CN114436977B - Fapirrevir multicomponent drug and preparation method and application thereof - Google Patents
Fapirrevir multicomponent drug and preparation method and application thereof Download PDFInfo
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- CN114436977B CN114436977B CN202210164509.4A CN202210164509A CN114436977B CN 114436977 B CN114436977 B CN 114436977B CN 202210164509 A CN202210164509 A CN 202210164509A CN 114436977 B CN114436977 B CN 114436977B
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- fampicin
- dihydroxybenzoic acid
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a fampicin multicomponent drug, a preparation method and application thereof, and belongs to the field of pharmaceutical co-crystals. The invention improves the physicochemical properties of the fampicin by adopting a mode of preparing the crystal form medicament. Through researches and screening, a pharmaceutical co-crystal form capable of obviously improving the solubility of the fampicin and improving the tabletting property of the fampicin is provided, and experiments prove that the fampicin and the m-hydroxybenzoic acid, the 3,4-dihydroxybenzoic acid and the 3,5-dihydroxybenzoic acid form a co-crystal drug, so that the tablet property and the solubility of the fampicin in aqueous solution of the fampicin are effectively improved, and meanwhile, the clinical curative effect of the fampicin is improved, and the toxic and side effects of the drug are reduced, so that the fampicin has good practical application value.
Description
Technical Field
The invention belongs to the field of pharmaceutical co-crystals, and particularly relates to a fampicin multicomponent drug as well as a preparation method and application thereof.
Background
The information disclosed in the background of the invention is only for enhancement of understanding of the general background of the invention and is not necessarily to be taken as an admission or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art.
Fadipirvir (English name: favipiravir, chinese name: 6-fluoro-3-hydroxy pyrazine-2-carboxamide) is a broad spectrum antiviral drug having activity against a variety of pathogens including ebola virus, norovirus, RSV, rhinovirus, poliovirus, yellow fever virus and influenza virus. The drug can selectively inhibit influenza virus RNA polymerase without generating toxic effect on mammalian cells, can be used for treating infection of drug-resistant virus strains in the current antiviral treatment, and has synergistic effect with oseltamivir and peramivir. The fampicvir can selectively inhibit RNA polymerase related to influenza virus replication, is an antiviral drug with a brand-new action mechanism, can be phosphoribosylated by host cell enzyme to generate fampicvir Wei Funan ribosyl-5-inositol triphosphate (fampicvir RTP) with bioactivity, and can be used for incorrectly identifying the fampicvir RTP by the viral RNA polymerase, so that the fampicvir RTP is inserted into a viral RNA chain or combined with a viral RNA polymerase domain, thereby preventing replication and transcription of the viral RNA chain. The fampicin is mainly used for treating new or re-epidemic influenza of adults and is one of candidate medicines for treating new coronaries pneumonia (COVID-19).
M-hydroxybenzoic acid (English name: 3-Hydroxybenzoic acid) is often used as an intermediate for bactericides, paints, preservatives, ion exchangers, plasticizers and medicines, and can also be used for synthesizing azo dyes and the like. 3,4-dihydroxybenzoic acid (English name: 3,4-Dihydroxybenzoic acid) is a simple phenolic acid, is a precursor for synthesizing other complex molecules, has various biological activities aiming at different molecular targets, has antibacterial, antioxidant, antihyperglycemic and neuroprotective effects, and is a commonly used drug multi-group dispenser. 3,5-dihydroxybenzoic acid (English name: 3,5-Dihydroxybenzoic acid) is an organic synthesis intermediate, and is used for preparing medicines, synthetic resins and the like, and the three ligands are selected for preparing pharmaceutical co-crystals.
The crystal form of the medicine has great influence on the subsequent processing process of the medicine, and the physicochemical properties of the medicine, such as solubility, machinability and the like, are influenced. The oral administration is the most convenient and commonly used administration route at present, does not need complex formulation design, has low requirements on storage environment compared with liquid formulation, and has low cost and high practicability. However, the greatest challenges of the current oral administration are low bioavailability, and the oral bioavailability is mainly influenced by factors such as water solubility, permeability, dissolution rate, biological metabolism and the like. The most common causes of low bioavailability are low solubility and low permeability.
Solubility is one of the important parameters for achieving the required concentration of a drug in the systemic circulation, and generally, drugs with poor water solubility require high doses of medication to achieve therapeutic plasma concentrations after oral administration, and low water solubility is a major problem encountered in the development of simulated drugs. The water solubility of the fampicregion is 8.7mg/ml, belongs to the BCS IV class of drugs, and the low solubility limits the application of the fampicregion, so that the improvement of the solubility is necessary for improving the bioavailability of the fampicregion. In addition, the inventor discovers that the fampicin has the problems of poor fluidity and poor tabletting property, and influences the subsequent processing technology.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a fampicin multicomponent medicament as well as a preparation method and application thereof. The invention improves the physicochemical properties of the fampicin by adopting a mode of preparing the crystal form medicament. Through research and screening, a pharmaceutical eutectic form capable of obviously improving the solubility of the fampicin and improving the tabletting property of the fampicin is provided, the tabletting property of the fampicin and the solubility of the fampicin aqueous solution are effectively improved, and the invention is completed based on the research results.
