Crystalline nitroxquinoline as well as preparation method and application thereof
Nitroxyquinoline A-type crystals were prepared by anti-solvent method and cooling crystallization method, which solved the gap in the study of nitroxyquinoline crystal forms, and obtained non-hygroscopic and stable crystals, which improved the biological activity and solubility of the drug. , optimized the process and efficacy of drug preparations.
Patent Information
- Application Number
- CN202411311870.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2019-12-27
- Filing Date
- 2020-12-25
- Publication Date
- 2024-12-27
AI Technical Summary
There are currently no research or reports on the crystal form of nitrohydroxyquinoline, which has affected its application in drug research and development and drug quality control, including drug biological activity, stability and solubility, and thus affects the development of drug preparations and Clinical efficacy.
A-type crystals of nihydroxyquinoline were prepared by anti-solvent method and cooling crystallization method. X-ray powder diffraction and DVS detection were used to obtain nihydroxyquinoline crystals with no hygroscopicity and good stability. The characteristic peaks were located at specific 2θ. At the diffraction angle, it was dried to improve yield and particle size.
The crystal preparation of nitrohydroxyquinoline is achieved, its stability and bioavailability are improved, the bioactivity and solubility of the drug are enhanced, and the drug preparation process and clinical efficacy are optimized.
Smart Images
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Abstract
Description
[0001] This application is a divisional application of the Chinese patent application with application number 202011559101.4, application date December 25, 2020, and invention name “Crystalline Nitroquinoline, Preparation Method and Use thereof”. Technical Field
[0002] The invention relates to crystalline nitroquinoline and a preparation method and application thereof. Background Art
[0003] Nitroxoline, chemically known as 5-nitro-8-hydroxyquinoline, was developed as an oral antibiotic in the 1960s, mainly for urinary tract infections. It has a relatively safe history of use, but was later replaced by the discovery and use of new antibiotics. In recent years, new studies have found that nitroxoline can simultaneously inhibit methionine aminopeptidase MetAP2 and silent information regulator 2-related enzyme SIRT1 in vascular endothelial cells, exerting a synergistic inhibitory effect on tumor angiogenesis, while also inhibiting the proliferation of tumor cells. Therefore, nitroxoline has been redeveloped for the treatment of tumors including bladder cancer.
[0004] Drug polymorphism has become an essential and important part of drug development and drug quality control. The study of drug polymorphism is helpful for the selection of drug compound biological activity, and helps to increase the stability, solubility and other properties of drugs, which is beneficial to the development of drug preparations and drug storage, improves the quality of drug production, etc., and can also improve the bioavailability of compounds and enhance clinical efficacy.
[0005] At present, there is no research and report on the crystal form of nitroquinoline. Summary of the invention
[0006] The technical problem to be solved by the present invention is to provide a crystalline nitroxanol and a preparation method and use thereof. The inventor has discovered a preparation method capable of preparing nitroxanol crystals after a large number of experimental studies, and has conducted X-ray powder diffraction and DVS detection on the obtained crystals, and unexpectedly discovered non-hygroscopic and stable nitroxanol crystals.
[0007] The present invention solves the above technical problems through the following technical solutions:
[0008] The invention provides a type A crystal of nitroquinoline, wherein an X-ray powder diffraction spectrum of the crystal comprises characteristic peaks at 2θ diffraction angles of 11.3°±0.2°, 12.9°±0.2°, 16.9°±0.2°, 19.7°±0.2°, 22.1°±0.2°, 23.7°±0.2°, 24.2°±0.2°, 25.9°±0.2°, 27.1°±0.2° and 28.0°±0.2°.
[0009] The present invention also provides a type A crystal of nitroquinoline, wherein the X-ray powder diffraction spectrum comprises characteristic peaks at 2θ diffraction angles of 11.3°±0.2°, 12.9°±0.2°, 16.9°±0.2°, 18.1°±0.2°, 19.7°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 22.8°±0.2°, 23.7°±0.2°, 24.2°±0.2°, 25.9°±0.2°, 27.1°±0.2°, 28.0°±0.2°, 29.4°±0.2° and 29.9°±0.2°.
