CN107325096B - Crystallization of avibactam monosodium salt - Google Patents
Crystallization of avibactam monosodium salt Download PDFInfo
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- -1 avibactam monosodium salt Chemical class 0.000 title claims abstract description 22
- 238000002425 crystallisation Methods 0.000 title claims description 7
- 230000008025 crystallization Effects 0.000 title claims description 7
- 229960002379 avibactam Drugs 0.000 title abstract description 19
- 239000013078 crystal Substances 0.000 claims abstract description 97
- 150000001875 compounds Chemical class 0.000 claims description 74
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 claims description 10
- 239000005660 Abamectin Substances 0.000 claims description 9
- 229950008167 abamectin Drugs 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 229960000484 ceftazidime Drugs 0.000 claims description 7
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 7
- 208000035143 Bacterial infection Diseases 0.000 claims description 6
- 239000003242 anti bacterial agent Substances 0.000 claims description 6
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 229940036735 ceftaroline Drugs 0.000 claims description 4
- ZCCUWMICIWSJIX-NQJJCJBVSA-N ceftaroline fosamil Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OCC)C=2N=C(NP(O)(O)=O)SN=2)CC=1SC(SC=1)=NC=1C1=CC=[N+](C)C=C1 ZCCUWMICIWSJIX-NQJJCJBVSA-N 0.000 claims description 4
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 claims description 3
- 229930186147 Cephalosporin Natural products 0.000 claims description 3
- 206010037596 Pyelonephritis Diseases 0.000 claims description 3
- 229940124587 cephalosporin Drugs 0.000 claims description 3
- 150000001780 cephalosporins Chemical class 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000007912 intraperitoneal administration Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 208000019206 urinary tract infection Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical group O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 3
- NDCUAPJVLWFHHB-UHNVWZDZSA-N avibactam Chemical compound C1N2[C@H](C(N)=O)CC[C@@]1([H])N(OS(O)(=O)=O)C2=O NDCUAPJVLWFHHB-UHNVWZDZSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- YXPFBLLXYNCOJF-UHFFFAOYSA-M [Na+].C12C(CCC(NC1)C2)C(=O)[NH-] Chemical compound [Na+].C12C(CCC(NC1)C2)C(=O)[NH-] YXPFBLLXYNCOJF-UHFFFAOYSA-M 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000010512 thermal transition Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Images
Classifications
-
- 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
- C07D471/08—Bridged systems
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new crystal of avibactam monosodium salt. The novel crystal of the avibactam monosodium salt provided by the invention has excellent stability.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to novel crystal of avibactam monosodium salt.
Background
Avibactam, a novel beta lactamase inhibitor with a non-beta-lactam structure. In 2015 FDA approved a compound intravenous formulation of avibactam with ceftazidime (ceftazidime) a cephalosporin class compound for the treatment of complex intraperitoneal infections in combination with metronidazole and for the treatment of complex urinary tract infections including pyelonephritis.
Abamebactam is clinically supplied in the form of monosodium salt, the chemical name of the monosodium salt is (1R,2S,5R) -6-sulfonyloxy-7-oxo-1, 6-azabicyclo [3.2.1] octane-2-formamide monosodium salt, and the structure is shown as a formula I:
patent document WO2011042560 is known to disclose various crystalline forms of avibactam monosodium salt, including B and D crystals in anhydrous form, a and E crystals in hydrate form, and C crystals only observed in mixture with a crystals.
On the basis of the research, the invention discovers the novel crystal of the avibactam monosodium salt, which has good stability.
Disclosure of Invention
The invention provides a new crystal of avibactam monosodium salt. In the avibactam monosodium salt, the molar ratio of avibactam to sodium is about 1: 1.
In particular, the invention provides a crystal of a compound shown as a formula I,
in the crystal of the compound shown in the formula I, the mol ratio of the abamectin to the sodium is about 1: 1.
Wherein the crystallization of the compound of formula I is substantially free of crystallization water and/or other solvents.