In a first aspect of the invention, there is provided the use of any one or more of m-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid in improving the solubility of fampicin, improving the Wei Yapian properties of fampicin and/or improving the clinical efficacy, reducing the toxic or side effects of a drug.
According to the invention, researches show that the method for preparing the fampicvir eutectic medicament by adding the m-hydroxybenzoic acid, the 3,4-dihydroxybenzoic acid and the 3,5-dihydroxybenzoic acid into the fampicvir and adopting grinding and solution volatilization can obviously improve the solubility and tabletting property of the fampicvir, and compared with a common formula, the fampicvir eutectic medicament provided by the invention obviously improves the clinical curative effect and reduces the toxic and side effects of the medicament.
Accordingly, in a second aspect of the present invention, there is provided a multi-component drug of fampicin comprising at least the following raw material components:
a) Fampicvir;
b) Any one or more of m-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid.
In a third aspect of the present invention, there is provided a method for preparing the above-mentioned fampicvir multicomponent drug, the method comprising: mixing the raw materials a) and b) and adopting a grinding method and/or a solution method.
In a fourth aspect of the present invention, there is provided the use of a fampicin multicomponent medicament as described above in the preparation of a fampicin pharmaceutical formulation.
In a fifth aspect of the present invention, there is provided a formulation of a famprivir drug comprising a famprivir multicomponent drug as described above, and comprising one or more pharmaceutically acceptable carriers.
The beneficial technical effects of one or more of the technical schemes are as follows:
the technical scheme reports that the physicochemical property of the fampicin is improved by adopting a mode of preparing the crystal form medicament, and the fampicin eutectic medicament is prepared by adding the hydroxybenzoic acid into the fampicin, so that the solubility of the fampicin can be obviously improved, the tabletting property of the fampicin can be improved, the clinical curative effect of the fampicin can be improved, and the toxic and side effects of the medicament can be reduced, so that the fampicin has good practical application value.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a molecular structural formula of Fapila Wei Ji m-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid;
FIG. 2 is a powder diffraction pattern of a co-crystal of fampicvir and m-hydroxybenzoic acid prepared in accordance with the present invention;
FIG. 3 is a powder diffraction pattern of a co-crystal of fampicvir-3, 5-dihydroxybenzoic acid prepared in accordance with the invention;
FIG. 4 is a powder diffraction pattern of the co-crystal hydrate of fampirvir-3, 4-dihydroxybenzoic acid prepared in accordance with the present invention
FIG. 5 shows the eutectic supermolecular structure of fampicvir and m-hydroxybenzoic acid prepared in the present invention;
FIG. 6 shows the eutectic supermolecular structure of fampicvir-3, 5-dihydroxybenzoic acid prepared in the present invention;
FIG. 7 shows the supermolecular structure of the co-crystal hydrate of fampicvir-3, 4-dihydroxybenzoic acid prepared by the method;
FIG. 8 shows the unit cell structure of the eutectic crystal of fampicvir and m-hydroxybenzoic acid prepared in the present invention;
FIG. 9 shows the unit cell structure of the co-crystal of fampicvir-3, 5-dihydroxybenzoic acid prepared in accordance with the invention;
FIG. 10 shows the unit cell structure of the crystalline co-crystal hydrate of fampicvir-3, 4-dihydroxybenzoic acid prepared in accordance with the invention;
FIG. 11 is a thermogravimetric analysis (TG) plot of a co-crystal of fampirir-m-hydroxybenzoic acid prepared according to the present invention;
FIG. 12 is a thermogravimetric analysis (TG) plot of a co-crystal of fampicvir-3, 5-dihydroxybenzoic acid prepared in accordance with the invention;
FIG. 13 is a thermogravimetric analysis (TG) plot of the co-crystal hydrate of fampirvir-3, 4-dihydroxybenzoic acid prepared in accordance with the present invention;
FIG. 14 is a Differential Scanning Calorimetric (DSC) plot of a co-crystal of fampicvir and m-hydroxybenzoic acid prepared in accordance with the present invention;
FIG. 15 is a Differential Scanning Calorimetric (DSC) plot of a co-crystal of fampicvir-3, 5-dihydroxybenzoic acid prepared in accordance with the present invention;
FIG. 16 is a Differential Scanning Calorimetric (DSC) plot of a co-crystal hydrate of fampicvir-3, 4-dihydroxybenzoic acid prepared in accordance with the present invention;
FIG. 17 is an infrared spectrum (IR) diagram of a co-crystal of fampicvir and m-hydroxybenzoic acid prepared in accordance with the invention;
FIG. 18 is an Infrared (IR) spectrum of a co-crystal of fampicvir-3, 5-dihydroxybenzoic acid prepared in accordance with the invention;
FIG. 19 is an Infrared (IR) spectrum of a co-crystal hydrate of fampicvir-3, 4-dihydroxybenzoic acid prepared in accordance with the invention;
fig. 20 is a graph of solubility test of a fampicin co-crystal prepared in accordance with the present invention.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. 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 application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
The invention will now be further illustrated with reference to specific examples, which are given for the purpose of illustration only and are not intended to be limiting in any way. If experimental details are not specified in the examples, it is usually the case that the conditions are conventional or recommended by the reagent company; reagents, consumables, etc. used in the examples described below are commercially available unless otherwise specified.
