CN115572292A - Berberine succinate crystal form, preparation method, composition and application thereof - Google Patents
Berberine succinate crystal form, preparation method, composition and application thereof Download PDFInfo
- Publication number
- CN115572292A CN115572292A CN202211320647.3A CN202211320647A CN115572292A CN 115572292 A CN115572292 A CN 115572292A CN 202211320647 A CN202211320647 A CN 202211320647A CN 115572292 A CN115572292 A CN 115572292A
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- CN
- China
- Prior art keywords
- berberine
- succinate
- crystal form
- succinate crystal
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229940093265 berberine Drugs 0.000 title claims abstract description 120
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 title claims abstract description 119
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 title claims abstract description 114
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid group Chemical group C(CCC(=O)O)(=O)O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 35
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- 230000007704 transition Effects 0.000 description 1
- JFJZZMVDLULRGK-URLMMPGGSA-O tubocurarine Chemical compound C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CCN3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 JFJZZMVDLULRGK-URLMMPGGSA-O 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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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
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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
- A61P31/04—Antibacterial agents
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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
- A61P31/10—Antimycotics
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
-
- 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a berberine succinate crystal form, a preparation method, a composition and an application thereof. Specifically, the invention discloses a solid state form of berberine succinate crystal form; a preparation method of berberine succinate crystal form; the berberine succinate crystal form is used as a medicinal active ingredient in the application of medicaments for treating and preventing bacteria, inflammation, blood fat and blood sugar, viruses, cardiovascular and cerebrovascular diseases, cancers and infection resistance. The berberine succinate crystal form formed by the invention has good stability, the solubility of the berberine succinate crystal form is obviously improved compared with the berberine hydrochloride sold in the market, the problems of poor stability and low solubility of the berberine hydrochloride sold in the market can be solved, and the berberine hydrochloride crystal form is beneficial to exerting the curative effect of the berberine; in addition, the method has the advantages of simple reaction conditions, good reproducibility, easy industrial production and good application and development prospects.
Description
Technical Field
The invention discloses a berberine succinate crystal form, a preparation method, a composition and an application thereof; specifically, the invention discloses a solid state form of berberine succinate crystal form; a method for preparing a crystalline solid form of berberine succinate; the solid form containing berberine succinate crystal is used in preparing medicine for preventing and treating bacteria, inflammation, blood fat and blood sugar, virus and cardiovascular and cerebrovascular diseases, cancer and infection.
Background
The solid crystal forms of the drug mainly include polymorphism, hydrate, solvate, salt, eutectic and the like, the physicochemical properties of different solid forms of the same active ingredient, such as solubility, dissolution rate, stability and the like, may have great differences, and the physicochemical properties are different, which may affect the stability and absorption of the drug and further affect the curative effect of the drug. The search for suitable solid forms of drugs, which often exert the best therapeutic effect, has been the focus of research in pharmaceutics. Among them, the salt formation of ionizable drugs is one of the most effective means for improving the physicochemical properties thereof.
Berberine hydrochloride (formula 1) is an isoquinoline alkaloid, and is mainly used for treating gastroenteritis and diarrhea caused by bacteria in clinic. In recent years, berberine is found to have good activities of resisting arrhythmia, resisting platelet aggregation, resisting cerebral ischemia, resisting tumor, reducing blood sugar, resisting virus, resisting inflammation and the like. Therefore, researchers have been working on developing berberine drugs with new clinical indications. Berberine hydrochloride exists in four solid forms including anhydrate, monohydrate, dihydrate and tetrahydrate. The anhydrate and monohydrate are significantly hygroscopic and readily convert to the dihydrate at 12% humidity. Humidity above 70% will further induce the transition from dihydrate to tetrahydrate. Thus, commercially available berberine hydrochloride is usually a mixture of its dihydrate and tetrahydrate. Environmental changes may also promote changes in the solid state form of commercially available berberine hydrochloride, however, changes in the solid state form are detrimental to its clinical treatment. In addition, the bioavailability of berberine hydrochloride is very low, only about 1%. Poor solubility is one of the main reasons for low bioavailability, and seriously affects further development thereof.
