CN115710263A - Crystal form of berberine new salt and preparation method thereof - Google Patents
Crystal form of berberine new salt and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 83
- 229940093265 berberine Drugs 0.000 title claims abstract description 61
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- 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 41
- 150000003839 salts Chemical class 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 133
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- 238000010586 diagram Methods 0.000 claims description 45
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 30
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 28
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- RYYVLZVUVIJVGH-UHFFFAOYSA-N trimethylxanthine Natural products CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of salt formation in a solid form of a medicament and crystal form research, and particularly relates to a crystal form of a novel berberine salt and a preparation method thereof. The crystal form of the novel berberine salt comprises 1-berberine-1-malonic acid, 1-berberine-2-malonic acid-2-water, 2-berberine-2-citric acid, 1-berberine-1-L-tartaric acid-1-water, 1-berberine-1-methanesulfonic acid-2-water and 1-berberine-1-p-toluenesulfonic acid-3-water. The crystal form of the new salt formed by the invention has good stability, the solubility of the new salt is obviously improved compared with the commercially available berberine hydrochloride, the problems of poor stability and low solubility of the commercially available berberine hydrochloride can be improved, the curative effect of the berberine can be exerted, in addition, the reaction condition of the new salt is simple, the industrial production is easy to realize, and the new salt has good application and development prospects.
Description
Technical Field
The invention belongs to the technical field of salt formation and crystal form research in a solid form of a medicament, and particularly relates to a crystal form of a novel berberine salt and a preparation method thereof.
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 an ionizable drug is one of the most effective means for improving its physicochemical properties.
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 the development of 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.
To overcome the disadvantages of berberine stability and poor bioavailability, one of the most effective strategies for ionizable berberine is to change its salt form. The eutectic crystal of berberine hydrochloride and citric acid is synthesized by Lu and the like; wang et al synthesized berberine acesulfame and berberine saccharinate; wang et al synthesized berberine hydrochloride succinic acid co-crystal, berberine hydrochloride glutaric acid co-crystal, berberine hydrochloride adipic acid co-crystal and berberine pimelic acid co-crystal; yang et al synthesized berberine hydrochloride-fumaric acid co-crystal; wang et al synthesized berberine hydrochloride L-lactic acid co-crystal; the berberine rhein hydrochloride eutectic is synthesized by deng and the like; berberine ursodesoxycholic acid salt is synthesized by the people; lu et al synthesized berberine hydrochloride caffeine cocrystal, berberine hydrochloride ibuprofen cocrystal, berberine hydrochloride fumaric acid cocrystal and malic acid cocrystal. The preparation of the above salt and eutectic mainly adopts berberine hydrochloride as reactant, the stability of the obtained product is obviously improved, but the solubility is not obviously improved, even some products such as berberine acesulfame eutectic and berberine saccharin eutectic have lower solubility in water than berberine hydrochloride.
Disclosure of Invention
In order to improve the solubility and stability of berberine, the invention discloses a crystal form of a novel berberine salt and a preparation method thereof, 8-hydroxy-dihydroberberine (formula 2) is adopted as a reactant to react with pharmaceutically acceptable acids including malonic acid, L-tartaric acid, citric acid, methanesulfonic acid and p-toluenesulfonic acid, and the obtained crystal form of the novel berberine salt not only enhances the stability of berberine, but also obviously improves the solubility of berberine and promotes the further development of berberine.
In order to achieve the purpose, the invention adopts the technical scheme that:
the crystal form of the novel berberine salt is characterized in that 8-hydroxy-dihydroberberine and a pharmaceutically acceptable acid are taken as raw materials, are dissolved in a proper solvent according to a molar ratio of 1 to 1.
As mentioned above, when the pharmaceutically acceptable acid is malonic acid, the crystal form of the new salt is 1-berberine-1-malonic acid, and the basic structural unit consists of 1 berberine cation and 1 malonic acid anion.
Malonic acid, molecular formula C 3 H 4 O 4 The structural formula is as follows:
the 1-berberine-1-malonic acid belongs to monoclinic system and has a space group ofP 21/cUnit cell parameters a/a =6.943 (1), b/= 19.818 (2), c/a =14.669 (2), α/° γ/° =90, β/° 97.08 (1), volume =2003.1 (3)/a 3 Z =4, molecular formula: c 20 H 18 NO 4 ·C 3 H 3 O 4 。
The X-ray diagram positions of powder of the crystal form of 1-berberine-1-malonic acid expressed by 2 theta angles at 7.5 +/-0.2 degrees, 8.9 +/-0.2 degrees, 10.8 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.7 +/-0.2 degrees, 17.2 +/-0.2 degrees, 17.8 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.6 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.9 +/-0.2 degrees and 27.5 +/-0.2 degrees represent main diffraction peaks.
As mentioned above, when the pharmaceutically acceptable acid is malonic acid, the crystal form of the new salt is 1-berberine-2-malonic acid-2-water, and the basic structural unit consists of 1 berberine cation, 1 malonic acid anion, 1 malonic acid molecule and 2 water molecules.
1-berberine-2-malonic acid-2-water belongs to triclinic system and has a space group ofP -1Unit cell parameters a/a =7.587 (1), b/a =12.937 (1), c/a =13.964 (1), α/° 71.32 (1), β/° 83.35 (1), γ/° 81.36 (1), volume =1280.4 (2)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 3 H 4 O 4 ·C 3 H 3 O 4 ·2(H 2 O)。
The X-ray diagram positions of the powder of the 1-berberine-2-malonic acid-2-crystal form are represented by 2 theta angles at 6.7 +/-0.2 degrees, 7.2 +/-0.2 degrees, 13.4 +/-0.2 degrees, 14.5 +/-0.2 degrees, 16.0 +/-0.2 degrees, 16.4 +/-0.2 degrees, 17.1 +/-0.2 degrees, 17.6 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 25.3 +/-0.2 degrees, 26.2 +/-0.2 degrees and 26.4 +/-0.2 degrees, and the main diffraction peaks are shown.
When the pharmaceutically acceptable acid is citric acid, the crystal form of the new salt is 2-berberine-2-citric acid, and the basic structural unit consists of 2 berberine cations and 2 citric acid anions.
