CN117105856A - Milrinone-sulfamic acid crystal and preparation method thereof - Google Patents
Milrinone-sulfamic acid crystal and preparation method thereof Download PDFInfo
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- CN117105856A CN117105856A CN202210782160.0A CN202210782160A CN117105856A CN 117105856 A CN117105856 A CN 117105856A CN 202210782160 A CN202210782160 A CN 202210782160A CN 117105856 A CN117105856 A CN 117105856A
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- milrinone
- sulfamic acid
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- 239000013078 crystal Substances 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000002425 crystallisation Methods 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 3
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 claims description 44
- 229960003574 milrinone Drugs 0.000 claims description 43
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 14
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 238000002441 X-ray diffraction Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 229910017488 Cu K Inorganic materials 0.000 description 4
- 229910017541 Cu-K Inorganic materials 0.000 description 4
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000002447 crystallographic data Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- ILRVKOYYFFNXDB-UHFFFAOYSA-N 1-pyridin-4-ylpropan-2-one Chemical compound CC(=O)CC1=CC=NC=C1 ILRVKOYYFFNXDB-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000005496 eutectics Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- -1 inorganic acid salts Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000009378 Low Cardiac Output Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004041 inotropic agent Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960001720 milrinone lactate Drugs 0.000 description 1
- VWUPWEAFIOQCGF-UHFFFAOYSA-N milrinone lactate Chemical compound [H+].CC(O)C([O-])=O.N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C VWUPWEAFIOQCGF-UHFFFAOYSA-N 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000001020 rhythmical effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and provides a high-purity milrinone-sulfamic acid crystal, which has the advantages of simple preparation method, easy control of crystallization process and good reproducibility. Compared with the free alkali and the crystal form thereof, the prepared milrinone-sulfamic acid crystal has obviously enhanced stability and solubility, thereby being beneficial to the storage, transportation and application in preparation of the product and having enhanced bioavailability and absorption performance.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to milrinone-sulfamic acid crystals and a preparation method thereof.
Background
Milrinone (milrinone) with chemical name 1, 6-dihydro-2-methyl-6-oxo- [3, 4-bipyridine]-5-carbonitrile of formula C 12 H 9 N 3 O, molecular weight 211.22, is white or white-like crystalline powder, and has the structural formula:
cardiovascular disease is the first killer of human beings, deprives 1700 or more tens of thousands of lives every year, accounts for nearly 31% of the worldwide deaths, and is a key factor seriously affecting human life. In order to reduce the incidence and mortality of cardiovascular diseases, research on related drugs, including development of new drugs and modification of existing drugs, has received extensive attention from academia and drug developers. However, the limitations of long period and high failure rate cannot meet the urgent demands of the market for innovative pharmaceutical entities. Therefore, the modification of the existing cardiovascular drugs to improve the clinical efficacy thereof has important practical significance. Milrinone is a positive inotropic agent with vasodilating effect and is commonly used to treat congestive heart failure and low cardiac output states. However, as a third class of drugs in biopharmaceutical drug treatment classification systems, milrinone has the most serious drawbacks of poor permeability, limited solubility, serious adverse reactions upon oral administration, and serious influence on bioavailability, thereby limiting the therapeutic effect thereof to some extent. To overcome these drawbacks, various methods such as nano-preparation technology and chemical structure modification have been adopted, and although a series of progress has been made in these efforts, the successful application of these methods in industrial production has been long-sought due to the complexity and expense of nano-preparation technology and the by-products generated in chemical synthesis process. The prior art also discloses some methods for attempting to improve the solubility or stability of milrinone, but none of them achieves the desired effect, nor improves the disadvantages of poor absorption and the like. For example, patent CN1951919a discloses that the inorganic acid salts of milrinone series are used for preparing freeze-dried formulations for injection, and although the solubility of milrinone can be improved, stability problems still exist generally; for example, patent CN102558044a discloses a crystallization method of milrinone, and the milrinone obtained by the method has high purity and good crystal form, but the physicochemical properties of milrinone are not improved yet; in addition, patent CN106361710a describes that, in order to solve the problems of poor stability of milrinone lactate, easy degradation and obvious increase of related substances in the prior art, the stability of injection is increased by adding a certain amount of vitamin E and glutathione in the prescription and using a new crystal form, and the degradation reaction is reduced, but the problem of poor solubility of milrinone is not overcome by using a new crystal form.
