CN113045490A - Crystal nitroxoline and preparation method and application thereof - Google Patents

Crystal nitroxoline and preparation method and application thereof Download PDF

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CN113045490A
CN113045490A CN202011559101.4A CN202011559101A CN113045490A CN 113045490 A CN113045490 A CN 113045490A CN 202011559101 A CN202011559101 A CN 202011559101A CN 113045490 A CN113045490 A CN 113045490A
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nitroxoline
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water
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刘江华
郭玉申
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Shanghai Yahong Pharmaceutical Technology Co ltd
Jiangsu Yahong Pharmaceutical Technology Co ltd
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Jiangsu Yahong Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Abstract

The invention discloses a crystalline nitroxoline and a preparation method and application thereof. The X-ray powder diffraction pattern of the crystalline nitroxoline comprises characteristic peaks at 2 theta diffraction angles of 11.3 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 16.9 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees, 22.1 degrees +/-0.2 degrees, 23.7 degrees +/-0.2 degrees, 24.2 degrees +/-0.2 degrees, 25.9 degrees +/-0.2 degrees, 27.1 degrees +/-0.2 degrees and 28.0 degrees +/-0.2 degrees. The crystal nitroxoline has no hygroscopicity and good stability, and is further beneficial to selection of administration routes and optimization of pharmaceutical preparation processes, so that the production quality of the medicine is improved, and the effect of the medicine is improved.

Description

Crystal nitroxoline and preparation method and application thereof
Technical Field
The invention relates to a crystal type nitroxoline and a preparation method and application thereof.
Background
Nitroxoline (Nitroxoline), chemically known as 5-nitro-8-hydroxyquinoline, was developed in the sixties as an oral antibiotic drug, primarily for urinary infections, with a safer history of use, and was later replaced by the discovery and use of new antibiotics. In recent years, new researches show that the nitroxoline can simultaneously inhibit methionine aminopeptidase MetAP2 and a sirtuin 2-related enzyme SIRT1 in vascular endothelial cells, play a synergistic inhibition effect on tumor angiogenesis, and simultaneously have an inhibition effect on the proliferation of tumor cells. Thus, nitroxoline has been newly developed for the treatment of tumors including bladder cancer.
Polymorphism of drugs has become an essential and important component in drug development and drug quality control. The research on the polymorphism of the medicine is helpful for the selection of the biological activity of the medicine compound, and is helpful for improving the properties of the medicine such as stability, solubility and the like, thereby being beneficial to the development of the medicine preparation and the storage of the medicine, improving the production quality of the medicine and the like, improving the bioavailability of the compound, and enhancing the clinical curative effect.
At present, no research and report about the crystal form of nitroxoline exists.
Disclosure of Invention
The invention aims to solve the technical problem of providing a crystalline nitroxoline and a preparation method and application thereof. The inventors of the present invention have found, through a large number of experimental studies, a preparation method capable of producing a nitroxoline crystal, and have carried out X-ray powder diffraction and DVS detection on the obtained crystal, and as a result, have unexpectedly found a nitroxoline crystal which is free from hygroscopicity and has good stability.
The invention solves the technical problems through the following technical scheme:
the invention provides a crystal form A of nitroxoline, the X-ray powder diffraction pattern of which comprises characteristic peaks at 2 theta diffraction angles of 11.3 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 16.9 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees, 22.1 degrees +/-0.2 degrees, 23.7 degrees +/-0.2 degrees, 24.2 degrees +/-0.2 degrees, 25.9 degrees +/-0.2 degrees, 27.1 degrees +/-0.2 degrees and 28.0 degrees +/-0.2 degrees.
