CN117430557A - Preparation and application of eutectic crystal form of dibazoles and mandelic acid and pharmaceutical composition - Google Patents
Preparation and application of eutectic crystal form of dibazoles and mandelic acid and pharmaceutical composition Download PDFInfo
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- CN117430557A CN117430557A CN202311351204.5A CN202311351204A CN117430557A CN 117430557 A CN117430557 A CN 117430557A CN 202311351204 A CN202311351204 A CN 202311351204A CN 117430557 A CN117430557 A CN 117430557A
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- dibazol
- mandelic acid
- degrees
- hydrochloride
- dibazoles
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- 229960002510 mandelic acid Drugs 0.000 title claims abstract description 102
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 title claims abstract description 99
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 title claims abstract description 99
- 239000013078 crystal Substances 0.000 title claims abstract description 99
- 230000005496 eutectics Effects 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- YTLQFZVCLXFFRK-UHFFFAOYSA-N bendazol Chemical class N=1C2=CC=CC=C2NC=1CC1=CC=CC=C1 YTLQFZVCLXFFRK-UHFFFAOYSA-N 0.000 claims abstract description 87
- 229950000900 bendazol Drugs 0.000 claims abstract description 80
- CJTQARUHALKPGG-UHFFFAOYSA-N 2-benzyl-1h-benzimidazole;hydron;chloride Chemical compound Cl.N=1C2=CC=CC=C2NC=1CC1=CC=CC=C1 CJTQARUHALKPGG-UHFFFAOYSA-N 0.000 claims abstract description 59
- 239000003814 drug Substances 0.000 claims abstract description 23
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 10
- 206010020772 Hypertension Diseases 0.000 claims abstract description 7
- 238000000498 ball milling Methods 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 238000000227 grinding Methods 0.000 claims description 5
- XUCIJNAGGSZNQT-JHSLDZJXSA-N (R)-amygdalin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O[C@@H](C#N)C=2C=CC=CC=2)O1 XUCIJNAGGSZNQT-JHSLDZJXSA-N 0.000 claims description 3
- 229940089837 amygdalin Drugs 0.000 claims description 3
- YZLOSXFCSIDECK-UHFFFAOYSA-N amygdalin Natural products OCC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC(C#N)c3ccccc3 YZLOSXFCSIDECK-UHFFFAOYSA-N 0.000 claims description 3
- YGHHWSRCTPQFFC-UHFFFAOYSA-N eucalyptosin A Natural products OC1C(O)C(O)C(CO)OC1OC1C(OC(C#N)C=2C=CC=CC=2)OC(CO)C(O)C1O YGHHWSRCTPQFFC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229960002274 atenolol Drugs 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 24
- 238000002425 crystallisation Methods 0.000 abstract description 6
- 239000000725 suspension Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- HVLVEEDEXQWMGZ-UHFFFAOYSA-N 2-hydroxy-2-phenylacetic acid;hydrochloride Chemical compound Cl.OC(=O)C(O)C1=CC=CC=C1 HVLVEEDEXQWMGZ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QMYTXCUSWCFXLY-UHFFFAOYSA-N methanol;triethylazanium;hydroxide Chemical compound [OH-].OC.CC[NH+](CC)CC QMYTXCUSWCFXLY-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
- C07C59/50—Mandelic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Epidemiology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to preparation and application of a eutectic crystal form of a dibazol drug and mandelic acid and a pharmaceutical composition, and the preparation method comprises a cooling crystallization method, a suspension stirring method and a mechanical ball milling method. Compared with the prior art, the preparation method of the co-crystal forms of the dibazol/the dibazol hydrochloride and the mandelic acid is simple, easy to control and good in reproducibility, the stable co-crystal forms of the dibazol and the mandelic acid and the dibazol hydrochloride and the mandelic acid can be obtained, the purity of the crystal forms is high and reaches more than 99.9%, the dissolution speed of the dibazol/the dibazol hydrochloride is high, and the preparation method has wide application prospects in preparing medicines for preventing or treating hypertension.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical co-crystal forms, and relates to a preparation method and application of a pharmaceutical co-crystal form of dibazol (2-benzyl benzimidazole) and hydrochloride form drugs thereof and mandelic acid, and a pharmaceutical composition containing the pharmaceutical co-crystal form.
