CN111320596A - Mefurapine hydrochloride polymorphic substance and preparation method thereof - Google Patents
Mefurapine hydrochloride polymorphic substance and preparation method thereof Download PDFInfo
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a cefuroxime hydrochloride polymorph and a preparation method and application thereof. Specifically, the invention discloses 2- [4- (methylamino methyl) phenyl]D, E, F and G four crystal forms of (E) -5-fluoro-benzofuran-7-formamide hydrochloride (formula I) and preparation method thereofAnd use in the manufacture of a medicament.
Description
Technical Field
The invention particularly relates to a polymorph of the hydrochloride of the metfurapine, namely 2- [4- (methylamino methyl) phenyl ] -5-fluoro-benzofuran-7-formamide hydrochloride, a preparation method of the polymorph hydrochloride of the metfurapine and application of the polymorph hydrochloride in preparation of medicines, and belongs to the field of pharmaceutical chemistry.
Background
Different crystalline forms of a compound may have different properties, such as solubility, dissolution rate, suspension stability, stability during grinding, vapour pressure, optical and mechanical properties, hygroscopicity, crystal form size, filtration properties, drying, density, melting point, stability against degradation, stability against phase transition to other crystalline forms, colour and even chemical reactivity, and the like. More importantly, the different crystal forms of the small molecule compound drug can cause the change of the dissolution, pharmacokinetics and bioavailability of the small molecule compound drug, thereby affecting the curative effect and safety of the drug, so the problem of the polymorphism of the small molecule compound drug should be considered comprehensively in the process of developing the small molecule drug. Therefore, the research and control of the crystal form become one of important research contents in the research and development process of small molecule drugs.
An example of a pharmaceutically valuable selective PARP inhibitor is disclosed in WO2013117120, wherein the series of inhibitors is specifically described (see example 21 on page 37) as 2- [4- (methylaminomethyl) phenyl ] -5-fluoro-benzofuran-7-carboxamide hydrochloride (hereinafter referred to as mefurapine hydrochloride) having the structure of formula i:
the characterization of the compound obtained by the method disclosed in WO2013117120 is by1HMR analysis and/or measurement of melting point. In the prior art, the observation of different crystalline forms of cefuroxime hydrochloride has not been described, nor has any characterization of a particular crystalline form and preparation methods for obtaining a particular crystalline form been described. Different crystal forms of the mefurapine hydrochloride can cause the dissolution, pharmacokinetics and bioavailability of the mefurapine hydrochloride to change, thereby influencing the curative effect and safety performance of the medicine. Thus, it is possible to provideFor large scale preparation of mefurapine hydrochloride, it is important to know if different crystalline forms of this compound (also often referred to as polymorphs, or pseudopolymorphs in the case of solvent inclusion) are present, how to obtain them, and how their characteristic properties are.
Disclosure of Invention
Against the background, the invention discloses various crystal forms, characterization and preparation methods and applications of the mefurapine hydrochloride. Therefore, the invention aims to provide a polymorphic form of the mefuripide hydrochloride and provide technical support for further deep development of the mefuripide hydrochloride.
The invention provides a first aspect of a polymorphic substance of cefuroxime axetil hydrochloride shown in a formula I.
In another preferred embodiment, the polymorph is a crystalline form D of mefurapril hydrochloride, is an acetic acid compound of mefurapril hydrochloride, and has an X-ray powder diffraction pattern including 3 or more 2 θ values selected from the group consisting of: 5.354 +/-0.1 degree, 6.466 +/-0.1 degree, 10.298 +/-0.1 degree, 12.101 +/-0.1 degree, 12.947 +/-0.1 degree, 14.286 +/-0.1 degree, 15.232 +/-0.1 degree, 15.950 +/-0.1 degree, 17.859 +/-0.1 degree, 19.642 +/-0.1 degree, 20.705 +/-0.1 degree, 22.209 +/-0.1 degree, 24.379 +/-0.1 degree, 25.097 +/-0.1 degree, 26.059 +/-0.1 degree, 26.982 +/-0.1 degree, 31.999 +/-0.1 degree and 37.248 +/-0.1 degree.
Preferably, the DSC spectrogram of the cefuroxime axetil hydrochloride crystal form D has a characteristic endothermic peak within the range of about 280-300 ℃;
preferably, the infrared spectrum of the cefuroxime axetil crystal form D is at least 3487cm-1、3182cm-1、2923cm-1、2706cm-1、2432cm-1、1666cm-1、1604cm-1、1468cm-1、1434cm-1、1273cm-1、1192cm-1、1115cm-1、1018cm-1、891cm-1、838cm-1、779cm-1And 513cm-1Has a characteristic peak with an error range of + -2 cm-1。
Further preferably, the crystalline form D of cefuroxime axetil hydrochloride has an X-ray powder diffraction pattern substantially as shown in figure 1;
in another preferred embodiment, the form D further has one or more characteristics selected from the group consisting of:
(1) said form D having a DSC profile substantially as shown in figure 2;
(2) said form D having an infra-red spectrum substantially as shown in figure 3;
(3) said form D having a TG profile substantially as shown in figure 4; and
(4) the form D has a raman spectrum substantially as shown in figure 5.