As described above, the fampicvir has a problem of poor water solubility, poor flowability, poor tabletting property, and the like, which affects the subsequent processing process.
In view of this, the present invention provides a co-crystal formed by Fampicvir (FPV) and m-hydroxybenzoic acid (3 DHBA), 3,4-dihydroxybenzoic acid (34 DHBA), 3,5-dihydroxybenzoic acid (35 DHBA), wherein FPV-34DHBA-H 2 O contains water molecules, which may also be referred to as eutectic hydrates. The characterization and physicochemical property test of Cu-kα show that the X-ray diffraction spectrum has sharp diffraction peak,the prepared eutectic obviously improves the solubility and tabletting property of the fampicvir. Makes up for the defects of the prior art. In addition, compared with the common prescription, the pharmaceutical co-crystal can improve the clinical curative effect and reduce the toxic and side effects of the medicine.
Specifically, in one exemplary embodiment of the present invention, there is provided the use of any one or more of m-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, and 3,5-dihydroxybenzoic acid in improving the solubility of fampicin, improving the Wei Yapian properties of fampicin, and/or improving the clinical efficacy, and reducing the toxic or side effects of drugs.
In still another embodiment of the present invention, there is provided a multi-component drug of fampicin comprising at least the following raw materials:
a) Fampicvir;
b) Any one or more of m-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid;
wherein the molar ratio of a) to b) is controlled to be 1:0.1-10, preferably 1:1.
When the raw material components are the fampicvir and the m-hydroxybenzoic acid, the characteristic peak 2 theta angle of the eutectic powder of the fampicvir multicomponent drug can be:
13.25±1°，14.31±1°，14.59±1°，15.14±1°，16.75±1°，17.75±1°，23.29±1°，23.68±1°，25.17±1°，25.39±1°，26.72±1°，27.89±1°，28.33±1°，29.05±1°，30.27±1°，31.93±1°，32.88±1°，33.87±1°，34.82±1°，35.43±1°，36.26±1°，39.19±1°，39.75±1°。
when the raw material components are the fampicvir and the 3,4-dihydroxybenzoic acid, the characteristic peak 2 theta angle of the eutectic powder of the fampicvir multicomponent drug can be:
6.51±1°，13.00±1°，13.67±1°，14.02±1°，14.41±1°，15.12±1°，16.81±1°，18.89±1°，19.67±1°，21.59±1°，23.08±1°，24.18±1°，24.89±1°，26.38±1°，26.77±1°，26.97±1°，28.22±1°，28.46±1°，29.05±1°，32.58±1°，35.05±1°，35.83±1°，36.62±1°，38.39±1°，39.17±1°，40.51±1°，41.88±1°。
when the raw material components are the fampicvir and the 3,5-dihydroxybenzoic acid, the characteristic peak 2 theta angle of the eutectic powder of the fampicvir multicomponent drug can be:
13.54±1°，14.37±1°，14.71±1°，17.09±1°，17.53±1°，19.32±1°，21.89±1°，22.91±1°，24.32±1°，24.76±1°，26.02±1°，27.33±1°，28.01±1°，29.13±1°，31.17±1°，32.18±1°，34.03±1°，34.61±1°，36.99±1°，38.06±1°，39.23±1°，40.82±1°。
in still another embodiment of the present invention, there is provided a method for preparing the above-mentioned fampicvir multicomponent drug, the method comprising: mixing the raw materials a) and b), and adopting a grinding method and/or a solution method;
wherein the grinding method comprises the steps of mixing the raw materials a) and b) and directly grinding or grinding by adding a solvent;
the solvent can be water and an organic solvent, and the organic solvent comprises any one or more of methanol, ethanol, acetone, acetic acid, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, N-butanol, chloroform, dichloromethane, chloroform, carbon tetrachloride, hexane tetrahydrofuran, dimethyl maple and N, N-dimethylformamide;
in one specific embodiment of the invention, the solvent is acetonitrile or a mixed solution of acetonitrile and water, and the volume ratio of acetonitrile to water in the mixed solution is 1:0.1-10, preferably 1:1.
The grinding may be performed by using a grinding apparatus, and in one embodiment of the present invention, the grinding apparatus includes a grinding device, the grinding frequency is controlled to be 10-50Hz, preferably 30Hz, and the grinding time is controlled to be 10-100min, preferably 70min, and the above-mentioned grinding process may be performed at room temperature (20-30 ℃).
The solution method comprises the steps of mixing the raw materials a) and b), adding a solvent, and stirring and dissolving at a high temperature.
The solvent can be water and an organic solvent, and the organic solvent comprises any one or more of methanol, ethanol, acetone, acetic acid, ethyl acetate, acetonitrile, trifluoroethanol, isopropanol, N-butanol, chloroform, dichloromethane, chloroform, carbon tetrachloride, hexane tetrahydrofuran, dimethyl maple and N, N-dimethylformamide;
in one specific embodiment of the invention, the solvent is acetonitrile or a mixed solution of acetonitrile and water, and the volume ratio of acetonitrile to water in the mixed solution is 1:0.1-10, preferably 1:1.