Drug co-crystallization refers to the incorporation of drug molecules into the same crystal lattice with other physiologically acceptable acid, base, salt, and non-ionic compound molecules by non-covalent bonding such as hydrogen bonding, pi-pi stacking, van der Waals forces, etc. On the premise of not damaging covalent bonds of the medicine, the formation of eutectic crystals can change physicochemical properties of the medicine, including stability, solubility, bioavailability and the like. Because of the capabilities and advantages in the modification and optimization of bulk drugs, the development of pharmaceutical co-crystals has received more attention and attention from industry, academia and regulatory authorities. Therefore, the method fully plays the unique advantages of the eutectic technology, overcomes the serious defects of milrinone, and has important practical significance.
Disclosure of Invention
Aiming at the defects of poor solubility and low stability of milrinone provided by the prior art, the invention aims to provide a novel crystal form of milrinone with higher solubility and stability, namely a milrinone-sulfamic acid crystal. In addition, the invention provides a method for preparing milrinone-sulfamic acid crystals, which is simple, convenient and suitable for industrial production.
The specific technical content of the invention is as follows:
in one aspect, the present invention provides a high purity milrinone-sulfamic acid crystal.
Preferably, the milrinone-sulfamic acid crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 6.8+/-0.2 DEG, 10.2+/-0.2 DEG, 10.4+/-0.2 DEG, 21.4+/-0.2 DEG, 24.2+/-0.2 DEG, 31.1+/-0.2 DEG and 38.3+/-0.2 DEG.
Preferably, the milrinone-sulfamic acid crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 6.8+/-0.2 degrees, 10.2+/-0.2 degrees, 10.4+/-0.2 degrees, 17.3+/-0.2 degrees, 17.7+/-0.2 degrees, 21.4+/-0.2 degrees, 24.2+/-0.2 degrees, 24.8+/-0.2 degrees, 25.5+/-0.2 degrees, 25.6+/-0.2 degrees, 25.9+/-0.2 degrees, 28.7+/-0.2 degrees, 31.1+/-0.2 degrees and 38.3+/-0.2 degrees.
Preferably, the milrinone-sulfamic acid crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the milrinone-sulfamic acid crystal has a molecular formula of C 12 H 12 N 4 O 4 S, the crystallographic parameters are: monoclinic system with space group P2 1 And/n, the unit cell parameters are: α=90°, β= 90.130 (2) °, γ=90°, unit cell volume +.>
In another aspect, the present invention provides a method for preparing the milrinone-sulfamic acid crystals, comprising the steps of:
and (3) dissolving milrinone and sulfamic acid in a mixed solvent, heating, stirring, reacting at a constant temperature, cooling for crystallization, filtering, washing and drying to obtain milrinone-sulfamic acid crystals.
Preferably, the mixed solvent is selected from mixed solvents of DMSO and methanol, ethanol, acetone or acetonitrile, and particularly preferably mixed solvents of DMSO and ethanol or methanol.
Preferably, the mass-volume ratio of the milrinone to the organic solvent is 10:0.9-1.8; preferably 10:1 to 1.5, wherein the mass is in mg and the volume is in mL.
Preferably, the molar ratio of milrinone to sulfamic acid is 1:0.9-1.5, preferably 1:0.95-1.2.
Preferably, the heating temperature is 50 to 70 ℃, preferably 60 ℃.
Preferably, the temperature of the cooling crystallization is 10-30 ℃, and the temperature of the cooling crystallization is more preferably 15-20 ℃.
Preferably, the crystallization time is 48-72 hours.
Preferably, the drying temperature is 55-65 ℃ and the drying time is 8-10 hours.
In yet another aspect, the present invention provides a pharmaceutical composition comprising milrinone-sulfamic acid crystals of the invention and other pharmaceutically acceptable ingredients.
Preferably, the other pharmaceutically acceptable components may be pharmaceutically active ingredients that may be used in combination and/or pharmaceutically acceptable auxiliary ingredients.