Formula 1: molecular structural formula of berberine hydrochloride
In view of changing the berberine salt type and hopefully improving the physicochemical property, the invention adopts succinic acid as counter ion (formula 2) to synthesize berberine succinate to improve the problems of poor stability and low solubility of the market-sold form; found by the research of the literature, no report of the crystal form of the berberine succinate still exists at present, so that the development of the crystal form of the berberine succinate has important significance and good application prospect.
Formula 2: the molecular structural formula of the succinic acid is shown.
Disclosure of Invention
One of the objects of the present invention is: provides the existence state and the characterization mode of the crystal form of the berberine succinate.
The second purpose of the invention is that: provides a preparation method of berberine succinate crystal form.
The third purpose of the invention is: provides crystal forms containing berberine succinate and pharmaceutical compositions thereof.
The fourth purpose of the invention is: provides a pharmaceutical composition using the crystal form of berberine succinate as a pharmaceutical active ingredient, wherein the daily dosage of the crystal form of berberine succinate is within the range of 20-5000 mg. The pharmaceutical composition comprises tablets, capsules, injection preparations, pills and sustained-release or controlled-release preparation medicaments.
The fifth purpose of the invention is: provides berberine succinate crystal form substance which is obviously superior to berberine hydrochloride in stability.
The sixth purpose of the invention is: provides berberine succinate crystal form substance which is obviously superior to berberine hydrochloride in solubility.
The seventh purpose of the invention is: the berberine succinate crystal form is used as the effective component of the medicine in preparing the medicine for preventing and treating bacteria, inflammation, blood fat and blood sugar, virus and cardiovascular and cerebrovascular diseases, cancer and infection.
In order to achieve the purpose, the invention adopts the technical scheme that:
1. the morphological characteristics of the berberine succinate crystal form sample are as follows:
1.1 the berberine succinate crystal form related to the invention is a salt formed by berberine and succinic acid in a non-covalent bond according to the molar ratio of 2.
1.2 the berberine succinate crystal form of the invention is represented as monoclinic system when 100K is analyzed by single crystal X-ray diffraction, and the space group isP21/cUnit cell parameters a/a =14.920 (2), b/a =21.908 (2), c/a =14.555 (2), α/° γ/° 90, β/° 107.68 (2), V =4533.1 (4)/a 3 Z =4, molecular formula: 2 (C) 20 H 18 NO 4 )·C 4 H 4 O 4 ·2(C 4 H 6 O 4 )。
1.3 Berberine succinate Crystal form according to the invention, when analyzed by powder X-ray diffraction Using CuKαWhen the radiation experiment condition is adopted, the diffraction peak positions are mainly located at the degrees of 7.4 +/-0.2, 8.0 +/-0.2, 10.8 +/-0.2, 12.4 +/-0.2, 12.9 +/-0.2, 13.5 +/-0.2, 14.7 +/-0.2, 16.0 +/-0.2, 16.8 +/-0.2, 17.0 +/-0.2, 17.6 +/-0.2, 18.9 +/-0.2, 19.4 +/-0.2, 19.7 +/-0.2, 20.3 +/-0.2, 21.8 +/-0.2, 22.5 +/-0.2, 22.9 +/-0.2, 23.5 +/-0.2, 23.9 +/-0.2, 24.6, 26.5 +/-0, 26.0, 26.9 +/-0.2, 26.0.2, 26.9 +/-0.2, 26.2, 26.0.2.2º,30.7±0.2º,31.6±0.2º,35.4±0.2º。
1.4 when the crystal form of berberine succinate related to the invention is analyzed by attenuated total reflection Fourier infrared spectroscopy, the crystal form is mainly 3093 +/-5, 3061 +/-5, 3042 +/-5, 3008 +/-5, 2946 +/-5, 2915 +/-5, 2848 +/-5, 1693 +/-5, 1634 +/-5, 1615 +/-5, 1597 +/-5, 1567 +/-5, 1499 +/-5, 1474 +/-5, 1451 +/-5, 1435 +/-5, 1386 +/-5, 1365 +/-5, 1337 +/-5, 1367 +/-5, 1255 +/-5, 1225 +/-1199 +/-5, 1141 +/-5, 1097 +/-5, 1064 +/-5, 1024 +/-5, 995 +/-5, 968 +/-5, 927 +/-5, 909 +/-5 and 618 +/-5 cm -1 There exists a characteristic peak of infrared spectrum.
