CN117430558A - Preparation and application of drug-drug co-crystal of dibazol hydrochloride and atenolol and drug composition - Google Patents
Preparation and application of drug-drug co-crystal of dibazol hydrochloride and atenolol and drug composition Download PDFInfo
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- CN117430558A CN117430558A CN202311351206.4A CN202311351206A CN117430558A CN 117430558 A CN117430558 A CN 117430558A CN 202311351206 A CN202311351206 A CN 202311351206A CN 117430558 A CN117430558 A CN 117430558A
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- atenolol
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- dibazol
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- 229960002274 atenolol Drugs 0.000 title claims abstract description 90
- 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 title claims abstract description 79
- 239000013078 crystal Substances 0.000 title claims abstract description 64
- 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 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims description 51
- 229940079593 drug Drugs 0.000 title claims description 48
- 239000000203 mixture Substances 0.000 title description 7
- YTLQFZVCLXFFRK-UHFFFAOYSA-N bendazol Chemical compound N=1C2=CC=CC=C2NC=1CC1=CC=CC=C1 YTLQFZVCLXFFRK-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229950000900 bendazol Drugs 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 238000000498 ball milling Methods 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 239000003960 organic solvent Substances 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 206010020772 Hypertension Diseases 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 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 claims description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 3
- 239000005456 alcohol based solvent Substances 0.000 claims description 3
- 229960002510 mandelic acid Drugs 0.000 claims description 3
- 238000003801 milling Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 230000005496 eutectics Effects 0.000 abstract description 35
- 238000004090 dissolution Methods 0.000 abstract description 23
- 238000002425 crystallisation Methods 0.000 abstract description 6
- 239000000890 drug combination Substances 0.000 abstract description 3
- 239000000725 suspension Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 7
- 238000001514 detection method Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 3
- 239000002220 antihypertensive agent Substances 0.000 description 3
- 229940127088 antihypertensive drug Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 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
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003276 anti-hypertensive 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
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- 238000004364 calculation method Methods 0.000 description 1
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- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000001573 invertase Substances 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 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
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Chemistry (AREA)
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical co-crystals, and relates to preparation and application of a drug-pharmaceutical co-crystal of dibazol hydrochloride and atenolol and a pharmaceutical composition, wherein 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 dibazol hydrochloride-atenolol eutectic is simple, easy to control and good in reproducibility, stable eutectic of the dibazol hydrochloride and atenolol can be obtained, the purity of the crystal form is high and reaches more than 99.9%, the eutectic dissolution speed is high, and the method has the potential of drug combination.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical co-crystals, and relates to a novel pharmaceutical co-crystal form of dibazol hydrochloride (2-benzyl benzimidazole hydrochloride) and atenolol, and a preparation method and application thereof, and a pharmaceutical composition.
Background
Primary hypertension is one of the common diseases worldwide, and is an important cause of serious cardiovascular and cerebrovascular diseases, kidney diseases and the like. Treatment of hypertensive disorders can significantly reduce the patient's premature cardiovascular morbidity and mortality. The pathogenesis of hypertension is complex and is the result of interaction of genetic and environmental factors, and about 50% of patients with hypertension show refractory hypertension, which brings great challenges to effective treatment of hypertension. The existing medicines for treating hypertension are mainly favorable for diuretics, calcium ion channel antagonists, vascular invertase inhibitors (ACEI), angiotensin II receptor inhibitors, beta-receptor blockers, alpha-receptor antagonists and the like. In order to enhance the treatment effect of hypertension, the combined use of antihypertensive drugs is a common clinical medication strategy, and the two drugs can be independently prescribed or compound preparations with fixed dosages. Antihypertensive drugs of two different mechanisms of action often have synergistic or at least additive effects, and the dose of each drug is reduced, reducing its adverse effects.
Drug-drug co-crystals refer to a crystalline composition formed by joining two drug molecules in a stoichiometric ratio through non-covalent bond forms such as hydrogen bonds. The research shows that the drug-drug co-crystal has the potential advantages of improving the stability or solubility of drug molecules and the like when being used together, and has more development prospect compared with a compound preparation.