In another preferred embodiment, the polymorph is a crystalline form E of cefuroxime hydrochloride, which is a1, 4-dioxane compound of cefuroxime hydrochloride, and the X-ray powder diffraction spectrum of the polymorph comprises 3 or more than 32 theta values selected from the following group: 6.49 +/-0.1 degrees, 12.625 +/-0.1 degrees, 15.271 +/-0.1 degrees, 20.727 +/-0.1 degrees, 22.933 +/-0.1 degrees, 23.913 +/-0.1 degrees, 25.139 +/-0.1 degrees, 25.618 +/-0.1 degrees, 26.082 +/-0.1 degrees, 27.084 +/-0.1 degrees, 27.406 +/-0.1 degrees and 28.828 +/-0.1 degrees.
Preferably, the DSC spectrogram of the cefuroxime axetil hydrochloride crystal form E has a characteristic endothermic peak within the range of about 280-300 ℃;
preferably, the infrared spectrum of the cefuroxime axetil crystal form E is at least 3480cm-1、3168cm-1、2957cm-1、2708cm-1、2475cm-1、1670cm-1、1613cm-1、1592cm-1、1467cm-1、1431cm-1、1377cm-1、1338cm-1、1199cm-1、1115cm-1、948cm-1、869cm-1And 470cm-1Has a characteristic peak with an error range of + -2 cm-1。
Further preferably, the crystalline form E of cefuroxime axetil hydrochloride has an X-ray powder diffraction pattern substantially as shown in figure 6;
in another preferred embodiment, the form E further has one or more characteristics selected from the group consisting of:
(1) said crystalline form E having a DSC profile substantially as shown in figure 7;
(2) said crystalline form E having an infrared spectrum substantially as shown in figure 8;
(3) said crystalline form E having a TG profile substantially as shown in figure 9; and
(4) the crystalline form E has a raman spectrum substantially as shown in figure 10.
In another preferred embodiment, the polymorph is cefuroxime axetil hydrochloride form F, a dimethyl sulfoxide compound, and has an X-ray powder diffraction pattern including 3 or more 2 θ values selected from the group consisting of: 6.266 +/-0.1 degree, 12.686 +/-0.1 degree, 15.532 +/-0.1 degree, 17.035 +/-0.1 degree, 17.675 +/-0.1 degree, 20.045 +/-0.1 degree, 20.727 +/-0.1 degree, 22.449 +/-0.1 degree, 23.114 +/-0.1 degree, 24.897 +/-0.1 degree, 25.536 +/-0.1 degree, 26.242 +/-0.1 degree, 27.166 +/-0.1 degree, 31.352 +/-0.1 degree and 32.033 +/-0.1 degree.
Preferably, the DSC spectrogram of the cefuroxime axetil hydrochloride crystal form F has a characteristic endothermic peak within the range of about 280-300 ℃;
preferably, the infrared spectrum of the cefuroxime axetil crystal form F is at least 3389cm-1、3168cm-1、2987cm-1、2741cm-1、2463cm-1、1662cm-1、1610cm-1、1596cm-1、1468cm-1、1434cm-1、1419cm-1、1385cm-1、1345cm-1、1205cm-1、1183cm-1、1116cm-1、1015cm-1、947cm-1、833cm-1、780cm-1And 558cm-1Has a characteristic peak with an error range of + -2 cm-1。
Further preferably, the crystalline form F of cefuroxime hydrochloride has an X-ray powder diffraction pattern substantially as shown in figure 11;
in another preferred embodiment, the crystalline form F further has one or more characteristics selected from the group consisting of:
(1) said crystalline form F having a DSC profile substantially as shown in figure 12;
(2) said crystalline form F having an ir spectrum substantially as shown in figure 13;
(3) said crystalline form F having a TG profile substantially as shown in figure 14; and
(4) the crystalline form F has a raman spectrum substantially as shown in figure 15.
In another preferred embodiment, the polymorph is a crystalline form G of cefuroxime hydrochloride, and the X-ray powder diffraction pattern thereof comprises 3 or more than 32 θ values selected from the group consisting of: 6.428 +/-0.1 degree, 8.374 +/-0.1 degree, 10.281 +/-0.1 degree, 12.566 +/-0.1 degree, 15.231 +/-0.1 degree, 15.794 +/-0.1 degree, 18.043 +/-0.1 degree, 19.405 +/-0.1 degree, 20.667 +/-0.1 degree, 22.912 +/-0.1 degree, 23.874 +/-0.1 degree, 25.087 +/-0.1 degree, 26.040 +/-0.1 degree, 29.849 +/-0.1 degree and 232.656 +/-0.1 degree.
Preferably, the DSC spectrum of the crystal form G of the cefuroxime axetil hydrochloride has a characteristic endothermic peak within the range of about 280-300 ℃.
Preferably, the infrared spectrum of the cefuroxime axetil crystal form G hydrochloride is at least 3486cm-1、3171cm-1、2923cm-1、2709cm-1、2475cm-1、1665cm-1、1608cm-1、1591cm-1、1508、1468cm-1、1429cm-1、1377cm-1、1338cm-1、1190cm-1、1173cm-1、1115cm-1、1018cm-1、947cm-1、838cm-1、779cm-1And 470cm-1Has a characteristic peak with an error range of + -2 cm-1。
Further preferably, the crystalline form G of cefuroxime axetil hydrochloride has an X-ray powder diffraction pattern substantially as shown in figure 16.
In another preferred embodiment, the form G further has one or more characteristics selected from the group consisting of:
(1) said form G having a DSC profile substantially as shown in figure 17;
(2) said crystalline form G having an infra red spectrum substantially as shown in figure 18;
(3) the crystalline form G has a TG profile substantially as shown in figure 19; and
(4) the crystalline form G has a raman spectrum substantially as shown in figure 20.