1.5 when analyzed by differential scanning calorimetry, the crystal form of berberine succinate of the invention shows that 1 endothermic peak exists at 223 +/-5 ℃ in a DSC chart when the temperature rise rate is 10 ℃ per minute.
2. The preparation method of the berberine succinate crystal form and the mixed solid substance is characterized in that:
2.1 the berberine succinate crystal form related to the invention is prepared by taking 8-hydroxy-dihydroberberine (formula 3) and succinic acid as raw materials, putting the raw materials into water or a mixed solvent of water and an organic solvent according to a molar ratio of 1: 0.7-1, stirring or dissolving the raw materials at 20-70 ℃, volatilizing or dissolving the mixture by the solvent, cooling and recrystallizing the mixture, and finally filtering and drying the mixture. The organic solvent is methanol, ethanol, N-propanol, isopropanol, N-butanol, ethylene glycol, acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N-dimethylacetamide or N, N-dimethylformamide; the ratio of the total mass of the 8-hydroxy-dihydroberberine and the succinic acid to the dosage of the solvent is 1g: (1 to 200) ml.
Formula 3: molecular structural formula of 8-hydroxy-dihydroberberine
3. The pharmaceutical preparation composition containing the berberine succinate crystal form component, the administration dosage characteristics and the pharmaceutical application are as follows:
3.1 the pharmaceutical composition of the invention contains berberine succinate crystal form and pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition of the invention has the daily dosage of the berberine succinate crystal form within the range of 20-5000 mg.
3.3 the pharmaceutical composition of the present invention is characterized in that the pharmaceutical composition is various tablets, capsules, injectable preparations, pills, sustained-release preparations or controlled-release preparations.
3.4 the invention relates to the application of berberine succinate crystal form or pharmaceutical composition in preparing the medicines for preventing and treating bacteria, inflammation, blood fat and blood sugar, virus, cardiovascular and cerebrovascular diseases, cancer and infection.
The invention relates to a pharmaceutical composition taking the crystal form of berberine succinate as an active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The berberine succinate crystal form component can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or auxiliary agents to prepare any preparation formulation suitable for human or animal use.
The content of the berberine succinate crystal form in the pharmaceutical composition is within the range of 1-99% by weight.
The berberine succinate crystal form can be administrated in a unit dosage form, and the administration route can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, lung, skin, vagina, rectum and the like.
The administration form according to the invention is preferably a solid form. The solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, etc.
The berberine succinate crystal form can be prepared into a common preparation, a slow release preparation, a controlled release preparation, a targeting preparation and various microparticle drug delivery systems. In order to prepare the crystal form of berberine succinate of the invention into tablets, various excipients known in the art can be widely used, including diluents, wetting agents, binders, disintegrants, lubricants, glidants. The diluent can be dextrin, starch, sucrose, lactose, glucose, sorbitol, mannitol, xylitol, microcrystalline cellulose, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, etc.; the humectant can be water, ethanol, etc.; the binder can be dextrin, starch slurry, syrup, glucose solution, mel, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be microcrystalline cellulose, dry starch, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. In order to prepare the administration unit into a capsule, the crystal form of berberine succinate as an active ingredient can be mixed with a diluent and a glidant, and the mixture is directly placed into a hard capsule or a soft capsule. Or the crystal form of the berberine succinate of the effective component can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrating agents and glidants used for preparing the berberine succinate crystal form tablets can also be used for preparing the berberine succinate crystal form capsules. In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired. For the purpose of administration and enhancing the therapeutic effect, the drug of the present invention can be administered by any known administration method.
The administration dosage of the berberine succinate crystal form pharmaceutical composition can be widely changed according to the nature and severity of diseases to be prevented and treated, individual conditions of patients or animals, administration routes, dosage forms and the like. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The berberine succinate crystal form or the composition can be independently taken or used together with other therapeutic drugs or symptomatic drugs. When the berberine succinate crystal form of the invention has synergistic effect with other therapeutic drugs, the dosage of the berberine succinate crystal form of the invention is adjusted according to actual conditions.
