CN113754660A - Crystal form of beta-lactamase inhibitor - Google Patents

Crystal form of beta-lactamase inhibitor Download PDF

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Publication number
CN113754660A
CN113754660A CN202010487918.9A CN202010487918A CN113754660A CN 113754660 A CN113754660 A CN 113754660A CN 202010487918 A CN202010487918 A CN 202010487918A CN 113754660 A CN113754660 A CN 113754660A
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degrees
crystal form
beta
ray powder
formula
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王文贵
汪旭凡
胡永韩
刘霄
刘存刚
吴予川
陈曦
吴振伟
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Evopoint Bioscience Co Ltd
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Suzhou Sinovent Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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

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Abstract

The invention discloses a crystal form A of a beta-lactamase inhibitor compound shown as a formula I, which uses Cu-Kalpha radiation, and an X-ray powder diffraction pattern expressed by a 2 theta angle has diffraction peaks at the following positions: 9.82 +/-0.20 degrees, 12.42 +/-0.20 degrees, 13.35 +/-0.20 degrees, 15.83 +/-0.20 degrees, 16.94 +/-0.20 degrees, 18.05 +/-0.20 degrees, 20.21 +/-0.20 degrees and 22.81 +/-0.20 degrees. The crystal form has small hygroscopicity and high stability.