[0010] The present invention also provides a type A crystal of nitroquinoline, whose X-ray powder diffraction pattern is as follows: Figure 1 shown.
[0011] The present invention also provides a method for preparing the aforementioned type A crystal of nitroquinoline (also known as an anti-solvent method), which comprises the following steps: a solution I containing nitroquinoline and an organic solvent is contacted with an anti-solvent, crystallized, and solid-liquid separated to obtain the type A crystal.
[0012] In some preferred embodiments, the solution I consists of nitroquinoline and an organic solvent.
[0013] In some preferred embodiments, the organic solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, C1-C4 fatty acids, C3-C6 fatty ketones and C1-C4 fatty alcohols, preferably one or more of dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, acetic acid, acetone and methanol, more preferably one or more of dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidone, and further more preferably dimethyl sulfoxide.
[0014] In some preferred embodiments, the mass volume ratio of the nitroquinoline to the organic solvent is 5:1 to 100:1, such as 50:0.6, and the unit is mg / mL.
[0015] In some preferred embodiments, the anti-solvent is water.
[0016] In some preferred embodiments, the volume ratio of the organic solvent to the anti-solvent is 1:6 to 1:2, such as 1:3, 1:4 or 1:5.
[0017] In some preferred embodiments, the solid-liquid separation is centrifugal separation. The rotation speed of the centrifugal separation is preferably 3500-4500 r / min, such as 4000 r / min. The time of the centrifugal separation is preferably 4-6 min, such as 5 min.
[0018] In some preferred embodiments, the solid-liquid separation is followed by drying, wherein the drying temperature is preferably 30-50°C, such as 40°C.
[0019] In some preferred embodiments, the organic solvent is dimethyl sulfoxide, the anti-solvent is water, and the volume ratio of dimethyl sulfoxide to water is 1:4; or,
[0020] The organic solvent is N,N-dimethylformamide, the anti-solvent is water, and the volume ratio of N,N-dimethylformamide to water is 1:6; or,
[0021] The organic solvent is N-methylpyrrolidone, the anti-solvent is water, and the volume ratio of N-methylpyrrolidone to water is 1:3; or,
[0022] The organic solvent is acetic acid, the anti-solvent is water, and the volume ratio of acetic acid to water is 1:2; or,
[0023] The organic solvent is acetone, the anti-solvent is water, and the volume ratio of acetone to water is 1:5; or,
[0024] The organic solvent is methanol, the anti-solvent is water, and the volume ratio of methanol to water is 1:5.
[0025] The present invention also provides a method for preparing the aforementioned type A crystal of nitroquinoline (also known as an anti-solvent method), which comprises the following steps:
[0026] (1) dissolving nitroquinoline in an organic solvent at room temperature to obtain a clear solution;
[0027] (2) gradually adding an anti-solvent to the clear solution obtained in step (1) to crystallize and obtain crystals;
[0028] (3) Drying the crystals obtained in step (2) to obtain type A crystals of nitroquinoline.
[0029] In some preferred embodiments, in step (1), the organic solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, C1-C4 fatty acids, C3-C6 fatty ketones and C1-C4 fatty alcohols, preferably one or more of dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, acetic acid, acetone and methanol, more preferably one or more of dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidone, and even more preferably dimethyl sulfoxide.
[0030] In some preferred embodiments, in step (1), the mass volume ratio of the nitroquinoline to the organic solvent is 5:1 to 100:1, for example 50:0.6, in units of mg / mL.
[0031] In some preferred embodiments, in step (2), the anti-solvent is water.
[0032] In some preferred embodiments, the volume ratio of the organic solvent in step (1) to the anti-solvent in step (2) is 1:6 to 1:2, for example 1:4.
[0033] In some preferred embodiments, in step (2), the crystallization is followed by solid-liquid separation to obtain the crystals. The solid-liquid separation is preferably centrifugal separation. The speed of the centrifugal separation is preferably 3500-4500 r / min, such as 4000 r / min. The time of the centrifugal separation is preferably 4-6 min, such as 5 min.