Compared with the prior art, the invention has the technical effects that:
the milrinone-sulfamic acid crystal provided by the invention has the advantages of simple operation, easy control of crystallization process and good reproducibility. The milrinone-sulfamic acid crystal phase has obviously enhanced stability and solubility compared with the free alkali and the crystal form thereof, thereby being beneficial to the storage, transportation and application in preparation of products and having enhanced bioavailability and absorption performance. The pharmaceutical polycrystal provided by the invention has good physicochemical properties, provides good pharmaceutical raw materials for treating diseases in clinic, and has great clinical research and development values.
Drawings
Fig. 1: x-ray powder diffraction pattern of milrinone-sulfamic acid.
Fig. 2: ORTEP diagram of milrinone-sulfamic acid.
Fig. 3: a plot of milrinone-sulfamic acid accumulation.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
Example 1
Milrinone (22.3 mg) and sulfamic acid (10.4 mg) are dissolved in a mixed solvent of ethanol (2 mL) and DMSO (0.5 mL), the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is subjected to heat preservation reaction for 6 hours, the mixture is slowly cooled to 15 to 20 ℃, then the mixture is subjected to temperature control and standing crystallization for 52 hours, filtration is carried out, a filter cake is washed by trifluoroethanol, and vacuum drying is carried out at 60 ℃ for 10 hours, thus obtaining milrinone-sulfamic acid crystals, the yield is: 98.7%, purity: 99.95%.
Example 2
Milrinone (25.2 mg) and sulfamic acid (12.5 mg) are dissolved in a mixed solvent of methanol (3 mL) and DMSO (0.5 mL), heated and stirred in a water bath at 60 ℃ until the milrinone and sulfamic acid are completely dissolved, the temperature is kept for 6 hours, the temperature is slowly reduced to 15-20 ℃, then the milrinone is subjected to temperature control and standing crystallization for 50 hours, filtration is carried out, a filter cake is washed by trifluoroethanol, and vacuum drying is carried out at 60 ℃ for 10 hours, thus obtaining milrinone-sulfamic acid crystals, the yield is: 98.1%, purity: 99.93%.
Example 3
Milrinone (46.0 mg) and sulfamic acid (31.7 mg) are dissolved in a mixed solvent of acetone (6 mL) and DMSO (2 mL), heated and stirred in a water bath at 60 ℃ until the milrinone and sulfamic acid are completely dissolved, the temperature is kept for 6h, the temperature is slowly reduced to 15-20 ℃, then the milrinone is subjected to temperature control and standing crystallization for 48h, filtration is carried out, a filter cake is washed by trifluoroethanol, and vacuum drying is carried out for 10h at 60 ℃ to obtain milrinone-sulfamic acid crystals, and the yield is: 93.1%, purity: 99.92%.
Example 4
Milrinone (50.0 mg) and sulfamic acid (26.7 mg) are dissolved in a mixed solvent of acetonitrile (4.5 mL) and DMSO (1 mL), heated and stirred in a water bath at 50 ℃ until the milrinone and sulfamic acid are completely dissolved, the temperature is kept for 6h, after the reaction is slowly reduced to 30 ℃, the temperature is controlled and the milrinone is statically crystallized for 72h, the filtration is carried out, the filter cake is washed by trifluoroethanol, and the milrinone-sulfamic acid crystal is obtained after the vacuum drying at 60 ℃ for 10h, the yield is: 94.1%, purity: 99.91%.
Confirmation of Crystal Structure
In the drug crystal test of milrinone, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is measured, cu-Ka radiation is used, and data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
The crystallographic data (as in table 1) for testing and resolving the crystalline form of milrinone-sulfamic acid prepared according to the invention are: monoclinic system, space group P21/n, unit cell parameters of： α=90°, β= 90.130 (2) °, γ=90°, unit cell volume +.>
TABLE 1 Milrinon-sulfamic acid Crystal major crystallographic data
The ORTEP diagram of the milrinone-sulfamic acid crystals of the invention shows that the crystalline form contains one molecule of milrinone and one molecule of sulfamic acid, as shown in figure 2. The stacking diagram of milrinone-sulfamic acid crystals of the invention is shown in figure 3. According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in the accompanying figures 1 and 2.