Citric acid of formula C 6 H 8 O 7 The structural formula is as follows:
the 2-berberine-2-citric acid belongs to a triclinic system and has a space group ofP -1Unit cell parameters a/a =7.585 (1), b/a =14.686 (1), c/a =22.789 (1), α/° 101.25 (1), β/° 97.33 (1), γ/° 100.89 (1), volume =2409.2 (2)/a 3 Z =2, molecular formula: 2C 20 H 18 NO 4 , 2C 6 H 7 O 7 。
The powder X-ray diagram positions of the 2-berberine-2-citric acid show main diffraction peaks at angles of 2 theta, namely 6.7 +/-0.2 degrees, 8.1 +/-0.2 degrees, 13.3 +/-0.2 degrees, 14.8 +/-0.2 degrees, 16.3 +/-0.2 degrees, 16.8 +/-0.2 degrees, 18.1 +/-0.2 degrees, 18.3 +/-0.2 degrees, 20.1 +/-0.2 degrees, 24.2 +/-0.2 degrees, 25.4 +/-0.2 degrees and 27.6 +/-0.2 degrees.
When the medicinal acid is L-tartaric acid, the crystal form of the new salt is 1-berberine-1-L-tartaric acid, and the basic structural unit consists of 1 berberine cation, 1L-tartaric acid anion and 1 water molecule.
L-tartaric acid of the formula C 4 H 6 O 6 The structural formula is as follows:
1-berberine-1-L-tartaric acid belongs to monoclinic system, and has space group ofP 21Unit cell parameters a/a =12.111 (1), b/a =7.093 (1), c/a =12.703 (1), α/° γ/° 90, β/° 99.43 (1), volume =1076.6 (1)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 4 H 5 O 6 ·H 2 O。
The powder X-ray diagram positions of the crystal form of 1-berberine-1-L-tartaric acid are represented by 2 theta angles at 7.0 +/-0.2 degrees, 7.4 +/-0.2 degrees, 9.3 +/-0.2 degrees, 14.0 +/-0.2 degrees, 14.8 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.5 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.7 +/-0.2 degrees, 21.1 +/-0.2 degrees, 22.1 +/-0.2 degrees, 25.0 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.7 +/-0.2 degrees, 27.3 +/-0.2 degrees, 29.4 +/-0.2 degrees and present main diffraction peaks.
When the medicinal acid is methanesulfonic acid, the crystal form of the new salt is 1-berberine-1-methanesulfonic acid-2-water, and the basic structural unit consists of 1 berberine cation, 1 methanesulfonic acid anion and 2 water molecules.
Methanesulfonic acid, molecular formula CH 4 O 3 S, the structural formula is as follows:
1-berberine-1-methanesulfonic acid-2-water belongs to triclinic system, and space group isP -1Unit cell parameters a/A =7.465 (1), b/A =11.923 (1),c/Å=12.921(1)，α/°=69.46(1)，β/°=76.50(1)，γ/°=84.92(1)， Volume=1047.1(2)/Å 3 z =2, molecular formula: c 20 H 18 NO 4 ·CH 3 O 3 S·2(H 2 O)。
The X-ray diagram positions of powder of the 1-berberine-1-methanesulfonic acid-2-crystal form are represented by 2 theta angles at 7.9 +/-0.2 degrees, 8.9 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.4 +/-0.2 degrees, 17.8 +/-0.2 degrees, 19.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.1 +/-0.2 degrees, 25.2 +/-0.2 degrees, 25.8 +/-0.2 degrees, 26.5 +/-0.2 degrees and 26.9 +/-0.2 degrees to show main diffraction peaks.
When the pharmaceutically acceptable acid is p-toluenesulfonic acid, the crystal form of the new salt is 1-berberine-1-p-toluenesulfonic acid-3-water, and the basic structural unit consists of 1 berberine cation, 1 p-toluenesulfonic acid anion and 3 water molecules.
P-toluenesulfonic acid of the formula C 7 H 8 O 3 S, the structural formula is as follows:
1-berberine-1-p-toluenesulfonic acid-3-water belongs to a triclinic system, and the space group isP -1Unit cell parameters a/a =7.327 (1), b/a =12.480 (1), c/a =14.639 (1), α/° =95.61 (1), β/° =102.89 (1), γ/° =92.51 (1), volume =1295.7 (2)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 7 H 7 O 3 S·3(H 2 O)。
The powder X-ray diagram positions of the 1-berberine-1-p-toluenesulfonic acid-3-water crystal form are represented by 2 theta angles at 6.3 +/-0.2 degrees, 7.2 +/-0.2 degrees, 11.0 +/-0.2 degrees, 12.5 +/-0.2 degrees, 14.4 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.9 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.1 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.6 +/-0.2 degrees, 23.5 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.2 +/-0.2 degrees and 27.0 +/-0.2 degrees to present main diffraction peaks.
The crystal form of the new berberine salt is prepared by the following steps under the same dissolution experiment conditions: the concentration of berberine in the solution obtained after 3 hours is 1.14 to 32.7 times of berberine hydrochloride; the crystal form of the new salt of berberine does not undergo solid phase transition at a humidity of 75% RH-92.5% RH.
Wherein, 3h dissolution concentration:
the content of berberine hydrochloride is 2.1 mu mol/mL;
the 1-berberine-1-malonic acid is 68.8 mu mol/mL, which is 32.76 times of berberine hydrochloride;
the 1-berberine-2-malonic acid-2-water is 34.8 mu mol/mL and is 16.57 times of berberine hydrochloride;
the 2-berberine-2-citric acid is 9.5 mu mol/mL which is 4.52 times of berberine hydrochloride;
the content of 1-berberine-1-L-tartaric acid-1-water is 13.1 mu mol/mL which is 6.23 times of berberine hydrochloride;
the 1-berberine-1-methanesulfonic acid-2-water is 7.5 micromole/mL, which is 3.57 times of berberine hydrochloride;
the content of 1-berberine-1-p-toluenesulfonic acid-3-water is 2.4 mu mol/mL, which is 1.14 times of that of berberine hydrochloride;
moisture absorption:
1-berberine-1-malonic acid is stable at a moisture content of 92.5% RH without solid phase change;
1-berberine-2-malonate-2-water is stable without solid phase change under the condition that the humidity reaches 92.5 percent RH;
2-Berberine-2-citric acid is stable with no solid phase change at a moisture content of 92.5% RH;
1-berberine-1-L-tartaric acid-1-water is stable without solid phase change under the conditions of humidity up to 92.5% rh;
1-berberine-1-methanesulfonic acid-2-water is stable, without solid phase change, at a humidity of 92.5% RH;
1-Berberine-1-p-toluenesulfonate-3-water is stable under conditions of a humidity of 92.5% RH and no solid phase change.