Background
The chemical name of the dibazol (Bendazol) is 2-benzyl benzimidazole (C) 14 H 12 N 2 The dibazol is soluble in ethanol, hot benzene and glacial acetic acid and has poor solubility in water. The dibazol can directly relax vascular smooth muscle, expand blood vessel, reduce resistance and lower blood pressure, and is suitable for treating mild hypertension or enhancing blood pressure reducing curative effect by being combined with other antihypertensive drugs. The current drug of dibazol on the market is dibazol hydrochloride (C 14 H 12 N 2 HCl, formula II), solubility in water has not yet increased to the desired state. The dibazol has low solubility and high permeability in a biopharmaceutical classification system, and belongs to BCS II compounds.
Disclosure of Invention
The invention aims to provide a co-crystal form of a bazole drug and mandelic acid, which has outstanding advantages in the aspects of stability, dissolution, bioavailability and the like, a preparation method thereof and application thereof in preparing a drug for preventing or treating hypertension.
The aim of the invention can be achieved by the following technical scheme:
in order to improve the solubility and bioavailability, the invention improves the solubility property of the dibazol by a co-crystallization technology, which is beneficial to improving the therapeutic effect. The choice of the eutectic crystal form former is a critical step in order to obtain the desired pharmaceutical eutectic crystal form. The mandelic acid is also called mandelic acid, is white orthorhombic flaky crystal, is easily dissolved in hot water, diethyl ether, isopropanol and ethanol, has no toxic or side effect, and is an ideal eutectic crystal form formation.
The first aspect of the invention provides a crystal form of a co-crystal of the dibazol/the dibazol hydrochloride and the mandelic acid, which comprises the dibazol medicine and atenolol in a molar ratio of 2:1; wherein the dibazoles are dibazoles or dibazoles hydrochloride;
an X-ray powder diffraction pattern measured using Cu ka radiation has characteristic peaks at diffraction angles 2θ of 9.2 °, 13.8 °, 15.9 °, 17.2 °, 17.8 °, 18.4 °, 19.5 °, 20.1 °, 20.5 °, 22.0 °, 23.1 °, 24.1 °, 27.7 °;
the crystalline form of the co-crystal of the dibazol hydrochloride and the mandelic acid has characteristic peaks at diffraction angles 2 theta of 8.3 degrees, 10.9 degrees, 11.9 degrees, 13.6 degrees, 14.7 degrees, 16.0 degrees, 17.7 degrees, 18.2 degrees, 19.6 degrees, 19.9 degrees, 21.1 degrees, 22.6 degrees, 24.7 degrees, 25.7 degrees, 27.4 degrees, 28.0 degrees, 28.6 degrees and 29.5 degrees according to an X-ray powder diffraction pattern measured by Cu K alpha rays.
Further, the differential scanning calorimetric curve of the dibazol and mandelic acid eutectic crystal form has an endothermic peak at 150 ℃; the differential scanning calorimetric curve of the crystal forms of the dibazol hydrochloride and the amygdalin acid eutectic has an endothermic peak at 126 ℃.
The second aspect of the invention provides a preparation method of a crystal form of a eutectic of dibazol/dibazol hydrochloride and mandelic acid, which comprises the following steps: mixing the dibazol medicine and the mandelic acid in an organic solvent at 40-90 ℃, cooling to 5-25 ℃, continuously stirring, filtering, and drying at 30-80 ℃ to obtain the dibazol medicine and the mandelic acid eutectic crystal form.
Further, the ratio of the total mass of the dibazoles and the mandelic acid to the volume of the organic solvent is 1g (5-25 mL); the organic solvent is one of water, alcohol solvent, ethyl acetate, chloroform, acetonitrile or acetone.
Further, after cooling, stirring is continued for 1 to 10 hours.