A second aspect of the present invention provides a process for the preparation of a polymorph of cefuroxime axetil hydrochloride according to the first aspect of the present invention, comprising the steps of:
(i) dissolving amorphous metformin hydrochloride in acetic acid at 80 ℃ to form a metformin hydrochloride-containing acetic acid solution;
(ii) slowly returning the acetic acid solution containing the cefuroxime axetil hydrochloride in the step i) to the room temperature, standing, and separating out crystals; and (iii) separating and drying the precipitated crystals, thereby obtaining the crystalline form D of cefuroxime hydrochloride;
or the preparation method comprises the following steps:
(a) dissolving amorphous cefuroxime hydrochloride in a water system at 0-80 ℃ to form an aqueous solution containing cefuroxime hydrochloride;
(b) slowly dripping 1, 4-dioxane into the water solution containing the cefuroxime hydrochloride in the step a), and stirring at room temperature until crystals are separated out; and
(c) separating and drying the precipitated crystal to obtain a crystal form E of the cefuroxime hydrochloride;
or the preparation method comprises the following steps:
(i) dissolving amorphous cefuroxime hydrochloride in dimethyl sulfoxide at 0-80 ℃ to form a dimethyl sulfoxide solution containing cefuroxime hydrochloride;
(ii) dripping an organic solvent into the dimethyl sulfoxide solution containing the cefuroxime hydrochloride in the step i), stirring, standing, and separating out crystals; and
(iii) separating and drying the precipitated crystal to obtain a crystal form F of the cefuroxime hydrochloride;
wherein the organic solvent is selected from one or more of the following organic solvents: ethanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, ethyl acetate, methyl tert-butyl ether, dichloromethane, and the like;
or the preparation method comprises the following steps:
(i) dissolving amorphous cefuroxime hydrochloride in alcohol at 0-80 ℃ to form an alcohol solution containing cefuroxime hydrochloride;
(ii) dripping tetrahydrofuran into the alcohol solution containing the cefuroxime hydrochloride in the step i), stirring, standing, and separating out crystals; and
(iii) separating and drying the precipitated crystal to obtain a crystal form G of the cefuroxime hydrochloride;
wherein, the alcohol is selected from one or more of the following alcohols: methanol, ethanol, propanol, tert-butanol, octanol, pentanol, hexanol, heptanol, decanol.
Preferably, in the preparation method of the crystal form D of the amorphous cefuroxime axetil hydrochloride, the mass-to-volume ratio of the amorphous cefuroxime axetil hydrochloride to acetic acid is 5: 1-30: 1 mg/mL; more preferably 10: 1-20: 1 mg/mL;
preferably, in the preparation method of the crystal form E of the amorphous cefuroxime axetil hydrochloride, the mass-to-volume ratio of the amorphous cefuroxime axetil hydrochloride to the 1, 4-dioxane is 1: 1-10: 1 mg/mL; more preferably 1: 1-2: 1 mg/mL;
preferably, in the preparation method of the crystal form F of the amorphous cefuroxime axetil hydrochloride, the mass-to-volume ratio of the amorphous cefuroxime axetil hydrochloride to the dimethyl sulfoxide is 10: 1-50: 1 mg/mL; more preferably 20: 1-30: 1 mg/mL;
preferably, in the preparation method of the crystal form F of the amorphous cefuroxime axetil hydrochloride, the mass-to-volume ratio of the amorphous cefuroxime axetil hydrochloride to the organic solvent is 1: 1-10: 1 mg/mL; more preferably 3: 1-5: 1 mg/mL;
preferably, in the preparation method of the crystal form G of the cefuroxime axetil hydrochloride, the mass-to-volume ratio of the amorphous cefuroxime axetil hydrochloride to the alcohol is 10: 1-50: 1 mg/mL; more preferably 20: 1-30: 1 mg/mL;
preferably, in the preparation method of the crystal form G of the amorphous cefuroxime axetil hydrochloride, the mass-to-volume ratio of the amorphous cefuroxime axetil hydrochloride to tetrahydrofuran is 1: 1-10: 1 mg/mL; more preferably 1:1 to 5:1 mg/mL.
A third aspect of the invention provides a pharmaceutical composition comprising a pharmaceutically effective dose of a polymorph of cefuroxime axetil hydrochloride according to the first aspect of the invention, and a pharmaceutically acceptable excipient or carrier therefor.
The fourth aspect of the present invention provides a use of the polymorph of cefuroxime axetil hydrochloride according to the first aspect of the present invention or the composition according to the third aspect of the present invention for the preparation of a medicament for the treatment and/or prevention of diseases associated with poly (adenosine diphosphate ribose) polymerase PARP.
In another preferred embodiment, the disease comprises: tumors, inflammation, cardiovascular disease, diabetes, rheumatoid arthritis, endotoxic shock and stroke.
In another preferred embodiment, the tumor comprises: BRCA1 or BRCA2 deleted or mutated tumors.
In another preferred embodiment, the tumor comprises: ovarian cancer, breast cancer, prostate cancer, gastric cancer, pancreatic cancer, cervical cancer, glioma, and ewing's sarcoma.
