CN115477647A - Berberine fumarate crystal form, preparation method, composition and application thereof - Google Patents
Berberine fumarate crystal form, preparation method, composition and application thereof Download PDFInfo
- Publication number
- CN115477647A CN115477647A CN202211321204.6A CN202211321204A CN115477647A CN 115477647 A CN115477647 A CN 115477647A CN 202211321204 A CN202211321204 A CN 202211321204A CN 115477647 A CN115477647 A CN 115477647A
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- Prior art keywords
- berberine
- fumarate
- crystalline form
- crystal form
- preparation
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Abstract
The invention discloses a berberine fumarate crystal form, a preparation method, a composition and an application thereof. Specifically, the invention discloses solid-state forms of 3 berberine fumarate crystal forms; a preparation method of 3 berberine fumarate crystal forms; the 3 berberine fumarate crystal forms are used as medicinal active ingredients for treating and preventing antibacterial, antiinflammatory, blood lipid reducing, blood glucose reducing, antivirus, cardiovascular disease and cerebrovascular disease, anticancer and anti-infective drugs. The 3 berberine fumarate crystal forms formed by the invention have good stability, and can solve the problem of poor stability of commercially available berberine hydrochloride; compared with the commercially available berberine hydrochloride, the solubility of the new salt obtained by the invention is obviously improved; 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 3 berberine fumarate crystal forms, a preparation method, a composition and an application thereof; specifically, the invention discloses solid-state forms of 3 berberine fumarate crystal forms; a process for the preparation of 3 crystalline solid forms of berberine fumarate; the solid form containing berberine fumarate crystal form is used for preparing medicines for preventing and treating antibacterial, antiinflammatory, blood lipid and blood glucose reducing, antivirus, cardiovascular disease and cerebrovascular disease, anticancer and anti-infection.
Background
The solid crystal form of the drug mainly comprises a polymorphism, a hydrate, a solvate, a salt, a eutectic crystal and the like, the physical and chemical properties of different solid forms of the same active ingredient, such as solubility, dissolution rate, stability and the like, can have great difference, and the physical and chemical properties are different, so that the stability and absorption of the drug can be influenced, and the curative effect of the drug can be further influenced. The search for suitable solid forms of drugs, which often exert the best therapeutic effect of the drug, 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 clinically treating gastroenteritis and diarrhea caused by bacteria. In recent years, berberine is found to have good activities of resisting arrhythmia, resisting platelet aggregation, resisting cerebral ischemia, resisting tumors, reducing blood sugar, resisting viruses, 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% may further induce the transition from dihydrate to tetrahydrate. Therefore, 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 influences further development of the medicine.
Formula 1: molecular structural formula of berberine hydrochloride
In view of the hope of improving the physicochemical property of the berberine salt, the invention adopts fumaric acid as a counter ion (formula 2) to synthesize the berberine fumarate so as to improve the problems of poor stability and solubility of the commercially available form; according to the research of the literature, no report of the crystal form of the berberine fumarate exists at present, so that the development of the crystal form of the berberine fumarate has important significance and good application prospect.
Formula 2: the molecular structural formula of the fumaric acid.
Disclosure of Invention
One of the objects of the present invention is: provides the existence state and the characterization mode of 3 berberine fumarate crystal forms.
The second purpose of the invention is that: provides a preparation method of 3 berberine fumarate crystal forms.
The third purpose of the invention is: provides a pure product containing 3 crystal forms of berberine fumarate and a pharmaceutical composition thereof.
The fourth purpose of the invention is: provides a pharmaceutical composition using 3 berberine fumarate crystal forms as pharmaceutical active ingredients, wherein the daily dosage of the berberine fumarate crystal forms 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: the 3 berberine fumarate crystal-form substances provided are obviously superior to berberine hydrochloride in stability.
The sixth purpose of the invention is: the 3 berberine fumarate crystal-form substances provided are obviously superior to berberine hydrochloride in solubility
The seventh purpose of the invention is: the 3 berberine fumarate crystal forms are used as effective components of medicine in preparing medicine for preventing and treating bacteria, inflammation, blood fat, blood sugar, virus, 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 crystal form sample of the berberine fumarate are as follows:
1.1 the invention relates to a berberine fumarate crystal form, which is a salt formed by berberine and fumaric acid by non-covalent bonds according to the molar ratio of 2-berberine-1-fumarate to 2-berberine-1-fumarate.
1.2 the 2-berberine-1-fumarate of the present invention exhibits a triclinic system and a space group ofP-1Unit cell parameters a/a =8.58 (2), b/a =11.09 (2), c/a =23.29 (2), α/° 103.3 (2), β/° 97.1 (2), γ/° 92.5 (2), V =2134 (2)/a 3 Z =2, molecular formula: 2 (C) 20 H 18 NO 4 )·C 4 H 2 O 4 ·8(H 2 O)。
1.3 the 2-berberine-1-fumarate salt of the invention, when analyzed by powder X-ray diffraction using CuKαWhen the experimental conditions are radiated, the diffraction peak positions are mainly at 7.8 +/-0.2 degrees, 8.1 +/-0.2 degrees, 9.8 +/-0.2 degrees, 12.5 +/-0.2 degrees, 13.2 +/-0.2 degrees, 15.7 +/-0.2 degrees, 16.3 +/-0.2 degrees, 17.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.5 +/-0.2 degrees, 22.3 +/-0.2 degrees, 22.8 +/-0.2 degrees, 23.4 +/-0.2 degrees, 24.2 +/-0.2 degrees, 24.8 +/-0.2 degrees, 25.9 +/-0.2 degrees,26.3±0.2º,26.8±0.2º,28.5±0.2º,29.2±0.2º,29.5±0.2º,30.6±0.2º,31.9±0.2º,32.3±0.2º。
1.4 the 2-berberine-1-fumarate of the invention is mainly 3342 + -5, 3250 + -5, 3082 + -5, 3067 + -5, 3054 + -5, 3024 + -5, 2951 + -5, 2919 + -5, 2852 + -5, 1633 + -5, 1621 + -5, 1599 + -5, 1563 + -5, 1557 + -5, 1505 + -5, 1482 + -5, 1454 + -5, 1441 + -5, 1389 + -5, 1364 + -5, 1347 + -5, 1328 + -5, 1270 + -5, 1257 + -5, 1235 + -5, 1206 + -5, 1140 + -5, 1103 + -5, 1033 + -5, 991 + -5, 935 + -5, 909 + -5, 888 + -5, 807 + -5, 660 + -5, 625 + -5 cm + -5 -1 There exists a characteristic peak of infrared spectrum.