The third aspect of the invention provides a preparation method of a crystal form of a eutectic of dibazol/dibazol hydrochloride and mandelic acid, which comprises the following steps: mixing the dibazoles and the mandelic acid in an organic solvent, continuously stirring for 2-48 hours at 15-60 ℃, filtering, and drying at 30-80 ℃ to obtain the eutectic crystal form of the dibazoles and the mandelic acid.
Further, the ratio of the total mass of the dibazoles and the mandelic acid to the volume of the organic solvent is 1g (5-25 mL); the organic solvent is one of water, alcohol solvent, ethyl acetate, chloroform, acetonitrile or acetone.
The fourth aspect of the invention provides a preparation method of a crystal form of a eutectic of dibazol/dibazol hydrochloride and mandelic acid, comprising the following steps: mixing the dibazoles and the mandelic acid in an organic solvent, and mechanically ball milling to obtain the eutectic crystal form of the dibazoles and the mandelic acid.
Further, the ratio of the total mass of the dibazoles and the mandelic acid to the volume of the organic solvent is 1g (20-200 mu L).
Further, the organic solvent is one of water, an alcohol solvent, ethyl acetate, acetonitrile or acetone.
Further, the mechanical ball milling conditions are as follows: the frequency is 1-10 times/second, and the grinding time is 10-100 minutes.
In a fifth aspect, the invention provides a pharmaceutical composition comprising a crystalline co-crystal form of dibazol/dibazol hydrochloride and mandelic acid, and a pharmaceutically acceptable excipient.
The sixth aspect of the invention provides an application of a crystal form of the co-crystal of the dibazol/the dibazol hydrochloride and the mandelic acid, which comprises the step of preparing a medicine for preventing or treating hypertension by using the crystal form of the co-crystal of the dibazol and the mandelic acid.
The invention prepares the dibazol-mandelic acid eutectic crystal form and the dibazol-mandelic acid hydrochloride eutectic crystal form by co-crystallizing the dibazol/dibazol hydrochloride and the mandelic acid through a crystal engineering technology. By utilizing the characteristic that the water solubility of the amygdalin is far higher than that of the dibazole or the dibazole hydrochloride, the foundation is laid for improving the bioavailability of the dibazole by enhancing the dissolution behavior of the dibazole or the dibazole hydrochloride on the premise of not changing the antihypertensive pharmacological action of the dibazole.
Compared with the prior art, the invention has the following characteristics:
1) The preparation method of the co-crystal forms of the dibazol/the dibazol hydrochloride and the mandelic acid is simple, easy to control and good in reproducibility, and can obtain stable co-crystal forms of the dibazol and the mandelic acid and the dibazol hydrochloride and the mandelic acid, and the purity of the crystal forms is high and reaches more than 99.9%;
2) The dissolution speed of the eutectic crystal form of the dibazol/the dibazol hydrochloride and the mandelic acid is high, and the dissolution rate of the eutectic crystal form of the dibazol-the mandelic acid is 6 times of that of the dibazol in 10 minutes; the dissolution rate of the crystal form of the dibazol hydrochloride-mandelic acid eutectic is 9 times of that of the dibazol hydrochloride at 15 minutes, and the crystal form is faster than that of the dibazol hydrochloride/dibazol hydrochloride. In conclusion, the dissolution rate of the obtained eutectic crystal form is greatly improved, and an improved preparation of the dibazol/dibazol hydrochloride with higher bioavailability and better curative effect can be developed;
3) The co-crystal form of the dibazol/dibazol hydrochloride and the mandelic acid has wide application prospect in preparing the medicines for preventing or treating hypertension.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of a co-crystal form of dibazol and mandelic acid prepared in example 1;
FIG. 2 is an X-ray powder diffraction pattern of the co-crystal form of dibazol hydrochloride and mandelic acid prepared in example 4;
FIG. 3 is a DSC of a eutectic crystal form of dibazol and mandelic acid prepared in example 1;
FIG. 4 is a DSC of a eutectic crystal form of dibazol hydrochloride and mandelic acid prepared in example 4;
FIG. 5 is a graph of the eutectic dissolution profile of dibazol and dibazol with mandelic acid in example 6;
FIG. 6 is a graph showing the eutectic dissolution profile of the dibazol hydrochloride and mandelic acid in example 6.