The invention also provides a preparation method of the crystal form of the berberine new salt, which comprises the following steps:
(1) Dissolving 8-hydroxy-dihydroberberine and pharmaceutically acceptable acid in solvent;
(2) Cooling or slowly volatilizing the solvent for crystallization, and the separated crystal is the crystal form of the berberine new salt.
In the preparation method of the crystal form of the berberine new salt, the mass volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the acid to the solvent is 1 to 10 to 80 g/mL; the dissolving temperature is 30 to 65 ℃; the dissolution is also assisted by ultrasound, the ultrasonic frequency is 40KHZ, the power is 120W, and the power supply is 50HZ;
the preparation method of the 1-berberine-1-malonic acid comprises the steps that the solvent is a mixed solvent system of water and alcohols, acetonitrile or tetrahydrofuran; the molar ratio of the 8-hydroxy-dihydroberberine to the malonic acid is 1 to 1.4;
the preparation method of the 1-berberine-2-malonic acid-2-water is characterized in that the solvent is a mixed solvent system of water and ketones, alcohols, acetonitrile or tetrahydrofuran; 1-1 to 1 molar ratio of 8-hydroxy-dihydroberberine to malonic acid;
the preparation method of 2-berberine-2-citric acid, 1-berberine-1-L-tartaric acid-1-water, 1-berberine-1-methanesulfonic acid-2-water and 1-berberine-1-p-toluenesulfonic acid-3-water as described above, wherein the solvent is a mixed solvent system of water and alcohols, ketones, acetonitrile or tetrahydrofuran; 1-1 to 1 molar ratio of 8-hydroxy-dihydroberberine to acid.
The principle of the invention is as follows: the change of the drug salt type can obviously improve the physicochemical property of the berberine, and aiming at the problems of poor stability and low solubility of the berberine, the existing research mainly adopts the berberine hydrochloride as the raw material to react with acid, and the solubility of the obtained product is not obviously improved. In view of interconversion between 8-hydroxy-dihydroberberine and berberine free alkali, the invention adopts 8-hydroxy-dihydroberberine as a raw material, and obtains a crystal form of berberine new salt by proton transfer with acid, so that the solubility of berberine is obviously improved.
The beneficial effects of the invention are:
(1) The crystal form of the berberine new salt obtained by the invention obviously improves the solubility of the berberine and can better play the treatment effect of the berberine;
(2) The crystal form of the new berberine salt obtained by the invention is stable under the condition of humidity 75-92.5% RH without solid phase transformation, and can solve the problem that the berberine hydrochloride is unstable to humidity;
(3) The preparation method of the crystal form of the novel berberine salt is simple, easy to control conditions, good in reproducibility, low in cost, easy for large-scale industrial production and high in application value.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of 1-berberine-1-propanedioic acid;
FIG. 2 is a crystal structure diagram of 1-berberine-1-propanedioic acid;
FIG. 3 is a schematic diagram of the unit cell stacking of 1-berberine-1-propanedioic acid;
FIG. 4 is a thermal analysis (TG-DSC) chart of 1-berberine-1-propanedioic acid;
FIG. 5 is an Infrared (IR) spectrum of 1-berberine-1-propanedioic acid;
FIG. 6 is an X-ray powder diffractogram of 1-berberine-2-malonic acid-2-water;
FIG. 7 is a crystal structure diagram of 1-berberine-2-malonic acid-2-water;
FIG. 8 is a unit cell stacking diagram of 1-berberine-2-malonate-2-water;
FIG. 9 is a thermal analysis (TG-DSC) chart of 1-berberine-2-propanedioic acid-2-water;
FIG. 10 is an Infrared (IR) spectrum of 1-berberine-2-malonate-2-water;
FIG. 11 is an X-ray powder diffraction pattern of 2-berberine-2-citric acid;
FIG. 12 is a crystal structure diagram of 2-berberine-2-citric acid;
FIG. 13 is a schematic representation of the stacking cell of 2-berberine-2-citric acid;
FIG. 14 is a thermal analysis (TG-DSC) chart of 2-berberine-2-citric acid;
FIG. 15 is an Infrared (IR) spectrum of 2-berberine-2-citric acid;
FIG. 16 is an X-ray powder diffraction pattern of 1-berberine-1-L-tartaric acid-1-water;
FIG. 17 is a crystal structure diagram of 1-berberine-1-L-tartaric acid-1-water;
FIG. 18 is a schematic diagram showing the stacking of the unit cell of 1-berberine-1-L-tartaric acid-1-water;
FIG. 19 is a thermal analysis (TG-DSC) chart of 1-berberine-1-L-tartaric acid-1-water;
FIG. 20 is an Infrared (IR) spectrum of 1-berberine-1-L-tartaric acid-1-water;
FIG. 21 is an X-ray powder diffraction pattern of 1-berberine-1-methanesulfonic acid-2-water;
FIG. 22 is a crystal structure diagram of 1-berberine-1-methanesulfonic acid-2-water;
FIG. 23 is a schematic diagram showing the stacking of the unit cell of 1-berberine-1-methanesulfonic acid-2-water;
FIG. 24 is a thermal analysis (TG-DSC) of 1-berberine-1-methanesulfonate-2-water;
FIG. 25 is an Infrared (IR) spectrum of 1-berberine-1-methanesulfonate-2-water;
FIG. 26 is an X-ray powder diffractogram of 1-berberine-1-p-toluenesulfonic acid-3-water;
FIG. 27 is a crystal structure diagram of 1-berberine-1-p-toluenesulphonic acid-3-water;
FIG. 28 is a unit cell stacking diagram of 1-berberine-1-p-toluenesulfonic acid-3-water;
FIG. 29 is a thermal analysis (TG-DSC) chart of 1-berberine-1-p-toluenesulfonic acid-3-water;
FIG. 30 is an Infrared (IR) spectrum of 1-berberine-1-p-toluenesulphonic acid-3-water;
FIG. 31 is a powder elution graph of berberine hydrochloride, 1-berberine-1-propanedioic acid, 1-berberine-2-propanedioic acid-2-water, 2-berberine-2-citric acid, 1-berberine-1-L-tartaric acid-1-water, 1-berberine-1-methanesulfonic acid-2-water and 1-berberine-1-p-toluenesulfonic acid-3-water.