1.5 the 2-berberine-1-fumarate of the invention, when analyzed by differential scanning calorimetry, shows that 3 endothermic peaks are respectively at 115 +/-5 ℃, 135 +/-5 ℃ and 216 +/-5 ℃ in a DSC chart with a temperature rise rate of 10 ℃ per minute.
1.6 the invention relates to a berberine fumarate crystal form, which is a salt formed by berberine and fumaric acid by non-covalent bonds according to a molar ratio of 1.
1.7 the 1-berberine-1-fumarate according to the present invention exhibits a triclinic system with a space group of triclinic system when analyzed by single crystal X-ray diffraction at 100KP-1Unit cell parameters a/a =8.06 (2), b/a =10.92 (2), c/a =13.30 (2), α/° 70.0 (2), β/° 88.5 (2), γ/° 72.5 (2), V =1045 (2)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 4 H 3 O 4 ·H 2 O。
1.8 the 1-berberine-1-fumarate salt of the invention, when analyzed by powder X-ray diffraction using CuKαWhen the radiation experiment condition is adopted, the diffraction peak positions are mainly at 6.9 +/-0.2 degrees, 8.9 +/-0.2 degrees, 9.3 +/-0.2 degrees, 12.9 +/-0.2 degrees, 13.9 +/-0.2 degrees, 16.9 +/-0.2 degrees, 17.4 +/-0.2 degrees, 18.7 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.6 +/-0.2 degrees, 23.2 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.4 +/-0.2 degrees, 25.9 +/-0.2 degrees, 26.4 +/-0.2 degrees, 27.0 +/-0.2 degrees, 28.2 degrees and 29.2 degrees, wherein the degrees are +/-0.2 degrees.
1.9 the 1-berberine-1-fumarate of the invention is mainly characterized in that when attenuated total reflection Fourier infrared spectroscopy is used for analysis, the concentration is 3466 + -5, 3360 + -5, 3257 + -5, 3067 + -5, 3047 + -5, 2982 + -5, 2944 + -5, 2917 + -5, 2844 + -5, 1692 + -5, 1651 + -5, 1618 + -5, 1599 + -5, 1566 + -5, 1502 + -5, 1479 + -5, 1457 + -5, 1387 + -5, 1364 + -5, 1330 + -5, 1301 + -5, 1256 + -5, 1233 + -5, 1171 + -5, 1140 + -5, 1098 + -5, 1062 + -5, 1130 + -5, 991 + -5, 972 + -5, 955 + -5, 926 + -5, 910 + -5, 875 + -5, 829 + -5, 794 + -5, 636 + -5 cm + -5 -1 There exists a characteristic peak of infrared spectrum.
1.10 the 1-berberine-1-fumarate of the invention, when analyzed by differential scanning calorimetry, shows that 2 endothermic peaks in a DSC chart with a temperature rise rate of 10 ℃ per minute are respectively 110 ℃ plus or minus 5 ℃ and 246 ℃ plus or minus 5 ℃.
1.11 the invention relates to a berberine fumarate crystal form, which is a salt formed by berberine and fumaric acid by non-covalent bonds according to a molar ratio of 1:1.5, wherein the crystal form is 1-berberine-1.5-fumaric acid.
1.12 the 1-berberine-1.5-fumaric acid of the present invention exhibits a monoclinic system and a space group ofI2/aUnit cell parameters a/a =14.63 (2), b/a =22.16 (2), c/a =14.89 (2), α/° γ/° =90, β/° 107.7 (2), V =4599 (2)/a 3 Z =8, formula: c 20 H 18 NO 4 ·0.5(C 4 H 2 O 4 )·C 4 H 4 O 4 。
1.13 the 1-berberine-1.5-fumaric acid of the present invention, when analyzed by powder X-ray diffraction using CuKαWhen the radiation experiment condition is adopted, the diffraction peak positions are mainly located at 7.3 +/-0.2 degrees, 7.9 +/-0.2 degrees, 10.8 +/-0.2 degrees, 12.4 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.5 +/-0.2 degrees, 14.7 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.6 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.5 +/-0.2 degrees, 20.1 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.4 +/-0.2 degrees, 22.8 +/-0.2 degrees, 23.4 +/-0.2 degrees, 24.0 +/-0.2 degrees, 25.3 +/-0.2 degrees, 26.2 +/-0.2 degrees, 26.5 +/-0.2 degrees, 26.8 +/-0.2 degrees, and 13.8 +/-0.2 degrees.
1.14 the 1-berberine-1.5-fumaric acid of the invention is obtained by attenuated total reflection Fourier infrared spectroscopyOn line analysis, 3093 + -5, 3047 + -5, 2998 + -5, 2950 + -5, 2917 + -5, 2848 + -5, 1689 + -5, 1634 + -5, 1615 + -5, 1598 + -5, 1567 + -5, 1499 + -5, 1475 + -5, 1386 + -5, 1365 + -5, 1338 + -5, 1297 + -5, 1254 + -5, 1190 + -5, 1141 + -5, 1099 + -5, 1065 + -5, 1045 + -5, 1028 + -5, 998 + -5, 969 + -5, 963 + -5, 919 + -5, 909 + -5, 850 + -5, 831 + -5, 628 + -5 cm + -5 -1 There exists a characteristic peak of infrared spectrum.