Description

Crystal form of beta-lactamase inhibitor
Technical Field
The invention relates to a crystal form of a beta-lactamase inhibitor, a preparation method and application thereof. The invention also relates to a pharmaceutical composition containing the crystal form and application thereof.
Background
Beta-lactam antibiotics were the first antibiotics introduced clinically. Beta-lactam antibiotics with different structural types are developed and are applied in a large amount clinically, and good effects are achieved. However, as bacterial cells can produce beta-lactamases, the antibiotics are inactivated, resulting in bacterial resistance to beta-lactam antibiotics. Beta-lactamases are enzymes that catalyze the hydrolysis of the beta-lactam ring, which inactivate the antibacterial activity of the beta-lactam antibiotic and allow the bacteria to have resistance to the beta-lactam antibiotic. Resistance of bacteria, particularly gram-negative bacteria, to beta-lactam antibiotics is generally mediated by beta-lactamases.
WO2019144912A1 discloses a series of beta-lactamase inhibitors, and the compounds have good inhibition effect on beta-lactamase.
Disclosure of Invention
The invention provides a crystal form A of a beta-lactamase inhibitor compound shown as a formula I, which is characterized in that Cu-Kalpha radiation is used, and an X-ray powder diffraction pattern expressed by a 2 theta angle has diffraction peaks at the following positions: 9.82 +/-0.20 degrees, 12.42 +/-0.20 degrees, 13.35 +/-0.20 degrees, 15.83 +/-0.20 degrees, 16.94 +/-0.20 degrees, 18.05 +/-0.20 degrees, 20.21 +/-0.20 degrees and 22.81 +/-0.20 degrees.
Figure BDA0002519986610000011
In a certain embodiment, the X-ray powder diffraction pattern of the above crystalline form expressed by 2 θ angle further has diffraction peaks at the following positions: 23.28 +/-0.20 degrees and 24.07 +/-0.20 degrees.
In a certain embodiment, the X-ray powder diffraction pattern of the above crystalline form expressed by 2 θ angle further has diffraction peaks at the following positions: 14.63 +/-0.20 degrees and 19.66 +/-0.20 degrees.
In a certain embodiment, the X-ray powder diffraction pattern of the above crystalline form expressed by 2 θ angle further has diffraction peaks at the following positions: 25.41 +/-0.20 degrees, 26.82 +/-0.20 degrees and 28.30 +/-0.20 degrees.
In one embodiment, the X-ray powder diffraction pattern of the above crystalline form expressed by 2 θ angle has diffraction peaks as shown in the following table:
Figure BDA0002519986610000021
Figure BDA0002519986610000031
in one embodiment, form a has an X-ray powder diffraction pattern expressed in degrees 2 θ as shown in figure 1.
DVS test results show that the moisture absorption weight gain of the crystal form A in the range of 0% RH to 80% RH is about 1.3% at 25 ℃, which indicates that the crystal form A has slight hygroscopicity, and the crystal form remains unchanged before and after DVS test.
The physical and chemical stability of the crystal form A at 25 ℃/60% RH and 40 ℃/75% RH for one week is researched, and the results show that the samples of the crystal form A before and after the stability experiment are all the crystal form A unchanged, and the HPLC purity has no obvious change. Under the conditions of one day at 80 ℃, two hours at 160 ℃ and 15/30 minutes at 121 ℃/damp heat, the samples before and after the stability experiment are all the crystal form A unchanged, and the HPLC purity is not obviously reduced.
TGA results indicate 2.4% weight loss of form a upon heating to 230 ℃; the DSC results showed that form a had no significant endothermic and exothermic peaks.
The invention also provides form B and form C of the compound of formula (I). The crystal form identification result shows that the crystal form A is an anhydrous crystal form, and the crystal forms B and C are solvates, wherein the crystal form C is converted into the crystal form B after being dried in vacuum at room temperature, and the crystal form B is converted into the crystal form A after being heated to 200 ℃.
TABLE 1 polymorphic form characterization and identification results
Figure BDA0002519986610000032
*: the form C sample turned to form B after vacuum drying at room temperature and therefore lacked characterization data.
The invention also provides a pharmaceutical composition taking the crystal form A, the crystal form B and the crystal form C as active ingredients.
The crystal form A, the crystal form B and the crystal form C provided by the invention can be used for treating and/or preventing diseases caused by bacterial infection. Furthermore, the present invention relates to a method of inhibiting bacteria or treating and/or preventing diseases caused by bacterial infections comprising administering to a patient or subject in need thereof a therapeutically and/or prophylactically effective amount of form a, form B, form C of the present invention. In one embodiment, the bacteria in the disease caused by bacterial interference are selected from the group consisting of gram positive bacteria and gram negative bacteria.
Description of the drawings:
FIG. 1: x-ray powder diffraction pattern of form a.
FIG. 2: x-ray powder diffraction contrast plots of forms A, B and C.
FIG. 3: differential scanning calorimetry of form a.
FIG. 4: thermogravimetric analysis of form a.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The tests, instruments and methods involved in the examples of the invention are as follows:
x-ray powder diffraction (XRPD) patterns were collected on a PANALYtic Empyrean and X' Pert3 ray powder diffraction analyzer with the scan parameters shown in Table 2.
TABLE 2 XRPD test parameters
Figure BDA0002519986610000041
Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC) plots were taken on a TA Q5000/Discovery 5500 thermogravimetric analyzer and a TA Q2000/Discovery 2500 differential scanning calorimeter, respectively, with the test parameters listed in table 3.
TABLE 3 TGA and DSC test parameters
Figure BDA0002519986610000042
Dynamic water sorption (DVS) curves were collected on a DVS Intrasic in SMS (surface Measurement systems). The relative humidity at 25 ℃ was corrected for the deliquescence point of LiCl, Mg (NO3)2 and KCl. The DVS test parameters are listed in table 4.
TABLE 4 DVS test parameters
Figure BDA0002519986610000051
High Performance Liquid Chromatography (HPLC) the purity and concentration of the samples in the test were determined by Agilent 1260 HPLC, the analytical conditions are given in Table 5.
TABLE 5
Figure BDA0002519986610000052
XRPD, DSC, TGA and DVS spectra may have detection errors due to variations in the detection instruments and variations in the detection conditions. Detection errors should be taken into account when screening and determining various crystal structures. Example 1 preparation of crystalline forms A, B and C
Gas-solid diffusion:
the following different solvents were used: water, dichloromethane, trichloromethane, ethanol, methanol, acetonitrile, tetrahydrofuran, isopropyl acetate, acetone, DMSO, ethyl acetate and isopropanol, and 12 gas-solid diffusion tests are set. About 20 mg of each starting sample was weighed into a 3 ml vial, about 4 ml of solvent was added to the 20 ml vial, and after the 3 ml vial was placed open into the 20 ml vial, the 20 ml vial was sealed. Standing at room temperature for 7 days, collecting solids, and carrying out XRPD test to obtain the crystal form A in the gas-solid permeation test.
