracy of the 2 ⁇ angle is ⁇ 0.2°, so each characteristic peak of the above-mentioned crystal form is within the range of the peak ⁇ 0.2° for its error tolerance.
  • FIG. 1 X-ray powder diffraction pattern of PAC-1 crystal form A of the present invention is shown in FIG. 1.
  • thermogravimetric analysis was performed on the PAC-1 crystal form A prepared in Examples 1-9.
  • the differential scanning calorimetry DSC curve of this crystal form shows a single dominant endotherm in the temperature range of 130°C to 140°C.
  • the melting point of the sample is 136.2°C
  • the peak endothermic peak is 137.3°C ⁇ 2°C
  • the peak area is- 94.54J/g.
  • the value of X-ray powder diffraction may be similar to the value of X-ray powder diffraction.
  • the value quoted by the differential scanning calorimetry technique cannot be interpreted as an absolute value.
  • the temperature measurement accuracy is ⁇ 2°C. Therefore, the endothermic peak of the above crystal form The peak value is within the range of ⁇ 2°C for its error tolerance.
  • the TGA curve of PAC-1 crystal form A shows that the crystal form A has a weight loss of about 2.03% at 120°C and has high thermal stability.
  • the present invention measured the solubility of PAC-1 crystal form A prepared in Examples 1-9.
  • PAC-1 crystal form A prepared in each example put an appropriate amount of about 20 mg of the PAC-1 crystal form A solid into the vial, and then divide into four steps (respectively 50, 50, 200, 700 ml) Shake after adding the corresponding solvent, and stop if the solid is dissolved.
  • the rough solubility of PAC-1 crystal form A prepared in Examples 1-9 at room temperature is shown in Table 10 below.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation d'une forme cristalline de PAC-1. La forme cristalline A de PAC-1 selon la présente invention, présente des pics caractéristiques à 8,92 ± 0,2°, 17,14 ± 0,2°, 17,82 ± 0,2°, 18,90 ± 0,2°, 20,37 ± 0,2° et 26,06 ± 0,2° par l'utilisation d'un rayonnement CuKα et d'un diffractogramme de rayons X sur poudre représenté avec des angles de diffraction 2θ. La forme cristalline A de PAC-1 selon la présente invention peut être préparée au moyen d'un procédé d'addition anti-solvant, un procédé d'agitation de suspension, un procédé de perméation gaz-liquide, un procédé de perméation gaz-solide, un procédé de refroidissement lent, un procédé de volatilisation lente, un procédé d'induction de haut polymère, un procédé d'induction d'humidité ou un procédé de broyage et de recristallisation. La forme cristalline A de PAC-1 selon la présente invention est appropriée pour une application industrielle en pharmacie. La forme cristalline présente une bonne solubilité et peut améliorer l'efficacité d'un produit. De plus, le procédé de préparation est simple et stable, présente une bonne fonctionnalité et est approprié pour une production industrielle. La forme cristalline a une stabilité élevée.
PCT/CN2020/094138 2019-07-01 2020-06-03 Procédé de préparation d'une forme cristalline de pac-1 WO2021000687A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910585127.7A CN110372637A (zh) 2019-07-01 2019-07-01 Pac-1晶型的制备方法
CN201910585127.7 2019-07-01

Publications (1)

Publication Number Publication Date
WO2021000687A1 true WO2021000687A1 (fr) 2021-01-07

Family

ID=68251463

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/094138 WO2021000687A1 (fr) 2019-07-01 2020-06-03 Procédé de préparation d'une forme cristalline de pac-1

Country Status (2)