The invention also provides a crystal of nitroxoline A type, and the X-ray powder diffraction pattern of the crystal comprises characteristic peaks at 2 theta diffraction angles of 11.3 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 16.9 degrees +/-0.2 degrees, 18.1 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees, 21.2 degrees +/-0.2 degrees, 22.1 degrees +/-0.2 degrees, 22.8 degrees +/-0.2 degrees, 23.7 degrees +/-0.2 degrees, 24.2 degrees +/-0.2 degrees, 25.9 degrees +/-0.2 degrees, 27.1 degrees +/-0.2 degrees, 28.0 degrees +/-0.2 degrees, 29.4 degrees +/-0.2 degrees and 29.9 degrees +/-0.2 degrees.
The invention also provides an A-type crystal of nitroxoline, and the X-ray powder diffraction pattern of the A-type crystal is shown in figure 1.
The invention also provides a preparation method (also called an anti-solvent method) of the A-type crystal of nitroxoline, which comprises the following steps: and (3) contacting the solution I containing the nitroxoline and the organic solvent with an anti-solvent, crystallizing, and carrying out solid-liquid separation to obtain the nitroxoline.
In some preferred embodiments, the solution I consists of nitroxoline and an organic solvent.
In some preferred embodiments, the organic solvent is selected from one or more of dimethyl sulfoxide, 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-dimethylformamide, N-methylpyrrolidone, acetic acid, acetone, and methanol, more preferably one or more of dimethyl sulfoxide, N-dimethylformamide, and N-methylpyrrolidone, and even more preferably dimethyl sulfoxide.
In some preferred embodiments, the mass to volume ratio of the nitroxoline to the organic solvent is from 5:1 to 100:1, e.g. 50:0.6, in mg/mL.
In some preferred embodiments, the anti-solvent is water.
In some preferred embodiments, the volume ratio of the organic solvent to the anti-solvent is from 1:6 to 1:2, such as 1:3, 1:4, or 1: 5.
In some preferred embodiments, the solid-liquid separation is centrifugal separation. The rotational speed of the centrifugal separation is preferably 3500-. The time for the centrifugation is preferably 4-6min, e.g. 5 min.
In some preferred embodiments, the solid-liquid separation further comprises drying. The temperature of the drying is preferably 30 to 50 c, for example 40 c.
In some preferred embodiments, the organic solvent is dimethylsulfoxide, the antisolvent is water, and the volume ratio of dimethylsulfoxide to water is 1: 4; or,
the organic solvent is N, N-dimethylformamide, the anti-solvent is water, and the volume ratio of the N, N-dimethylformamide to the water is 1: 6; or,
the organic solvent is N-methyl pyrrolidone, the anti-solvent is water, and the volume ratio of the N-methyl pyrrolidone to the water is 1: 3; or,
the organic solvent is acetic acid, the anti-solvent is water, and the volume ratio of the acetic acid to the water is 1: 2; or,
the organic solvent is acetone, the anti-solvent is water, and the volume ratio of the acetone to the water is 1: 5; or,
the organic solvent is methanol, the anti-solvent is water, and the volume ratio of the methanol to the water is 1: 5.
The invention also provides a preparation method (also called an anti-solvent method) of the A-type crystal of nitroxoline, which comprises the following steps:
(1) dissolving nitroxoline in an organic solvent at room temperature to obtain a clear solution;
(2) gradually adding an anti-solvent into the clear solution obtained in the step (1), and crystallizing to obtain crystals;
(3) and (3) drying the crystal obtained in the step (2) to obtain the A-type crystal of the nitroxoline.
In some preferred embodiments, in step (1), the organic solvent is selected from one or more of dimethyl sulfoxide, 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-dimethylformamide, N-methylpyrrolidone, acetic acid, acetone, and methanol, more preferably one or more of dimethyl sulfoxide, N-dimethylformamide, and N-methylpyrrolidone, and even more preferably dimethyl sulfoxide.
In some preferred embodiments, in step (1), the mass to volume ratio of the nitroxoline to the organic solvent is 5:1 to 100:1, e.g. 50:0.6, in mg/mL.
In some preferred embodiments, in step (2), the anti-solvent is water.