Gas-liquid diffusion:
in a 3 ml vial, about 20 mg of each starting sample was weighed and dissolved in 2.0 ml of good solvent (DMSO/H)2O9: 1), after all samples were filtered through a PTFE filter with a pore size of 0.45 μm, about 4 ml of an anti-solvent (tetrahydrofuran, water, ethanol, acetone, respectively) was added to another 20 ml vial, and after the 3 ml vial containing the clear solution was opened to the 20 ml vial, the 20 ml vial was sealed and allowed to stand at room temperature. After standing for 7 days, 3 mm of the solution was addedThe liter vials were removed and allowed to volatilize at room temperature, after which the 3 ml vials were transferred to a 50 ℃ vacuum oven to dry to give a solid which was then tested for XRPD. And obtaining the crystal form B in a gas-liquid diffusion test.
Suspension stirring at room temperature:
about 20 mg of each starting sample was weighed into an HPLC vial, and 0.5 ml of each of the following solvents was added: ethanol, methanol, isopropanol, acetone, methyl isobutyl ketone, butanone, tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform, N-heptane, toluene, ethyl acetate, cyclopentyl methyl ether, dimethylacetamide, N-methylpyrrolidone, anisole, water, ethyl acetate/2-methyltetrahydrofuran (1:1), chloroform/N-heptane (1:1), methanol/DMSO (1:1), tetrahydrofuran/water (1:2), isopropanol/acetonitrile (1:1), tetrahydrofuran/toluene (1:1), ethanol/2-methyltetrahydrofuran (1:1), acetone/water (982:18, aw-0.2; 956: 44, aw-0.4; 919: 81, aw-0.6; 847: 153, aw-0.8), the resulting suspension was stirred magnetically (800 rpm) at room temperature for about 3 days, the solids were centrifuged and tested for XRPD. The crystal form A is obtained in the room temperature suspension stirring test.
Suspension stirring at 50 ℃:
about 20 mg of each starting sample was weighed into an HPLC vial, and 0.5 ml of each of the following solvents was added: isopropanol, ethanol, methyl isobutyl ketone, isopropyl acetate, butanone, methyl tert-butyl ether, acetonitrile, 2-methyltetrahydrofuran, water, chloroform, acetone/water (1:1), 1, 4-dioxane/water (1:1), methanol/DMSO (3:1), DMSO/water (1:4), tetrahydrofuran/water (1:1), isopropanol/acetonitrile (1:1), tetrahydrofuran/toluene (1:1), ethanol/2-methyltetrahydrofuran (1:1), methanol/water (3:1), acetonitrile/water (1:1), and after the resulting suspension was placed at 50 ℃ and magnetically stirred (800 rpm) for about 3 days, the solids were centrifuged and tested for XRPD. The crystal form A is obtained by suspension stirring test at 50 ℃.
Anti-solvent addition:
weighing about 20 mg of each part of the initial sample, adding the initial sample into a 20 ml small bottle, dissolving the initial sample by using 2.0-2.6 ml of good solvent, adding the anti-solvent into the clear solution, stirring the solution while dropwise adding until solid is separated out, and stopping the stirring if no solid is separated out after adding about 10 ml of anti-solvent. Solids were separated by centrifugation and tested for XRPD. When the good solvent is water/DMSO (1:9) and the anti-solvent is isopropanol, water, acetone, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, toluene and ethyl acetate, the crystal form C is obtained. When the good solvent is methanol/DMSO (1:9) and the anti-solvents are tetrahydrofuran, methyl isobutyl ketone, toluene and ethyl acetate respectively, crystal form C and crystal form B are obtained respectively, and the layered undistracted solid and the layered crystal form B are obtained.
Grinding:
about 20 mg of each of the starting samples was weighed into a mortar without or with a small amount of methanol, and after manually milling for 5 minutes the solid was collected for XRPD, which gave form a in the milling experiment.
Inducing a high polymer:
about 20 mg of each starting sample was weighed out and dissolved in 2.0 ml of the following solvents: acetone, chloroform, ethyl acetate, methanol, methyl ethyl ketone, and methylene chloride to obtain a suspension, adding about 2 mg of mixed polymer a (mass mixture of polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, and methylcellulose) or mixed polymer B (mass mixture of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate, and hydroxyethyl cellulose) to the suspension, stirring at room temperature (about 1000rpm) for about 3 days, centrifuging the solid, and performing XRPD test. The crystal form A is obtained in the high polymer induction test.
Humidity induction:
about 20 mg of each starting sample was weighed into a 3 ml vial, and the 3 ml vial was placed in a humidity chamber at room temperature (40% RH, 50% RH, 70% RH, 90% RH), and after standing for 7 days at room temperature, the solid was collected and tested for XRPD. The crystal form A is obtained in a humidity induction test.
Temperature cycle:
about 20 mg of each starting sample was weighed into an HPLC vial, and 2 ml of the solvent or mixture of solvents shown below were added: ethanol, acetone, tetrahydrofuran, chloroform, ethyl acetate/2-methyltetrahydrofuran (1:1), methanol/acetonitrile (1:1), dimethylacetamide/water (1:1) to obtain a suspension, and magnetically stirring the suspension at 50 ℃ for 2 hours. The temperature was reduced to 5 ℃ at a rate of 0.1 ℃/min and stirred at 5 ℃ for 2 hours. The temperature was raised to 50 ℃ at a rate of 0.1 ℃/min and stirred at 50 ℃ for 2 hours. After repeating the above cooling and heating processes, the temperature was finally reduced to 5 ℃ at a rate of 0.1 ℃/min and stirred at 5 ℃ for about 3 days, the solids were centrifuged and subjected to XRPD testing. Crystal form a is obtained in the temperature cycle test.
Example 2 solid state stability study of form a
To evaluate the solid state stability of form a, physical and chemical stability studies were performed on form a at 25 ℃/60% RH and 40 ℃/75% RH for one week, one day at 80 ℃, two hours at 160 ℃ and 15/30 minutes at 121 ℃/damp heat. Solid samples under different conditions were evaluated for physical and chemical stability by XRPD and HPLC tests, respectively. In addition, the weight content of the sample is tested under the conditions of 25 ℃/60% RH and 40 ℃/75% RH for one week, the initial sample purity preserved at the temperature of 2-8 ℃ is used as a reference, and the default purity is 100%. The results of the evaluation are summarized in table 6, and the results of the solid state stability studies show that form a remains physically stable under the above conditions. The results of chemical stabilization are complex: 1) the control sample is stored at the temperature of 2-8 ℃, but the HPLC purity is reduced along with the increase of the storage time (the single impurity result is shown in a table 3-2); 2) the HPLC purity is not obviously reduced under the conditions of one day at 80 ℃, two hours at 160 ℃ and 15/30 minutes at 121 ℃/damp and hot; 3) the weight content of the sample decreased significantly after one week at 25 ℃/60% RH and 40 ℃/75% RH (95.7% and 94.3%, respectively), but there was no significant change in HPLC purity, which may not accurately reflect the chemical stability of the sample.
Table 6 summary of solid state stability evaluation results for form a
Figure BDA0002519986610000081
Control samples were stored at 2-8 ℃, but HPLC purity decreased with increasing storage time.
Control as standard.