1.15 the 1-berberine-1.5-fumaric acid of the invention shows that 1 endothermic peak exists at 241 ℃ plus or minus 5 ℃ in a DSC chart when the temperature rising rate is 10 ℃ per minute when being analyzed by a differential scanning calorimetry technology.
2. The preparation method of the crystal form of the berberine fumarate is characterized by comprising the following steps:
2.1 the berberine fumarate crystal form related to the invention is prepared by taking 8-hydroxy-dihydroberberine (formula 3) and fumaric acid as raw materials, placing the raw materials in a mixed solvent of water and an organic solvent, stirring or dissolving the raw materials at the temperature of 20 to 70 ℃, volatilizing or dissolving the raw materials by the solvent, cooling and recrystallizing the mixture, and finally filtering and drying the mixture. Wherein, the crystal form of the 2-berberine-1-fumarate is prepared, the molar ratio of the 8-hydroxy-dihydroberberine to the fumaric acid is 1 to 0.3 to 1; preparing a 1-berberine-1-fumarate crystal form, wherein the molar ratio of 8-hydroxy-dihydroberberine to fumaric acid is 1; 1-berberine-1.5-fumarate, wherein the molar ratio of the 8-hydroxy-dihydroberberine to the fumaric acid is 1.3 to 1. 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 fumaric 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 fumarate crystal form component, the administration dosage characteristics and the pharmaceutical application are as follows:
3.1 the invention relates to a pharmaceutical composition, which contains the crystal form of berberine fumarate and a pharmaceutically acceptable carrier.
3.2 the daily dosage of the berberine fumarate crystal form prepared by the invention of the pharmaceutical composition is 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 fumarate crystal form or pharmaceutical composition in the preparation of the drugs 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 berberine fumarate crystal form as an active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The berberine fumarate 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 fumarate crystal form in the pharmaceutical composition is within the range of 1-99% by weight.
The crystal form of the berberine fumarate 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, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, etc.
The crystal form of the berberine fumarate can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems. In order to form the crystalline form of berberine fumarate salt of the present invention into tablets, a wide variety of excipients known in the art may be 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, etc. 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 active ingredient of the berberine fumarate crystal form of the invention 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 effective component of the berberine fumarate crystal form of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. Various diluents, adhesives, wetting agents, disintegrating agents and glidants used for preparing the berberine fumarate crystal form tablets can also be used for preparing the berberine fumarate 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 fumarate crystal form pharmaceutical composition can be widely changed according to the nature and severity of diseases to be prevented and treated, the individual condition of patients or animals, the administration route, the dosage form 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 crystal form or the composition of the berberine fumarate can be taken alone or combined with other treatment medicines or symptomatic medicines. When the crystal form of the berberine fumarate has synergistic effect with other therapeutic drugs, the dosage of the crystal form of the berberine fumarate is adjusted according to actual conditions.
4. The invention has the beneficial technical effects that:
4.1 the 3 berberine fumarates crystal forms of the invention have good stability, can not generate phase change under the conditions of high temperature, high humidity and illumination, and are more stable as the raw materials of the medicine in the preparation production and storage processes.
4.2 the crystal form of the berberine fumarate does not contain any organic crystallization solvent, and has good safety and patent medicine advantages.
4.3 the solubility of the crystal form of the berberine fumarate formed by the invention is obviously higher than that of berberine hydrochloride.
4.4 the preparation method of the crystal form of berberine fumarate 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
FIG. 1 is a powder X-ray diffraction pattern of a 2-berberine-1-fumarate crystal form;
FIG. 2 is a crystal structure diagram of 2-berberine-1-fumarate crystal form;
FIG. 3 is a unit cell stacking diagram of a crystal form of 2-berberine-1-fumarate;
FIG. 4 is a thermal analysis (TG-DSC) chart of 2-berberine-1-fumarate crystal form;
FIG. 5 is an Infrared (IR) spectrum of the crystalline form of 2-berberine-1-fumarate;
FIG. 6 is an influence factor test spectrum of the crystal form of 2-berberine-1-fumarate;
FIG. 7 is a powder X-ray diffraction pattern of the crystalline form of 1-berberine-1-fumarate;
FIG. 8 is a crystal structure diagram of 1-berberine-1-fumarate crystal form;
FIG. 9 is a unit cell stacking diagram of a crystalline form of 1-berberine-1-fumarate;
FIG. 10 is a thermal analysis (TG-DSC) chart of a crystalline form of 1-berberine-1-fumarate;
FIG. 11 is an Infrared (IR) spectrum of the crystalline form of 1-berberine-1-fumarate;
FIG. 12 is a test chart of the influencing factors of the 1-berberine-1.5-fumarate crystal form;
FIG. 13 is a powder X-ray diffraction pattern of the 1-berberine-1.5-fumarate crystal form;
FIG. 14 is a crystal structure diagram of a 1-berberine-1, 5-fumarate crystal form;
FIG. 15 is a unit cell stacking diagram of the 1-berberine-1.5-fumarate crystal form;
FIG. 16 is a thermal analysis (TG-DSC) chart of the crystalline form of 1-berberine-1.5-fumarate;
FIG. 17 is an Infrared (IR) spectrum of the crystalline form of 1-berberine-1.5-fumarate;
FIG. 18 is a test chart of the influencing factors of the 1-berberine-1.5-fumarate crystal form;
figure 19 is a solubility profile of a crystalline form of berberine fumarate.
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 may 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 present invention defined by the appended claims.
The instrument and the method for detecting the crystal structure and the property of the berberine fumarate 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 structural map.
Powder X-ray diffraction (PXRD) characterization: the instrument comprises the following steps: 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 corporation, nicoletnuxusIS 5, 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 fumarate crystal form sample in an open clean surface dish, respectively placing the sample in an environment of 40 ℃, 90% +/-5% (25 ℃) or 4500lx +/-500 lx (25 ℃) for 10 days for sampling, and testing by using IR.
And (3) drug dissolution: 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 excessive samples 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; after sampling 0.5mL, the sample was filtered and diluted by an appropriate factor for testing.