In another preferred embodiment, the drug comprises an anti-tumor drug and/or an anti-inflammatory drug.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
Figure 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form D of cefuroxime hydrochloride;
figure 2 is a DSC profile of crystalline form D of cefuroxime hydrochloride;
figure 3 is an Infrared (IR) spectrum of crystalline form D of cefuroxime hydrochloride;
figure 4 is a TG spectrum of cefuroxime hydrochloride form D;
figure 5 is a Raman spectrum of crystalline form D of cefuroxime hydrochloride;
figure 6 is an X-ray powder diffraction (XRPD) pattern of crystalline form E of cefuroxime hydrochloride;
figure 7 is a DSC profile of crystalline form E of cefuroxime hydrochloride;
figure 8 is an Infrared (IR) spectrum of crystalline form E of cefuroxime hydrochloride;
figure 9 is a TG spectrum of cefuroxime hydrochloride crystalline form E;
figure 10 is a Raman light (Raman) spectrum of crystalline form E of cefuroxime hydrochloride;
figure 11 is an X-ray powder diffraction (XRPD) pattern of crystalline form F of cefuroxime hydrochloride;
figure 12 is a DSC profile of cefuroxime hydrochloride crystalline form F;
figure 13 is an Infrared (IR) spectrum of crystalline form F of cefuroxime hydrochloride;
figure 14 is a TG spectrum of cefuroxime hydrochloride crystalline form F;
figure 15 is a Raman light (Raman) spectrum of crystalline form F of cefuroxime hydrochloride;
figure 16 is an X-ray powder diffraction (XRPD) pattern of crystalline form G of cefuroxime hydrochloride;
figure 17 is a DSC profile of cefuroxime hydrochloride form G;
figure 18 is an Infrared (IR) spectrum of crystalline form G of cefuroxime hydrochloride;
figure 19 is a TG spectrum of cefuroxime hydrochloride form G;
figure 20 is a Raman light (Raman) spectrum of crystalline form G of cefuroxime hydrochloride;
figure 21 is an X-ray powder diffraction (XRPD) pattern of amorphous cefuroxime axetil hydrochloride after 15 days at 25 ℃.
Detailed Description
The inventor of the invention has conducted extensive and intensive research, and unexpectedly found four novel polymorphic substances of the mefurapine hydrochloride, the preparation process is simple and efficient, the repeatability is good, and the large-scale industrial production can be realized. On the basis of this, the present invention has been completed.
Description of the terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
For a characteristic diffraction peak expressed in terms of 2 θ angle, the term "about" means that the value recited does not shift by more than 0.2 °, e.g., about X °, then X ± 0.2 °, preferably X ± 0.1 °.
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
As used herein, the term "room temperature" generally means 4-30 deg.C, preferably 20. + -. 5 deg.C.
As used herein, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.
As used herein, the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The precise effective amount for a subject will depend upon the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation and can be readily determined by a clinician.
Crystallization of
Production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method to reduce the liquid volume. The solubility of the compound of interest may be reduced by adding an anti-solvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of the Crystallization see crystallation, third edition, J W Mullins, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
If salt formation is desired to occur simultaneously with crystallization, addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Also, in media where the final desired form is less soluble than the reactants, completion of the synthesis reaction can result in direct crystallization of the final product.
Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this point, seeds of the desired form may be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.
Polymorphs of the invention
The cefuroxime hydrochloride polymorph comprises four crystal forms: namely crystal form D, crystal form E, crystal form F and crystal form G.
D crystal form
The powder X-ray diffraction spectrum of the Mefuraprezrin hydrochloride crystal form D has obvious characteristic absorption peaks at diffraction angles (2 theta) of about 5.354, 6.466, 10.298, 12.101, 12.947, 14.286, 15.232, 15.950, 17.859, 19.642, 20.705, 22.209, 24.379, 25.097, 26.059, 26.982, 31.999 and 37.248.
The X-ray powder diffraction spectrum of the D crystal form of the cefuroxime hydrochloride is basically consistent with that of figure 1; the DSC, ir, TG and raman spectra are substantially in accordance with figures 2, 3, 4 and 5.
As can be seen from FIG. 2, the form D has a characteristic endothermic peak within the range of about 280-300 ℃.
As can be seen from FIG. 3, the infrared spectrum of said form D is at least 3487cm-1、3182cm-1、2923cm-1、2706cm-1、2432cm-1、1666cm-1、1604cm-1、1468cm-1、1434cm-1、1273cm-1、1192cm-1、1115cm-1、1018cm-1、891cm-1、838cm-1、779cm-1And 513cm-1Has a characteristic peak with an error range of + -2 cm-1。
From fig. 4, it can be analytically concluded that: thermogravimetric analysis of form D starts to decompose at 280 ± 20 ℃.
E crystal form
The powder X-ray diffraction spectrum of the crystal form E of the Mefuraprepin hydrochloride of the invention is about 6.49, 12.625, 15.271, 20.727, 22.933, 23.913, 25.139, 25.618, 26.082, 27.084, 27.406 and 28.828 at the diffraction angle (2 theta). Has obvious characteristic absorption peaks.
The X-ray powder diffraction spectrum of the E crystal form cefuroxime hydrochloride is basically consistent with that of figure 6; the DSC, ir, TG and raman spectra are substantially in accordance with figures 7, 8, 9 and 10.
As can be seen from FIG. 7, the form E has a characteristic endothermic peak within the range of about 280-300 ℃.
As can be seen from FIG. 8, the infrared spectrum of the form E is at least 3480cm-1、3168cm-1、2957cm-1、2708cm-1、2475cm-1、1670cm-1、1613cm-1、1592cm-1、1467cm-1、1431cm-1、1377cm-1、1338cm-1、1199cm-1、1115cm-1、948cm-1、869cm-1And 470cm-1Has a characteristic peak with an error range of + -2 cm-1。
From fig. 9, it can be analytically concluded that: the thermogravimetric analysis of form a starts to decompose at 280 ± 20 ℃.