4. The invention has the beneficial technical effects that:
4.1 the berberine succinate crystal form of the invention has good stability, can not generate phase change under the conditions of high temperature, high humidity and illumination, and is more stable as a medicine raw material in the preparation production and storage processes.
4.2 the berberine succinate crystal form does not contain any crystallization solvent, and has good safety and patent medicine advantages.
4.3 the solubility of berberine succinate formed by the invention is obviously higher than that of berberine hydrochloride.
4.4 the preparation method of the berberine succinate crystal form of the invention is simple and easy to implement, has mild and easily controlled conditions, good reproducibility, easy realization of large-scale industrial production, low production cost and great commercial application value.
Drawings
Figure 1 powder X-ray diffraction pattern of berberine succinate crystal form;
figure 2 crystal structure diagram of berberine succinate crystal form;
figure 3 unit cell stacking diagram of berberine succinate crystal form;
FIG. 4 thermal analysis (TG-DSC) of berberine succinate crystal form;
figure 5 Infrared (IR) spectrum of berberine succinate crystal form;
figure 6 dissolution profile of berberine succinate crystal form;
figure 7 is an influence factor test map of berberine succinate crystal form.
Detailed Description
The technical features of the present invention are further illustrated by the following specific embodiments and the accompanying drawings, which are intended to enable persons skilled in the relevant art to understand the present invention and to implement the present invention, but not to limit the protection scope of the present invention. Further, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the teaching of the present invention, but these equivalents also fall within the scope of the claims appended to the present application.
The instrument and the method for detecting the crystal structure and the property of the berberine succinate provided by the invention are as follows:
single crystal diffraction characterization: bruker APEX-IID 8X-ray single crystal diffractometer usingSHELXTLAndOLEXcarrying out structural analysis and correction; using Mercury andOLEXthe software obtains a structure map.
Powder X-ray diffraction (PXRD) characterization: the instrument comprises: bruker D8Advance, cuKαRadiation, power 40kV,40mA; detection conditions are as follows: the scanning range 2 theta is 5-50 degrees, the scanning speed is 4 degrees/min, and the testing temperature is 20 degrees.
Thermal analysis (TG-DSC) characterization: the instrument comprises the following steps: the detection conditions of ZCT-BDSC/TGA of Beijing, kyoto, kogaku instruments Co., ltd: placing the sample in an open crucible, and raising the temperature: 10 ℃/min, temperature range: 40 to 300 ℃.
Fourier Infrared (IR) characterization: the instrument comprises the following steps: fourier transform Infrared Spectroscopy (ThermoFisher, inc., nicolet NexusIS5, ATR method, USA); detection conditions are as follows: the scanning wave band is 4000-500 cm -1 Resolution ratio: 5cm -1 。
Influence factor experiment: placing the berberine succinate crystal form sample in an open clean surface dish, respectively placing the sample in an environment of 60 ℃, 90% +/-5% (25 ℃) or 4500lx +/-500 lx (25 ℃) for 10 days for sampling, and testing by using IR.
And (3) dissolving out the medicine: the instrument is an SHZ-A water bath constant temperature oscillator (Shanghai Boxun industries, ltd.) medical equipment factory; a detector: an L8 ultraviolet spectrophotometer (shanghai seminaceae analytical instrument ltd); the dissolution medium is dilute hydrochloric acid solution (pH = 1.2); weighing an excessive sample into 30mL of medium; shaking rate: 100 revolutions per minute; temperature: 37 ℃; sampling time: 5. 10, 20, 30, 45, 60, 90, 120 and 180 minutes; sampling 0.5mL, filtering, diluting berberine hydrochloride and berberine succinate by 100 and 400 times respectively, and testing.
Preparation method of berberine succinate crystal sample 1
Weighing 8-hydroxy-dihydroberberine and succinic acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the succinic acid to the solvent is 1.
Preparation method of berberine succinate crystal form sample 2
Weighing 8-hydroxy-dihydroberberine and succinic acid in a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the succinic acid to the solvent is 1.