The chemical name of the dibazol (Bendazol) is 2-benzyl benzimidazole (C) 14 H 12 N 2 ) The dibazol is dissolved in ethanol, hot benzene and glacial acetic acid, and has poor solubility in water. The current drug of dibazol on the market is dibazol hydrochloride (C 14 H 12 N 2 HCl). The dibazol belongs to vasodilator antihypertensive drugs, and can directly relax vascular smooth muscle to reduce blood pressure. The dibazol has low solubility and high permeability and belongs to class II compounds in a biopharmaceutical classification system. Although it isThe dibazol is used in its hydrochloride form, dibazol hydrochloride, in order to increase its solubility, but its solubility is also poor. Atenolol (Atenolol) is beta-receptor blocker, widely used for treating cardiovascular diseases, and is suitable for treating moderate and mild hypertension, and its molecular formula is C 14 H 22 N 2 O 3 . Atenolol has low solubility and poor permeability.
Disclosure of Invention
The invention aims to provide a drug-drug co-crystal of dibazol hydrochloride and atenolol, and preparation and application thereof and a pharmaceutical composition. The invention prepares the dibazol hydrochloride-atenolol eutectic by co-crystallizing the dibazol hydrochloride and atenolol through a eutectic technology. The mechanism of action of the dibazol hydrochloride and the atenolol for treating the hypertension is different, and the dibazol hydrochloride-atenolol eutectic can improve the in-situ dissolution rate of the dibazol hydrochloride, has good stability and has quite large application prospect in combined drug treatment for treating the hypertension.
The aim of the invention can be achieved by the following technical scheme:
in the existing crystallization technology, the types of solvents capable of being 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 cannot be predicted before experiments.
The first aspect of the invention provides a drug-drug co-crystal form of the dibazol hydrochloride and atenolol, which comprises the dibazol hydrochloride and atenolol in a molar ratio of 2:1;
the crystal forms of the drug co-crystals of the dibazol hydrochloride and the atenolol have characteristic peaks at diffraction angles 2 theta of 7.1 degrees, 10.8 degrees, 11.3 degrees, 11.8 degrees, 14.3 degrees, 14.8 degrees, 17.2 degrees, 18.5 degrees, 19.0 degrees, 19.8 degrees, 20.4 degrees, 21.1 degrees, 21.8 degrees, 22.2 degrees, 23.6 degrees, 24.1 degrees, 26.2 degrees, 27.4 degrees, 28.0 degrees and 29.0 degrees according to an X-ray powder diffraction pattern measured by Cu K alpha rays.
Further, the differential scanning calorimetry curve of the eutectic crystal form has an endothermic peak at 137+ -5deg.C.
The second aspect of the invention provides a preparation method of a drug-drug co-crystal form of dibazol hydrochloride and atenolol, which comprises the following steps: mixing the dibazol hydrochloride and atenolol in an organic solvent at 30-80 ℃, cooling to 5-35 ℃, continuously stirring, filtering and drying at 30-80 ℃.
Further, the ratio of the total mass of the dibazol hydrochloride and the atenolol to the volume and the dosage of the organic solvent is 1g (3-25) 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 drug-drug co-crystal of dibazol hydrochloride and atenolol, which comprises the following steps: mixing the dibazol hydrochloride and atenolol in an organic solvent, continuously stirring at 15-60 ℃, filtering and drying at 30-80 ℃.
Further, the ratio of the total mass of the dibazol hydrochloride and the atenolol to the volume and the dosage of the organic solvent is 1g (3-25) mL; the organic solvent is one of water, alcohol solvent, ethyl acetate, chloroform, acetonitrile or acetone.
The fourth aspect of the present invention provides a method for preparing a drug-drug co-crystal of dibazol hydrochloride and atenolol, comprising: mixing the dibazol hydrochloride and atenolol in an organic solvent, and carrying out mechanical ball milling.
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); the organic solvent is one of water, alcohol solvents, ethyl acetate, acetonitrile or acetone; the mechanical ball milling condition comprises frequency of 1-10 times/second and milling time period of 10-100min.
In a fifth aspect the invention provides a pharmaceutical composition comprising a drug-drug co-crystal of dibazol hydrochloride and atenolol, and a pharmaceutically acceptable excipient.
The sixth aspect of the invention provides an application of the drug-drug co-crystal of the dibazol hydrochloride and the atenolol, which comprises the step of preparing a drug for preventing or treating hypertension by using the drug-drug co-crystal of the dibazol hydrochloride and the atenolol.