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 properties of the novel berberine salt are as follows:
single crystal diffraction characterization: bruker APEX-II D8X-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: rigaku D/max-2550,CuKαradiation, power 40kV,150mA; examination ofAnd (3) testing conditions: the scanning range 2 theta is 5-50 degrees, the step width is 0.02 degree, the scanning speed is 8 degrees/min, and the testing temperature is 20 degrees.
Thermal analysis (TG-DSC) characterization: the instrument comprises: the detection conditions of ZCT-B DSC/TGA of Beijing Gaokou instruments Ltd are as follows: temperature rise rate: 10 ℃/min, temperature range: 40 to 270 ℃.
Fourier Infrared (IR) characterization: the instrument comprises the following steps: fourier transform infrared spectroscopy (Thermo fisher, usa, nicolet Nexus IS5 type, ATR method); detection conditions are as follows: the scanning wave band is 4000-500 cm -1 Resolution ratio: 4cm -1 。
And (3) dissolving out the medicine: the instrument is an SHZ-A water bath constant temperature oscillator (Shanghai Boxun industry Co., ltd.) medical equipment factory; a detector: an L8 ultraviolet spectrophotometer (shanghai seminiferous analytical instruments 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: at 37 ℃; sampling time: 5. 10, 20, 30, 45, 60, 90, 120 and 180 minutes; after sampling for 0.5 mL, filtering, and testing after diluting berberine hydrochloride, 1-berberine-1-malonic acid, 1-berberine-2-malonic acid-2-water, 2-berberine-2-citric acid, 1-berberine-1-L-tartaric acid-1-water, 1-berberine-1-methanesulfonic acid and 1-berberine-1-p-toluenesulfonic acid-3-water by 100, 4000, 2000, 800, 500, 1000 and 100 times respectively.
Moisture absorption: 1-berberine-1-malonic acid, 1-berberine-2-malonic acid-2-water, 2-berberine-2-citric acid, 1-berberine-1-L-tartaric acid-1-water, 1-berberine-1-methanesulfonic acid-2-water and 1-berberine-1-p-toluenesulfonic acid-3-water are mixed at a humidity of 75 + -5% (25 ℃ saturated NaCl) and 92.5 + -5% (25 ℃ saturated KNO-3-water 3 ) After standing in the environment for 10 days, the test was carried out by IR.
Example 1
Weighing 8-hydroxy-dihydroberberine and malonic acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the malonic acid to the solvent is 1.
Example 2
Weighing 8-hydroxy-dihydroberberine and malonic acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the malonic acid to the solvent is 1.
Example 3
Weighing 8-hydroxy-dihydroberberine and malonic acid with a molar ratio of 1.2 to 1.2, adding into acetonitrile-water (volume ratio 5; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the malonic acid to the solvent is 1.
Example 4
Weighing 8-hydroxy-dihydroberberine and malonic acid in a molar ratio of 1; wherein the mass volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the malonic acid to the solvent is 1.
The basic structural unit of 1-berberine-1-malonic acid prepared in examples 1 to 4 consists of 1 berberine cation and 1 malonic acid anion; the unit cell parameters of the 1-berberine-1-malonic acid are as follows: a/a =6.943 (1), b/a =19.818 (2), c/a =14.669 (2), α/° γ/° =90, β/° 97.08 (1), volume =2003.1 (3)/a 3 Z =4, molecular formula: c 20 H 18 NO 4 ·C 3 H 3 O 4 . The positions of a powder X-ray diagram are represented by 2 theta angles, and main diffraction peaks are shown at 7.5 +/-0.2 degrees, 8.9 +/-0.2 degrees, 10.8 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.7 +/-0.2 degrees, 17.2 +/-0.2 degrees, 17.8 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.6 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.9 +/-0.2 degrees and 27.5 +/-0.2 degrees.
The 1-berberine-1-malonic acid crystals prepared in example 1 were tested, and the test results are shown in fig. 1 to 5. FIG. 1 is a PXRD diagram of 1-berberine-1-propanedioic acid. FIG. 2 is a crystal structure diagram of 1-berberine-1-propanedioic acid; FIG. 3 is a unit cell stacking diagram of 1-berberine-1-propanedioic acid. The crystallographic parameters are shown in table 1.
Table 1: crystallographic parameters of 1-berberine-1-propanedioic acid
FIG. 4 is a TG and DSC spectra of 1-berberine-1-propanedioic acid; in the temperature range of 185-215 ℃, the mass loss is 20.4 +/-5.0%, and the sample is known to melt and decompose at the temperature when an endothermic peak appears at 197 +/-5 ℃ in combination with a DSC curve.
FIG. 5 is an IR chart of 1-berberine-1-propanedioic acid, the characteristic peak position (cm) of infrared spectrum -1 ) At 3051, 2990, 2947, 2911, 2853, 1622, 1599, 1566, 1505, 1456, 1421, 1385, 1357, 1327, 1273, 1230, 1143, 1100, 1065, 1032, 956, 928, 871, 815.
Example 5
Weighing 8-hydroxy-dihydroberberine and malonic acid in a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the malonic acid to the solvent is 1.
Example 6
Weighing 8-hydroxy-dihydroberberine and malonic acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the malonic acid to the solvent is 1.
Example 7
Weighing 8-hydroxy-dihydroberberine and malonic acid with a molar ratio of 1.5 to 1.5, adding into acetone-water (volume ratio 2; wherein the mass volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the malonic acid to the solvent is 1.
Example 8
Weighing 8-hydroxy-dihydroberberine and malonic acid with a molar ratio of 1; wherein, the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the malonic acid to the solvent is 1.
The basic structural unit of 1-berberine-2-malonate-2-water prepared in the embodiments 5 to 8 is composed of 1 berberine cation, 1 malonate anion, 1 malonate molecule and 2 water molecules; the unit cell parameters of the 1-berberine-2-malonic acid-2-water are as follows: a/a =7.587 (1), b/a =12.937 (1), c/a =13.964 (1), α/° =71.32 (1), β/° =83.35 (1), γ/° =81.36 (1), volume =1280.4 (2)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 3 H 4 O 4 ·C 3 H 3 O 4 ·2(H 2 O). The X-ray diagram positions of the powder show main diffraction peaks at angles of 2 theta, namely 6.7 +/-0.2 degrees, 7.2 +/-0.2 degrees, 13.4 +/-0.2 degrees, 14.5 +/-0.2 degrees, 16.0 +/-0.2 degrees, 16.4 +/-0.2 degrees, 17.1 +/-0.2 degrees, 17.6 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 25.3 +/-0.2 degrees, 26.2 +/-0.2 degrees and 26.4 +/-0.2 degrees.