Crystal form F
The powder X-ray diffraction spectrum of the Mefuraprepin hydrochloride F crystal form has obvious characteristic absorption peaks at diffraction angles (2 theta) of about 6.266, 12.686, 15.532, 17.035, 17.675, 20.045, 20.727, 22.449, 23.114, 24.897, 25.536, 26.242, 27.166, 31.352 and 32.033.
The X-ray powder diffraction spectrum of the cefuroxime axetil crystal form F hydrochloride is basically consistent with that of figure 11; the DSC, ir, TG and raman spectra are substantially in accordance with figures 12, 13, 14 and 15.
As can be seen from FIG. 12, the form F has a characteristic endothermic peak within the range of about 280-300 ℃.
From the figure13, the infrared spectrum of said form F is at least 3389cm-1、3168cm-1、2987cm-1、2741cm-1、2463cm-1、1662cm-1、1610cm-1、1596cm-1、1468cm-1、1434cm-1、1419cm-1、1385cm-1、1345cm-1、1205cm-1、1183cm-1、1116cm-1、1015cm-1、947cm-1、833cm-1、780cm-1And 558cm-1Has a characteristic peak with an error range of + -2 cm-1。
From fig. 14, it can be analytically concluded that: thermogravimetric analysis of form F starts to decompose at 280 ± 20 ℃.
G crystal form
The powder X-ray diffraction spectrum of the Mefuraprepin hydrochloride G crystal form has obvious characteristic absorption peaks at diffraction angles (2 theta) of about 6.428, 8.374, 10.281, 12.566, 15.231, 15.794, 18.043, 19.405, 20.667, 22.912, 23.874, 25.087, 26.040, 29.849 and 232.656.
The X-ray powder diffraction spectrum of the G crystal form of the cefuroxime hydrochloride is basically consistent with that in figure 16; the DSC, ir, TG and raman spectra are substantially in accordance with figures 17, 18, 19 and 20.
As can be seen from FIG. 17, the form G has a characteristic endothermic peak in the range of about 280-300 ℃.
As can be seen in FIG. 18, the infrared spectrum of said form G is at least 3486cm-1、3171cm-1、2923cm-1、2709cm-1、2475cm-1、1665cm-1、1608cm-1、1591cm-1、1508、1468cm-1、1429cm-1、1377cm-1、1338cm-1、1190cm-1、1173cm-1、1115cm-1、1018cm-1、947cm-1、838cm-1、779cm-1And 470cm-1Has a characteristic peak with an error range of + -2 cm-1。
From fig. 19, it can be analytically concluded that: thermogravimetric analysis of said form G starts to decompose at 250 ± 20 ℃.
Process for the preparation of polymorphs
The invention also provides a preparation method of the cefuroxime hydrochloride D, E, F and G four crystals, which comprises the following specific steps.
Preparation of Mefurapine hydrochloride D crystal form
Dissolving amorphous Mefuriperizine hydrochloride in hot acetic acid, slowly cooling to room temperature, standing, filtering the solution, and drying the solid part at 25 ℃ to obtain the Mefuriperizine hydrochloride of the D crystal form.
Preparation of Mefurapine hydrochloride E crystal form
Dissolving amorphous cefuroxime hydrochloride in water, slowly dropwise adding an organic solvent 1, 4-dioxane which is highly insoluble to the raw material, stirring, standing, filtering the solution, and drying the solid part at 25 ℃ to obtain the E crystal form of cefuroxime hydrochloride.
Preparation of Mefurapine hydrochloride F crystal form
Dissolving amorphous cefuroxime hydrochloride in dimethyl sulfoxide, slowly dropwise adding an organic solvent which is highly insoluble in the raw material, stirring, standing, filtering the solution, and drying the solid part at 25 ℃ to obtain the F crystal form of cefuroxime hydrochloride.
Wherein the organic solvent highly insoluble in the raw material is selected from ethanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, ethyl acetate, methyl tert-butyl ether, dichloromethane and the like, and more preferably, ethyl acetate.
Preparation of Mefurapirin hydrochloride G crystal form
Dissolving amorphous cefuroxime hydrochloride in alcohol, slowly dropwise adding organic solvent tetrahydrofuran which is highly insoluble in raw materials, stirring, standing, filtering the solution, and drying the solid part at 25 ℃ to obtain the G crystal form of cefuroxime hydrochloride.
The alcohol is selected from methanol, ethanol, propanol, tert-butanol, octanol, pentanol, hexanol, heptanol and decanol.
Pharmaceutical composition
The pharmaceutical composition comprises a safe and effective amount range of the cefuroxime hydrochloride polymorphic substance, namely the crystal form D, the crystal form E, the crystal form F or the crystal form G, and the pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition can be blended with the polymorphs of the present invention and with each other without significantly reducing the potency of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The polymorph of the invention is typically admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Preferably, the excipient comprises one or more of a filler, a disintegrant, a binder and a lubricant.
Preferably, the filler is any one or a mixture of more of starch, lactose, microcrystalline cellulose, dextrin, mannitol, oxidase and calcium sulfate.
Preferably, the disintegrating agent comprises one or more of carboxymethyl cellulose and salt thereof, cross-linked povidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.
Preferably, the binder comprises any one or more of povidone, hydroxypropyl methyl cellulose, starch slurry and pregelatinized starch.
Preferably, the lubricant comprises any one or more of sodium stearyl fumarate, magnesium stearate and calcium stearate.