Preparation method of 2-berberine-1-fumarate crystal form sample 1
Weighing 8-hydroxy-dihydroberberine and fumaric acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
Preparation method of 2-berberine-1-fumarate crystal form sample 2
Weighing 8-hydroxy-dihydroberberine and fumaric acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
Preparation method of 2-berberine-1-fumarate crystal form sample 3
Weighing 8-hydroxy-dihydroberberine and fumaric acid in a molar ratio of 1:0.5, adding the mixture into acetonitrile-water (volume ratio is 2: 1), heating to 50 ℃, clarifying the solution, filtering, standing at normal temperature, filtering after 72h till complete precipitation, and drying to obtain yellow solid powder which is 2-berberine-1-fumarate crystal form; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
Preparation method of 2-berberine-1-fumarate crystal form sample 4
Weighing 8-hydroxy-dihydroberberine and fumaric acid in a molar ratio of 1:0.5, adding into acetone-water (volume ratio is 2: 1), stirring at 30 ℃ for 10h, filtering, and drying the obtained solid at 40 ℃ to obtain yellow solid powder which is 2-berberine-1-fumarate crystal form; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
The berberine fumarate crystal prepared by the preparation methods 1-4 belongs to a triclinic crystal system when tested at 100K, and the space group isP-1Unit cell parameters a/a =8.58 (2), b/a =11.09 (2), c/a =23.29 (2), α/° =103.3 (2), β/° =97.1 (2), γ/° =92.5 (2), V =2134 (2)/a 3 Z =2, molecular formula: 2 (C) 20 H 18 NO 4 )·C 4 H 2 O 4 ·8(H 2 O)。
The X-ray diagram positions of the powder are represented by 2 theta angles at the angles of 7.8 +/-0.2 degree, 8.1 +/-0.2 degree, 9.8 +/-0.2 degree, 12.5 +/-0.2 degree, 13.2 +/-0.2 degree, 15.7 +/-0.2 degree, 16.3 +/-0.2 degree, 17.6 +/-0.2 degree, 19.3 +/-0.2 degree, 20.5 +/-0.2 degree, 22.3 +/-0.2 degree, 22.8 +/-0.2 degree, 23.4 +/-0.2 degree, 24.2 +/-0.2 degree, 24.8 +/-0.2 degree, 25.9 +/-0.2 degree, 26.3 +/-0.2 degree, 26.8 +/-0.2 degree, 28.5 +/-0.2 degree, 29.2 +/-0.2 degree, 29.5 +/-0.2 degree, 29.2 degree, 30.2 degree, and 30.3 +/-0.2 degree.
The 2-berberine-1-fumarate crystal form prepared by the preparation method 1 is tested, and the test result is shown in figures 1-5. FIG. 1 is a PXRD pattern of the 2-berberine-1-fumarate crystal form. FIG. 2 is a crystal structure diagram of a crystal form of 2-berberine-1-fumarate; FIG. 3 is a unit cell stacking diagram of a crystal form of 2-berberine-1-fumarate. The crystallographic parameters are shown in table 1.
Table 1: crystallographic parameters of 2-berberine-1-fumarate crystal form
FIG. 4 is a TG and DSC spectra of berberine fumarate crystal form; TG atlas shows that the mass loss is 13.0 +/-5.0% in a temperature range of 60-140 ℃, and DSC atlas shows that 3 endothermic peaks exist at 115 +/-5 ℃, 135 +/-5 ℃ and 216 +/-5 ℃ respectively according to DSC curve.
FIG. 5 shows characteristic peak positions (cm) of crystal form of berberine fumarate -1 ) 3342 plus or minus 5, 3250 plus or minus 5, 3082 plus or minus 5, 3067 plus or minus 5, 3054 plus or minus 5, 3024 plus or minus 5, 2951 plus or minus 5, 2919 plus or minus 5, 2852 plus or minus 5, 1633 plus or minus 5, 1621 plus or minus 5, 1599 plus or minus 5, 1563 plus or minus 5, 1557 plus or minus 5, 1505 plus or minus 5, 1482 plus or minus 5, 1454 plus or minus 5, 1441 plus or minus 5, 1389 plus or minus 5, 1364 plus or minus 5, 1347 plus or minus 5, 1328 plus or minus 5, 1270 plus or minus 5, 1257 plus or minus 5, 1235 plus or minus 5, 1206 plus or minus 5, 1140 plus or minus 5, 1103 plus or minus 5, 1033 plus or minus 5, 991 plus or minus 5, 935 plus or minus 5, 909 plus or minus 5, 807 plus or minus 5, 660 plus or minus 5, 625 plus or minus 5cm 5 -1 There exists a characteristic peak of infrared spectrum.
Preparation method of 1-berberine-1-fumarate crystal form sample 1
Weighing 8-hydroxy-dihydroberberine and fumaric acid in a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
Preparation method of 2-berberine-1-fumarate crystal form sample 2
Weighing 8-hydroxy-dihydroberberine and fumaric acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
Preparation method of 2-berberine-1-fumarate crystal form sample 3
Weighing 8-hydroxy-dihydroberberine and fumaric acid with a molar ratio of 1; wherein the mass volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
Preparation method of 2-berberine-1-fumarate crystal form sample 4
Weighing 8-hydroxy-dihydroberberine and fumaric acid in a molar ratio of 1; wherein the mass volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
The berberine fumarate crystals prepared by the preparation methods 1-4 belong to a triclinic system and a space group triclinic system when tested at 100K, wherein the space group isP-1Unit cell parameters a/a =8.06 (2), b/a =10.92 (2), c/a =13.30 (2), α/° =70.0 (2), β/° =88.5 (2), γ/° =72.5 (2), V =1045 (2)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 4 H 3 O 4 ·H 2 O。
The X-ray diagram positions of the powder are represented by 2 theta angles at an angle of 6.9 +/-0.2 degree, 8.9 +/-0.2 degree, 9.3 +/-0.2 degree, 12.9 +/-0.2 degree, 13.9 +/-0.2 degree, 16.9 +/-0.2 degree, 17.4 +/-0.2 degree, 18.7 +/-0.2 degree, 19.3 +/-0.2 degree, 20.9 +/-0.2 degree, 21.3 +/-0.2 degree, 22.6 +/-0.2 degree, 23.2 +/-0.2 degree, 23.7 +/-0.2 degree, 24.2 +/-0.2 degree, 24.7 +/-0.2 degree, 25.4 +/-0.2 degree, 25.9 +/-0.2 degree, 26.4 +/-0.2 degree, 27.0 +/-0.2 degree, 28.2 degree and 30.1 degree, and main +/-0.2 degree.