[0034] In some preferred embodiments, in step (3), the drying temperature is 30-50°C, for example 40°C.
[0035] In some preferred embodiments, the organic solvent in step (1) is dimethyl sulfoxide, the anti-solvent in step (2) is water, and the volume ratio of dimethyl sulfoxide to water is 1:4; or,
[0036] The organic solvent in step (1) is N,N-dimethylformamide, the anti-solvent in step (2) is water, and the volume ratio of N,N-dimethylformamide to water is 1:6; or,
[0037] The organic solvent in step (1) is N-methylpyrrolidone, the anti-solvent in step (2) is water, and the volume ratio of N-methylpyrrolidone to water is 1:3; or,
[0038] The organic solvent in step (1) is acetic acid, the anti-solvent in step (2) is water, and the volume ratio of acetic acid to water is 1:2; or,
[0039] The organic solvent in step (1) is acetone, the anti-solvent in step (2) is water, and the volume ratio of acetone to water is 1:5; or,
[0040] The organic solvent in step (1) is methanol, the anti-solvent in step (2) is water, and the volume ratio of methanol to water is 1:5.
[0041] In particular, the type A crystals of nitroquinoline prepared by the anti-solvent method have a higher yield and a finer particle size.
[0042] The present invention also provides a method for crystallizing the aforementioned type A of nitroquinoline (also known as a cooling crystallization method), which comprises the following steps: cooling a solution II containing nitroquinoline and an organic solvent, crystallizing under mixing, and separating the solid from the liquid to obtain the type A crystal.
[0043] In some preferred embodiments, the solution II consists of nitroquinoline and an organic solvent.
[0044] In some preferred embodiments, the organic solvent is selected from one or more of methanol, acetonitrile, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether and toluene.
[0045] In some preferred embodiments, the mass volume ratio of the nitroquinoline to the organic solvent is 10:3 to 25:1, and the unit is mg / mL.
[0046] In some preferred embodiments, the terminal temperature of the cooling is from room temperature to -20°C.
[0047] In some preferred embodiments, the mixing is stirring.
[0048] In some preferred embodiments, the mixing time is 0.4-0.6 h, such as 0.5 h.
[0049] In some preferred embodiments, the solid-liquid separation is centrifugal separation. The rotation speed of the centrifugal separation is preferably 3500-4500 r / min, such as 4000 r / min. The time of the centrifugal separation is preferably 4-6 min, such as 5 min.
[0050] In some preferred embodiments, the solid-liquid separation is followed by drying, wherein the drying temperature is preferably 30-50°C, such as 40°C.
[0051] The present invention also provides a method for the aforementioned A-type crystallization of nitroquinoline (also known as a cooling crystallization method), which comprises the following steps:
[0052] (1) dissolving nitroquinoline in an organic solvent under heating, preferably at 50-60° C., to obtain a clear solution;
[0053] (2) cooling the clear solution obtained in step (1), preferably to -20°C to room temperature, and crystallizing under stirring to obtain crystals;
[0054] (3) Drying the crystals obtained in step (2) to obtain type A crystals of nitroquinoline.
[0055] In some preferred embodiments, according to the method for preparing type A crystals of nitroquinoline of the present invention, the organic solvent in step (1) is selected from one or more of C1-C4 fatty alcohol, acetonitrile, acetone, ethyl acetate, methyl tert-butyl ether and toluene, preferably C1-C4 fatty alcohol.
[0056] In some preferred embodiments, in step (1), the mass volume ratio of nitroquinoline to the organic solvent is 1:40-300, expressed in g / mL.
[0057] The present invention also provides a pharmaceutical composition, which comprises the aforementioned nitroquinoline type A crystal and a pharmaceutically acceptable carrier.
[0058] The present invention also provides use of the aforementioned nitroquinoline type A crystal or the aforementioned pharmaceutical composition in preparing a drug for treating cancer.
[0059] In the above use, the cancer is, for example, bladder cancer.
[0060] The "normal temperature" mentioned herein refers to 10-30°C.