Applications of
The polymorphic substance of the cefuroxime axetil hydrochloride is used for preparing a medicament for preventing and/or treating diseases related to poly (adenosine diphosphate ribose) polymerase (PARP); can also be used for preparing medicaments for preventing and/or treating tumors; can also be used for preparing anti-inflammatory drugs.
Diseases associated with poly (adenosine diphosphate ribose) PARP include tumors, inflammation and ischemia-reperfusion-complicated diseases such as cardiovascular diseases, diabetes, rheumatoid arthritis, endotoxic shock, stroke, etc. The tumor is a tumor with homologous recombination repair defect, namely BRCA1 or BRCA2 deletion or mutation tumor, such as ovarian cancer, breast cancer, prostatic cancer, gastric cancer, pancreatic cancer, cervical cancer, glioma, Ewing sarcoma and the like.
The main advantages of the invention include:
compared with the prior art, the invention has the main advantages that:
1. the invention provides different crystal forms of Mefurapine hydrochloride, which can be respectively converted into D, E, F, G four crystal forms under the crystal forms of different solvent ratios. The four polymorphic substances have simple preparation method, high purity of crystal form, good stability and convenient storage.
2. The preparation method of the four polymorphic substances has the advantages of simple preparation process, easy operation, good process repeatability and high purity of the obtained crystal form of the product.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
The experimental conditions are as follows:
1) XRPD method
Bruker D8advance, target Cu K α (40kV, 40mA), sample-to-detector distance of 30cm, scan range of 3-40 ° (2theta values), scan step size of 0.1. it should be noted that in the X-ray diffraction spectrum of the powder sample, the diffraction spectrum specific crystal form obtained from the crystalline compound tends to be characteristic, wherein the relative intensities of the bands (especially at low angles) may vary due to the dominant orientation effects caused by differences in crystallization conditions, particle size, relative content of the mixture, and other test conditions.
2) DSC method, instrument model: perkin Elmer DSC 8500, temperature range 50-320 deg.C, scanning rate 10 deg.C/min, and nitrogen flow rate 50 ml/min.
3) The IR method adopts a Nicolot-Magna FT-IR750 infrared spectrometer of Nikoy, Inc. in America to detect at room temperature, and the detection range is 4000--1The wave number of (c).
4) TGA method instrument model: netzsch TG 209F3, temperature range 30-400 deg.C, sweep rate of 10K/min, purge gas flow rate of 25mL/min, guard gas flow rate of 15 mL/min.
5) Raman method instrument model: thermo Scientific DXR, laser wavelength: 780nm, scanning range: 3500to 50cm-1Resolution ratio: 2cm-1。
6) DVS method instrument model: SMS DVS Intrasic, 0-95% RH, temperature: at 25 ℃.
Example 1
A method for preparing form D:
approximately 25mg of amorphous metformin hydrochloride (see WO2013117120) was taken and added to 80 ℃ acetic acid (2mL) until the starting material was completely dissolved, filtered while hot and then allowed to cool to room temperature slowly on standing. Filtering, and drying the filter cake to constant weight in vacuum at room temperature to obtain the crystal form D.
X-ray powder diffraction measurement shows that the specific peak position of the obtained crystal form D of the cefuroxime axetil hydrochloride is shown in the table 1, and the figure 1 is shown.
TABLE 1X-ray powder diffraction (XRPD) data for crystalline form D of cefuroxime hydrochloride
The resulting sample was subjected to other tests to obtain a DSC profile, an infrared profile, a TG profile and a raman profile substantially in accordance with figures 2, 3, 4 and 5.
Example 2
A method of preparing form E:
approximately 25mg of amorphous metformin hydrochloride was taken and water (2mL) was added at 25 ℃ until the starting material was completely dissolved, followed by slow dropwise addition of 1, 4-dioxane (18 mL). After the dropwise addition, stirring for 6h at the temperature, filtering, and vacuum-drying the filter cake at 25 ℃ to constant weight to obtain the crystal form E.
X-ray powder diffraction measurement shows that the specific peak position of the obtained crystal form E of the cefuroxime axetil hydrochloride is shown in the table 2, and the figure 6 shows that the crystal form E of the cefuroxime axetil hydrochloride is a crystal form.
TABLE 2X-ray powder diffraction (XRPD) data for crystalline form E of cefuroxime hydrochloride
The resulting sample was subjected to other tests to obtain a DSC spectrum, an infrared spectrum, a TG spectrum and a raman spectrum substantially in accordance with fig. 7, 8, 9 and 10.
Example 3
A method of preparing form F:
approximately 25mg of amorphous metformin hydrochloride (1mL) was taken and dimethylsulfoxide (1mL) was added at 25 ℃ until complete dissolution of the starting material, followed by slow dropwise addition of ethyl acetate (6 mL). After the dropwise addition, stirring for 12h at the temperature, filtering, and vacuum drying a filter cake at 50-55 ℃ to constant weight to obtain the crystal form F.
X-ray powder diffraction measurement shows that the obtained crystal form is F, namely the specific peak position of the Mefurapine hydrochloride is shown in the table 3, and the figure 11 is shown.
TABLE 3X-ray powder diffraction (XRPD) data for crystalline form F of cefuroxime hydrochloride
The resulting sample was subjected to other tests to obtain a DSC spectrum, an infrared spectrum, a TG spectrum and a raman spectrum substantially in accordance with fig. 12, 13, 14 and 15.