The 1-berberine-1-fumarate crystal form prepared by the preparation method 1 is tested, and the test result is shown in figures 7-11. FIG. 7 is a PXRD pattern of the crystalline form of 1-berberine-1-fumarate. FIG. 8 is a crystal structure diagram of the 1-berberine-1-fumarate crystal form; FIG. 9 is a unit cell stacking diagram of the crystalline form of 1-berberine-1-fumarate. The crystallographic parameters are shown in table 2.
Table 2: crystallographic parameters of 1-berberine-1-fumarate crystal form
FIG. 10 is a TG and DSC spectra of berberine fumarate crystalline form; TG atlas shows that the mass loss is 3.8 +/-5.0% in a temperature range of 70-120 ℃, and DSC atlas shows that 2 endothermic peaks exist at 110 +/-5 ℃ and 246 +/-5 ℃ respectively by combining with a DSC curve.
FIG. 11 shows the crystal form of berberine fumarate and the position of characteristic peak (cm) of infrared spectrum -1 ) 3466 + -5, 3360 + -5, 3257 + -5, 3067 + -5, 3047 + -5, 2982 + -5, 2944 + -5, 2917 + -5, 2844 + -5, 1692 + -5, 1651 + -5, 1618 + -5, 1599 + -5, 1566 + -5, 1502 + -5, 1479 + -5, 1457 + -5, 1387 + -5, 1364 + -5, 1330 + -5, 1301 + -5, 1256 + -5, 1233 + -5, 1171 + -5, 1140 + -5, 1098 + -5, 1062 + -5, 1130 + -5, 991 + -5, 972 + -5, 955 + -5, 926 + -5, 910 + -5, 875 + -5, 829 + -5, 794 + -5, 636 + -5 cm + -5 -1 There exists a characteristic peak of infrared spectrum.
Preparation method of 1-berberine-1, 5-fumarate crystal form sample 1
Weighing 8-hydroxy-dihydroberberine and fumaric acid in a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
Preparation method of 1-berberine-1, 5-fumarate crystal form sample 2
Weighing 8-hydroxy-dihydroberberine and fumaric acid in a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
Preparation method of 1-berberine-1, 5-fumarate crystal form sample 3
Weighing 8-hydroxy-dihydroberberine and fumaric acid with a molar ratio of 1.5 to 1.5, adding the mixture into acetonitrile-water (volume ratio is 2; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
Preparation method of 1-berberine-1.5-fumarate crystal form sample 4
Weighing 8-hydroxy-dihydroberberine and fumaric acid in a molar ratio of 1; wherein the mass volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the fumaric acid to the solvent is 1.
The 1-berberine-1, 5-fumaric acid crystals prepared by the preparation methods 1-4 belong to a monoclinic system when tested at 100K, and have a space group ofI2/aUnit cell parameters a/a =14.63 (2), b/a =22.16 (2), c/a =14.89 (2), α/° γ/° 90, β/° 107.7 (2), V =4599 (2)/a 3 Z =8, formula: c 20 H 18 NO 4 ·0.5(C 4 H 2 O 4 )·C 4 H 4 O 4 。
The X-ray diagram positions of the powder are represented by 2 theta angles at the angles of 7.3 +/-0.2 degree, 7.9 +/-0.2 degree, 10.8 +/-0.2 degree, 12.4 +/-0.2 degree, 12.8 +/-0.2 degree, 13.5 +/-0.2 degree, 14.7 +/-0.2 degree, 15.9 +/-0.2 degree, 17.0 +/-0.2 degree, 17.6 +/-0.2 degree, 18.8 +/-0.2 degree, 19.5 +/-0.2 degree, 20.1 +/-0.2 degree, 21.6 +/-0.2 degree, 22.4 +/-0.2 degree, 22.8 +/-0.2 degree, 23.4 +/-0.2 degree, 24.0 +/-0.2 degree, 25.3 +/-0.2 degree, 26.2 +/-0.2 degree, 26.5 +/-0.2 degree, and the main degree, 26.8 +/-0.2 degree, 26.2 degree and 26.8 +/-0.2 degree.
The 1-berberine-1, 5-fumarate crystal form prepared by the preparation method 1 is tested, and the test result is shown in figures 13-17. FIG. 13 is a PXRD pattern of the 1-berberine-1.5-fumarate crystal form. FIG. 14 is a crystal structure diagram of a crystalline form of 1-berberine-1, 5-fumarate; FIG. 15 is a unit cell stacking diagram of the crystalline form of 1-berberine-1.5-fumarate. The crystallographic parameters are shown in table 3.
Table 3: crystallographic parameters of 1-berberine-1, 5-fumarate crystal form
FIG. 16 is a TG and DSC spectra of the crystalline form of 1-berberine-1.5-fumarate; the DSC profile showed the presence of 1 endothermic peak at 241 ℃ ± 5 ℃.