More specifically, the high temperature condition is not lower than 40 ℃, such as 40-80 ℃, preferably 60 ℃, and the raw materials are accelerated to be dissolved by heating and stirring, so that the preparation efficiency is improved, and the preparation time is shortened.
The stirring can be performed in a magneton mode, and in a specific embodiment of the invention, the fampicin multicomponent drug can be obtained after cooling and crystallizing a clear solution obtained by a solvent method.
In yet another embodiment of the present invention, there is provided the use of the above-described fampicvir multicomponent medicament in the preparation of a fampicvir pharmaceutical formulation.
In yet another embodiment of the present invention, a pharmaceutical formulation of famprivir is provided comprising a famprivir multicomponent drug as described above, and one or more pharmaceutically acceptable carriers. The pharmaceutical preparation can further comprise conventional adjuvants such as odorant, flavoring agent, etc.
The famprivir pharmaceutical formulations may be in a variety of dosage forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols and the like, and may be presented in a suitable solid or liquid carrier or diluent and in a suitable sterilizing device for injection or instillation.
These pharmaceutical compositions are generally safe, non-toxic and biologically desirable, and therefore, the pharmaceutically acceptable carriers and the like described herein are non-toxic and safe, as well as their combination with the fampicin multicomponent drug. Pharmaceutically acceptable carriers as described herein are generally well known to those skilled in the art or can be determined by those skilled in the art depending on the actual situation.
Such pharmaceutically acceptable excipients include, but are not limited to, excipients and the like. One skilled in the art can select a suitable excipient depending on the purpose for which the excipient has. Such as a common excipient such as a solvent, a solubilizer, a surfactant, a preservative, a filler, an emulsifier, a binder, a disintegrant, a stabilizer, a flavoring agent, an antioxidant, a colorant, a diluent, a pH adjustor, a pressure adjustor, or the like, or a combination of two or more of these, or the like, depending on the pharmaceutical properties or mode of administration.
The above-described famprivir multicomponent drug or famprivir pharmaceutical formulation is administered in unit dosage form. The dosage form may be conventional, such as liquid, e.g. emulsion, colloidal, true solution, particulate, mixed spin; such as other conventional dosage forms, e.g., tablets, capsules, drops, aerosols, pills, oral liquids, powders, injections, solutions, suspensions, emulsions, granules, clathrates, landfill agents, etc. These dosage forms may be prepared according to conventional preparation methods in the pharmaceutical arts, such as mixing, granulating, tabletting, filling, dissolving, or suspension-dispersing, and the like.
The multi-component drug of the fampicin or the pharmaceutical formulation of the fampicin of the invention can be clinically used for mammals, including human beings and animals, and can be used by oral, nasal, skin, lung, gastrointestinal tract or other administration routes. Most preferably orally. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Typically starting from a small dose, the dose is gradually increased until the most suitable dose is found.
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The following examples are test methods in which specific conditions are noted, and are generally conducted under conventional conditions.
Example 1
The embodiment provides a method for preparing a fampicin-m-hydroxybenzoic acid pharmaceutical co-crystal based on a grinding method, which comprises the following steps: 62.84mg (0.4 mol) of raw material fampicrevir and 55.25mg (0.4 mol) of m-hydroxybenzoic acid are precisely weighed, a sample is placed in a grinding tank, a Retsch MM200 grinding instrument is used, the frequency is 30Hz, grinding is carried out for 70min, the temperature is room temperature (20-30 ℃), and 0.2ml of acetonitrile is added for grinding, so that a eutectic product can be obtained.
Example 2
The embodiment provides a method for preparing a fampicin-m-hydroxybenzoic acid pharmaceutical co-crystal based on a solution method, which comprises the following steps: 62.84mg (0.4 mol) of fampicvir as a raw material and 55.25mg (0.4 mol) of m-hydroxybenzoic acid as a raw material were precisely weighed, and the weighed raw materials were put into a clean glass bottle (volume 20 ml) at room temperature, and 6ml of acetonitrile was added. Adding cleaned magneton into glass bottle containing solution, placing into oil bath at 60deg.C, dissolving medicine sufficiently at 500rpm, clarifying, placing into fume hood, volatilizing at room temperature, and cooling and crystallizing for a period of time to obtain eutectic medicine of fampicin and m-hydroxybenzoic acid.
For the fepimara-m-hydroxybenzoic acid co-crystal powder obtained in example 1, powder diffraction analysis was performed using a D8 Advance X-ray powder diffractometer manufactured by bruck company, cu-kα, tube voltage 40kV, tube current 40mA, step size 0.1, scan range 10-50 °, room temperature conditions. The obtained powder X-ray diffraction pattern is shown in figure 2, wherein the angle of the eutectic characteristic peak 2 theta is as follows:
13.25±1°，14.31±1°，14.59±1°，15.14±1°，16.75±1°，17.75±1°，23.29±1°，23.68±1°，25.17±1°，25.39±1°，26.72±1°，27.89±1°，28.33±1°，29.05±1°，30.27±1°，31.93±1°，32.88±1°，33.87±1°，34.82±1°，35.43±1°，36.26±1°，39.19±1°，39.75±1°。
example 1 the milled product was dissolved in acetonitrile or organic solvents such as ethanol, methanol, isopropanol, acetonitrile, acetone, DMSO, etc. to be slowly evaporated and crystallized, and a single crystal with a good quality suitable for single crystal analysis was obtained. Example 2 can directly obtain a single crystal with a good quality suitable for single crystal analysis. The structure of fampicvir-m-hydroxybenzoic acid obtained by single crystal structure analysis was shown in fig. 5 and 8 using a D8 VENTURE double micro focal spot X-ray single crystal diffractometer manufactured by bruck corporation, germany, and the crystallographic information thereof was shown in table 1.