Detailed Description
The invention will now be described in detail with reference to the drawings and specific examples.
In the existing crystallization technology, the types of solvents which can be used for crystallization are various, the number of mixed solvents with different types and proportions is not counted, the crystallized crystal forms cannot be predicted according to crystallization conditions before crystallization experiments, particularly, the formation of pharmaceutical eutectic crystal forms cannot be predicted before experiments.
The preparation method of the dibazol/dibazol hydrochloride and mandelic acid eutectic crystal form based on the cooling crystallization method comprises the following steps:
1) Mixing the dibazol medicine with the mandelic acid according to the molar ratio of 2:1, adding the mixture into an organic solvent, and heating the mixture to 40-90 ℃ to form a clear solution; wherein the dibazoles are dibazoles or dibazoles hydrochloride; the ratio of the total mass of the dibazoles and the mandelic acid to the volume of the organic solvent is 1g (5-25) mL; the organic solvent is one of water, alcohol solvent, ethyl acetate, chloroform, acetonitrile or acetone; preferably, the alcoholic solvent is ethanol or methanol; more preferably, the organic solvent is acetone;
2) Cooling to 5-25 deg.c and stirring for 1-10 hr;
3) Filtering, and drying the filter cake at 30-80deg.C to obtain the crystal form of the eutectic crystal of the dibazol and the mandelic acid.
The preparation method of the dibazol/dibazol hydrochloride and mandelic acid eutectic crystal form based on the suspension stirring method comprises the following steps:
1) Adding the dibazoles and the mandelic acid into an organic solvent according to a molar ratio of 2:1; wherein the ratio of the total mass of the dibazoles and the mandelic acid to the volume of the organic solvent is 1g (5-25) mL; the organic solvent is one of water, alcohol solvent, ethyl acetate, chloroform, acetonitrile or acetone; preferably, the alcoholic solvent is ethanol or methanol; more preferably, the organic solvent is acetone;
2) Continuously stirring for 2-48 h at 15-60 ℃;
3) Filtering, and drying the filter cake at 30-80deg.C to obtain the crystal form of the eutectic crystal of the dibazol and the mandelic acid.
Preferably, the alcohol solvent is ethanol or methanol. More preferably, the organic solvent is acetone.
A preparation method of a crystal form of a eutectic of dibazol/dibazol hydrochloride and mandelic acid based on a mechanical ball milling method comprises the following steps: mixing the dibazoles and the mandelic acid in a molar ratio of 2:1, and mechanically ball milling to obtain the eutectic crystal form of the dibazoles and the mandelic acid.
A pharmaceutical composition comprising a crystalline form of dibazol/dibazol hydrochloride and mandelic acid, and a pharmaceutically acceptable excipient.
The application of the dibazol/dibazol hydrochloride and mandelic acid eutectic crystal form comprises the step of preparing a medicament for preventing or treating hypertension by using the dibazol medicament and the mandelic acid eutectic crystal form.
The following examples are given with the above technical solutions of the present invention as a premise, and detailed embodiments and specific operation procedures are given, but the scope of protection of the present invention is not limited to the following examples.
Example 1: preparation of eutectic crystal form of dibazol and mandelic acid
According to the mole ratio of 2:1, dispersing 416.52g of dibazol and 152.14g of mandelic acid in 3L of ethyl acetate to form supersaturated solution, stirring for 48h at 40 ℃, filtering, collecting crystals, and drying at 60 ℃ for 2h to obtain 360.54g of white crystals, namely the eutectic crystal form of the dibazol and the mandelic acid, wherein the crystal form has the X-ray powder diffraction pattern characteristics shown in figure 1 and the DSC pattern characteristics shown in figure 3.
Using Cu kα rays, an X-ray powder diffraction pattern shown in fig. 1 was obtained at a diffraction angle 2θ (°, ±0.2): characteristic peaks at 9.2 °, 13.8 °, 15.9 °, 17.2 °, 17.8 °, 18.4 °, 19.5 °, 20.1 °, 20.5 °, 22.0 °, 23.1 °, 24.1 °, 27.7 °.