In some preferred embodiments, the volume ratio of organic solvent in step (1) to anti-solvent in step (2) is from 1:6 to 1:2, e.g., 1: 4.
In some preferred embodiments, in step (2), the crystallization is followed by a solid-liquid separation to obtain the crystals. The solid-liquid separation is preferably centrifugal separation. The rotational speed of the centrifugal separation is preferably 3500-. The time for the centrifugation is preferably 4-6min, e.g. 5 min.
In some preferred embodiments, in step (3), the temperature of the drying is in the range of 30 to 50 ℃, e.g. 40 ℃.
In some preferred embodiments, the organic solvent in step (1) is dimethyl sulfoxide, the antisolvent in step (2) is water, and the volume ratio of dimethyl sulfoxide to water is 1: 4; or,
the organic solvent in the step (1) is N, N-dimethylformamide, the anti-solvent in the step (2) is water, and the volume ratio of the N, N-dimethylformamide to the water is 1: 6; or,
the organic solvent in the step (1) is N-methyl pyrrolidone, the anti-solvent in the step (2) is water, and the volume ratio of the N-methyl pyrrolidone to the water is 1: 3; or,
the organic solvent in the step (1) is acetic acid, the anti-solvent in the step (2) is water, and the volume ratio of the acetic acid to the water is 1: 2; or,
the organic solvent in the step (1) is acetone, the anti-solvent in the step (2) is water, and the volume ratio of the acetone to the water is 1: 5; or,
the organic solvent in the step (1) is methanol, the anti-solvent in the step (2) is water, and the volume ratio of the methanol to the water is 1: 5.
Particularly, the A-type crystal of the nitroxoline prepared by the anti-solvent method has higher yield and finer granularity.
The invention also provides a method for crystallizing the form A of the nitroxoline (also called as a cooling crystallization method), which comprises the following steps: and (3) cooling the solution II containing the nitroxoline and the organic solvent, crystallizing under mixing, and carrying out solid-liquid separation to obtain the nitroxoline hydrochloride.
In some preferred embodiments, the solution II consists of nitroxoline and an organic solvent.
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.
In some preferred embodiments, the mass to volume ratio of the nitroxoline to the organic solvent is 10:3 to 25:1 in mg/mL.
In some preferred embodiments, the end point temperature of the temperature reduction is from room temperature to-20 ℃.
In some preferred embodiments, the mixing is stirring.
In some preferred embodiments, the time of mixing is from 0.4 to 0.6h, for example 0.5 h.
In some preferred embodiments, the solid-liquid separation is centrifugal separation. The rotational speed of the centrifugal separation is preferably 3500-. The time for the centrifugation is preferably 4-6min, e.g. 5 min.
In some preferred embodiments, the solid-liquid separation further comprises drying. The temperature of the drying is preferably 30 to 50 c, for example 40 c.
The invention also provides a method for crystallizing the form A of the nitroxoline (also called as a cooling crystallization method), which comprises the following steps:
(1) dissolving nitroxoline in an organic solvent under heating, preferably at 50-60 deg.C, to obtain a clear solution;
(2) cooling the clear solution obtained in the step (1), preferably cooling to-20 ℃ to room temperature, and crystallizing under stirring to obtain crystals;
(3) and (3) drying the crystal obtained in the step (2) to obtain the A-type crystal of the nitroxoline.
In some preferred embodiments, the preparation method of the form a crystal of nitroxoline according to the invention, wherein 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.
In some preferred embodiments, in step (1), the mass-to-volume ratio of nitroxoline to organic solvent is 1:40-300 in g/mL.
The invention also provides a pharmaceutical composition which comprises the A-type crystal of the nitroxoline and a pharmaceutically acceptable carrier.
The invention also provides application of the crystal A of the nitroxoline or the pharmaceutical composition in preparation of medicines for treating cancers.
In the above-mentioned use, the cancer is, for example, bladder cancer.