Example 5 the 1-berberine-2-malonate-2-crystal prepared was tested and the results are shown in fig. 6-10. FIG. 6 is a PXRD pattern of 1-berberine-2-malonate-2-water. FIG. 7 is a crystal structure diagram of 1-berberine-2-malonic acid-2-water; FIG. 8 is a diagram showing the stacking of unit cells of 1-berberine-2-malonate-2-water. The crystallographic parameters are shown in table 2.
Table 2: crystallographic parameters of 1-berberine-2-malonic acid-2-water
FIG. 9 is a TG and DSC spectra of 1-berberine-2-malonate-2-water; as can be seen from the TG diagram, the mass loss is between 75 ℃ and 115 ℃, between 115 ℃ and 170 ℃ and between 185 ℃ and 210 ℃, which are respectively: 6.2 + -2.0%, 16.9 + -5.0% and 16.6 + -5.0% combined with the DSC curve, and respectively have endothermic peaks at 101 + -5 deg.C, 154 + -5 deg.C and 195 + -5 deg.C.
FIG. 10 is an IR chart of 1-berberine-2-propanedioic acid-2-water, the characteristic peak position (cm) of infrared spectrum -1 ) At 3464, 3353, 3210, 3055, 2988, 2950, 2908, 2846, 1708, 1659, 1599, 1567, 1504, 1483, 1388, 1336, 1271, 1215, 1143, 1169, 1101, 1038, 956, 937, 887, 828.
Example 9
Weighing 8-hydroxy-dihydroberberine and citric acid with a molar ratio of 1; wherein, the mass volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the citric acid to the solvent is 1.
Example 10
Weighing 8-hydroxy-dihydroberberine and citric acid with a molar ratio of 1; wherein the mass volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the citric acid to the solvent is 1.
Example 11
Weighing 8-hydroxy-dihydroberberine and citric acid with a molar ratio of 1:1.5, adding into acetone-water (volume ratio of 2: 1), heating to 55 deg.C, clarifying the solution, filtering, standing at normal temperature, filtering after 72h to precipitate completely, and oven drying to obtain yellow solid powder, which is 2-berberine-2-citric acid; wherein the mass volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the citric acid to the solvent is 1.
Example 12
Weighing 8-hydroxy-dihydroberberine and citric acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the citric acid to the solvent is 1.
The basic structural unit of 2-berberine-2-citric acid prepared in examples 9-12 consists of 2 berberine cations and 2 citric acid anions; the unit cell parameters of the 2-berberine-2-citric acid are as follows: a/a =7.585 (1), b/a =14.686 (1), c/a =22.789 (1), α/° =101.25 (1), β/° =97.33 (1), γ/° =100.89 (1), volume =2409.2 (2)/a 3 Z =2, molecular formula: 2C 20 H 18 NO 4 , 2C 6 H 7 O 7 . The positions of a powder X-ray diagram are represented by 2 theta angles at 6.7 +/-0.2 degrees, 8.1 +/-0.2 degrees, 13.3 +/-0.2 degrees, 14.8 +/-0.2 degrees, 16.3 +/-0.2 degrees, 16.8 +/-0.2 degrees, 18.1 +/-0.2 degrees, 18.3 +/-0.2 degrees, 20.1 +/-0.2 degrees, 24.2 +/-0.2 degrees, 25.4 +/-0.2 degrees and 27.6 +/-0.2 degrees to form main diffraction peaks.
The 2-berberine-2-citric acid crystals prepared in example 9 were tested, and the test results are shown in FIGS. 11 to 15. FIG. 11 is a PXRD pattern of 2-berberine-2-citric acid. FIG. 12 is a crystal structure diagram of 2-berberine-2-citric acid; FIG. 13 is a unit cell stacking diagram of 2-berberine-2-citric acid. The crystallographic parameters are shown in table 3.
Table 3: crystallographic parameters of 2-berberine-2-citric acid
FIG. 14 is a TG and DSC spectra of 2-berberine-2-citric acid; as can be seen from the TG plot, there is a mass loss at 180 ℃ to 220 ℃ of: 26.5 +/-5.0 percent, and has an endothermic peak at 208 +/-5 ℃ combined with a DSC curve.
FIG. 15 is an IR chart of 2-berberine-2-citric acid, an infrared spectrum of characteristic peak position (cm) -1 ) At 3444, 3069, 2945, 2905, 2845, 1718, 1600, 1567, 1503, 1479, 1453, 1422, 1386, 1335, 1313, 1269, 1230, 1198, 1098, 1064, 1033, 972, 930.
Example 13
Weighing 8-hydroxy-dihydroberberine and L-tartaric acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the L-tartaric acid to the solvent is 1.
Example 14
Weighing 8-hydroxy-dihydroberberine and L-tartaric acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the L-tartaric acid to the solvent is 1.
Example 15
Weighing 8-hydroxy-dihydroberberine and L-tartaric acid with a molar ratio of 1.5 to 1, adding into acetone-water (volume ratio of 2; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the L-tartaric acid to the solvent is 1.
Example 16
Weighing 8-hydroxy-dihydroberberine and L-tartaric acid in a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the L-tartaric acid to the solvent is 1.
The basic structural unit of 1-berberine-1-L-tartaric acid-1-water prepared in examples 13 to 16 consists of 1 berberine cation, 1L-tartaric acid anion and 1 water molecule; the unit cell parameters of the 1-berberine-1-L-tartaric acid-1-water are as follows: a/a =12.111 (1), b/a =7.093 (1), c/a =12.703 (1), α/° γ/° 90, β/° 99.43 (1), volume =1076.6 (1)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 4 H 5 O 6 ·H 2 And O. The X-ray diagram positions of the powder are expressed by 2 theta angles at 7.0 +/-0.2 degrees, 7.4 +/-0.2 degrees, 9.3 +/-0.2 degrees, 14.0 +/-0.2 degrees, 14.8 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.5 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.7 +/-0.2 degrees, 21.1 +/-0.2 degrees, 22.1 +/-0.2 degrees, 25.0 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.7 +/-0.2 degrees, 27.3 +/-0.2 degrees and 29.4 +/-0.2 degrees to show main diffraction peaks.