The X-ray powder diffraction pattern of the eutectic form shows characteristic peaks at diffraction angles 2θ in table 1, wherein the error range of the 2θ values is ±0.2 °.
TABLE 1
| 2θ(°)±0.2° | 2θ(°)±0.2° | 2θ(°)±0.2° |
| 9.2 | 19.1 | 24.9 |
| 13.8 | 19.5 | 26.0 |
| 14.2 | 20.1 | 27.7 |
| 15.9 | 20.5 | 31.5 |
| 17.2 | 22.0 | 32.6 |
| 17.8 | 23.1 | 37.4 |
| 18.4 | 24.1 |
As shown in the DSC profile of fig. 3, the differential scanning calorimetry trace of the co-crystal form of dibazol and mandelic acid showed an endothermic peak at 150 ℃ (±5℃).
In the present invention, the term "having an X-ray powder diffraction pattern substantially as shown in the figure" for the X-ray diffraction peak positions means taking into consideration representative peak positions and intensity variations; similarly, "substantially the same" with respect to DSC profile is also meant to cover variations known to those skilled in the art that are related to analytical techniques.
Example 2: preparation of eutectic crystal form of dibazol and mandelic acid
The molar ratio is 2:1, 104.13g of dibazol and 38.04g of mandelic acid are dispersed in 400ml of acetonitrile, heated to 65 ℃ for dissolution, cooled to room temperature, stirred at room temperature for precipitation of solid, filtered after 5 hours, and the collected crystal is dried for 2 hours at 40 ℃ to obtain 65.78g of white crystal, namely the eutectic crystal form of the dibazol and the mandelic acid.
Example 3: preparation of eutectic crystal form of dibazol and mandelic acid
The molar ratio is 2:1 putting 20.83mg of dibazol and 7.61mg of mandelic acid into an adapter of a ball mill, adding 3 zirconia grinding balls with the diameter of 4mm, dripping 20 mu L of acetonitrile, fully grinding and mixing for 1h by using a ball mill, and collecting a sample, namely the eutectic crystal form of the dibazol and the mandelic acid.
Example 4: preparation of eutectic crystal form of dibazol hydrochloride and mandelic acid
According to the mole ratio of 2:1, 489.44g of dibazol hydrochloride and 152.14g of mandelic acid are dispersed in 4L of acetonitrile to form supersaturated solution, stirred for 24 hours at 50 ℃, filtered, and the collected crystals are dried for 2 hours at 60 ℃ to obtain 438.69g of white crystals, namely the eutectic crystal form of the dibazol hydrochloride and the mandelic acid, and the crystal form has the X-ray powder diffraction characteristics shown in figure 2 and the DSC spectrum characteristics shown in figure 4.
Using Cu kα rays, an X-ray powder diffraction pattern shown in fig. 2 was obtained at a diffraction angle 2θ (°, ±0.2): characteristic peaks at 8.3 °, 10.9 °, 11.9 °, 13.6 °, 14.7 °, 16.0 °, 17.7 °, 18.2 °, 19.6 °, 19.9 °, 21.1 °, 22.6 °, 24.7 °, 25.7 °, 27.4 °, 28.0 °, 28.6 °, 29.5 °.
The X-ray powder diffraction pattern of the eutectic form shows characteristic peaks at diffraction angles 2θ in table 2, wherein the error range of the 2θ values is ±0.2 °.
TABLE 2
As shown in the DSC profile of fig. 4, the differential scanning calorimetry trace of the co-crystal form of dibazol hydrochloride and mandelic acid showed an endothermic peak at 126 ℃ (±5℃).
Example 5: preparation of eutectic crystal form of dibazol hydrochloride and mandelic acid
The molar ratio is 2:1, dispersing 122.36g of dibazol hydrochloride and 38.04g of mandelic acid in 500ml of methanol, heating to 60 ℃ for dissolution, cooling to 15 ℃, stirring at room temperature for precipitation of solid, filtering after 4 hours, and collecting crystals and drying at 50 ℃ for 2 hours to obtain 112.48g of white crystals, namely the eutectic crystal form of the dibazol hydrochloride and the mandelic acid.