Preparation method of berberine succinate crystal sample 3
Weighing 8-hydroxy-dihydroberberine and succinic acid with a molar ratio of 1.5 to 1.5, adding into acetonitrile-water (volume ratio is 2; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the succinic acid to the solvent is 1.
Preparation method of berberine succinate crystal form sample 4
Weighing 8-hydroxy-dihydroberberine and succinic acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the succinic acid to the solvent is 1.
Preparation method of berberine succinate crystal form sample 5
Weighing 8-hydroxy-dihydroberberine and succinic acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the succinic acid to the water is 1.
When tested at 100K, the berberine succinate crystals prepared by the preparation methods 1-5 belong to a monoclinic system with a space group ofP21/cUnit cell parameters a/a =14.920 (2), b/a =21.908 (2), c/a =14.555 (2), α/° γ/° 90, β/° 107.68 (2), V =4533.1 (4)/a 3 Z =4, formula: 2 (C) 20 H 18 NO 4 )·C 4 H 4 O 4 ·2(C 4 H 6 O 4 )。
The powder X-ray diagram positions are represented by 2 theta angles at the angles of 7.4 +/-0.2, 8.0 +/-0.2, 10.8 +/-0.2, 12.4 +/-0.2, 12.9 +/-0.2, 13.5 +/-0.2, 14.7 +/-0.2, 16.0 +/-0.2, 16.8 +/-0.2, 17.0 +/-0.2, 17.6 +/-0.2, 18.9 +/-0.2, 19.4 +/-0.2, 19.7 +/-0.2, 20.3 +/-0.2, 21.8 +/-0.2, 22.5 +/-0.2, 22.9 +/-0, 23.5 +/-0.2, 23.9 +/-0.2, 24.6, 25.5 +/-0, 25.5 +/-0.2, 25.0.2, 25 +/-0.2, 25.0.2, 25.9 +/-0.2, 25.2, 26.0.2, 25.0.2, 25 +/-0.2, 26.0.2, 26.1.0.2, 26, 25 +/-0.2, 26.2, 26.0.2.
The crystal form of berberine succinate prepared by the preparation method 1 is tested, and the test result is shown in figures 1-5. Figure 1 is a PXRD pattern for the berberine succinate crystal form. FIG. 2 is a crystal structure diagram of berberine succinate crystal form; figure 3 is a diagram of the stacking of the unit cells of the berberine succinate crystal form. The crystallographic parameters are shown in table 1.
Table 1: crystallographic parameters of berberine succinate crystal form
FIG. 4 is a TG and DSC spectra of berberine succinate crystal form; TG atlas shows that the mass loss is 28.5 +/-5.0% in the temperature range of 210-290 ℃, and DSC atlas shows that 1 endothermic peak exists at 223 +/-5 ℃ in combination with DSC curve.
FIG. 5 shows berberine succinate crystal form, infrared spectrum characteristic peak position (cm) -1 ) 3093 + -5, 3061 + -5, 3042 + -5, 3008 + -5, 2946 + -5, 2915 + -5, 2848 + -5, 1693 + -5, 1634 + -5, 1615 + -5, 1597 + -5, 1567 + -5, 1499 + -5, 1474 + -5, 1451 + -5, 1435 + -5, 1386 + -5, 1365 + -5, 1337 + -5, 1367 + -5, 1255 + -5, 1225 + -5, 1199 + -5, 1141 + -5, 1097 + -5, 1064 + -5, 1024 + -5, 995 + -5, 968 + -5, 927 + -5, 909 + -5, 618 + -5 cm -1 There exists a characteristic peak of infrared spectrum.
FIG. 6 is a graph showing the dissolution profile of berberine succinate powder of example 1; the amounts of berberine dissolved out in 3 hours by berberine hydrochloride and berberine succinate are respectively 2.1 [ mu ] mol/mL and 19.1 [ mu ] mol/mL.
Stability characteristics of berberine succinate crystal form
Figure 7 is a stability profile of the berberine succinate crystal form of example 1.
High-temperature test: placing the berberine succinate crystal form sample in a clean surface dish with an opening, placing the sample at the temperature of 60 ℃ for 10 days, sampling and carrying out IR analysis, wherein the spectrum of the sample is consistent with 0 day, and the result shows that the berberine succinate crystal form is stable under a high-temperature influence factor test.