A crystal of a compound of formula i characterized by the absence of a characteristic peak at an angle of diffraction (2 Θ ± 0.2 °) of about 10.36 ° in an X-ray powder diffraction pattern using a Cu target.
A crystal of a compound of formula i characterized by having no diffraction peak at a diffraction angle (2 θ ± 0.2 °) of about 10.36 ° in an X-ray powder diffraction pattern using a Cu target.
A crystal of a compound of formula I, characterized by having diffraction peaks at diffraction angles (2 θ + -0.2 °) of about 12.92 °, 16.37 °, 17.31 °, 17.34 °, 22.19 ° and no characteristic peak at diffraction angles (2 θ + -0.2 °) of about 10.36 ° in an X-ray powder diffraction pattern using a Cu target.
A crystal of a compound of formula I, characterized by having diffraction peaks at diffraction angles (2 θ ± 0.2 °) of about 12.92 °, 16.37 °, 17.31 °, 17.34 °, 22.19 ° and no diffraction peaks at diffraction angles (2 θ ± 0.2 °) of about 10.36 ° in an X-ray powder diffraction pattern using a Cu target.
A crystal of a compound of formula I characterized by having diffraction peaks at diffraction angles (2 θ ± 0.2 °) of about 12.92 °, 16.37 °, 17.31 °, 17.34 °, and 22.19 ° in an X-ray powder diffraction pattern using a Cu target.
A crystal of the compound of formula I, characterized by having diffraction peaks at diffraction angles (2 theta + -0.2 DEG) of about 12.92 DEG, 16.37 DEG, 17.31 DEG, 17.34 DEG, 19.12 DEG, 19.38 DEG and 22.19 DEG and by having no characteristic peak at diffraction angles (2 theta + -0.2 DEG) of about 10.36 DEG in an X-ray powder diffraction pattern using a Cu target.
A crystal of the compound of formula I, characterized by having diffraction peaks at diffraction angles (2 theta + -0.2 DEG) of about 12.92 DEG, 16.37 DEG, 17.31 DEG, 17.34 DEG, 19.12 DEG, 19.38 DEG and 22.19 DEG and by having no diffraction peak at diffraction angles (2 theta + -0.2 DEG) of about 10.36 DEG in an X-ray powder diffraction pattern using a Cu target.
A crystal of a compound of formula I characterized by having diffraction peaks at diffraction angles (2 θ ± 0.2 °) of about 12.92 °, 16.37 °, 17.31 °, 17.34 °, 19.12 °, 19.38 °, and 22.19 ° in an X-ray powder diffraction pattern using a Cu target.
A crystal of the compound of formula I, characterized by having diffraction peaks at diffraction angles (2 θ ± 0.2 °) of about 12.92 °, 16.37 °, 17.31 °, 17.34 °, 19.12 °, 19.38 °, 19.75 °, 21.87 °, 22.19 °, 25.08 °, 28.11 ° and no characteristic peak at diffraction angles (2 θ ± 0.2 °) of about 10.36 ° in an X-ray powder diffraction pattern using a Cu target.
A crystal of a compound of formula I, characterized by having diffraction peaks at diffraction angles (2 θ ± 0.2 °) of about 12.92 °, 16.37 °, 17.31 °, 17.34 °, 19.12 °, 19.38 °, 19.75 °, 21.87 °, 22.19 °, 25.08 °, 28.11 ° and no diffraction peak at diffraction angles (2 θ ± 0.2 °) of about 10.36 ° in an X-ray powder diffraction pattern using a Cu target.
A crystal of a compound of formula I characterized by having diffraction peaks at diffraction angles (2 θ ± 0.2 °) of about 12.92 °, 16.37 °, 17.31 °, 17.34 °, 19.12 °, 19.38 °, 19.75 °, 21.87 °, 22.19 °, 25.08 °, 28.11 ° in an X-ray powder diffraction pattern using a Cu target.