[0061] The "C1-C4 fatty acid" described herein refers to an aliphatic hydrocarbon chain containing a carboxyl group at one end, which has 1-4 carbon atoms. Examples of C1-C4 fatty acids include, but are not limited to, formic acid, acetic acid, propionic acid and butyric acid.
[0062] The "C3-C6 fatty ketone" described herein refers to a compound formed by a carbonyl group connected to two aliphatic hydrocarbon groups, which has 3-6 carbon atoms. Examples of C3-C6 fatty ketones include, but are not limited to, acetone, butanone, pentanone and hexanone.
[0063] The "C1-C4 fatty alcohol" described herein refers to a compound formed by connecting a hydroxyl group to an aliphatic hydrocarbon group, which has 1 to 4 carbon atoms. Examples of C1-C4 fatty alcohols include, but are not limited to, methanol, ethanol, propanol, and butanol.
[0064] The term "pharmaceutically acceptable" means that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, biologically satisfactory and acceptable for veterinary or human pharmaceutical use.
[0065] As used herein, "carrier" refers to a diluent, adjuvant or excipient that is administered with the compound. Pharmaceutically acceptable carriers can be liquids, such as water and oils, including oils of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, rapeseed oil. Pharmaceutically acceptable carriers can also be saline, gum arabic, gelatin, starch paste, talc, keratin, silica gel, urea. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants can also be used.
[0066] Those skilled in the art will appreciate that the pharmaceutical composition of the present invention can be prepared into various preparation forms well known in the art according to the specific mode of administration, such as oral dosage forms (powders, tablets, capsules, soft capsules, liquid medicines, syrups, elixirs, powders, capsules, granules), or topical preparations (creams, ointments, lotions, gels, balms, plasters, pastes, sprays, aerosols, etc.), or injection preparations (solutions, suspensions, emulsions). The pharmaceutical composition of the present invention can especially be mentioned as those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, such as tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, skin gels, injectable preparations, drinkable suspensions.
[0067] The pharmaceutical composition of the present invention may include pharmaceutically acceptable carriers, adjuvants or diluents, such as fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, and bases. Among them, fillers may be, for example, starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, and sucrose; disintegrants may be, for example, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinyl pyrrole, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose; lubricants may be, for example, magnesium stearate, sodium lauryl sulfate, talc, and silicon dioxide; suspending agents may be, for example, polyvinyl pyrrolidone, microcrystalline cellulose, sucrose, agar, and hydroxypropyl methylcellulose; binders may be, for example, starch slurry, polyvinyl pyrrolidone, and hydroxypropyl methylcellulose. The composition of the present invention may be prepared by any known method in the art so that the active ingredient can be provided to the patient for rapid, sustained, or slow release after administration.
[0068] The pharmaceutical compositions of the present invention are administered to individual animals such as mammals (rats, mice, domesticated animals or humans) by various routes, all of which are conventional, for example, oral administration, topical administration, rectal administration, or intravenous, intramuscular, transdermal, intrathecal, epidural or intraventricular injection.
[0069] The dosage of the active ingredient of the present invention can be different according to the individual's condition and weight, the nature and severity of the disease, the drug form, the route of administration and the administration cycle, and it can also be selected by those skilled in the art based on animal experiments or clinical trials. The dosage of the active ingredient of the present invention can be changed between 1-100 mg / day, and can also be changed between 10-1000 mg / day, and can be administered once a day or multiple times a day.
[0070] The type A crystal of nitroquinoline of the present invention is non-hygroscopic and has good stability, which is helpful for the selection of administration routes and the optimization of drug preparation processes, thereby improving the production quality of drugs and improving the effects of drugs. BRIEF DESCRIPTION OF THE DRAWINGS
[0071] Figure 1 The X-ray powder diffraction (XRPD) pattern of the nitroquinoline type A crystal of the present invention;
[0072] Figure 2 The thermogravimetric analysis (TGA) spectrum of the nitroquinoline type A crystal of the present invention;
[0073] Figure 3 is a differential scanning calorimetry (DSC) spectrum of the nitroquinoline type A crystal of the present invention;
[0074] Figure 4 The figure is the dynamic water adsorption (DVS) spectrum of the nitroquinoline type A crystal of the present invention. DETAILED DESCRIPTION
[0075] The present invention will be described in more detail below in conjunction with embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and are not intended to limit the essence and scope of the present invention.