Country Link
CN (1) CN110372637A (fr)
WO (1) WO2021000687A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110372637A (zh) * 2019-07-01 2019-10-25 北京科佑爱科技有限责任公司 Pac-1晶型的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101307038A (zh) * 2008-02-02 2008-11-19 深圳市湘雅生物医药研究院 4-苄基哌连乙亚胺酰(亚胺甲基苯)肼类化合物、其制备方法、药物组合物和用途
US20130096133A1 (en) * 2011-10-14 2013-04-18 The Board of Trustees of the University lllinois Procaspase-activating compounds and compositions
CN104910100A (zh) * 2014-03-11 2015-09-16 王智民 化合物pac-1或其盐及包含它们的药物组合物
CN110372637A (zh) * 2019-07-01 2019-10-25 北京科佑爱科技有限责任公司 Pac-1晶型的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101307038A (zh) * 2008-02-02 2008-11-19 深圳市湘雅生物医药研究院 4-苄基哌连乙亚胺酰(亚胺甲基苯)肼类化合物、其制备方法、药物组合物和用途
US20130096133A1 (en) * 2011-10-14 2013-04-18 The Board of Trustees of the University lllinois Procaspase-activating compounds and compositions
CN104910100A (zh) * 2014-03-11 2015-09-16 王智民 化合物pac-1或其盐及包含它们的药物组合物
CN110372637A (zh) * 2019-07-01 2019-10-25 北京科佑爱科技有限责任公司 Pac-1晶型的制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GU HUIKE : "The influence of polymers on the crystallization process of drugs", THE 6TH CHINA INDUSTRIAL CRYSTALLIZATION SCIENCE AND TECHNOLOGY SYMPOSIUM (2012); PROCEEDINGS, 15 March 2013 (2013-03-15), pages 184 - 188 *
ZHANG QI; MEI XUE-FENG: "Polymorph transformation of solid drugs", ACTA PHARMACEUTICA SINICA, vol. 50, no. 5, 31 December 2015 (2015-12-31), pages 521 - 527, XP009525410, ISSN: 0513-4870, DOI: 10.16438/j.0513-4870.2015.05.019 *
ZHAO, LINXIANG: "Chemical Pharmaceutical Technology, 1st edition", 31 January 2003, CHINA MEDICAL SCIENCE PRESS, CN, ISBN: 7-5067-2676-9, article ZHAO, LINXIANG: "non-official translation: Recrystallization Technology", pages: 102 - 106, XP009525437 *

Also Published As

Publication number Publication date
CN110372637A (zh) 2019-10-25

Similar Documents

Publication Publication Date Title
WO2018108101A1 (fr) Nouvelles formes cristallines d'acide {[5-(3-chlorophényl)-3-hydroxypyridine-2-carbonyl]amino} acétique et leur procédé de préparation
US8252805B2 (en) Forms of lapatinib ditosylate and processes for preparation thereof
JP6727419B2 (ja) ナトリウム−グルコース共輸送体阻害薬の新規な結晶形及びその製造方法並びに用途
WO2014008794A1 (fr) Forme cristallisée i du dimaléate inhibiteur de tyrosine kinase et ses méthodes de préparation
US20090076272A1 (en) Polymorphs of eszopiclone malate
WO2017193914A1 (fr) Formes cristallines de crisaborole sous forme libre et procédé de préparation et utilisation de celles-ci
WO2014082354A1 (fr) Forme cristalline de chidamide, procédé de préparation et utilisation correspondants
WO2022170864A1 (fr) Forme cristalline du mésylate de beumosul, son procédé de préparation et son utilisation
WO2018157803A1 (fr) Formes cristallines de vénétoclax et leur procédé de préparation
JP2020500912A (ja) ブロモドメインタンパク質阻害薬の結晶形及びその製造方法並びに用途
JP7295025B2 (ja) （ｓ）－［２－クロロ－４－フルオロ－５－（７－モルホリン－４－イルキナゾリン－４－イル）フェニル］－（６－メトキシ－ピリダジン－３－イル）メタノールの結晶性形態
WO2021000687A1 (fr) Procédé de préparation d'une forme cristalline de pac-1
WO2020061996A1 (fr) Nouvelles formes cristallines d'un composé azd9291 deutéré, et utilisation associée
WO2018133705A1 (fr) Forme cristalline de gft-505 et procédé de préparation et d'utilisation de celle-ci
WO2023193563A1 (fr) Forme cristalline d'un composé thiénopyridine, son procédé de préparation et composition pharmaceutique associée
WO2020164565A1 (fr) Nouvelle forme cristalline de chlorhydrate d'oxypipérone et procédé de préparation correspondant
US20150150868A1 (en) Aripiprazole-organic acid cocrystal, preparation or composition containing same, and preparation method therefor
EP3551617A1 (fr) Compositions et procédés se rapportant à des agonistes de pyridinoylpipéridine 5-ht1f
JP7152122B2 (ja) エダラボン塩
JP2022525125A (ja) ブレイアコニチンａのｅ結晶形及びその製造方法と応用
WO2019205812A1 (fr) Nouvelle forme cristalline de l'acalabrutinib, son procédé de préparation et son utilisation
WO2018196681A1 (fr) Eutectique de nifédipine et d'isonicotinamide
WO2022110842A1 (fr) Forme cristalline a du fluoropyrrolidone lévogyre et son procédé de préparation
CN103059013B (zh) 达沙替尼一水合物的晶型及其制备方法
WO2018137670A1 (fr) Forme cristalline du médicament inhibiteur de protéine virale (vx-287), et son procédé de préparation et d'utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20835410

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC, EPO FORM 1205A DATED 14.02.2022

122 Ep: pct application non-entry in european phase

Ref document number: 20835410

Country of ref document: EP

Kind code of ref document: A1