Example 4
A method of preparing form F:
approximately 25mg of amorphous metformin hydrochloride (1mL) was taken and dimethylsulfoxide (1mL) was added at 25 ℃ until complete dissolution of the starting material, followed by slow dropwise addition of ethanol (6 mL). After the dropwise addition, stirring for 12h at the temperature, filtering, and vacuum drying a filter cake at 50-55 ℃ to constant weight to obtain the crystal form F. The results of X-ray powder diffraction data are shown in Table 3.
Example 5
A method of preparing form F:
the difference from example 4 is that the slowly added solvent is replaced by acetone. The results of X-ray powder diffraction data are shown in Table 3.
Example 6
A method of preparing form F:
in contrast to example 4, the slowly added solvent was replaced by methyl tert-butyl ether. The results of X-ray powder diffraction data are shown in Table 3.
Example 7
A method for preparing form G:
approximately 25mg of amorphous metformin hydrochloride was taken and methanol (1mL) was added at 25 ℃ until the starting material was completely dissolved, followed by slow dropwise addition of tetrahydrofuran (10 mL). After the dropwise addition, stirring for 12h at the temperature, filtering, and vacuum drying the filter cake at 25 ℃ to constant weight to obtain the crystal form G.
X-ray powder diffraction measurement shows that the obtained crystal form G of the Mefurapine hydrochloride has specific peak positions shown in Table 4 and shown in figure 16.
TABLE 4X-ray powder diffraction (XRPD) data for crystalline form G of cefuroxime hydrochloride
The resulting sample was subjected to other tests to obtain a DSC spectrum, an infrared spectrum, a TG spectrum and a raman spectrum substantially in accordance with fig. 17, 18, 19 and 20.
Test examples stability test
50mg of amorphous cefuroxime axetil hydrochloride, the crystal form D obtained in example 1, the crystal form E obtained in example 2, the crystal form F obtained in example 3 and the crystal form G obtained in example 7 are respectively taken, and the amorphous cefuroxime axetil hydrochloride, the crystal form F obtained in example 3 and the crystal form G obtained in example 7 are placed at 25 ℃ for 15 days, and the solid state of each group of samples is measured, so that the diffraction peaks of the crystal forms D, E, F and G are basically unchanged and can be stably stored. While amorphous state is unstable in solid state and crystallization occurs, XRPD (fig. 21) shows distinct diffraction peaks.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (12)
1. A polymorphic substance of cefuroxime axetil hydrochloride shown in a formula I.
2. The polymorph of mefurapine hydrochloride according to claim 1, wherein the polymorph is a form D of mefurapine hydrochloride, is an acetate of mefurapine hydrochloride, and has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 5.354 +/-0.1 degree, 6.466 +/-0.1 degree, 10.298 +/-0.1 degree, 12.101 +/-0.1 degree, 12.947 +/-0.1 degree, 14.286 +/-0.1 degree, 15.232 +/-0.1 degree, 15.950 +/-0.1 degree, 17.859 +/-0.1 degree, 19.642 +/-0.1 degree, 20.705 +/-0.1 degree, 22.209 +/-0.1 degree, 24.379 +/-0.1 degree, 25.097 +/-0.1 degree, 26.059 +/-0.1 degree, 26.982 +/-0.1 degree, 31.999 +/-0.1 degree and 37.248 +/-0.1 degree.
3. The polymorph of mefurapine hydrochloride of claim 2, wherein said form D further has one or more characteristics selected from the group consisting of:
(1) said form D having a DSC profile substantially as shown in figure 2;
(2) said form D having an infra-red spectrum substantially as shown in figure 3;
(3) said form D having a TG profile substantially as shown in figure 4; and
(4) the form D has a raman spectrum substantially as shown in figure 5.
4. The polymorph of mefurapine hydrochloride according to claim 1, wherein the polymorph is a form E of mefurapine hydrochloride, is a1, 4-dioxane compound of mefurapine hydrochloride, and has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 6.49 +/-0.1 degrees, 12.625 +/-0.1 degrees, 15.271 +/-0.1 degrees, 20.727 +/-0.1 degrees, 22.933 +/-0.1 degrees, 23.913 +/-0.1 degrees, 25.139 +/-0.1 degrees, 25.618 +/-0.1 degrees, 26.082 +/-0.1 degrees, 27.084 +/-0.1 degrees, 27.406 +/-0.1 degrees and 28.828 +/-0.1 degrees.
5. The polymorph of mefurapine hydrochloride of claim 4, wherein said form E further has one or more characteristics selected from the group consisting of:
(1) said crystalline form E having a DSC profile substantially as shown in figure 7;
(2) said crystalline form E having an infrared spectrum substantially as shown in figure 8;
(3) said crystalline form E having a TG profile substantially as shown in figure 9; and
(4) the crystalline form E has a raman spectrum substantially as shown in figure 10.
6. The polymorph of mefurapine hydrochloride according to claim 1, wherein the polymorph is a crystalline form F of mefurapine hydrochloride, a dimethyl sulfoxide compound, and has an X-ray powder diffraction pattern comprising 3 or more 2 θ values selected from the group consisting of: 6.266 +/-0.1 degree, 12.686 +/-0.1 degree, 15.532 +/-0.1 degree, 17.035 +/-0.1 degree, 17.675 +/-0.1 degree, 20.045 +/-0.1 degree, 20.727 +/-0.1 degree, 22.449 +/-0.1 degree, 23.114 +/-0.1 degree, 24.897 +/-0.1 degree, 25.536 +/-0.1 degree, 26.242 +/-0.1 degree, 27.166 +/-0.1 degree, 31.352 +/-0.1 degree and 32.033 +/-0.1 degree.