The 1-berberine-1-L-tartaric acid-1-water crystals prepared in example 13 were tested, and the results are shown in FIGS. 16 to 20. FIG. 16 is a PXRD pattern for 1-berberine-1-L-tartaric acid-1-water. FIG. 17 is a crystal structure diagram of 1-berberine-1-L-tartaric acid-1-water; FIG. 18 is a unit cell stacking diagram of 1-berberine-1-L-tartaric acid-1-water. The crystallographic parameters are shown in table 4.
Table 4: crystallographic parameters of 1-berberine-1-L-tartaric acid-1-water
FIG. 19 is a TG and DSC spectra of 1-berberine-1-L-tartaric acid-1-water; as can be seen from the TG diagram, there is mass loss at 80 ℃ to 115 ℃ and 200 ℃ to 240 ℃ which are respectively: 3.6 +/-1.0 percent and 26.88 +/-5.0 percent, and has endothermic peaks at the temperature of 101 +/-5 ℃ and 225 +/-5 ℃ combined with a DSC curve.
FIG. 20 is an IR chart of 1-berberine-1-L-tartaric acid-1-water, an infrared spectrum characteristic peak position (cm) -1 ) In 3421, 3100, 3077, 3019, 2952, 2928, 2897, 1660, 1632, 1616, 1597, 1564, 1501, 1456, 1388、1358、1273、1231、1137、1101、1029、957、823、788、643。
Example 17
Weighing 8-hydroxy-dihydroberberine and methanesulfonic acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the methanesulfonic acid to the solvent is 1.
Example 18
Weighing 8-hydroxy-dihydroberberine and methanesulfonic acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the methanesulfonic acid to the solvent is 1.
Example 19
Weighing 8-hydroxy-dihydroberberine and methanesulfonic acid with a molar ratio of 1.5 to 1.5, adding the mixture into acetone-water (volume ratio is 3; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the methanesulfonic acid to the solvent is 1.
Example 20
Weighing 8-hydroxy-dihydroberberine and methanesulfonic acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the methanesulfonic acid to the solvent is 1.
The basic structural unit of 1-berberine-1-methanesulfonic acid-2-water prepared in examples 17 to 20 consists of 1 berberine cation, 1 methanesulfonic acid anion and 2 waterA sub-constitution; the unit cell parameters of the 1-berberine-1-methanesulfonic acid-2-water are as follows: a/a =7.465 (1), b/a =11.923 (1), c/a =12.921 (1), α/° =69.46 (1), β/° =76.50 (1), γ/° =84.92 (1), volume =1047.1 (1)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·CH 3 O 3 S·2(H 2 O). The main diffraction peaks are shown at the positions of a powder X-ray diagram at 7.9 +/-0.2 degrees, 8.9 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.4 +/-0.2 degrees, 17.8 +/-0.2 degrees, 19.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.1 +/-0.2 degrees, 25.2 +/-0.2 degrees, 25.8 +/-0.2 degrees, 26.5 +/-0.2 degrees and 26.9 +/-0.2 degrees.
The 1-berberine-1-methanesulfonic acid-2-water crystals prepared in example 17 were tested, and the test results are shown in fig. 21 to 25. FIG. 21 is a PXRD pattern of 1-berberine-1-methanesulfonic acid-2-water. FIG. 22 is a crystal structure diagram of 1-berberine-1-methanesulfonic acid-2-water; FIG. 23 is a unit cell stacking diagram of 1-berberine-1-methanesulfonic acid-2-water. The crystallographic parameters are shown in table 5.
Table 5: crystallographic parameters of 1-berberine-1-methanesulfonic acid-2-water
FIG. 24 is a TG and DSC spectra of 1-berberine-1-methanesulfonic acid-2-water; as can be seen from the TG plot, there is a mass loss at 60 to 100 ℃ as follows: 7.1 +/-2.0 percent and has endothermic peaks at 90 +/-5 ℃ combined with a DSC curve.
FIG. 25 is an IR chart of 1-berberine-1-methanesulfonic acid-2-water, an infrared spectrum characteristic peak position (cm) -1 ) At 3411, 3064, 3047, 3010, 2976, 2943, 2915, 2843, 1635, 1598, 1568, 1503, 1482, 1459, 1425, 1389, 1363, 1333, 1276, 1179, 1102, 1040, 932, 834, 774, 551.
Example 21
Weighing 8-hydroxy-dihydroberberine and p-toluenesulfonic acid with a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the p-toluenesulfonic acid to the solvent is 1.
Example 22
Weighing 8-hydroxy-dihydroberberine and p-toluenesulfonic acid in a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the p-toluenesulfonic acid to the solvent is 1.
Example 23
Weighing 8-hydroxy-dihydroberberine and p-toluenesulfonic acid with a molar ratio of 1.5 to 1.5, adding into ethanol-water (volume ratio 3; wherein the mass volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the p-toluenesulfonic acid to the solvent is 1.
Example 24
Weighing 8-hydroxy-dihydroberberine and p-toluenesulfonic acid in a molar ratio of 1; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the p-toluenesulfonic acid to the solvent is 1.
The basic structural unit of 1-berberine-1-p-toluenesulfonate-3-water prepared in examples 21 to 24 is 1-berberine-1-p-toluenesulfonate-3-water, and the basic structural unit is composed of 1 berberine cation, 1 p-toluenesulfonate anion and 3 water molecules; the unit cell parameters of the 1-berberine-1-p-toluenesulfonic acid-3-water are as follows: a/a =7.327 (1), b/a =12.480 (1), c/a =14.639 (1), α/° =95.61 (1), β/° =102.89 (1), γ/° =92.51 (1), 1295.7 (2)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 7 H 7 O 3 S·3(H 2 O). The main diffraction peaks are shown at the positions of the powder X-ray diagram at 6.3 +/-0.2 degrees, 7.2 +/-0.2 degrees, 11.0 +/-0.2 degrees, 12.5 +/-0.2 degrees, 14.4 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.9 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.1 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.6 +/-0.2 degrees, 23.5 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.2 +/-0.2 degrees and 27.0 +/-0.2 degrees.