The obtained fapirrevir-m-hydroxybenzoic acid eutectic was subjected to thermogravimetric analysis, data were collected in a TA thermogravimetric analyzer TGA5500 in the united states, the sample was warmed from room temperature to 300 ℃ under the protection of nitrogen at a warming rate of 10 ℃/min, and the mass change of the sample during warming was recorded, and the obtained results are shown in fig. 11.
The obtained fapirrevir-m-hydroxybenzoic acid eutectic drug was subjected to differential scanning calorimetric analysis, the data were collected on a german relaxation-resistant DSC 214Polyma thermal analyzer, the temperature of the sample was raised from room temperature to 250 ℃ under nitrogen protection, and the heat change of the sample during the temperature raising process was recorded by using software, and the obtained results are shown in fig. 14.
In addition, the obtained fapirrevir-m-hydroxybenzoic acid eutectic drug is subjected to infrared spectrum analysis, and the data is collected at room temperature by a Nicolet Nexus670 Fourier infrared spectrometer of Nigao company of America, and the wave number is 4000-500cm -1 Resolution of 0.09cm -1 The obtained infrared spectrum is shown in fig. 17.
The obtained fepirrevir-m-hydroxybenzoic acid co-crystal drug was subjected to solubility test, resulting in its solubility in a buffer solution having ph=6.8. The testing method comprises the following steps: high Performance Liquid Chromatography (HPLC), SHIMAZU, LC-20AT, detection wavelength 225nm, mobile phase 0.01mol/L monoammonium phosphate solution (pH=3.2.+ -. 0.1 adjusted with trifluoroacetic acid): acetonitrile-methanol (50-50) =80:20 (volume ratio), flow rate 1.0mL/min, column temperature 25 ℃. The solubility of the co-crystals was determined in phosphate buffer at ph=6.8. Test temperature: 25.+ -. 0.1 ℃. The sample was sieved to a particle size in the range of 80-150 μm, an excess of sample of uniform particle size was added to a round bottom flask containing 5ml of buffer solution, and the round bottom flask containing the saturated solution was then placed in an oil bath at 25.+ -. 0.1 ℃ and stirred with a magnetic stirrer at 500rpm for a total of 1600 minutes. Extracting 0.2ml saturated solution at 2min, 5min, 10min, 20min, 30min, 40min, 60min, 80min, 120min, 1200min, 1400min, 1600min with a disposable syringe, filtering with a filter membrane with pore size of 0.22 μm, and measuring FPV content of the filtrate by high performance liquid chromatography. The test results are shown in figure 20, and the solubility of the fampicvir-m-hydroxybenzoic acid eutectic medicine is obviously improved compared with that of the fampicvir medicine.
And finally, carrying out flowability and tabletting tests on the obtained fampicvir-m-hydroxybenzoic acid eutectic medicament, and carrying out repose angle tests by adopting a vertical funnel method. For tabletting property test, weighing proper amount of pure component of fampicvir or fampicvir eutectic medicine, placing in a 10ml measuring cylinder, recording the initial scale, vibrating the measuring cylinder up and down with amplitude of 5-10mm, recording the scale after compaction, and finally calculating the ratio of the Carl coefficient to House according to a formula. The test results are shown in table 2, and the flowability and tabletting property of the fepimara-m-hydroxybenzoic acid eutectic drug are improved compared with those of the fepimara drug per se.
Example 3
The embodiment provides a method for preparing a fampicvir-35-dihydroxybenzoic acid eutectic based on a grinding method, which comprises the following steps: the starting material, fampicvir 62.84mg (0.4 mol), 3,5-dihydroxybenzoic acid 61.65mg (0.4 mol) was weighed into a milling jar and milled using a Retsch MM200 mill at 30Hz for 70min at room temperature (20-30 ℃), with 0.2ml acetonitrile added to give the co-crystal product.
Example 4
The embodiment provides a method for preparing a fapirrevir-3, 5-dihydroxybenzoic acid pharmaceutical co-crystal based on a solution method, which comprises the following steps: the starting material, fampicvir 62.84mg (0.4 mol), 3,5-dihydroxybenzoic acid 61.65mg (0.4 mol) was weighed into a clean glass bottle (volume 20 ml) at room temperature and 6ml acetonitrile was added. Adding cleaned magnons into a glass bottle filled with the solution, putting the glass bottle into an oil bath pot at 60 ℃ to fully dissolve the medicines at the rotation speed of 500rpm, clarifying the solution, then placing the glass bottle into a fume hood, volatilizing at room temperature, and cooling and crystallizing for a period of time to obtain a eutectic product of the fampicvir and the 3,5-dihydroxybenzoic acid.