FIG. 17 shows the characteristic peak position (cm) of infrared spectrum of 1-berberine-1, 5-fumarate crystal form -1 ) 3093 plus or minus 5, 3047 plus or minus 5, 2998 plus or minus 5, 2950 plus or minus 5, 2917 plus or minus 5, 2848 plus or minus 5, 1689 plus or minus 5, 1634 plus or minus 5, 1615 plus or minus 5, 1598 plus or minus 5, 1567 plus or minus 5, 1499 plus or minus 5, 1475 plus or minus 5, 1386 plus or minus 5, 1365 plus or minus 5, 1338 plus or minus 5, 1297 plus or minus 5, 1254 plus or minus 5, 1190 plus or minus 5, 1141 plus or minus 5, 1099 plus or minus 5, 1065 plus or minus 5, 1045 plus or minus 5, 1028 plus or minus 5, 998 plus or minus 5, 969 plus or minus 5, 963 plus or minus 5, 919 plus or minus 5, 909 plus or minus 5, 850 plus or minus 5, 831 plus or minus 5, 628 plus or minus 5cm -1 There exists a characteristic peak of infrared spectrum.
Stability characteristics of berberine fumarate crystal form
High-temperature test: placing the berberine fumarate crystal form sample in a clean surface dish with an opening, placing the clean surface dish at the temperature of 40 ℃ for 10 days, and sampling for IR analysis.
High humidity test: placing the berberine fumarate crystal form sample in a clean surface dish with an opening, placing the clean surface dish for 10 days under the condition of humidity of 90% +/-5% (25 ℃), and sampling for IR analysis.
And (3) illumination test: placing the berberine fumarate crystal form sample in an open clean surface dish, placing for 10 days under the condition of 4500lx +/-500 lx (25 ℃), and sampling for IR analysis.
The spectrum of the crystal form of the 2-berberine-1-fumarate under the conditions of high temperature, high humidity and illumination is shown in figure 6, and is consistent with the spectrum of 0 day, which indicates that the stability of the crystal form sample is good.
The spectrum of the 1-berberine-1-fumarate crystal form under the conditions of high temperature, high humidity and illumination is shown in figure 12, and is consistent with the spectrum of 0 day, which shows that the stability of the crystal form sample is good.
The spectrum of the 1-berberine-1.5-fumarate crystal form under the conditions of high temperature, high humidity and illumination is shown in figure 18, and is consistent with the spectrum of 0 day, which shows that the stability of the crystal form sample is good.
Method for the preparation of a combined pharmaceutical preparation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that any one of 3 crystal forms of berberine fumarate 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 the 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 4:
TABLE 4 preparation of berberine fumarate crystal form tablet formulation
The method for preparing the pure crystal form product of the berberine fumarate 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 any one of 3 crystal forms of berberine fumarate 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, a capsule sample with the medicine content of 20 to 500mg is prepared according to a certain proportion, and the formula proportion of the capsule is given in a table 5:
TABLE 5 bulk drug and adjuvant formulation of berberine fumarate crystal form combined drug capsule preparation
The method for preparing the berberine fumarate crystal form pure product 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% of berberine fumarate crystal form raw material medicine and a plurality of excipient auxiliary materials uniformly without using a granulating step, sieving, and directly encapsulating to obtain the berberine fumarate crystal form raw material medicine.
Administration dose 1 (tablet) of the berberine fumarate crystal form combination medicament:
any one of the 3 crystal forms of the berberine fumarate is used as a medicinal active ingredient to prepare and develop a medicinal composition, which is characterized in that the crystal form of the berberine fumarate is used as the medicinal active ingredient, the daily administration dose is 900mg, and the medicinal composition can be respectively prepared into 3 common tablets of 100mg 3 times a day per time and 1 common tablet of 300mg 3 times a day per time.
Administration dose 2 (capsule) of the berberine fumarate crystal form:
any sample in the 3 crystal forms of the berberine fumarate is used as a medicinal active ingredient to prepare and develop a medicinal composition, and the medicinal composition is characterized in that the crystal forms of the berberine fumarate are used as the medicinal active ingredient, the daily administration dose is 900mg, and the medicinal composition can be respectively prepared into 3 capsules of 100mg each time 3 times a day and 1 capsule of 300mg each time 3 times a day.
Problems to be explained are: the berberine fumarate crystal form pharmaceutical composition provided by the invention has many factors on the administration dosage of the effective ingredients, 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 difference of sex, age, body surface area of patients, administration route, administration frequency and treatment purpose causes the difference of daily dosage; in addition, the difference of absorption and blood concentration existing among samples also causes that the daily proper dosage range of the berberine fumarate 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 fumarate are made according to different requirements of actual prevention and treatment of different conditions, and the total dosage schemes can be completed in a multi-time or one-time administration mode.
Claims (22)
1. A berberine fumarate crystal form is characterized in that berberine and fumaric acid are combined through non-covalent bonds to form a salt crystal form.
2. The crystalline form of berberine fumarate according to claim 1, wherein the molar ratio of berberine to fumaric acid is 2.
3. The crystal form of 2-berberine-1-fumarate of claim 2, wherein the basic structural unit comprises 2 berberine cations, 1 fumarate anion and 8 water molecules, and under a test condition of 100K, the crystal form of berberine fumarate belongs to a triclinic system, and the space group isP-1Unit cell parameters a/a =8.58 (2), b/a =11.09 (2), c/a =23.29 (2), α/° =103.3 (2), β/° =97.1 (2), γ/° =92.5 (2), V =2134 (2)/a 3 Z =2, molecular formula: 2 (C) 20 H 18 NO 4 )·C 4 H 2 O 4 ·8(H 2 O)。
4. The crystalline form of 2-berberine-1-fumarate according to claim 2, characterized in that the powder X-ray diagram positions are represented at 7.8 ± 0.2 °,8.1 ± 0.2 °,9.8 ± 0.2 °,12.5 ± 0.2 °,13.2 ± 0.2 °,15.7 ± 0.2 °,16.3 ± 0.2 °,17.6 ± 0.2 °,19.3 ± 0.2 °,20.5 ± 0.2 °,22.3 ± 0.2 °,22.8 ± 0.2 °,23.4 ± 0.2 °,24.2 ± 0.2 °,24.8 ± 0.2 °,25.9 ± 0.2 °,26.3 ± 0.2 °,26.8 ± 0.2 °, 28.29.8 ± 0.2 °, 31.29.1 ± 0.2 °, 30.30.30 ± 0.2 ° and 1.29.2 ± 0.1 ± 0.2 ° in 2 ° as denoted by an angle of 2 θ.