As used herein, "ambient temperature" means 10-30 ℃.
As used herein, "C1-C4 fatty acid" refers to an aliphatic hydrocarbon chain containing a carboxyl group at one end, which has from 1 to 4 carbon atoms. Examples of C1-C4 fatty acids include, but are not limited to, formic, acetic, propionic, and butyric acids.
As used herein, the term "C3-C6 fatty ketone" refers to a compound having a carbonyl group attached to two aliphatic hydrocarbon groups, and having from 3 to 6 carbon atoms. Examples of C3-C6 fatty ketones include, but are not limited to, acetone, butanone, pentanone, and hexanone.
As used herein, the term "C1-C4 fatty alcohol" refers to a compound having 1-4 carbon atoms wherein a hydroxyl group is bonded to a fatty hydrocarbon group. Examples of C1-C4 aliphatic alcohols include, but are not limited to, methanol, ethanol, propanol, and butanol.
The term "pharmaceutically acceptable" means that it is used to prepare pharmaceutical compositions that are generally safe, non-toxic, biologically desirable and acceptable for veterinary or human pharmaceutical use.
As used herein, "carrier" refers to a diluent, adjuvant, or excipient with which the compound is administered. Pharmaceutically acceptable carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, rapeseed oil. The pharmaceutically acceptable carrier may also be physiological saline, gum arabic, gelatin, starch paste, talc, keratin, silica gel, urea. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants may also be used.
It will be appreciated by those skilled in the art that the pharmaceutical composition of the present invention may be formulated into various formulations well known in the art, such as oral dosage forms (powder, tablet, capsule, soft capsule, liquid drug, syrup, elixir pill, powder, sachet, granule), or topical formulations (cream, ointment, lotion, gel, balm, plaster, paste, spray, aerosol, etc.), or injectable formulations (solution, suspension, emulsion), depending on the particular mode of administration. Pharmaceutical compositions according to the invention, which may be mentioned in particular are those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, for example, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions.
The pharmaceutical compositions of the present invention may comprise pharmaceutically acceptable carriers, adjuvants or diluents, such as fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, bases. The filler can be starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.; disintegrants may be, for example, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinyl pyrrole, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose; lubricants may be, for example, magnesium stearate, sodium lauryl sulfate, talc, silica; suspending agents may be, for example, polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropylmethylcellulose; the binder may be, for example, starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose. The compositions of the present invention may be formulated by any method known in the art to provide rapid, sustained or slow release of the active ingredient after administration to a patient.
The pharmaceutical composition of the present invention is administered to an individual animal such as a mammal (rat, mouse, domesticated animal or human) by various routes, and all administration modes are conventional, and for example, may be oral administration, topical administration, rectal administration, or administration by intravenous, intramuscular, transdermal, intrathecal, epidural or intracerebroventricular injection.
The administration dose of the active ingredient of the present invention may vary depending on the condition and weight of an individual, the nature and severity of a disease condition, the form of a drug, the route of administration, and the administration period, which may also be selected by those skilled in the art based on animal tests or clinical tests. The dosage of the active ingredient of the invention can vary from 1 to 100 mg/day, and also from 10 to 1000 mg/day, either as a single administration per day or as divided administrations per day.
The A-type crystal of the nitroxoline has no hygroscopicity and good stability, and is further beneficial to selection of administration routes and optimization of pharmaceutical preparation processes, so that the production quality of medicines is improved, and the action effect of the medicines is improved.
Drawings
FIG. 1 is an X-ray powder diffraction (XRPD) pattern of nitroxoline form A crystals of the present invention;
FIG. 2 is a thermogravimetric analysis (TGA) profile of nitroxoline form A crystals of the invention;
FIG. 3 is a Differential Scanning Calorimetry (DSC) profile of a nitroxoline form A crystal of the present invention;
FIG. 4 is a dynamic moisture sorption (DVS) profile of nitroxoline form A crystals of the present invention.