Compared with the prior art, the invention has the following characteristics:
1) The preparation method of the prepared dibazol hydrochloride-atenolol eutectic is simple, easy to control and good in reproducibility, stable eutectic of the dibazol hydrochloride and atenolol can be obtained, the purity of the crystal form is high and reaches more than 99.9%, and the stability is good;
2) The dissolution speed is high: the dissolution rate of the dibazol hydrochloride-atenolol eutectic is 3 times of that of the dibazol hydrochloride in 10 minutes, the highest dissolution point is reached in 30 minutes, and the highest dissolution rate is 5 times of that of the dibazol hydrochloride.
3) Has the potential of drug combination: the dibazol hydrochloride and atenolol have synergistic antihypertensive effect, and can develop a medicinal preparation for treating hypertension with better curative effect.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of the crystalline form of dibazol-atenolol hydrochloride prepared in example 1;
FIG. 2 is a DSC of the crystalline form of the co-crystal of dibazol hydrochloride-atenolol prepared in example 1;
FIG. 3 is an XRPD pattern for stability testing of the crystalline form of the co-crystal of dibazol-atenolol hydrochloride prepared in example 1;
fig. 4 is a graph showing the dissolution of the co-crystals of dibazol hydrochloride and dibazol hydrochloride-atenolol in example 6.
Detailed Description
The invention will now be described in detail with reference to the drawings and specific examples.
The preparation method of the drug-drug co-crystal of the dibazol hydrochloride and the atenolol based on the cooling crystallization method comprises the following steps:
1) Mixing the dibazol hydrochloride and atenolol in a molar ratio of 2:1 in an organic solvent at 30-80 ℃ to obtain a clear solution;
wherein the ratio of the total mass of the dibazol hydrochloride and the atenolol to the volume dosage of the organic solvent is 1g (3-25) 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 acetonitrile;
2) Cooling the clarified solution to 5-35 ℃, continuously stirring, and maintaining for 1-10 h;
3) Filtering, and drying the filter cake at 30-80 ℃.
The preparation method of the drug-drug co-crystal of the dibazol hydrochloride and the atenolol based on the suspension stirring method comprises the following steps:
1) Mixing the dibazol hydrochloride and atenolol in a molar ratio of 2:1 in an organic solvent;
wherein the ratio of the total mass of the dibazol hydrochloride and the atenolol to the volume dosage of the organic solvent is 1g (3-25) 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 acetonitrile;
2) Continuously stirring for 2-48 h at 15-60 ℃;
3) Filtering, and drying the filter cake at 30-80 ℃.
A preparation method of a drug-drug co-crystal of dibazol hydrochloride and atenolol based on a mechanical ball milling method comprises the following steps: mixing the dibazol hydrochloride and the atenolol, adding an organic solvent, performing liquid-phase auxiliary mechanical ball milling in a vibration ball mill, and performing ball milling for a period of time to obtain the dibazol hydrochloride-atenolol medicine-medicine eutectic.
Wherein, 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); the organic solvent is one of water, alcohol solvents, ethyl acetate, acetonitrile or acetone; preferably, the alcoholic solvent is ethanol or methanol. More preferably, the organic solvent is acetonitrile; the mechanical ball milling condition comprises frequency of 1-10 times/second and milling time period of 10-100min.
A pharmaceutical composition comprising a drug-drug co-crystal of dibazol hydrochloride and atenolol, and a pharmaceutically acceptable excipient.
An application of a drug-drug co-crystal of dibazol hydrochloride and atenolol, which comprises the step of preparing a drug for preventing or treating hypertension by using the drug-drug co-crystal of dibazol hydrochloride and atenolol.
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 dibazol hydrochloride-atenolol eutectic crystal form
26.6g of atenolol and 48.9g of dibazol hydrochloride are dispersed in 350mL of methanol solvent to form supersaturated solution, the supersaturated solution is stirred at room temperature for 48 hours, and then filtered, crystals are collected and dried at 50 ℃ to obtain a solid, namely the dibazol hydrochloride-atenolol eutectic, and the solid has the characteristics of X-ray powder diffraction patterns shown in figure 1 and the DSC spectrum characteristics of the dibazol hydrochloride-atenolol eutectic crystal form shown in figure 2.
Wherein, as shown in the X-ray powder diffraction pattern of the crystal form of the dibazol hydrochloride-atenolol eutectic shown in figure 1, cu K alpha rays are used, and the X-ray powder diffraction pattern of the X-ray powder diffraction pattern is at a diffraction angle of 2 theta (°, +/-0.2): characteristic peaks at 7.1 °, 10.8 °, 11.3 °, 11.8 °, 14.3 °, 14.8 °, 17.2 °, 18.5 °, 19.0 °, 19.8 °, 20.4 °, 21.1 °, 21.8 °, 22.2 °, 23.6 °, 24.1 °, 26.2 °, 27.4 °, 28.0 °, 29.0 °, and specifically characteristic peaks of the crystalline form X-ray powder diffraction pattern at diffraction angles 2θ of table 1, wherein the error range of 2θ values is ±0.2 °.