For example 3 Fapipavir-3, 5-dihydroxybenzoic acid eutectic powder, powder diffraction analysis was performed using a D8 Advance X-ray powder diffractometer manufactured by Brookfield, cu-kα, tube voltage 40kV, tube current 40mA, step size 0.1, scan range 10-50 °, room temperature conditions. The powder X-ray diffraction pattern obtained is shown in fig. 3, wherein the angle of the eutectic characteristic peak 2 theta is:
13.54±1°，14.37±1°，14.71±1°，17.09±1°，17.53±1°，19.32±1°，21.89±1°，22.91±1°，24.32±1°，24.76±1°，26.02±1°，27.33±1°，28.01±1°，29.13±1°，31.17±1°，32.18±1°，34.03±1°，34.61±1°，36.99±1°，38.06±1°，39.23±1°，40.82±1°。
example 3 the milled product was dissolved in acetonitrile or organic solvents such as ethanol, methanol, isopropanol, acetonitrile, acetone, DMSO, and slowly evaporated to crystallize, and a single crystal of good quality suitable for single crystal analysis was obtained. Example 4 can directly obtain a single crystal with a good quality suitable for single crystal analysis. The structure of the fampicvir-3, 5-dihydroxybenzoic acid eutectic obtained by single crystal structure analysis was shown in fig. 6 and 9, and the crystallographic information thereof was shown in table 1, using a D8 VENTURE double focal spot X-ray single crystal diffractometer manufactured by bruck corporation, germany, at room temperature.
The obtained fapirrevir-3, 5-dihydroxybenzoic acid eutectic is subjected to thermogravimetric analysis, data are collected in a American TA thermogravimetric analyzer TGA5500, a sample is heated from room temperature to 300 ℃ under the protection of nitrogen at a heating rate of 10 ℃/min, and meanwhile, the mass change of the sample in the heating process is recorded, and the obtained result is shown in figure 12.
The obtained fapirrevir-3, 5-dihydroxybenzoic acid eutectic drug was subjected to differential scanning calorimetric analysis, the data were collected on a germany relaxation-resistant DSC 214Polyma thermal analyzer, the temperature of the sample was raised from room temperature to 250 ℃ under nitrogen protection, and the heat change of the sample during the temperature raising process was recorded by using software, and the obtained results are shown in fig. 15.
In addition, the obtained fapirrevir-3, 5-dihydroxybenzoic acid eutectic drug is subjected to infrared spectrum analysis, and the data are collected at room temperature by a Nicolet Nexus670 Fourier infrared spectrometer of Nigaoli company of America, and the wave number is 4000-500cm -1 Resolution of 0.09cm -1 The obtained infrared spectrum is shown in fig. 18.
The obtained fepimara-3, 5-dihydroxybenzoic acid cocrystal drug was subjected to solubility test, resulting in its solubility in a buffer solution with ph=6.8. The testing method comprises the following steps: high Performance Liquid Chromatography (HPLC), SHIMAZU, LC-20AT, detection wavelength 225nm, mobile phase 0.01mol/L monoammonium phosphate solution (pH=3.2.+ -. 0.1 adjusted with trifluoroacetic acid): acetonitrile-methanol (50-50) =80:20 (volume ratio), flow rate 1.0mL/min, column temperature 25 ℃. The solubility of the co-crystals was determined in phosphate buffer at ph=6.8. Test temperature: 25.+ -. 0.1 ℃. The sample was sieved to a particle size in the range of 80-150 μm, an excess of sample of uniform particle size was added to a round bottom flask containing 5ml of buffer solution, and the round bottom flask containing the saturated solution was then placed in an oil bath at 25.+ -. 0.1 ℃ and stirred with a magnetic stirrer at 500rpm for a total of 1600 minutes. Extracting 0.2ml saturated solution at 2min, 5min, 10min, 20min, 30min, 40min, 60min, 80min, 120min, 1200min, 1400min, 1600min with a disposable syringe, filtering with a filter membrane with pore size of 0.22 μm, and measuring FPV content of the filtrate by high performance liquid chromatography. The test results are shown in figure 20, and the solubility of the fapirrevir-3, 5-dihydroxybenzoic acid eutectic medicament is improved by 4 times compared with that of the fapirrevir medicament.
And finally, carrying out flowability and tabletting tests on the obtained fapirrevir-3, 5-dihydroxybenzoic acid eutectic medicament, and carrying out repose angle tests by adopting a vertical funnel method. For tabletting property test, weighing proper amount of pure component of fampicvir or fampicvir pharmaceutical co-crystal, placing in a 10ml measuring cylinder, recording the initial scale, vibrating the measuring cylinder up and down with amplitude of 5-10mm, recording the scale after compaction, and finally calculating the ratio of the Carl coefficient to House according to a formula. The test results are shown in Table 2, and the tabletting property of the flow property of the fapirir-3, 5-dihydroxybenzoic acid eutectic medicament is improved compared with that of the fapirir medicament.
Example 5
The embodiment provides a method for preparing a fapirrevir-3, 4-dihydroxybenzoic acid eutectic based on a grinding method, which comprises the following steps: the starting material, fampicvir 62.84mg (0.4 mol), 3,4-dihydroxybenzoic acid 61.65mg (0.4 mol) was weighed into a milling jar and milled using a Retsch MM200 mill at 30Hz for 70min at room temperature (20-30 ℃), with 0.2ml acetonitrile to give the co-crystal product.