[0076] 1. Experimental instruments
[0077] 1. X-ray powder diffraction (XRPD)
[0078] Instrument model: Shimadzu XRD-6000
[0079] Radiation: Cu-Kα target
[0080] Voltage: 40kV, Current: 30mA
[0081] Scanning speed: 5° / min
[0082] Scanning range: 5°-50°(2θ)
[0083] 2. Thermogravimetric analysis (TGA)
[0084] Instrument model: PerkinElmer Pyris 1TGA
[0085] Purge gas: Nitrogen
[0086] Heating rate: 20℃ / min
[0087] Temperature range: 30℃-250℃
[0088] 3. Differential Scanning Calorimeter (DSC)
[0089] Instrument model: Mettler ToledoDSC3
[0090] Purge gas: Nitrogen
[0091] Heating rate: 20℃ / min
[0092] Temperature range: 30℃-300℃
[0093] 4. Dynamic moisture sorption (DVS)
[0094] Instrument model: SMSDVS intrinsic
[0095] Test temperature: 25℃
[0096] Equilibrium time: dm / dt: 0.01% / min;
[0097] Relative humidity range: 0%-95%-0%
[0098] RH(%) test humidity change per step: 5%
[0099] 2. Experimental reagents:
[0100] Nitroquinoline It is synthesized from the starting material 8-hydroxyquinoline by two steps of nitrosation and oxidation. The preparation method refers to "Research on Directed Nitration of 8-Hydroxyquinoline", Journal of Huaiyin Normal University, Vol. 4, No. 1, February 2005.
[0101] Example 1 Preparation Example 1 of Type A Crystal of Nitroxyquinoline
[0102] Weigh 50 mg of nitroquinoline, gradually add methanol (6 mL) at 50°C until nitroquinoline is completely dissolved into a clear solution. Then, cool the solution to room temperature, stir for 0.5 h, centrifuge (Eppendorf Centrifuge 5415, 4000 r / min, 5 min) to separate and collect the wet solid, and dry it under reduced pressure at 40°C to obtain about 40 mg of a yellow long needle-shaped solid, with a yield of 80%.
[0103] The X-ray powder diffraction pattern of the obtained solid is shown in Figure 1 , X-ray powder diffraction data are shown in Table 1 below, and it is defined as type A crystal.
[0104] Table 1 XRPD peaks and intensities of Form A
[0105] Peak 2θ(position) d(A)(spacing) strength Relative strength (I%) 1 11.3 7.8 747 24.8 2 12.9 6.8 3014 100.0 3 16.9 5.2 502 16.7 4 18.1 4.9 168 5.6 5 19.7 4.5 245 8.1 6 21.2 4.2 201 6.7 7 22.1 4.0 389 12.9 8 22.8 3.9 102 3.4 9 23.7 3.8 466 15.5 10 24.2 3.7 1364 45.3 11 25.9 3.4 1085 36.0 12 27.1 3.3 999 33.1 13 28.0 3.2 1521 50.5 14 29.4 3.0 207 6.9 15 29.9 3.0 137 4.5 16 30.7 2.9 62 2.1 17 31.5 2.8 83 2.8 18 32.3 2.8 122 4.0 19 32.8 2.7 210 7.0 20 33.9 2.6 146 4.8 21 34.3 2.6 137 4.5 22 35.9 2.5 33 1.1 23 38.5 2.3 100 3.3 24 39.5 2.3 92 3.1 25 40.1 2.2 220 7.3 26 41.1 2.2 69 2.3 27 42.3 2.1 57 1.9 28 43.3 2.1 174 5.8 29 43.8 2.1 59 2.0 30 45.1 2.0 44 1.5 31 47.8 1.9 39 1.3
[0106] Weigh about 5 mg of the crystalline sample into a crucible, protect with nitrogen, heat from 30°C to 250°C, heating rate is 20°C / min, keep at 250°C for 1 minute. Its TGA spectrum is shown in Figure 2 , which shows that the crystal form has no weight loss from room temperature to 120°C, but sublimates afterwards.