TABLE 1
The DSC diagram of the crystal form of the dibazol hydrochloride-atenolol eutectic is shown in figure 2, and the eutectic differential scanning calorimetry analysis spectrum has an endothermic peak at 137+/-5 ℃.
Example 2: preparation of dibazol hydrochloride-atenolol eutectic crystal form
13.3g of atenolol and 24.5g of dibazol hydrochloride are dispersed in 200mL of acetonitrile solvent, the mixture is heated to 50 ℃ to be completely dissolved, the temperature is reduced at the speed of 0.5 ℃/min, the mixture is stirred for 3 hours after the temperature is 10 ℃, the mixture is filtered, and crystals are collected and dried at 40 ℃ to obtain a solid, namely the dibazol hydrochloride-atenolol eutectic.
Example 3: preparation of dibazol hydrochloride-atenolol eutectic crystal form
48.94mg of dibazol hydrochloride and 26.63mg of atenolol are put into an adapter of a ball mill according to the mol ratio of 2:1, 3 zirconia grinding balls with the diameter of 4mm are added, 20 mu L of methanol is dripped, and after the mixture is fully ground and mixed for 1 hour by the ball mill, a sample is collected, namely the dibazol hydrochloride-atenolol eutectic crystal.
Example 4: detection of stability of dibazol hydrochloride-atenolol eutectic
The dibazol hydrochloride-atenolol co-crystal of example 1 was placed at 40 ℃/75% rh and sampled one month later for X-ray powder diffraction characterization. As a result, the XRPD pattern (fig. 3) showed only changes in peak intensity and peak width after one month of the dibazol hydrochloride-atenolol co-crystal was left at 40 ℃/75% rh, and neither conversion to a single drug molecule nor dissociation and degradation occurred, indicating that the dibazol hydrochloride-atenolol co-crystal could exist stably under this condition with some chemical stability.
Example 5: detection of hygroscopicity of dibazol hydrochloride-atenolol eutectic
The dibazol hydrochloride-atenolol eutectic and single drugs (dibazol hydrochloride and atenolol) are respectively placed under the condition of 40 ℃/75%RH, and the total mass change (table 1) is weighed for 1, 2, 3, 5, 10 and 15 days and calculated according to a moisture absorption rate calculation formula (formula 1). The maximum value of the moisture absorption rate is 0.79% by calculating the moisture absorption rate at the statistical time, and the maximum value of the moisture absorption rate is less than 1% in 15 days, which indicates that the moisture absorption rate can exist stably under the condition of 40 ℃/75% RH and meets the pharmacopoeia requirements, and the moisture absorption rate can be used for patent medicine.
TABLE 2 change in mass (mg) of dibazol hydrochloride, atenolol and its co-crystals after standing under specific conditions
Moisture absorption= (m) 1 -m 0 )/m 0 *100% equation 1
m 1 For the quality after placement, m 0 Is the original mass.
Example 6: in-situ dissolution rate detection of dibazol hydrochloride-atenolol eutectic crystal
In the study, the test of dissolution rate of the dibazol hydrochloride-atenolol eutectic prepared in the example 1 is selected, and compared with the dissolution of the dibazol hydrochloride bulk drug. Chromatographic conditions in this example: 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.
The experimental steps are as follows:
1) Preparation of standard solution: precisely weighing 1.0g of dibazol hydrochloride as a reference substance, adding 200ml of diluted hydrochloric acid to completely dissolve the dibazol hydrochloride, adding 2.0, 4.0, 8.0, 12.0, 16.0, 20.0 and 24.0ml of solution into a 25ml volumetric flask to fix the volume, and drawing a standard curve of the dibazol hydrochloride according to the 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 excessive dibazol hydrochloride into a dissolution cup conforming to the rule, 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 an excessive eutectic sample (the eutectic sample obtained in the example 1) in a dissolution cup conforming to the specification, 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;
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 the dissolution rate curves of the dibazol hydrochloride and the dibazol hydrochloride-atenolol eutectic are drawn.