Example 6: preparation of eutectic crystal form of dibazol hydrochloride and mandelic acid
The molar ratio is 2:1, 24.48mg of dibazol and 7.61mg of mandelic acid are put into an adapter of a ball mill, 3 zirconia grinding balls with the diameter of 4mm are added, the mixture is fully ground and mixed for 1.5 hours by a ball mill, and then a sample is collected, namely the eutectic crystal form of the dibazol hydrochloride and the mandelic acid.
The eutectic crystal forms of the dibazol/dibazol hydrochloride and the mandelic acid are obtained in different ways in the above examples. The intrinsic dissolution rate of the eutectic crystal form is researched, and compared with the dissolution of the dibazol bulk drug. The experiment comprises the following steps:
chromatographic conditions: the column was ODS column (250 mm. Times.4.6 mm,5 μm); mobile phase: triethylamine-water-methanol (0.5:19.5:80, V/V); the temperature of the chromatographic column is 26 ℃; the flow rate was set at 1.0mL/min; the detection wavelength was set to 275nm; the sample loading was set at 20. Mu.L.
1) Preparation of standard solution: precisely weighing 100mg of the dibazol reference substance, adding 1000ml of pure water to completely dissolve the reference substance, adding 2.0 ml of solution, 4.0 ml of solution, 8.0 ml of solution, 16.0 ml of solution and 20.0ml of solution into a 25ml volumetric flask to fix the volume, and drawing a concentration standard curve of the dibazol according to known concentration and peak area after high performance liquid chromatography detection;
2) Referring to the rule of measuring the dissolution rate and the release rate of 0931 in the 2020 edition of Chinese pharmacopoeia, taking an excessive amount of dibazole/dibazole hydrochloride sample into a dissolution cup which meets the regulations, adding a proper amount (10 ml) of 0.1N dilute hydrochloric acid solution into the dissolution cup, and taking 10ml of 0.1N hydrochloric acid solution as a dissolution medium;
3) Taking excessive eutectic samples (two eutectic samples obtained in examples 1 and 4) into a dissolution cup conforming to the regulations, and adding a proper amount (10 ml) of 0.1N dilute hydrochloric acid solution into the dissolution cup, wherein 10ml of 0.1N hydrochloric acid solution is used as a dissolution medium;
4) The dissolution cup is immediately placed into a constant temperature oscillating box (a magnetic stirrer is turned on, the constant rotation speed is kept, and timing is started) with the preset temperature of 37 ℃ and the rotation speed of 100 rpm;
5) After shaking, 0.5ml of the solution was filtered through a 0.22 μm filter membrane, the concentration of the solution was analyzed by high performance liquid chromatography, and after sampling, the same amount of dissolution medium was immediately replenished and stirring was continued.
The sampling time is nine time points of 5, 10, 15, 20, 30, 45, 60, 90 and 120min, and a dissolution curve of the dibazol and the eutectic of the dibazol hydrochloride and the mandelic acid is drawn;
as shown in fig. 5 and 6, the results indicate that: the eutectic crystal shows better dissolution behavior compared with single bulk drug. The eutectic dissolution speed of the dibazol/the dibazol hydrochloride and the mandelic acid is high, and the dissolution rate of the dibazol-mandelic acid eutectic is 6 times of that of the dibazol in 10 minutes; the dissolution rate of the dibazol hydrochloride-mandelic acid eutectic is 9 times that of the dibazol hydrochloride at 15 minutes, and the speed is faster than that of the dibazol hydrochloride/dibazol hydrochloride.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (10)
1. The crystal form of the co-crystal of the dibazol/the dibazol hydrochloride and the mandelic acid is characterized by comprising the dibazol medicine and atenolol in a molar ratio of 2:1; wherein the dibazoles are dibazoles or dibazoles hydrochloride;
an X-ray powder diffraction pattern measured using Cu ka radiation has characteristic peaks at diffraction angles 2θ of 9.2 °, 13.8 °, 15.9 °, 17.2 °, 17.8 °, 18.4 °, 19.5 °, 20.1 °, 20.5 °, 22.0 °, 23.1 °, 24.1 °, 27.7 °;
the crystalline form of the co-crystal of the dibazol hydrochloride and the mandelic acid has characteristic peaks at diffraction angles 2 theta of 8.3 degrees, 10.9 degrees, 11.9 degrees, 13.6 degrees, 14.7 degrees, 16.0 degrees, 17.7 degrees, 18.2 degrees, 19.6 degrees, 19.9 degrees, 21.1 degrees, 22.6 degrees, 24.7 degrees, 25.7 degrees, 27.4 degrees, 28.0 degrees, 28.6 degrees and 29.5 degrees according to an X-ray powder diffraction pattern measured by Cu K alpha rays.