A crystal of the compound of formula I, characterized by having diffraction peaks at diffraction angles (2 theta + -0.2 DEG) of about 8.54 DEG, 12.92 DEG, 16.37 DEG, 17.31 DEG, 17.34 DEG, 19.12 DEG, 19.38 DEG, 19.75 DEG, 21.87 DEG, 22.19 DEG, 25.08 DEG, 28.11 DEG, 29.61 DEG, 30.75 DEG, 34.97 DEG, 35.94 DEG, 42.35 DEG and by having no characteristic peak at diffraction angles (2 theta + -0.2 DEG) of about 10.36 DEG in an X-ray powder diffraction pattern using a Cu target.
A crystal of a compound of formula I, characterized by having diffraction peaks in an X-ray powder diffraction pattern using a Cu target at diffraction angles (2 θ ± 0.2 °) of about 8.54 °, 12.92 °, 16.37 °, 17.31 °, 17.34 °, 19.12 °, 19.38 °, 19.75 °, 21.87 °, 22.19 °, 25.08 °, 28.11 °, 29.61 °, 30.75 °, 34.97 °, 35.94 °, and 42.35 °, and having no diffraction peak at diffraction angles (2 θ ± 0.2 °) of about 10.36 °.
A crystal of a compound of formula I, characterized by having diffraction peaks at diffraction angles (2 θ ± 0.2 °) of about 8.54 °, 12.92 °, 16.37 °, 17.31 °, 17.34 °, 19.12 °, 19.38 °, 19.75 °, 21.87 °, 22.19 °, 25.08 °, 28.11 °, 29.61 °, 30.75 °, 34.97 °, 35.94 °, 42.35 ° in an X-ray powder diffraction pattern using a Cu target.
The crystals of the compound of formula i have the following characteristics using the X-ray powder diffraction (XRD) pattern of the Cu target:
the crystals of the compound of formula i have the following characteristics using the X-ray powder diffraction (XRD) pattern of the Cu target:
in a particular embodiment of the invention, the crystals of the compound of formula i have an XRD pattern substantially as shown in figure 1.
In a particular embodiment of the invention, the Differential Scanning Calorimetry (DSC) profile of the crystallization of the compound of formula i has an onset temperature of about 245.3 ℃, in particular, a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 2.
It should be noted that the present invention includes not only crystals in which the diffraction angles of the peaks in the X-ray powder diffraction are completely coincident or + -0.2 deg., but also crystals in which the diffraction angles are coincident with an error of + -0.2 deg..
The characteristic peaks refer to: diffraction peaks with relatively high peak intensities, for example, with relative peak intensities above 10%, in an X-ray powder diffraction (XRD) pattern.
The invention also provides a crystalline composition comprising crystals of the compound of formula i, wherein the crystals of the compound of formula i comprise more than 50% or more than 80% or more than 90% or more than 95% or more than 99% by weight of the crystalline composition.
In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound of formula i or a crystalline composition as described above, together with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions of the present invention may be prepared by crystallization of the compound of formula i or by combining the crystalline composition with a suitable pharmaceutically acceptable carrier.
The pharmaceutical compositions of the present invention may also include one or more additional antibacterial agents.
In another aspect, the invention provides a crystal of the compound of formula I, or a composition thereof, or a pharmaceutical composition thereof, for use in the treatment of bacterial infections. The present invention also provides crystalline forms of the compound of formula I or compositions thereof in combination with other antibacterial agents.
The other antibacterial agents are preferably cephalosporins such as ceftazidime (ceftazidime) and cefaclor (ceftaroline).
Bacterial infections include, but are not limited to, complex skin and structure infections and community-acquired pneumonia, preferably complex intraperitoneal infections and complex urinary tract infections including pyelonephritis.
In a further aspect, the present invention provides a process for the preparation of crystals of a compound of formula I:
dropwise adding the ethanol solution of the Abamebactam tetrabutylammonium salt into the ethanol/water mixed solution of 2-sodium ethylhexanoate within a certain time, stirring the reaction solution for 1-24 hours (h), cooling to 0-5 ℃, keeping for 1h, and filtering to obtain the compound crystal shown in the formula I.
Wherein the certain time is 1-2 h.
It is necessary to add a solution of the tetrabutylammonium salt of abamectin to a solution of sodium 2-ethylhexanoate.