High humidity test: placing a berberine succinate crystal form sample in a clean surface dish with an opening, placing for 10 days under the condition of humidity of 90% +/-5% (25 ℃), sampling for IR analysis, wherein the spectrum is consistent with 0 day, and the result shows that the berberine succinate crystal form is stable under the high-humidity influence factor test.
And (3) illumination test: placing the berberine succinate crystal form sample in a clean surface dish with an opening, placing the sample for 10 days under the condition of 4500lx +/-500 lx (25 ℃) of illumination, sampling and carrying out IR analysis, wherein the spectrum of the sample is consistent with 0 day, and the result shows that the berberine succinate crystal form is stable under the illumination influence factor test.
Method for the preparation of a combined pharmaceutical preparation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that a crystal form of berberine succinate is used as a raw material medicine of a combined medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, tablet samples with medicine content of 20 to 500mg are prepared according to a certain proportion, and the formula proportion of the tablet is given in a table 2:
TABLE 2 preparation formula of berberine succinate crystal form tablet
The method for preparing the berberine succinate crystal form into the tablet preparation comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into soft material, sieving, granulating, oven drying, sieving, grading, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Method 2 of preparation of the combined pharmaceutical preparation (capsule):
a preparation method of a combined medicine capsule is characterized in that a crystal form of berberine succinate is used as a raw material medicine of a combined medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine capsule, capsule samples with medicine content of 20 to 500mg are prepared according to a certain proportion, and the formula proportion of the capsule is given in a table 3:
TABLE 3 bulk drug and adjuvant formulation of berberine succinate crystal form combined drug capsule preparation
The method for preparing the berberine succinate crystal form into the capsule preparation comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into wet granules, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing 1-99% berberine succinate crystal form raw material medicine with a plurality of excipient auxiliary materials without granulating step, sieving, and directly encapsulating to obtain the final product.
The administration dose 1 (tablet) of the berberine succinate crystal form combined medicine is as follows:
the pharmaceutical composition prepared and developed by using the crystal form of the berberine succinate as the active ingredient of the medicine is characterized in that the crystal form of the berberine succinate is used as the active ingredient of the medicine, the daily administration dose is 900mg, and the pharmaceutical composition can be respectively prepared into 3 common tablets of 100mg 3 times a day each time and 1 common tablet of 300mg 3 times a day each time.
Administration dose 2 (capsule) of berberine succinate crystal form:
the berberine succinate crystal form sample is used as the active ingredient of the medicine for preparing and developing the medicine composition, which is characterized in that the berberine succinate crystal form is used as the active ingredient of the medicine, the daily administration dosage is 900mg, and 3 times/each time of 100mg capsules can be respectively prepared, and 3 times/1 time/3 mg capsules each time can be respectively prepared.
Problems to be explained are: the berberine succinate crystal form pharmaceutical composition provided by the invention has many factors on the administration dosage of the effective components, such as: the application of the composition for preventing and treating the diseases is different, so that the daily dosage is different; the nature and severity of the disease cause different daily doses; the daily dosage of the medicament is different due to different sexes, ages and body surface areas of patients, different administration routes, administration times and treatment purposes; in addition, the difference of absorption and blood concentration existing among samples also causes that the daily proper dosage range of the berberine succinate crystal form used in the invention is 0.3-70mg/kg body weight, preferably 5-30mg/kg body weight. When in use, different total dosage schemes of the crystal form active ingredients of the berberine succinate are made according to the actual requirements of preventing and treating different conditions, and the administration can be completed in a multi-time or one-time mode.
Claims (11)
1. A berberine succinate crystal form, characterized in that berberine and succinic acid form a salt crystal form in a molar ratio of 2.