[0107] Weigh about 5 mg of powder sample and place it in a closed aluminum crucible with a pinhole on the crucible cover. Under nitrogen protection, heat from 30°C to 300°C for differential thermal scanning, and keep at 300°C for 1 minute. The heating rate is 20°C / min. The DSC spectrum is shown in Figure 3 , which shows an obvious endothermic peak at 180.82 °C.
[0108] Example 2 Preparation Example 2 of Type A Crystal of Nitroxyquinoline
[0109] Weigh 50 mg of nitroquinoline, gradually add acetonitrile (2.5 mL) at 60°C until nitroquinoline is completely dissolved into a clear solution. Then, cool the solution to -20°C, stir for 0.5 h, centrifuge (Eppendorf Centrifuge 5415, 4000 r / min, 5 min) to separate and collect the wet solid, and dry it under reduced pressure at 40°C to obtain about 35 mg of a yellow long needle-shaped solid, with a yield of 70%.
[0110] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0111] Example 3 Preparation Example 3 of Type A Crystal of Nitroxanol
[0112] Weigh 50 mg of nitroquinoline, gradually add isopropanol (15 mL) at 55°C until nitroquinoline is completely dissolved into a clear solution. Then, cool the solution to -20°C, stir for 0.5 h, centrifuge (Eppendorf Centrifuge 5415, 4000 r / min, 5 min) to separate and collect the wet solid, and dry it under reduced pressure at 40°C to obtain about 35 mg of a yellow solid, with a yield of 70%.
[0113] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0114] Example 4 Preparation Example 4 of Type A Crystal of Nitroxyquinoline
[0115] Weigh 50 mg of nitroquinoline, gradually add ethyl acetate (2.5 mL) at 60°C until nitroquinoline is completely dissolved into a clear solution. Then, cool the solution to -10°C, stir for 0.5 h, centrifuge (Eppendorf Centrifuge 5415, 4000 r / min, 5 min) to separate and collect the wet solid, and dry under reduced pressure at 40°C to obtain about 40 mg of yellow-green long needle-shaped solid, with a yield of 80%.
[0116] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0117] Example 5 Preparation Example 5 of Type A Crystal of Nitroxyquinoline
[0118] Weigh 50 mg of nitroquinoline, gradually add acetone (2 mL) at 60°C until nitroquinoline is completely dissolved into a clear solution. Then, cool the solution to -20°C, stir for 0.5 h, centrifuge (Eppendorf Centrifuge 5415, 4000 r / min, 5 min) to separate and collect the wet solid, and dry it under reduced pressure at 40°C to obtain about 40 mg of a yellow long needle-shaped solid, with a yield of 80%.
[0119] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0120] Example 6 Preparation Example 6 of Type A Crystal of Nitroxyquinoline
[0121] Weigh 50 mg of nitroquinoline, gradually add methyl tert-butyl ether (10 mL) at 50°C until nitroquinoline is completely dissolved into a clear solution. Then, cool the solution to room temperature, stir for 0.5 h, centrifuge (Eppendorf Centrifuge 5415, 4000 r / min, 5 min) to separate and collect the wet solid, and dry it under reduced pressure at 40°C to obtain about 40 mg of a yellow flocculent solid, with a yield of 80%.
[0122] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0123] Example 7 Preparation Example 7 of Type A Crystal of Nitroxanol
[0124] Weigh 50 mg of nitroquinoline, gradually add toluene (4 mL) at 55°C until nitroquinoline is completely dissolved into a clear solution. Then, cool the solution to -20°C, stir for 0.5 h, centrifuge (Eppendorf Centrifuge 5415, 4000 r / min, 5 min) to separate and collect the wet solid, and dry it under reduced pressure at 40°C to obtain about 40 mg of a yellow long needle-shaped solid, with a yield of 80%.