7. The polymorph of mefurapine hydrochloride of claim 6, wherein said crystalline form F further has one or more characteristics selected from the group consisting of:
(1) said crystalline form F having a DSC profile substantially as shown in figure 12;
(2) said crystalline form F having an ir spectrum substantially as shown in figure 13;
(3) said crystalline form F having a TG profile substantially as shown in figure 14; and
(4) the crystalline form F has a raman spectrum substantially as shown in figure 15.
8. The polymorph of mefurapine hydrochloride of claim 1, wherein the polymorph is a crystalline form G of mefurapine hydrochloride, and the X-ray powder diffraction pattern thereof comprises 3 or more than 32 θ values selected from the group consisting of: 6.428 +/-0.1 degree, 8.374 +/-0.1 degree, 10.281 +/-0.1 degree, 12.566 +/-0.1 degree, 15.231 +/-0.1 degree, 15.794 +/-0.1 degree, 18.043 +/-0.1 degree, 19.405 +/-0.1 degree, 20.667 +/-0.1 degree, 22.912 +/-0.1 degree, 23.874 +/-0.1 degree, 25.087 +/-0.1 degree, 26.040 +/-0.1 degree, 29.849 +/-0.1 degree and 232.656 +/-0.1 degree.
9. The polymorph of mefurapine hydrochloride of claim 8, wherein said form G further has one or more characteristics selected from the group consisting of:
(1) said form G having a DSC profile substantially as shown in figure 17;
(2) said crystalline form G having an infra red spectrum substantially as shown in figure 18;
(3) the crystalline form G has a TG profile substantially as shown in figure 19; and
(4) the crystalline form G has a raman spectrum substantially as shown in figure 20.
10. A process for the preparation of the polymorph of mefurapine hydrochloride as claimed in claim 1, characterized in that it comprises the steps of:
(i) dissolving amorphous cefuroxime hydrochloride in acetic acid at 0-80 ℃ to form an acetic acid solution containing cefuroxime hydrochloride;
(ii) slowly returning the acetic acid solution containing the cefuroxime axetil hydrochloride in the step i) to the room temperature, standing, and separating out crystals; and
(iii) separating and drying the precipitated crystal to obtain the crystal form D of the cefuroxime hydrochloride;
or the preparation method comprises the following steps:
(a) dissolving amorphous cefuroxime hydrochloride in a water system at 0-80 ℃ to form an aqueous solution containing cefuroxime hydrochloride;
(b) slowly dripping 1, 4-dioxane into the water solution containing the cefuroxime hydrochloride in the step a), and stirring at room temperature until crystals are separated out; and
(c) separating and drying the precipitated crystal to obtain a crystal form E of the cefuroxime hydrochloride;
or the preparation method comprises the following steps:
(i) dissolving amorphous cefuroxime hydrochloride in dimethyl sulfoxide at 0-80 ℃ to form a dimethyl sulfoxide solution containing cefuroxime hydrochloride;
(ii) dripping an organic solvent into the dimethyl sulfoxide solution containing the cefuroxime hydrochloride in the step i), stirring, standing, and separating out crystals; and
(iii) separating and drying the precipitated crystal to obtain a crystal form F of the cefuroxime hydrochloride;
wherein the organic solvent is selected from one or more of the following organic solvents: ethanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, ethyl acetate, methyl tert-butyl ether, and dichloromethane;
or the preparation method comprises the following steps:
(a) dissolving amorphous cefuroxime hydrochloride in alcohol at 0-80 ℃ to form an alcohol solution containing cefuroxime hydrochloride;
(b) dripping tetrahydrofuran into the alcohol solution containing the cefuroxime hydrochloride in the step a), stirring, standing, and separating out crystals; and
(c) separating and drying the precipitated crystal to obtain a crystal form G of the cefuroxime hydrochloride;
wherein, the alcohol is selected from one or more of the following alcohols: methanol, ethanol, propanol, tert-butanol, octanol, pentanol, hexanol, heptanol, decanol.
11. A pharmaceutical composition comprising a pharmaceutically effective dose of a polymorph of mefurapine hydrochloride according to any one of claims 1 to 9, and a pharmaceutically acceptable excipient or carrier thereof.
12. Use of a polymorph of mefurapine hydrochloride according to any one of claims 1 to 9 or a composition according to claim 11 for the preparation of a medicament for the treatment and/or prevention of diseases associated with polyadenylic acid ribose polymerase PARP.
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| CN102627620A (en) * | 2012-04-10 | 2012-08-08 | 江苏先声药物研究有限公司 | One type of benzofuran derivatives and medical application thereof |
| WO2013117120A1 (en) * | 2012-02-09 | 2013-08-15 | 中国科学院上海药物研究所 | 2-arylbenzofuran-7-formamide compounds, preparation method and use thereof |
| CN109134409A (en) * | 2017-06-14 | 2019-01-04 | 中国科学院上海药物研究所 | Auspicious polymorph of hydrochloric acid U.S. furan piperazine and the preparation method and application thereof |
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| WO2013117120A1 (en) * | 2012-02-09 | 2013-08-15 | 中国科学院上海药物研究所 | 2-arylbenzofuran-7-formamide compounds, preparation method and use thereof |
| CN102627620A (en) * | 2012-04-10 | 2012-08-08 | 江苏先声药物研究有限公司 | One type of benzofuran derivatives and medical application thereof |
| CN109134409A (en) * | 2017-06-14 | 2019-01-04 | 中国科学院上海药物研究所 | Auspicious polymorph of hydrochloric acid U.S. furan piperazine and the preparation method and application thereof |
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