2. The crystal form of berberine succinate according to claim 1, wherein the basic structural unit consists of 2 berberine cations, 1 succinate anion and 2 succinate molecules, under the test condition of 100K, the crystal form of berberine succinate belongs to a monoclinic system, and the space group isP21/cUnit cell parameters a/a =14.920 (2), b/a =21.908 (2), c/a =14.555 (2), α/° γ/° =90, β/° 107.68 (2), V =4533.1 (4)/a 3 Z =4, formula: 2 (C) 20 H 18 NO 4 )·C 4 H 4 O 4 ·2(C 4 H 6 O 4 )·。
3. The crystalline form of berberine succinate according to claim 1, characterized in that the powder X-ray pattern positions are expressed at angles of 2 θ at 7.4 ± 0.2 °,8.0 ± 0.2 °,10.8 ± 0.2 °,12.4 ± 0.2 °,12.9 ± 0.2 °,13.5 ± 0.2 °,14.7 ± 0.2 °,16.0 ± 0.2 °,16.8 ± 0.2 °,17.0 ± 0.2 °,17.6 ± 0.2 °,18.9 ± 0.2 °,19.4 ± 0.2 °,19.7 ± 0.2 °,20.3 ± 0.2 °,21.8 ± 0.2 °,22.5 ± 0.2 °,22.9 ± 0.2 °,23.5 ± 0.2 °, 20.2 ± 0.0 °,21.8 ± 0.2 °,22.5 ± 0.2 °,22.9 ± 0.2 °, 23.0 ± 0.1.2 °, 25.1.0 ± 0.2 °, 12.1.0 °, 12.0.2 °, 12.0.1 ± 0.2 °, 26.1.2 °, 12.0.0 ° and 12.2 ° 2.0.1 ± 0.2 ° 2 ° 12.0.0.26.1.2 ° 1.2 ° of the main diffraction peaks.
4. A crystalline form of berberine succinate according to claim 1, characterised in that it has a crystal size, when analysed by IR spectroscopy, of 3093 ± 5, 3061 ± 5, 3042 ± 5, 3008 ± 5, 2946 ± 5, 2915 ± 5, 2848 ± 5, 1693 ± 5, 1634 ± 5, 1615 ± 5, 1597 ± 5, 1567 ± 5, 1499 ± 5, 1474 ± 5, 1451 ± 5, 1435 ± 5, 1386 ± 5, 1365 ± 5, 1337 ± 5, 1367 ± 5, 1255 ± 5, 1225, 1199 ± 5, 1141 ± 5, 1097 ± 5, 1064 ± 5, 1024 ± 5, 995 ± 5, 968 ± 5, 927 ± 5, 909 ± 5, 618 ± 5cm ± 5 -1 There exists a characteristic peak of infrared spectrum.
5. The crystalline form of berberine succinate according to claim 1, characterised in that it exhibits 1 endothermic peak at 223 ± 5 ℃ in a DSC profile when the temperature rise rate is 10 ℃ per minute, when analysed using differential scanning calorimetry.
6. The berberine succinate crystal form according to any one of claims 1 to 5, which is characterized in that 8-hydroxy-dihydroberberine and succinic acid are used as raw materials, the raw materials are placed in water or a mixed solvent of water and an organic solvent according to a molar ratio of 1.7 to 1, and the mixture is stirred or dissolved at 20 to 70 ℃, then volatilized or dissolved by the solvent, cooled and recrystallized, and finally filtered and dried to obtain the berberine succinate crystal form.
7. The method according to claim 6, wherein the organic solvent is methanol, ethanol, N-propanol, isopropanol, N-butanol, ethylene glycol, acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N-dimethylacetamide, or N, N-dimethylformamide; the ratio of the total mass of the 8-hydroxy-dihydroberberine and the succinic acid to the dosage of the solvent is 1g: (1 to 200) ml.
8. A pharmaceutical composition, comprising an effective amount of the crystalline solid berberine succinate substance according to claims 1-5 and a pharmaceutically acceptable carrier.
9. Pharmaceutical composition according to claim 8, characterized in that the daily dose of the crystalline form of berberine succinate is in the range of 20-5000 mg.
10. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is in the form of a tablet, a capsule, an injectable formulation, a pill, a sustained release formulation or a controlled release formulation.
11. Use of the crystalline form of berberine succinate according to claims 1-5 or the pharmaceutical composition according to claim 8 for the preparation of a medicament for the prevention and treatment of antibacterial, anti-inflammatory, hypolipidemic, hypoglycemic, antiviral, cardiovascular and cerebrovascular diseases, anticancer and anti-infective medicament.
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