The 1-berberine-1-p-toluenesulfonic acid-3-water crystals prepared in example 21 were tested, and the test results are shown in FIGS. 26 to 30. FIG. 26 is a PXRD pattern for 1-berberine-1-methanesulfonic acid-2-water. FIG. 27 is a crystal structure diagram of 1-berberine-1-p-toluenesulfonic acid-3-water; FIG. 28 is a schematic diagram showing the stacking of the unit cells of 1-berberine-1-p-toluenesulfonate-3-water. The crystallographic parameters are shown in table 6.
Table 6: crystallographic parameters of 1-berberine-1-p-toluenesulfonic acid-3-water
FIG. 29 is a TG and DSC spectra of 1-berberine-1-p-toluenesulfonic acid-3-water; as can be seen from the TG diagram, there is mass loss at 50 ℃ to 80 ℃ and 80 ℃ to 120 ℃ which are respectively: 5.5 +/-2.0 percent and 2.9 +/-1.0 percent, and has endothermic peaks at 70 +/-5 ℃ and 109 +/-5 ℃ combined with a DSC curve.
FIG. 30 is an IR chart of 1-berberine-1-p-toluenesulfonic acid-3-water, an infrared spectrum of characteristic peak positions (cm) -1 ) At 3397, 3047, 3003, 2944, 2905, 2844, 1600, 1567, 1499, 1474, 1457, 1385, 1360, 1336, 1259, 1182, 1121, 1099, 1032, 1009, 973, 957, 934, 811, 681, 562.
FIG. 31 is a graph showing the powder elution profiles of 1-berberine-1-propanedioic acid in example 1, 1-berberine-2-propanedioic acid-2-water in example 5, 2-berberine-2-citric acid in example 9, 1-berberine-1-L-tartaric acid-1-water in example 13, 1-berberine-1-methanesulfonic acid-2-water in example 17 and 1-berberine-1-p-toluenesulfonic acid-3-water in example 21; the amounts of berberine dissolved out by hydrochloric acid berberine, 1-berberine-1-malonic acid, 1-berberine-2-malonic acid-2-water, 2-berberine-2-citric acid, 1-berberine-1-L-tartaric acid-1-water, 1-berberine-1-methanesulfonic acid-2-water and 1-berberine-1 p-toluenesulfonic acid-3-water in 3 hours are respectively 2.1 [ mu ] mol/mL, 68.8 [ mu ] mol/mL, 34.8 [ mu ] mol/mL, 9.5 [ mu ] mol/mL, 13.1 [ mu ] mol/mL, 7.5 [ mu ] mol/mL and 2.4 [ mu ] mol/mL.
Table 7 shows the stability results of 1-berberine-1-propanedioic acid, 1-berberine-2-propanedioic acid-2-water, 2-berberine-2-citric acid, 1-berberine-1-L-tartaric acid-1-water, 1-berberine-1-methanesulfonic acid-2-water and 1-berberine-1-p-toluenesulfonic acid-3-water under the conditions of humidity of 75% and 92.5%, and none of these samples underwent solid phase transition.
Table 7: crystal form stability results of 6 new berberine salts
The chemical structure of the berberine is not changed by the prepared 1-berberine-1-malonic acid, 1-berberine-2-malonic acid-2-water, 2-berberine-2-citric acid, 1-berberine-1-L-tartaric acid-1-water, 1-berberine-1-methanesulfonic acid-2-water and 1-berberine-1-p-toluenesulfonic acid-3-water, the pharmacological activity of the berberine is retained, and the dissolution and stability of the berberine are improved.
Claims (10)
1. The crystal form of the novel berberine salt is characterized in that 8-hydroxy-dihydro berberine and a pharmaceutically acceptable acid are taken as raw materials, are dissolved in a solvent, and are obtained by slow solvent volatilization and cooling recrystallization, wherein the pharmaceutically acceptable acid is one of malonic acid, citric acid, L-tartaric acid, methanesulfonic acid and p-toluenesulfonic acid.
2. The crystalline form of the novel berberine salt according to claim 1, wherein when the pharmaceutically acceptable acid is malonic acid, the crystalline form of the novel salt is 1-berberine-1-malonic acid, and the basic structural unit consists of 1 berberine cation and 1 malonic acid anion; the 1-berberine-1-malonic acid belongs to monoclinic system and has a space group ofP 21/cUnit cell parameters a/a =6.943 (1), b/= 19.818 (2), c/a =14.669 (2), α/° γ/° =90, β/° 97.08 (1), volume =2003.1 (3)/a 3 Z =4, formula: c 20 H 18 NO 4 ·C 3 H 3 O 4 ；
The X-ray diagram positions of powder of the crystal form of 1-berberine-1-malonic acid expressed by 2 theta angles at 7.5 +/-0.2 degrees, 8.9 +/-0.2 degrees, 10.8 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.7 +/-0.2 degrees, 17.2 +/-0.2 degrees, 17.8 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.6 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.9 +/-0.2 degrees and 27.5 +/-0.2 degrees represent main diffraction peaks.
3. The crystal form of the berberine new salt according to claim 1, wherein when the pharmaceutically acceptable acid is malonic acid, the crystal form of the new salt is 1-berberine-2-malonic acid-2-water, and the basic structural unit consists of 1 berberine cation, 1 malonic acid anion, 1 malonic acid molecule and 2 water molecules; 1-berberine-2-malonic acid-2-water belongs to triclinic system and has a space group ofP -1Unit cell parameters a/a =7.587 (1), b/a =12.937 (1), c/a =13.964 (1), α/° 71.32 (1), β/° 83.35 (1), γ/° 81.36 (1), volume =1280.4 (2)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 3 H 4 O 4 ·C 3 H 3 O 4 ·2(H 2 O)；
The X-ray diagram positions of the powder of the 1-berberine-2-malonic acid-2-crystal form are represented by 2 theta angles at 6.7 +/-0.2 degrees, 7.2 +/-0.2 degrees, 13.4 +/-0.2 degrees, 14.5 +/-0.2 degrees, 16.0 +/-0.2 degrees, 16.4 +/-0.2 degrees, 17.1 +/-0.2 degrees, 17.6 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 25.3 +/-0.2 degrees, 26.2 +/-0.2 degrees and 26.4 +/-0.2 degrees, wherein the degrees show main diffraction peaks.