It is very necessary to stir the reaction solution for 1 to 24 hours, preferably 10 to 20 hours.
Wherein in the ethanol solution of the abamectin tetrabutylammonium salt, the ratio of the abamectin tetrabutylammonium salt to ethanol is 1 g: 10 ml.
In the ethanol/water mixed solution of the sodium 2-ethylhexanoate, the volume ratio of ethanol to water is 19:1, and the ratio of the sodium 2-ethylhexanoate to the mixed solution is 1 g: 2.6 ml.
The volume ratio of the ethanol solution of the abamectin tetrabutylammonium salt to the ethanol/water mixed solution of the sodium 2-ethylhexanoate is 1: 1.
The XRD patterns of the crystals of the above compound of formula i of the present invention are measured as follows:
the instrument comprises the following steps: d8ADVANCE, X-ray powder diffractometer
Scanning conditions are as follows: cu target, 40kv and 40mA, scanned at 0.02 ° steps from 3.00 to 60.00deg
The determination method comprises the following steps: taking a proper amount of crystal of the compound shown in the formula I, and grinding. Tabletting, scanning and recording the map.
The DSC chart of the crystals of the above compound of formula I of the present invention is measured as follows:
the instrument comprises the following steps: differential scanning calorimetry analyzer Mettler DSC1
The method comprises the following steps: taking a proper amount of crystal of the compound shown in the formula I, grinding, weighing a proper amount of fine powder, and operating according to the method. The temperature rise rate is 10 ℃/min, and the temperature rise range is 40/300(10 ℃) to record a map.
It is noted that in X-ray powder diffraction spectroscopy, the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystalline form, where the relative intensities of the bands (especially at low angles) may vary due to the dominant orientation effects resulting from differences in crystal conditions, particle size, and other measurement conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal form in question, and when judging whether the diffraction peaks are the same as the known crystal form, the relative positions of the peaks rather than their relative intensities should be noted. In addition, there may be slight errors in the position of the peaks for any given crystalline form, which are also well known in the crystallography art. For example, the position of the peak may shift due to a change in temperature when analyzing the sample, movement of the sample, calibration of the instrument, or the like, and the measurement error of the 2 θ value may be about ± 0.2 °. Therefore, this error should be taken into account when determining each crystalline structure. The peak position is usually expressed in the XRD pattern by 2 θ angle or plane distance d, with a simple conversion relationship between: d ═ λ/2sin θ, where d represents the interplanar spacing, λ represents the wavelength of the incident X-rays, and θ is the diffraction angle. For the same crystal form of the same compound, the peak positions of the XRD spectrum have similarity on the whole, and the error of relative intensity is likely to be larger. It should also be noted that in the identification of mixtures, the loss of a portion of the diffraction lines may be due to, for example, a reduction in the amount of the compound, in which case it is not necessary to rely on all the bands observed in the high purity sample, and even one band may be characteristic of a given crystal.
DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystal form of the same compound, the thermal transition temperature and melting point errors in successive analyses are typically within about 5 ℃, usually within about 3 ℃, which means ± 5 ℃ when we say that a compound has a given DSC peak or melting point. DSC provides an auxiliary method to distinguish different crystal forms. Different crystal morphologies can be identified by their different transition temperature characteristics. It is noted that the DSC peak or melting point for the mixture may vary over a larger range. Furthermore, the melting temperature is related to the rate of temperature rise due to decomposition that accompanies the process of melting the substance.
The crystal of the avibactam monosodium salt or the crystal of the compound in the formula I provided by the invention has excellent stability, and the water content of the crystal of the avibactam monosodium salt (the crystal of the compound in the formula I) is constant at different temperatures; when the crystals of the avibactam monosodium salt (the crystals of the compound shown in the formula I) and the raw material drug ceftazidime or ceftaroline are placed together, the generation amount of related substances is small, the mutual influence is small, and the crystals of the avibactam monosodium salt (the crystals of the compound shown in the formula I) and the ceftazidime or ceftaroline are further prepared into a freeze-dried powder preparation.