Claims (7)

1. A crystalline form of a compound of formula I, characterized in that it uses Cu-ka radiation, with an X-ray powder diffraction pattern expressed in 2 Θ angles having diffraction peaks at the following positions: 9.82 +/-0.20 degrees, 12.42 +/-0.20 degrees, 13.35 +/-0.20 degrees, 15.83 +/-0.20 degrees, 16.94 +/-0.20 degrees, 18.05 +/-0.20 degrees, 20.21 +/-0.20 degrees and 22.81 +/-0.20 degrees
Figure FDA0002519986600000011
2. A crystalline form of the compound of formula I according to claim 1, having an X-ray powder diffraction pattern expressed in degrees 2 Θ further having diffraction peaks at one or more of the following positions: 23.28 +/-0.20 degrees and 24.07 +/-0.20 degrees.
3. A crystalline form of the compound of formula I according to claim 2, having an X-ray powder diffraction pattern expressed in degrees 2 Θ further having diffraction peaks at one or more of the following positions: 14.63 +/-0.20 degrees and 19.66 +/-0.20 degrees.
4. A crystalline form of the compound of formula I according to claim 3, having an X-ray powder diffraction pattern expressed in degrees 2 Θ further having diffraction peaks at one or more of the following positions: 25.41 +/-0.20 degrees, 26.82 +/-0.20 degrees and 28.30 +/-0.20 degrees.
5. The crystalline form of the compound of formula I according to claim 4, having an X-ray powder diffraction pattern expressed in degrees 2 Θ as shown in figure 1.
6. A pharmaceutical composition comprising a crystalline form of a compound of formula I according to any one of claims 1-5 and a pharmaceutically acceptable excipient.
7. Use of a crystalline form of a compound of formula I according to any one of claims 1-5 in the manufacture of a medicament for the treatment of a disease caused by a bacterial infection.
CN202010487918.9A 2020-06-02 2020-06-02 Crystal form of beta-lactamase inhibitor Pending CN113754660A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024160247A1 (en) * 2023-02-02 2024-08-08 苏州信诺维医药科技股份有限公司 PHARMACEUTICAL COMPOSITION CONTAINING β-LACTAMASE INHIBITOR AND USE THEREOF

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024160247A1 (en) * 2023-02-02 2024-08-08 苏州信诺维医药科技股份有限公司 PHARMACEUTICAL COMPOSITION CONTAINING β-LACTAMASE INHIBITOR AND USE THEREOF

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