Detailed Description
The present invention will be described in more detail with reference to the following examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
First, laboratory glassware
1. X-ray powder diffraction (XRPD)
The instrument model is as follows: shimadzu XRD-6000
Ray: Cu-Kalpha target
Figure BDA0002859754480000071
Voltage: 40kV, current: 30mA
Scanning speed: 5 °/min
Scanning range: 5-50 degree (2 theta)
2. Thermogravimetric analysis (TGA)
The instrument model is as follows: PerkinElmer Pyris 1TGA
And (3) purging gas: nitrogen gas
The heating rate is as follows: 20 ℃/min
Temperature range: 30-250 deg.C
3. Differential Scanning Calorimeter (DSC)
The instrument model is as follows: mettler Toledo DSC3
And (3) purging gas: nitrogen gas
The heating rate is as follows: 20 ℃/min
Temperature range: 30-300 deg.C
4. Dynamic water adsorption (DVS)
The instrument model is as follows: SMS DVS inrinsic
And (3) testing temperature: 25 deg.C
The balance time is as follows: dm/dt: 0.01%/min;
relative humidity variation range: 0 to 95 to 0 percent
RH (%) test humidity change per step: 5 percent of
II, experimental reagent:
nitroxoline
Figure BDA0002859754480000081
The preparation method is characterized in that the 8-hydroxyquinoline is synthesized by two steps of nitrosation and oxidation, namely, the starting material 8-hydroxyquinoline, and the preparation method is shown in research on oriented nitration of 8-hydroxyquinoline, proceedings of Huaiyin academy of teachers and models, volume 4, phase 1 of 2005.
EXAMPLE 1 preparation example I of Crystal form A of nitroxoline
Nitroxoline 50mg was weighed and methanol (6mL) was added gradually at 50 ℃ until the nitroxoline was completely dissolved to a clear solution. Then, the solution was cooled to room temperature, stirred for 0.5h, centrifuged (eppendorf centrifue 5415, 4000r/min, 5min) to separate and collect the wet solid, which was dried under reduced pressure at 40 ℃ under vacuum to give about 40mg of yellow long needle-like solid, yield: 80 percent.
The X-ray powder diffraction pattern of the resulting solid is shown in fig. 1, and the X-ray powder diffraction data is shown in table 1 below and is defined as type a crystals.
Table 1 XRPD peak and intensity tabulation of form a
Figure BDA0002859754480000082
Figure BDA0002859754480000091
Approximately 5mg of the crystalline sample was weighed into a crucible, heated from 30 ℃ to 250 ℃ under nitrogen, at a rate of 20 ℃/min, and held at 250 ℃ for 1 minute. Its TGA profile is shown in fig. 2, which shows that the crystalline form has no weight loss from room temperature to 120 ℃, but is followed by sublimation.
Approximately 5mg of the powder sample was weighed into a closed aluminum crucible, which was covered with a pin hole. Under the protection of nitrogen, differential thermal scanning was performed by raising the temperature from 30 ℃ to 300 ℃ and maintaining the temperature at 300 ℃ for 1 minute. The heating rate was 20 ℃/min. The DSC pattern is shown in figure 3, which shows a distinct endothermic peak at 180.82 ℃.