[0125] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0126] Example 8 Preparation Example 8 of Type A Crystal of Nitroxyquinoline
[0127] Weigh 50 mg of nitrohydroxyquinoline, add dimethyl sulfoxide (0.6 mL) at room temperature to completely dissolve it until it is clear, then gradually add water (2.4 mL) to precipitate the solid, centrifuge and collect the wet solid, and dry it under reduced pressure at 40°C to obtain about 45 mg of yellow fine needle-like solid, with a yield of 90%.
[0128] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0129] Example 9 Preparation Example 9 of Type A Crystal of Nitroxanol
[0130] Weigh 50 mg of nitrohydroxyquinoline, add N,N-dimethylformamide (0.6 mL) at room temperature to completely dissolve it until it is clear, then gradually add water (3.6 mL) to precipitate the solid, centrifuge and collect the wet solid, and dry it under reduced pressure at 40°C to obtain about 45 mg of yellow fine needle-shaped solid, with a yield of 90%.
[0131] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0132] Example 10 Preparation Example 10 of Type A Crystal of Nitroxanol
[0133] Weigh 50 mg of nitroquinoline, add N-methylpyrrolidone (0.5 mL) at room temperature to completely dissolve it until it is clear, then gradually add water (1.5 mL) to precipitate the solid, centrifuge and collect the wet solid, and dry it under reduced pressure at 40°C to obtain about 45 mg of yellow fine needle-like solid, with a yield of 90%.
[0134] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0135] Example 11 Preparation of Type A Crystals of Nitroxanol
[0136] Weigh 50 mg of nitrohydroxyquinoline, add acetic acid (5 mL) at room temperature to completely dissolve it until it is clear, then gradually add water (10 mL) to precipitate the solid, centrifuge and collect the wet solid, and dry it in a vacuum at 40°C to obtain about 45 mg of a yellow fine needle-like solid, with a yield of 90%.
[0137] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0138] Example 12 Preparation Example 12 of Type A Crystal of Nitroxyquinoline
[0139] Weigh 50 mg of nitrohydroxyquinoline, add acetone (4 mL) at room temperature to completely dissolve it until it is clear, then gradually add water (20 mL) to precipitate the solid, centrifuge and collect the wet solid, and dry it in a vacuum at 40°C to obtain about 45 mg of a yellow fine needle-like solid, with a yield of 90%.
[0140] The XRPD spectrum was compared and the product was determined to be type A crystal.
[0141] Example 13 Preparation of Type A Crystals of Nitroxanol
[0142] Weigh 50 mg of nitroquinoline, add methanol (10 mL) at room temperature to completely dissolve it until it is clear, then gradually add water (50 mL) to precipitate the solid, centrifuge and collect the wet solid, and dry it in a vacuum at 40°C to obtain about 45 mg of a yellow fine needle-like solid.
[0143] The XRPD spectrum was compared and the product was determined to be type A crystal with a yield of 90%.
[0144] Test Example 1 Hygroscopicity test of nitroquinoline type A crystals of the present invention
[0145] Weigh 1-5 mg of the nitroquinoline type A crystals obtained in Example 8, place in a dynamic moisture adsorption instrument, and directly measure. Set the instrument parameters, sample test temperature: T = 25 ° C, equilibrium time: dm / dt: 0.01% / min, relative humidity change range: 0%-95%-0%; RH (%) test humidity change per step: 5%.
[0146] The evaluation criteria for hygroscopicity are shown in Table 2 below.
[0147] Table 2 Hygroscopicity classification
[0148] Hygroscopicity classification <![CDATA[Water Absorption Standard * > Deliquescent Absorb enough water to become liquid Very hygroscopic W％≥15％ Hygroscopic W％≥2％ Slightly hygroscopic W％≥0.2％ Non-hygroscopic W％<0.2％
[0149] *At 25±1℃ and 80±2%RH (European Pharmacopoeia 6.0)
[0150] The DVS test results of the A-type crystals of Example 8 are as follows: Figure 4 As shown, the moisture adsorption value W% is less than 0.2%, indicating that the type A crystal of the present invention is non-hygroscopic and has good stability.