Example 6
The embodiment provides a method for preparing a fapirrevir-3, 4-dihydroxybenzoic acid pharmaceutical co-crystal based on a solution method, which comprises the following steps: the starting material, fampicvir 62.84mg (0.4 mol), 3,4-dihydroxybenzoic acid 61.65mg (0.4 mol) was weighed into a clean glass bottle (volume 20 ml) at room temperature, and 6ml acetonitrile: water (volume ratio = 1:1) was added. Adding cleaned magnons into a glass bottle filled with the solution, putting the glass bottle into an oil bath pot at 60 ℃, fully dissolving the medicines at the rotation speed of 500rpm, placing the glass bottle into a fume hood after the solution becomes clear, volatilizing at room temperature, and cooling and crystallizing for a period of time to obtain a eutectic product of the fampicvir and the 3,4-dihydroxybenzoic acid.
For the fapirrevir-3, 4-dihydroxybenzoic acid eutectic powder obtained in example 5, powder diffraction analysis was performed using a D8 advanced X-ray powder diffractometer manufactured by bruck corporation, cu-kα, tube voltage 40kV, tube current 40mA, step size 0.1, scan range 10-50 °, room temperature conditions. The powder X-ray diffraction pattern obtained is shown in fig. 3, wherein the angle of the eutectic characteristic peak 2 theta is:
6.51±1°，13.00±1°，13.67±1°，14.02±1°，14.41±1°，15.12±1°，16.81±1°，18.89±1°，19.67±1°，21.59±1°，23.08±1°，24.18±1°，24.89±1°，26.38±1°，26.77±1°，26.97±1°，28.22±1°，28.46±1°，29.05±1°，32.58±1°，35.05±1°，35.83±1°，36.62±1°，38.39±1°，39.17±1°，40.51±1°，41.88±1°。
example 5 the milled product was dissolved in acetonitrile or organic solvents such as ethanol, methanol, isopropanol, acetonitrile, acetone, DMSO, and slowly evaporated to crystallize, and a single crystal of good quality suitable for single crystal analysis was obtained. Example 6 can directly obtain a single crystal with a good quality suitable for single crystal analysis. The structure of the fampicvir-3, 4-dihydroxybenzoic acid eutectic obtained by single crystal structure analysis was shown in fig. 7 and 10, and the crystallographic information thereof was shown in table 1, using a D8 VENTURE double focal spot X-ray single crystal diffractometer manufactured by bruck corporation, germany, at room temperature.
The obtained fapirrevir-3, 4-dihydroxybenzoic acid eutectic is subjected to thermogravimetric analysis, data are collected in a American TA thermogravimetric analyzer TGA5500, a sample is heated from room temperature to 300 ℃ under the protection of nitrogen at a heating rate of 10 ℃/min, and meanwhile, the mass change of the sample in the heating process is recorded, and the obtained result is shown in figure 13.
And performing differential scanning calorimetric analysis on the obtained fapirrevir-3, 4-dihydroxybenzoic acid eutectic medicament, collecting data from a German relaxation-resistant DSC 214Polyma thermal analyzer, heating a sample from room temperature to 250 ℃ under the protection of nitrogen, and recording the heat change of the sample in the heating process by using software, wherein the obtained result is shown in figure 16.
In addition, the obtained fapirrevir-3, 4-dihydroxybenzoic acid eutectic drug is subjected to infrared spectrum analysis, and the data are collected at room temperature by a Nicolet Nexus670 Fourier infrared spectrometer of Nigaoli company of America, and the wave number is 4000-500cm -1 Resolution of 0.09cm -1 The obtained infrared spectrum is shown in fig. 19.
The obtained fepimara-3, 4-dihydroxybenzoic acid cocrystal drug was subjected to solubility test, resulting in its solubility in a buffer solution with ph=6.8. The testing method comprises the following steps: high Performance Liquid Chromatography (HPLC), SHIMAZU, LC-20AT, detection wavelength 225nm, mobile phase 0.01mol/L monoammonium phosphate solution (pH=3.2.+ -. 0.1 adjusted with trifluoroacetic acid): acetonitrile-methanol (50-50) =80:20 (volume ratio), flow rate 1.0mL/min, column temperature 25 ℃. The solubility of the co-crystals was determined in phosphate buffer at ph=6.8. Test temperature: 25.+ -. 0.1 ℃. The sample was sieved to a particle size in the range of 80-150 μm, an excess of sample of uniform particle size was added to a round bottom flask containing 5ml of buffer solution, and the round bottom flask containing the saturated solution was then placed in an oil bath at 25.+ -. 0.1 ℃ and stirred with a magnetic stirrer at 500rpm for a total of 1600 minutes. Extracting 0.2ml saturated solution at 2min, 5min, 10min, 20min, 30min, 40min, 60min, 80min, 120min, 1200min, 1400min, 1600min with a disposable syringe, filtering with a filter membrane with pore size of 0.22 μm, and measuring FPV content of the filtrate by high performance liquid chromatography. The test results are shown in figure 20, and the solubility of the fapirrevir-3, 5-dihydroxybenzoic acid eutectic medicament is improved by 6 times compared with that of the fapirrevir medicament.