EXAMPLE 2 preparation example II of Crystal form A of Nitroxoquinoline
Nitroxoline 50mg was weighed and acetonitrile (2.5mL) was added gradually at 60 ℃ until the nitroxoline was completely dissolved to a clear solution. Then, the solution was cooled to-20 ℃, stirred for 0.5h, centrifuged (eppendorf Centrifuge 5415, 4000r/min, 5min) to separate and collect the wet solid, which was dried under reduced pressure at 40 ℃ under vacuum to give about 35mg of yellow long needle-like solid, yield: 70 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 3 preparation of nitroxoline form A crystals
Nitroxoline 50mg was weighed and isopropanol (15mL) was added gradually at 55 ℃ until the nitroxoline was completely dissolved to a clear solution. Then, the solution was cooled to-20 ℃, stirred for 0.5h, centrifuged (eppendorf Centrifuge 5415, 4000r/min, 5min) to separate and collect the wet solid, which was dried under reduced pressure at 40 ℃ under vacuum to give about 35mg of yellow solid, yield: 70 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 4 preparation of Crystal form A of Nitroxoquinoline IV
Nitroxoquinoline 50mg was weighed and ethyl acetate (2.5mL) was added gradually at 60 ℃ until the nitroxoquinoline was completely dissolved to a clear solution. Then, the solution was cooled to-10 ℃, stirred for 0.5h, centrifuged (eppendorf Centrifuge 5415, 4000r/min, 5min) to separate and collect the wet solid, which was dried under reduced pressure at 40 ℃ under vacuum to give a yellow-green long needle-like solid of about 40mg, yield: 80 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 5 preparation of Crystal form A of Nitroxoquinoline five
Nidroxyquinoline 50mg was weighed and acetone (2mL) was added gradually at 60 ℃ until the nitroxoline was completely dissolved to a clear solution. Then, the solution was cooled to-20 ℃, stirred for 0.5h, centrifuged (eppendorf Centrifuge 5415, 4000r/min, 5min) to separate and collect the wet solid, which was dried under reduced pressure at 40 ℃ under vacuum to give about 40mg of yellow long needle-like solid, yield: 80 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 6 preparation example VI of Crystal form A of nitroxoline
Nitroxoquinoline 50mg was weighed and methyl tert-butyl ether (10mL) was added gradually at 50 ℃ until the nitroxoquinoline was completely dissolved to a clear solution. Then, the solution was cooled to room temperature, stirred for 0.5h, centrifuged (eppendorf centrifue 5415, 4000r/min, 5min) to separate and collect the wet solid, which was dried under reduced pressure at 40 ℃ under vacuum to give a yellow flocculent solid of about 40mg, yield: 80 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 7 preparation of Crystal form A of nitroxoline
Nitroxoquinoline 50mg was weighed and toluene (4mL) was added gradually at 55 ℃ until the nitroxoquinoline was completely dissolved to a clear solution. Then, the solution was cooled to-20 ℃, stirred for 0.5h, centrifuged (eppendorf Centrifuge 5415, 4000r/min, 5min) to separate and collect the wet solid, which was dried under reduced pressure at 40 ℃ under vacuum to give about 40mg of yellow long needle-like solid, yield: 80 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 8 preparation example VIII of Crystal form A of nitroxoline
Weighing 50mg of nitroxoline, adding dimethyl sulfoxide (0.6mL) to dissolve it completely at room temperature until the solution is clear, then gradually adding water (2.4mL) to precipitate the solid, centrifuging and collecting the wet solid, and drying under reduced pressure at 40 ℃ in vacuum to obtain about 45mg of yellow fine needle-like solid with yield: 90 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 9 preparation example nine of Crystal form A of Nitroxoquinoline
Weighing 50mg of nitroxoline, adding N, N-dimethylformamide (0.6mL) at room temperature to completely dissolve the nitroxoline until the nitroxoline is clear, then gradually adding water (3.6mL) to separate out a solid, centrifuging and collecting a wet solid, and drying the wet solid at 40 ℃ under reduced pressure in vacuum to obtain about 45mg of yellow fine needle-shaped solid with yield: 90 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 10 preparation of Crystal form A of nitroxoline
Weighing 50mg of nitroxoline, adding N-methylpyrrolidone (0.5mL) at room temperature to completely dissolve the nitroxoline until the nitroxoline is clear, then gradually adding water (1.5mL) to separate out the solid, centrifugally separating and collecting the wet solid, and drying the wet solid at 40 ℃ under reduced pressure in vacuum to obtain about 45mg of yellow fine needle-shaped solid with yield: 90 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 11 preparation example eleven of Crystal form A of nitroxoline
Weighing 50mg of nitroxoline, adding acetic acid (5mL) at room temperature to completely dissolve the nitroxoline until the nitroxoline is clear, then gradually adding water (10mL) to separate out the solid, centrifuging and collecting the wet solid, and drying the wet solid at 40 ℃ under reduced pressure and vacuum to obtain yellow fine needle-shaped solid of about 45mg, yield: 90 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 12 preparation of Crystal form A of nitroxoline twelve
Weighing 50mg of nitroxoline, adding acetone (4mL) at room temperature to completely dissolve the nitroxoline until the nitroxoline is clear, then gradually adding water (20mL) to separate out the solid, centrifugally separating and collecting the wet solid, and drying the wet solid at 40 ℃ under reduced pressure and vacuum to obtain about 45mg of yellow fine needle-shaped solid, wherein the yield is as follows: 90 percent.