5. The crystalline form of 2-berberine-1-fumarate of claim 2, characterized in that it has a crystal size of 3342 ± 5, 3250 ± 5, 3082 ± 5, 3067 ± 5, 3054 ± 5, 3024 ± 5, 2951 ± 5, 2919 ± 5, 2852 ± 5, 1633 ± 5, 1621 ± 5, 1599 ± 5, 1563 ± 5, 1557 ± 5, 1505 ± 5, 1482 ± 5, 1454 ± 5, 1441 ± 5, 1389 ± 5, 1364 ± 5, 1347 ± 5, 1328 ± 5, 1270 ± 5, 1257 ± 5, 1235 ± 5, 1206 ± 5, 1140 ± 5, 1103 ± 5, 1033 ± 5, 991 ± 5, 935 ± 5, 909 ± 5, 888 ± 5, 807 ± 5, 660 ± 5, 625 ± 5cm ± 5, and 3260 ± 5cm when analyzed using infrared spectroscopy -1 There exists a characteristic peak of infrared spectrum.
6. The crystalline form of berberine fumarate of claim 1, wherein berberine and fumaric acid are in a 1.
7. The crystalline form of 1-berberine-1-fumarate according to claim 6, wherein the basic structural unit comprises 1 berberine cation, 1 fumarate anion and 1 water molecule, and under the test condition of 100K, the crystalline form of berberine fumarate belongs to a triclinic system, and the space group isP-1Unit cell parameters a/a =8.06 (2), b/a =10.92 (2), c/a =13.30 (2), α/° =70.0 (2), β/° =88.5 (2), γ/° =72.5 (2), V =1045 (2)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 4 H 3 O 4 ·H 2 O。
8. The crystalline form of 1-berberine-1-fumarate of claim 6, characterized in that the powder X-ray pattern positions are represented at 6.9 ± 0.2 °,8.9 ± 0.2 °,9.3 ± 0.2 °,12.9 ± 0.2 °,13.9 ± 0.2 °,16.9 ± 0.2 °,17.4 ± 0.2 °,18.7 ± 0.2 °,19.3 ± 0.2 °,20.9 ± 0.2 °,21.3 ± 0.2 °,22.6 ± 0.2 °,23.2 ± 0.2 °,23.7 ± 0.2 °,24.2 ± 0.2 °,24.7 ± 0.2 °,25.4 ± 0.2 °,25.9 ± 0.2 °, 26.7 ± 0.2 °,24.2 ± 0.0 °, 24.1 ± 0.2 ° and 1.29 ± 0.2 ° of the diffraction peaks are represented at an angle of 2 θ.
9. The crystalline form of 1-berberine-1-fumarate of claim 6, which is characterized by having a crystal size of 3466 ± 5, 3360 ± 5, 3257 ± 5, 3067 ± 5, 3047 ± 5, 2982 ± 5, 2944 ± 5, 2917 ± 5, 2844 ± 5, 1692 ± 5, 1651 ± 5, 1618 ± 5, 1599 ± 5, 1566 ± 5, 1502 ± 5, 1479 ± 5, 1457 ± 5, 1387 ± 5, 1364 ± 5, 1330 ± 5, 1301 ± 5, 1256 ± 5, 1233 ± 5, 1171 ± 5, 1140 ± 5, 1098 ± 5, 1062 ± 5, 1130 ± 5, 991 ± 5, 972 ± 5, 955 ± 5, 910 ± 5, 875 ± 5, 829 ± 5, 794 ± 5, 636 ± 5cm 5, 636 ± 5 -1 There exists a characteristic peak of infrared spectrum.
10. The crystalline form of berberine fumarate according to claim 1, wherein berberine and fumaric acid form a crystalline form of salt at a molar ratio of 1.
11. The crystalline form of 1-berberine-1.5-fumarate according to claim 10, wherein the basic building block consists of 1 berberine cation, 0.5 fumarate anion and 1 fumarate molecule, and under a test condition of 100K, the crystalline form of berberine fumarate belongs to monoclinic system with space group ofI2/aUnit cell parameters a/a =14.63 (2), b/a =22.16 (2), c/a =14.89 (2), α/° γ/° =90, β/° 107.7 (2), V =4599 (2)/a 3 Z =8, molecular formula: c 20 H 18 NO 4 ·0.5(C 4 H 2 O 4 )·C 4 H 4 O 4 。
12. The crystalline form of 1-berberine-1.5-fumarate according to claim 10, characterized in that the powder X-ray diagram positions show a diffraction pattern at 7.3 ± 0.2 °,7.9 ± 0.2 °,10.8 ± 0.2 °,12.4 ± 0.2 °,12.8 ± 0.2 °,13.5 ± 0.2 °,14.7 ± 0.2 °,15.9 ± 0.2 °,17.0 ± 0.2 °,17.6 ± 0.2 °,18.8 ± 0.2 °,19.5 ± 0.2 °,20.1 ± 0.2 °,21.6 ± 0.2 °,22.4 ± 0.2 °,22.8 ± 0.2 °,23.4 ± 0.2 °,24.0 ± 0.25.5 °, 25.26.26 ± 0.2 °, 25.8 ± 0.26 °, 26.26.26 ± 0.2 ° and 25.26 ± 0.26.26.2 ° 2.26.26 ± 0.26.26.26 ° 2 ° 2.26.26.26.26 ± 0.26.2 ° 2 ° 2.26.26.26 ° 2 ° 2.26.2 ° 2.26.26 ° 2 ° 2.26.26.2 ° 2.26.2 ° of a peak at an angle of 2.