And finally, carrying out flowability and tabletting tests on the obtained fapirrevir-3, 4-dihydroxybenzoic acid eutectic medicament, and carrying out repose angle tests by adopting a vertical funnel method. For tabletting property test, weighing proper amount of pure component of fampicvir or fampicvir pharmaceutical co-crystal, placing in a 10ml measuring cylinder, recording the initial scale, vibrating the measuring cylinder up and down with amplitude of 5-10mm, recording the scale after compaction, and finally calculating the ratio of the Carl coefficient to House according to a formula. The test results are shown in Table 2, and the tabletting property of the flow property of the fapirir-3, 4-dihydroxybenzoic acid eutectic medicament is improved compared with that of the fapirir medicament.
Table 1: crystal parameters of the co-crystal of famprivir and m-hydroxybenzoic acid, the co-crystal of famprivir and 3,5-dihydroxybenzoic acid and the co-crystal of famprivir and 3,4-dihydroxybenzoic acid
Table 2: flow and tabletting property test table for fapirrevir eutectic
The invention is not a matter of the known technology.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. The fapirrevir pharmaceutical co-crystal is characterized by comprising the following raw materials in parts by weight:
a) Fampicvir;
b) Any one of m-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid;
wherein the molar ratio of a) to b) is controlled to be 1:1;
when the raw material components are the fampicvir and the m-hydroxybenzoic acid, the space group in the fampicvir pharmaceutical co-crystal is P2 1 /cSpecific unit cell parameters are:
a=7.3142 Å；b=24.5457 Å；c=7.6447 Å；α=90°；β=114.902°；γ=90°；V=1244.87 Å 3 ；
when the raw material components are the fampicvir and the 3,4-dihydroxybenzoic acid, the space group in the fampicvir pharmaceutical co-crystal isCcSpecific unit cell parameters are:
a=7.5226 Å；b=24.0085 Å；c=7.9116 Å；α=90°；β=115.514°；γ=90°；V=1289.54 Å 3 ；
when the raw material components are the fampicvir and the 3,5-dihydroxybenzoic acid, the space group in the fampicvir pharmaceutical co-crystal is P2 1 /cSpecific unit cell parameters are:
a=7.1639 Å；b=27.1635 Å；c=7.8442 Å；α=90°；β=115.290°；γ=90°；V=1378.78 Å 3 。
2. a method for preparing a co-crystal of fampicvir and m-hydroxybenzoic acid according to claim 1, wherein 62.84mg of fampicvir and 55.25mg of m-hydroxybenzoic acid are precisely weighed, the sample is placed in a grinding pot, and a co-crystal product is obtained by grinding with a Retsch MM200 grinding instrument at a frequency of 30Hz for 70min at room temperature and adding 0.2ml of acetonitrile.
3. A method for preparing a co-crystal of fampicvir and 3,4-dihydroxybenzoic acid as claimed in claim 1, wherein the raw material fampicvir 62.84mg,3, 5-dihydroxybenzoic acid 61.65mg is precisely weighed, the sample is placed in a grinding tank, and a co-crystal product is obtained by grinding with a Retsch MM200 grinding instrument at a frequency of 30Hz for 70min at room temperature and adding 0.2ml acetonitrile.
4. A method for preparing a co-crystal of fampicvir and 3,5-dihydroxybenzoic acid as claimed in claim 1, wherein the raw material fampicvir 62.84mg,3, 4-dihydroxybenzoic acid 61.65mg is precisely weighed, the sample is placed in a grinding tank, and a co-crystal product is obtained by grinding with a Retsch MM200 grinding instrument at a frequency of 30Hz for 70min at room temperature and with 0.2ml acetonitrile.
5. The use of the fampicin pharmaceutical co-crystal of claim 1 in the preparation of a fampicin pharmaceutical formulation.
6. A pharmaceutical formulation of famprivir, comprising a famprivir pharmaceutical co-crystal according to claim 1, together with one or more pharmaceutically acceptable carriers.
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| CN113461621A (en) * | 2021-06-22 | 2021-10-01 | 北京石油化工学院 | Favipiravir pharmaceutical co-crystal and preparation method and application thereof |
| CN114057656A (en) * | 2020-08-05 | 2022-02-18 | 广东东阳光药业有限公司 | Favipiravir eutectic crystal and preparation method thereof |
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| CN114057656A (en) * | 2020-08-05 | 2022-02-18 | 广东东阳光药业有限公司 | Favipiravir eutectic crystal and preparation method thereof |
| CN113461621A (en) * | 2021-06-22 | 2021-10-01 | 北京石油化工学院 | Favipiravir pharmaceutical co-crystal and preparation method and application thereof |
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| Title |
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| "Mechanosynthesis, Characterization, and Physicochemical Property Investigation of a Favipiravir Cocrystal with Theophylline and GRAS Coformers";Poonam Deka，et al.;《Crystal Growth & Design》;第21卷(第8期);第4417−4425页 * |
| "药物-药物共晶的研究进展";孙晶晶等;《化工学报》;第72卷(第2期);第828-840页 * |
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