2. The crystalline form of dibazol/dibazol hydrochloride and mandelic acid according to claim 1, characterized in that the differential scanning calorimetric curve of the crystalline form of dibazol and mandelic acid has an endothermic peak at 150 ℃; the differential scanning calorimetric curve of the crystal forms of the dibazol hydrochloride and the amygdalin acid eutectic has an endothermic peak at 126 ℃.
3. A process for the preparation of the crystalline form of the co-crystals of dibazol/dibazol hydrochloride and mandelic acid according to claim 1 or 2, characterized in that it comprises: mixing the dibazol medicine and the mandelic acid in an organic solvent at 40-90 ℃, cooling to 5-25 ℃, continuously stirring, filtering, and drying at 30-80 ℃ to obtain the dibazol medicine and the mandelic acid eutectic crystal form.
4. The method for preparing the co-crystal forms of the dibazol/dibazol hydrochloride and mandelic acid according to claim 1, wherein the ratio of the total mass of the dibazol drug and the mandelic acid to the volume amount of the organic solvent is 1g (5-25) mL; the organic solvent is one of water, alcohol solvent, ethyl acetate, chloroform, acetonitrile or acetone.
5. A process for the preparation of the crystalline form of the co-crystals of dibazol/dibazol hydrochloride and mandelic acid according to claim 1 or 2, characterized in that it comprises: mixing the dibazoles and the mandelic acid in an organic solvent, continuously stirring for 2-48 hours at 15-60 ℃, filtering, and drying at 30-80 ℃ to obtain the eutectic crystal form of the dibazoles and the mandelic acid.
6. The method for preparing the co-crystal forms of the dibazol/dibazol hydrochloride and mandelic acid according to claim 5, wherein the ratio of the total mass of the dibazol drug and the mandelic acid to the volume amount of the organic solvent is 1g (5-25) mL; the organic solvent is one of water, alcohol solvent, ethyl acetate, chloroform, acetonitrile or acetone.
7. A process for the preparation of the crystalline form of the co-crystals of dibazol/dibazol hydrochloride and mandelic acid according to claim 1 or 2, characterized in that it comprises: mixing the dibazoles and the mandelic acid in an organic solvent, and mechanically ball milling to obtain the eutectic crystal form of the dibazoles and the mandelic acid.
8. The preparation method of the co-crystal forms of the dibazol/dibazol hydrochloride and the mandelic acid according to claim 7, wherein the ratio of the total mass of the dibazol drug and the mandelic acid to the volume amount of an organic solvent is 1g (20-200) mu L, the organic solvent is one of water, an alcohol solvent, ethyl acetate, acetonitrile or acetone, and the mechanical ball milling condition is as follows: the frequency is 1-10 times/second, and the grinding time is 10-100 minutes.
9. A pharmaceutical composition comprising the crystalline form of dibazol/dibazol hydrochloride and mandelic acid according to claim 1 or 2, and a pharmaceutically acceptable excipient.
10. Use of the crystalline form of the co-crystal of dibazol/dibazol hydrochloride and mandelic acid according to claim 1 or 2 for the preparation of a medicament for the prevention or treatment of hypertension.
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