13. The crystalline form of 1-berberine-1.5-fumarate of claim 10, which is characterized by a spectrum of wavelengths 3093 ± 5, 3047 ± 5, 2998 ± 5, 2950 ± 5, 2917 ± 5, 2848 ± 5, 1689 ± 5, 1634 ± 5, 1615 ± 5, 1598 ± 5, 1567 ± 5, 1499 ± 5, 1475 ± 5, 1386 ± 5, 1365, 1338 ± 5, 1297 ± 5, 1254 ± 5, 1190 ± 5, 1141 ± 5, 1099 ± 5, 1065 ± 5, 1045 ± 5, 1028 ± 5, 998 ± 5, 969 ± 5, 963 ± 5, 919 ± 5, 909 ± 5, 850 ± 5, 831 ± 5, 628 ± 5cm ± 5 -1 There exists a characteristic peak of infrared spectrum.
14. The preparation method of the crystal form of berberine fumarate according to claim 1, characterized in that 8-hydroxy-dihydroberberine and fumaric acid are used as raw materials, and the crystal form is prepared by putting the raw materials into a mixed solvent of water and an organic solvent, stirring or dissolving the raw materials at 20 to 70 ℃, volatilizing or dissolving the mixture by the solvent, cooling and recrystallizing the mixture, and finally filtering and drying the mixture.
15. The method according to claim 14, 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 fumaric acid to the dosage of the solvent is 1g: (1 to 200) ml.
16. The process for the preparation of crystalline forms of 2-berberine-1-fumarate according to any one of claims 2-5, characterised in that the molar ratio of 8-hydroxy-dihydroberberine to fumaric acid in claim 14 is from 1 to 0.3 to 1.
17. A process for the preparation of a crystalline form of the 1-berberine-1-fumarate according to any one of the claims 6-9, characterized in that the molar ratio of 8-hydroxy-dihydroberberine to fumaric acid in claim 14 is 1.
18. A process for the preparation of a crystalline form of 1-berberine-1-fumarate according to any one of claims 10-13, characterised in that the molar ratio of 8-hydroxy-dihydroberberine to fumaric acid in claim 14 is 1.3 to 1.
19. A pharmaceutical composition, which comprises an effective dose of the berberine fumarate crystalline solid substance as described in claims 1-13 and a pharmaceutically acceptable carrier.
20. Pharmaceutical composition according to any of the claims 19, characterized in that the daily dose of the crystalline form of berberine fumarate is in the range of 20-5000 mg.
21. The pharmaceutical composition according to any of the claims 19, wherein the pharmaceutical composition is in the form of a tablet, a capsule, an injectable preparation, a pill, a sustained release preparation or a controlled release preparation.
22. Use of the crystalline form of berberine fumarate as defined in claims 1-13 or the pharmaceutical composition as defined in claim 19 for the preparation of a medicament for the prevention and treatment of antibacterial, anti-inflammatory, hypolipidemic, hypoglycemic, antiviral, cardiovascular and cerebrovascular diseases, anti-cancer and anti-infective medicament.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008014661A1 (en) * | 2006-07-26 | 2008-02-07 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Tetrahydroprotoberberine compounds, their manufacture, medicinal composition and uses. |
| CN103421001A (en) * | 2012-05-22 | 2013-12-04 | 中国医学科学院药物研究所 | Berberine hydrochloride crystal E form substance, preparation method, pharmaceutical compositions and applications |
| CN103421000A (en) * | 2012-05-22 | 2013-12-04 | 中国医学科学院药物研究所 | Berberine hydrochloride crystal F form substance, preparation method, pharmaceutical compositions and applications |
| CN103421002A (en) * | 2012-05-22 | 2013-12-04 | 中国医学科学院药物研究所 | Berberine hydrochloride crystal D form substance, preparation method, pharmaceutical compositions and applications |
| CN108498590A (en) * | 2018-06-27 | 2018-09-07 | 浙江农林大学暨阳学院 | A kind of natural hypoglycemic agent that can be improved bioavilability and avoid hyperchloremia |
| CN108864077A (en) * | 2017-05-12 | 2018-11-23 | 深圳君圣泰生物技术有限公司 | The solid form and preparation method thereof of jamaicin acylate |
| CN109020968A (en) * | 2018-07-31 | 2018-12-18 | 南京中医药大学 | Jamaicin crystalline salt and preparation method thereof |
| CN111920777A (en) * | 2020-09-18 | 2020-11-13 | 四川迪菲特药业有限公司 | Berberine hydrochloride tablet and preparation method thereof |
-
2022
- 2022-10-26 CN CN202211321204.6A patent/CN115477647A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008014661A1 (en) * | 2006-07-26 | 2008-02-07 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Tetrahydroprotoberberine compounds, their manufacture, medicinal composition and uses. |
| CN103421001A (en) * | 2012-05-22 | 2013-12-04 | 中国医学科学院药物研究所 | Berberine hydrochloride crystal E form substance, preparation method, pharmaceutical compositions and applications |
| CN103421000A (en) * | 2012-05-22 | 2013-12-04 | 中国医学科学院药物研究所 | Berberine hydrochloride crystal F form substance, preparation method, pharmaceutical compositions and applications |
| CN103421002A (en) * | 2012-05-22 | 2013-12-04 | 中国医学科学院药物研究所 | Berberine hydrochloride crystal D form substance, preparation method, pharmaceutical compositions and applications |
| CN108864077A (en) * | 2017-05-12 | 2018-11-23 | 深圳君圣泰生物技术有限公司 | The solid form and preparation method thereof of jamaicin acylate |
| CN108498590A (en) * | 2018-06-27 | 2018-09-07 | 浙江农林大学暨阳学院 | A kind of natural hypoglycemic agent that can be improved bioavilability and avoid hyperchloremia |
| CN109020968A (en) * | 2018-07-31 | 2018-12-18 | 南京中医药大学 | Jamaicin crystalline salt and preparation method thereof |
| CN111920777A (en) * | 2020-09-18 | 2020-11-13 | 四川迪菲特药业有限公司 | Berberine hydrochloride tablet and preparation method thereof |
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