[0151] Test Example 2 Stability test of nitroquinoline type A crystal of the present invention
[0152] The nitroquinoline type A crystals obtained in Example 8 were weighed and placed under light (4500±500Lux), high temperature (60°C), and high humidity (RH90%±5%) conditions for 5 days and 10 days, and X-ray powder diffraction (XRPD) detection was performed to examine whether the crystal form changed.
[0153] The test results of factors affecting crystal stability are shown in Table 3 below.
[0154] Table 3 Test results of factors affecting crystal stability
[0155]
[0156] The A-type crystal form of the present invention has no change in crystal form after being subjected to light, high temperature and high humidity for 10 days, and has good stability.
[0157] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.
Claims
1. A method for preparing type A crystals of nitroquinoline, comprising the following steps: cooling a solution II containing nitroquinoline and an organic solvent, crystallizing under mixing, and separating the solid from the liquid to obtain the crystals; The X-ray powder diffraction pattern of the type A crystal of nitroquinoline includes characteristic peaks at 2θ diffraction angles of 11.3°±0.2°, 12.9°±0.2°, 16.9°±0.2°, 19.7°±0.2°, 22.1°±0.2°, 23.7°±0.2°, 24.2°±0.2°, 25.9°±0.2°, 27.1°±0.2° and 28.0°±0.2°.
2. The method for preparing type A crystal of nitroquinoline according to claim 1, wherein: The solution II consists of nitroquinoline and an organic solvent; and / or, the organic solvent is selected from one or more of methanol, acetonitrile, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether and toluene; And / or, the mass volume ratio of the nitroquinoline to the organic solvent is 10:3 to 25:1, in units of mg / mL; And / or, the end point temperature of the cooling is from room temperature to -20°C; And / or, the mixing is stirring; And / or, the mixing time is 0.4-0.6h; And / or, the solid-liquid separation is centrifugal separation; And / or, the solid-liquid separation further includes drying.
3. The method for preparing type A crystals of nitroquinoline according to claim 2, wherein the mixing time is 0.5 h.
4. The method for preparing type A crystals of nitroquinoline according to claim 2, wherein the rotation speed of the centrifugal separation is 3500-4500 r / min, and the time of the centrifugal separation is 4-6 min.
5. The method for preparing type A crystals of nitroquinoline according to claim 2, wherein the rotation speed of the centrifugal separation is 4000 r / min, and the time of the centrifugal separation is 5 min.
6. The method for preparing type A crystals of nitroquinoline according to claim 2, wherein the drying temperature is 30-50°C.
7. The method for preparing type A crystals of nitroquinoline according to claim 2, wherein the drying temperature is 40°C.
8. The method for preparing type A crystals of nitroquinoline according to claim 1, wherein the X-ray powder diffraction pattern of type A crystals of nitroquinoline comprises characteristic peaks at 2θ diffraction angles of 11.3°±0.2°, 12.9°±0.2°, 16.9°±0.2°, 18.1°±0.2°, 19.7°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 22.8°±0.2°, 23.7°±0.2°, 24.2°±0.2°, 25.9°±0.2°, 27.1°±0.2°, 28.0°±0.2°, 29.4°±0.2° and 29.9°±0.2°.
9. The method for preparing type A crystals of nitroquinoline according to claim 1, wherein the X-ray powder diffraction pattern of type A crystals of nitroquinoline is as shown in FIG1.
10. The method for preparing type A crystal of nitroquinoline according to claim 1, comprising the following steps: 1) dissolving nitroquinoline in an organic solvent under heating to obtain a clear solution; 2) cooling the clarified solution obtained in step 1), and crystallizing the solution under stirring to obtain crystals; 3) Drying the crystals obtained in step 2) to obtain type A crystals of nitroquinoline.
11. The method for preparing type A crystal of nitroquinoline according to claim 10, comprising the following steps: 1) dissolving nitroquinoline in an organic solvent at 50-60° C. to obtain a clear solution; 2) cooling the clear solution obtained in step 1) to -20°C to room temperature, and crystallizing under stirring to obtain crystals; 3) Drying the crystals obtained in step 2) to obtain type A crystals of nitroquinoline.