The XRPD pattern of the crystal is proved to be A type crystal by research and comparison.
EXAMPLE 13 preparation of nitroxoline form A crystals thirteen
Weighing 50mg of nitroxoline, adding methanol (10mL) at room temperature to completely dissolve the nitroxoline until the nitroxoline is clear, gradually adding water (50mL) to separate out a solid, centrifugally separating, collecting a wet solid, and drying the wet solid at 40 ℃ under reduced pressure in vacuum to obtain about 45mg of yellow fine needle-shaped solid.
The XRPD pattern of the crystal is compared by research, the product is determined to be A-type crystal, and the yield is as follows: 90 percent.
Test example 1 hygroscopicity test of nitroxoline form A crystals of the invention
1-5mg of the nitroxoline A-type crystal prepared in example 8 was weighed and placed in a dynamic moisture adsorption apparatus for direct measurement. Setting instrument parameters, sample testing temperature: t-25 ℃, equilibration time: dm/dt: 0.01%/min, relative humidity variation range: 0% -95% -0%; RH (%) test humidity change per step: 5 percent.
The evaluation criteria for hygroscopicity are shown in table 2 below.
TABLE 2 moisture absorption Classification
Moisture absorption classification Standard of water adsorption*
Deliquescent Absorb enough water to form liquid
Very hygroscopic W％≥15％
Is hygroscopic W％≥2％
Slightly hygroscopic W％≥0.2％
Non-hygroscopic W％<0.2％
At 25 + -1 deg.C and 80 + -2% RH (European pharmacopoeia 6.0)
The DVS test results of the form a crystal of example 8 are shown in fig. 4, which shows a moisture adsorption value W% < 0.2%, indicating that the form a crystal of the present invention is non-hygroscopic and has good stability.
Test example 2 stability test of nitroxoline form A crystals of the present invention
The nitroxoline A-type crystal prepared in example 8 was weighed, and subjected to influence factor examination under the conditions of light (4500 + -500 Lux), high temperature (60 ℃), and high humidity (RH 90% + -5%) for 5 days and 10 days, and then subjected to X-ray powder diffraction (XRPD) detection to examine whether the crystal form is changed.
The results of the crystal form stability influencing factor test are shown in table 3 below.
TABLE 3 Crystal form stability influencing factor test results
Figure BDA0002859754480000131
The crystal form A of the invention is not changed after being inspected for 10 days by illumination, high temperature and high humidity factors, and has good stability.
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the spirit and scope of the invention, and these changes and modifications are within the scope of the invention.

Claims (10)

1. A type A crystal of nitroxoline is characterized in that an X-ray powder diffraction pattern comprises characteristic peaks at 2 theta diffraction angles of 11.3 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 16.9 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees, 22.1 degrees +/-0.2 degrees, 23.7 degrees +/-0.2 degrees, 24.2 degrees +/-0.2 degrees, 25.9 degrees +/-0.2 degrees, 27.1 degrees +/-0.2 degrees and 28.0 degrees +/-0.2 degrees.