As shown in fig. 4, it was observed from the results that the dissolution rate of the dibazol hydrochloride in the dibazol hydrochloride-atenolol co-crystal was greater than that of the bulk drug, the dissolution rate was 3 times as high as that of the dibazol hydrochloride at 10 minutes, and the dissolution peak was reached at 30 minutes, 5 times as high as that of the dibazol hydrochloride, and the dissolution rate was faster than that of the dibazol hydrochloride.
The eutectic crystal forms of the dibazol hydrochloride and the atenolol are obtained in different ways in the examples. The above-mentioned eutectic of the present invention was subjected to an intrinsic dissolution rate study.
The invention provides a novel drug-drug eutectic crystal form of dibazol hydrochloride (2-benzyl benzimidazole hydrochloride) and atenolol, and a preparation method and application thereof. The co-crystal is characterized by means of X-ray powder diffraction analysis, differential thermal scanning calorimetric analysis and the like, and meanwhile, the newly prepared co-crystal has the advantage of higher dissolution rate compared with the dibazol hydrochloride, and has the potential of drug combination. The preparation method of the eutectic is simple, easy to control and good in reproducibility, and stable eutectic of the dibazol hydrochloride and the atenolol can be obtained.
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 drug-drug co-crystal of the dibazol hydrochloride and the atenolol is characterized by comprising the dibazol hydrochloride and the atenolol in a molar ratio of 2:1;
the crystal forms of the drug co-crystals of the dibazol hydrochloride and the atenolol have characteristic peaks at diffraction angles 2 theta of 7.1 degrees, 10.8 degrees, 11.3 degrees, 11.8 degrees, 14.3 degrees, 14.8 degrees, 17.2 degrees, 18.5 degrees, 19.0 degrees, 19.8 degrees, 20.4 degrees, 21.1 degrees, 21.8 degrees, 22.2 degrees, 23.6 degrees, 24.1 degrees, 26.2 degrees, 27.4 degrees, 28.0 degrees and 29.0 degrees according to an X-ray powder diffraction pattern measured by Cu K alpha rays.
2. The crystalline co-crystal form of dibazol hydrochloride and atenolol drug-drug according to claim 1, characterized in that the differential scanning calorimetry curve of the co-crystal form has an endothermic peak at 137±5 ℃.
3. A process for the preparation of the crystalline form of the drug-drug co-crystal of dibazol hydrochloride and atenolol as claimed in claim 1 or 2, characterized in that it comprises: mixing the dibazol hydrochloride and atenolol in an organic solvent at 30-80 ℃, cooling to 5-35 ℃, continuously stirring, filtering and drying at 30-80 ℃.
4. The method for preparing a drug-drug co-crystal of dibazol hydrochloride and atenolol according to claim 3, wherein the ratio of the total mass of the dibazol hydrochloride and atenolol to the volume amount of the organic solvent is 1g (3-25 mL); the organic solvent is one of water, alcohol solvent, ethyl acetate, chloroform, acetonitrile or acetone.
5. A process for the preparation of the drug-drug co-crystal of dibazol hydrochloride and atenolol according to claim 1 or 2, characterized in that it comprises: mixing the dibazol hydrochloride and atenolol in an organic solvent, continuously stirring at 15-60 ℃, filtering and drying at 30-80 ℃.
6. The method for preparing the drug-drug co-crystal of the dibazol hydrochloride and the atenolol according to claim 5, wherein the ratio of the total mass of the dibazol hydrochloride and the atenolol to the volume amount of the organic solvent is 1g (3-25 mL); the organic solvent is one of water, alcohol solvent, ethyl acetate, chloroform, acetonitrile or acetone.
7. A process for the preparation of the drug-drug co-crystal of dibazol hydrochloride and atenolol according to claim 1 or 2, characterized in that it comprises: mixing the dibazol hydrochloride and atenolol in an organic solvent, and carrying out mechanical ball milling.
8. The method for preparing a drug-drug co-crystal of dibazol hydrochloride and atenolol according to claim 7, 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 (20-200 μl); the organic solvent is one of water, alcohol solvents, ethyl acetate, acetonitrile or acetone; the mechanical ball milling condition comprises frequency of 1-10 times/second and milling time period of 10-100min.
9. A pharmaceutical composition comprising the drug-drug co-crystal of dibazol hydrochloride and atenolol according to claim 1 or 2, and a pharmaceutically acceptable excipient.
10. Use of a drug-drug co-crystal of dibazol hydrochloride and atenolol according to claim 1 or 2 for the preparation of a medicament for the prevention or treatment of hypertension.
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