Meanwhile, the crystal of the avibactam monosodium salt or the crystal of the compound in the formula I does not have the phenomenon of crystal transformation after being placed at 40 ℃ for 5 days, and does not have the phenomenon of crystal transformation after being placed for 10 days. The crystal of the avibactam monosodium salt or the crystal of the compound of the formula I does not have the phenomenon of crystal transformation after being placed at 60 ℃ for 5 days, and does not have the phenomenon of crystal transformation after being placed for 10 days.
Drawings
FIG. 1X-ray powder diffraction Pattern of the crystalline compound of formula I prepared in example 1
FIG. 2 Differential Scanning Calorimetry (DSC) measurement of crystals of the compound of formula I prepared in example 1
Detailed Description
EXAMPLE 1 preparation of crystals of the Compound of formula I
A solution of Abamebactam tetrabutylammonium salt (40.0g, 79.0mmol) in ethanol (400ml) was added dropwise to a solution of sodium 2-ethylhexanoate (15.2g, 91.4mmol) in ethanol (380ml) and water (20ml) over 1h, and the reaction solution was stirred for 12 h. Cooled to 0-5 ℃ for 1h, filtered and washed with ethanol (40 ml). Drying under reduced pressure at 35 ℃ for 6h gave crystalline compound of formula I (19.0g, yield: 83.8%).
EXAMPLE 2 preparation of crystals of the Compound of formula I
A solution of Abamebactam tetrabutylammonium salt (10.0g, 19.8mmol) in ethanol (100ml) was added dropwise over 1h to a solution of sodium 2-ethylhexanoate (3.8g, 22.8mmol) in ethanol (95ml) and water (5ml), and the reaction mixture was stirred for 13 h. Cooled to 0-5 ℃ for 1h, filtered and washed with ethanol (20 ml). Drying under reduced pressure at 35 ℃ for 6 hours gave the compound of formula I as crystals (4.7g, yield: 83.4%).
EXAMPLE 3 preparation of crystals of the Compound of formula I
A solution of abamectin tetrabutylammonium salt (100.0g, 197.4mmol) in ethanol (1000ml) was added dropwise over 1h to a solution of sodium 2-ethylhexanoate (38.1g, 229.2mmol) in ethanol (950ml) and water (50ml), and the reaction mixture was stirred for 14 h. Cooled to 0-5 ℃ for 1h, filtered and washed with ethanol (100 ml). Drying under reduced pressure at 35 ℃ for 6 hours gave crystalline compound of formula I (47.6g, yield: 84.0%).
Example 4 moisture determination (method is the first method 1 of the general Law 0832 in the pharmacopoeia 2015 year edition of China)
The crystal B is a crystal B of avibactam monosodium salt disclosed in patent document WO2011042560, and can be prepared according to the method described in the patent document.
Claims (22)
1. A crystal of a compound of formula I, having an X-ray powder diffraction pattern substantially as shown in figure 1, wherein the crystal of the compound of formula I is a crystal substantially free of water of crystallization and/or other solvents
2. The crystal of the compound of formula i as claimed in claim 1, characterized by a differential scanning calorimetry trace having an onset temperature of about 245.3 ℃.
3. A crystal of a compound of formula i as claimed in claim 1, having a differential scanning calorimetry trace substantially as shown in figure 2.
4. A process for the preparation of a crystal of a compound of formula i as claimed in any one of claims 1 to 3, comprising the steps of:
within 1-2h, dropwise adding the ethanol solution of the abamectin tetrabutylammonium salt into the ethanol/water mixed solution of 2-sodium ethylhexanoate, stirring the reaction solution for 1-24h, cooling to 0-5 ℃, keeping for 1h, and filtering to obtain the compound crystal shown in the formula I.
5. A crystal of a compound of formula I, having an X-ray powder diffraction pattern substantially as shown in figure 1
The crystal is prepared by the following steps:
within 1-2h, dropwise adding the ethanol solution of the abamectin tetrabutylammonium salt into the ethanol/water mixed solution of 2-sodium ethylhexanoate, stirring the reaction solution for 1-24h, cooling to 0-5 ℃, keeping for 1h, and filtering to obtain the compound crystal shown in the formula I.