2. A crystal form a of nitroxoline according to claim 1 characterized in that its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles 2 Θ 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 °.
3. The form a crystal of nitroxoline according to claim 1 or 2, characterized in that it has an X-ray powder diffraction pattern as shown in figure 1.
4. A method for preparing nitroxoline form a crystals as claimed in any one of claims 1 to 3, comprising the steps of: and (3) contacting the solution I containing the nitroxoline and the organic solvent with an anti-solvent, crystallizing, and carrying out solid-liquid separation to obtain the nitroxoline.
5. A method for preparing nitroxoline form A crystals as claimed in claim 4, wherein solution I is composed of nitroxoline and an organic solvent;
and/or the organic solvent is selected from one or more of dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone, C1-C4 fatty acid, C3-C6 fatty ketone and C1-C4 fatty alcohol, preferably one or more of dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone, acetic acid, acetone and methanol, more preferably one or more of dimethyl sulfoxide, N-dimethylformamide and N-methylpyrrolidone, and even more preferably dimethyl sulfoxide;
and/or the mass-to-volume ratio of the nitroxoline to the organic solvent is 5:1 to 100:1, such as 50:0.6, in mg/mL;
and/or, the anti-solvent is water;
and/or the volume ratio of the organic solvent to the anti-solvent is from 1:6 to 1:2, such as 1:3, 1:4 or 1: 5;
and/or, the solid-liquid separation is centrifugal separation; the rotation speed of the centrifugal separation is preferably 3500-;
and/or, drying is further included after the solid-liquid separation; the temperature of the drying is preferably 30 to 50 c, for example 40 c.
6. The method for preparing crystal form A of nitroxoline according to claim 4 or 5, wherein the organic solvent is dimethyl sulfoxide, the antisolvent is water, and the volume ratio of dimethyl sulfoxide to water is 1: 4; or,
the organic solvent is N, N-dimethylformamide, the anti-solvent is water, and the volume ratio of the N, N-dimethylformamide to the water is 1: 6; or,
the organic solvent is N-methyl pyrrolidone, the anti-solvent is water, and the volume ratio of the N-methyl pyrrolidone to the water is 1: 3; or,
the organic solvent is acetic acid, the anti-solvent is water, and the volume ratio of the acetic acid to the water is 1: 2; or,
the organic solvent is acetone, the anti-solvent is water, and the volume ratio of the acetone to the water is 1: 5; or,
the organic solvent is methanol, the anti-solvent is water, and the volume ratio of the methanol to the water is 1: 5.
7. A method for preparing nitroxoline form a crystals as claimed in any one of claims 1 to 3, comprising the steps of: and (3) cooling the solution II containing the nitroxoline and the organic solvent, crystallizing under mixing, and carrying out solid-liquid separation to obtain the nitroxoline hydrochloride.
8. A method for preparing nitroxoline form a crystals as claimed in claim 7, wherein solution II consists of nitroxoline 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 nitroxoline to the organic solvent is 10:3 to 25:1, and the unit is mg/mL;
and/or the temperature of the end point of the temperature reduction is between room temperature and-20 ℃;
and/or, the mixing is stirring;
and/or the mixing time is 0.4-0.6h, such as 0.5 h;
and/or, the solid-liquid separation is centrifugal separation; the rotation speed of the centrifugal separation is preferably 3500-;
and/or, drying is further included after the solid-liquid separation; the temperature of the drying is preferably 30 to 50 c, for example 40 c.
9. A pharmaceutical composition comprising the form a crystal of nitroxoline according to any one of claims 1-3 and a pharmaceutically acceptable carrier.
10. Use of the crystalline form a of nitroxoline according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of cancer; the cancer is preferably bladder cancer.
CN202011559101.4A 2019-12-27 2020-12-25 Crystal nitroxoline and preparation method and application thereof Pending CN113045490A (en)

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Citations (3)

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