4. The crystalline form of the novel berberine salt according to claim 1, wherein when the pharmaceutically acceptable acid is citric acid, the crystalline form of the novel salt is 2-berberine-2 citric acid, and the basic structural unit consists of 2 berberine cations and 2 citrate anions; the 2-berberine-2-citric acid belongs to a triclinic system and has a space group ofP -1Unit cell parameters a/a =7.585 (1), b/a =14.686 (1), c/a =22.789 (1), α/° 101.25 (1), β/° 97.33 (1), γ/° 100.89 (1), volume =2409.2 (2)/a 3 Z =2, molecular formula: 2C 20 H 18 NO 4 · 2C 6 H 7 O 7 ；
The X-ray diagram positions of the powder of the crystal form of 2-berberine-2-citric acid are expressed by 2 theta angles at 6.7 +/-0.2 degrees, 8.1 +/-0.2 degrees, 13.3 +/-0.2 degrees, 14.8 +/-0.2 degrees, 16.3 +/-0.2 degrees, 16.8 +/-0.2 degrees, 18.1 +/-0.2 degrees, 18.3 +/-0.2 degrees, 20.1 +/-0.2 degrees, 24.2 +/-0.2 degrees, 25.4 +/-0.2 degrees and 27.6 +/-0.2 degrees, so that main diffraction peaks are shown.
5. The crystal form of the berberine new salt according to claim 1, wherein when the pharmaceutically acceptable acid is L-tartaric acid, the crystal form of the new salt is 1-berberine-1-L-tartaric acid, and the basic structural unit consists of 1 berberine cation, 1L-tartaric anion and 1 water molecule; 1-berberine-1-L-tartaric acid belongs to monoclinic system, and has space group ofP 21Unit cell parameters a/a =12.111 (1), b/a =7.093 (1), c/a =12.703 (1), α/° γ/° =90, β/° 99.43 (1), volume =1076.6 (1)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 4 H 5 O 6 ·H 2 O；
The powder X-ray diagram positions of the crystal form of 1-berberine-1-L-tartaric acid are represented by 2 theta angles at 7.0 +/-0.2 degrees, 7.4 +/-0.2 degrees, 9.3 +/-0.2 degrees, 14.0 +/-0.2 degrees, 14.8 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.5 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.7 +/-0.2 degrees, 21.1 +/-0.2 degrees, 22.1 +/-0.2 degrees, 25.0 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.7 +/-0.2 degrees, 27.3 +/-0.2 degrees, 29.4 +/-0.2 degrees and present main diffraction peaks.
6. The crystal form of the berberine new salt according to claim 1, wherein when the pharmaceutically acceptable acid is methanesulfonic acid, the crystal form of the new salt is 1-berberine-1-methanesulfonic acid-2-water, and the basic structural unit consists of 1 berberine cation, 1 methanesulfonic acid anion and 2 water molecules; 1-berberine-1-methanesulfonic acid-2-water belongs to a triclinic system, and the space group isP -1Unit cell parameters a/a =7.465 (1), b/a =11.923 (1), c/a =12.921 (1), α/° =69.46 (1), β/° =76.50 (1), γ/° =84.92 (1), volume =1047.1 (2)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·CH 3 O 3 S·2(H 2 O)；
The main diffraction peaks are shown by the X-ray diagram positions of powder of the 1-berberine-1-methanesulfonic acid-2 crystal form, which are expressed by 2 theta angles at 7.9 +/-0.2 degrees, 8.9 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.4 +/-0.2 degrees, 17.8 +/-0.2 degrees, 19.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.1 +/-0.2 degrees, 25.2 +/-0.2 degrees, 25.8 +/-0.2 degrees, 26.5 +/-0.2 degrees and 26.9 +/-0.2 degrees.
7. The crystal form of the novel berberine salt according to claim 1, wherein when the pharmaceutically acceptable acid is p-toluenesulfonic acid, the crystal form of the novel salt is 1-berberine-1-p-toluenesulfonic acid-3-water, and the basic structural unit consists of 1 berberine cation, 1 p-toluenesulfonic acid anion and 3 water molecules; 1-berberine-1-p-toluenesulfonic acid-3-water belongs to a triclinic system, and the space group isP -1Unit cell parameters a/a =7.327 (1), b/a =12.480 (1), c/a =14.639 (1), α/° 95.61 (1), β/° 102.89 (1), γ/° 92.51 (1), 1295.7 (2)/a 3 Z =2, molecular formula: c 20 H 18 NO 4 ·C 7 H 7 O 3 S·3(H 2 O)；
The powder X-ray diagram positions of the 1-berberine-1-p-toluenesulfonic acid-3-water crystal form are represented by 2 theta angles at 6.3 +/-0.2 degrees, 7.2 +/-0.2 degrees, 11.0 +/-0.2 degrees, 12.5 +/-0.2 degrees, 14.4 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.9 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.1 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.6 +/-0.2 degrees, 23.5 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.2 +/-0.2 degrees and 27.0 +/-0.2 degrees to present main diffraction peaks.
8. The preparation method of the crystal form of the new berberine salt according to claim 2, wherein after the 8-hydroxy-dihydroberberine and the malonic acid are completely dissolved by a mixed solvent system of water, alcohols, acetonitrile and tetrahydrofuran in a molar ratio of 1 to 1.4, a crystal form sample is obtained by a method of removing a solvent through solvent volatilization at the temperature of 10 ℃ to 70 ℃ under the environment humidity of 10% to 75% and the temperature of 10 ℃ to 70 ℃, or cooling crystallization.
9. The preparation method of the crystal form of the berberine new salt according to claim 3, characterized by completely dissolving 8-hydroxy-dihydroberberine and malonic acid in a mixed solvent system of water, ketones, alcohols, acetonitrile and tetrahydrofuran according to a molar ratio of 1.5-1, and obtaining a crystal form sample by a method of removing a solvent through solvent volatilization at an environmental humidity of 10% -75% and a temperature of 10 ℃ -70 ℃, or cooling crystallization.
10. A preparation method of the crystal form of the berberine new salt according to any one of claims 4 to 7, which is characterized in that after 8-hydroxy-dihydroberberine and a pharmaceutically acceptable acid are completely dissolved by a mixed solvent system of water, alcohols, ketones, acetonitrile and tetrahydrofuran according to a molar ratio of 1-1.
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