6. The production process as claimed in claim 4 or the crystal as claimed in claim 5, wherein the stirring reaction time is selected from 10 to 20 hours.
7. The production method according to claim 4 or the crystal according to claim 5, wherein the ratio of the Abbactam tetrabutylammonium salt to ethanol in the ethanol solution of the Abbactam tetrabutylammonium salt is 1 g: 10 ml.
8. The production method according to claim 4 or the crystal according to claim 5, wherein in the ethanol/water mixed solution of sodium 2-ethylhexanoate, the volume ratio of ethanol to water is 19:1, and the ratio of sodium 2-ethylhexanoate to the mixed solution is 1 g: 2.6 ml.
9. The production method according to claim 4 or the crystal according to claim 5, wherein the volume ratio of the ethanol solution of the tetrabutylammonium salt of abamectin to the ethanol/water mixed solution of sodium 2-ethylhexanoate is 1: 1.
10. A crystalline composition comprising crystals of a compound of formula i as claimed in any one of claims 1 to 3 and 5 to 9, wherein the amount of crystals of the compound of formula i is more than 50% by weight of the crystalline composition.
11. A crystalline composition comprising crystals of a compound of formula i as claimed in any one of claims 1 to 3 and 5 to 9, wherein the amount of crystals of the compound of formula i is greater than 80% by weight of the crystalline composition.
12. A crystalline composition comprising crystals of a compound of formula i as claimed in any one of claims 1 to 3 and 5 to 9, wherein the amount of crystals of the compound of formula i is greater than 90% by weight of the crystalline composition.
13. A crystalline composition comprising crystals of a compound of formula i as claimed in any one of claims 1 to 3 and 5 to 9, wherein the amount of crystals of the compound of formula i is greater than 95% by weight of the crystalline composition.
14. A crystalline composition comprising crystals of a compound of formula i as claimed in any one of claims 1 to 3 and 5 to 9, wherein the amount of crystals of the compound of formula i is greater than 99% by weight of the crystalline composition.
15. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline compound of formula i as claimed in any one of claims 1 to 3, 5 to 9 or a crystalline composition as claimed in claims 10 to 14, together with one or more pharmaceutically acceptable carriers.
16. The pharmaceutical composition of claim 15, further comprising one or more additional antibacterial agents.
17. The pharmaceutical composition of claim 16, wherein the additional antibacterial agent is selected from the group consisting of cephalosporins.
18. A pharmaceutical composition according to claim 17 wherein the other antibacterial agent is selected from ceftazidime and ceftaroline.
19. Use of a crystalline compound of formula i as defined in any one of claims 1 to 3, 5 to 9 or a crystalline composition as defined in any one of claims 10 to 14 or a pharmaceutical composition as defined in claims 15 to 18 for the manufacture of a medicament for the treatment of a bacterial infection.
20. The use of claim 19, wherein the bacterial infection is selected from the group consisting of complex skin and structure infections and community-acquired pneumonia.
21. The use of claim 19, wherein the bacterial infection is selected from the group consisting of a complex intraperitoneal infection and a complex urinary tract infection.
22. The use according to claim 19, wherein the bacterial infection is selected from pyelonephritis.
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| CN111689964A (en) * | 2020-07-21 | 2020-09-22 | 海南海灵化学制药有限公司 | Stable crystal form of abamectin sodium and preparation method thereof |
| CN114249729B (en) * | 2020-09-23 | 2024-12-27 | 四川科伦药物研究院有限公司 | A method for preparing crystalline form B avibactam sodium by reactive crystallization |
| KR20240041506A (en) * | 2022-09-23 | 2024-04-01 | 주식회사 경보제약 | Stable monohydrate form of avibactam sodium and manufacturaing method thereof |
| CN117304188A (en) * | 2023-09-22 | 2023-12-29 | 北京理工大学 | Novel crystal form of avibactam monosodium salt |
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