TABLE 2 PXRD peaks for milrinone-sulfamic acid crystals
Comparative example 1
Into a 1000mL three-necked flask, 93.0g of 4-methylpyridine and 500mL of chloroform were added, and the mixture was placed in an ice-water bath to control the temperature below 50 ℃ and 80.0g of acetyl chloride was added dropwise, and after the dropwise addition was completed, the mixture was heated to 55 ℃ and reacted for 2.5 hours. After the reaction, saturated sodium carbonate aqueous solution is added dropwise into the system under ice bath cooling to adjust the pH to 5-7, 30.0g sodium hydroxide solution (30 wt%) is added, and the mixture is stirred at 30-50 ℃ for 2.5h. After the reaction, the layers are separated, the water layer is removed, the anhydrous sodium sulfate is dried, and after the solvent is recovered, the fraction of 100-105 ℃/217kPa, namely 1- (4-pyridyl) -2-acetone is collected by reduced pressure distillation.
60.0g of 1- (4-pyridyl) -2-acetone is added into a 500mL round bottom flask, 40.5g of triethyl orthoformate, 92.2g of acetic anhydride and 80.0g of glacial acetic acid are added into a reaction flask under stirring, and the reaction is carried out for 4 hours under stirring at 35-45 ℃ to finish the reaction of the raw materials. The solvent was removed by concentration under reduced pressure at 80℃to give a dark red oil which was used directly in the next reaction without purification.
600mL of absolute methanol and the above oil were added to 5000mL of the mixture, and then 64.0g of α -cyanoacetamide and 210g of 50% sodium hydroxide solution were added with stirring, and the reaction time was 1.5 hours. And after the reaction is finished, regulating the pH to 6.5-7.2 by using an acetic acid solution to separate out solids, and filtering to obtain a milrinone crude product. Recrystallizing the solid by an ethanol-water system to obtain the white milrinone crystal.
Comparative example 2
Placing 10g milrinone in a 500mL beaker, dropwise adding 0.1N sodium hydroxide aqueous solution, stirring to dissolve the solution until the pH value is 7-8, adding acetone with the volume of 5 times of the solution, cooling, precipitating white precipitate, filtering, washing a filter cake with acetone for 2 times, air-drying, and then drying at 105 ℃ for 2 hours to obtain milrinone sodium salt.
Comparative example 3
Placing 10g milrinone in a 500mL beaker, dropwise adding 0.1N hydrochloric acid solution, stirring to dissolve the solution to enable the pH value of the solution to be 4-4.5, adding acetone with the volume of 5 times of the solution, cooling, precipitating white precipitate, filtering, washing a filter cake with acetone for 2 times, airing, and then drying at 105 ℃ for 2 hours to obtain milrinone hydrochloride.
Comparative example 4
Mirinone (169.0 mg) and gallic acid (136.1 mg) were mixed uniformly in equimolar ratio, 50. Mu.L of water was gradually added and sufficiently ground in mortar for 45 minutes. Dissolving the ground powder sample in a minimum amount of methanol/acetonitrile/H 2 In O-mixed solvent (v) Methanol ：v Acetonitrile ：v Water and its preparation method =2:1:1), rapidly vigorously stirred at 60 ℃ for about 3h. After cooling to room temperature, the resulting reaction mixture was filtered. The above powder sample was added to the filtrate as seed crystal, and the solution was allowed to stand for slow evaporation for 1 day to obtain colorless crystals.
Stability test
The specific stability test method is carried out by referring to the guidance method of the fourth section of the Chinese pharmacopoeia on stability investigation.
High temperature test: placing the sample in a clean container, standing at 60deg.C for 10 days, sampling at 5 th and 10 th days, and detecting purity by HPLC;
high humidity test: placing the sample in a constant humidity closed container at 25 ℃ under the conditions of 90% and 5% relative humidity for 10 days, sampling on the 5 th day and the 10 th day, and detecting the purity by using an HPLC method;
strong light irradiation test: the sample was placed in an illumination device equipped with a fluorescent lamp, and left for 10 days under the condition of an illuminance of 4500lx and 500lx, and samples were taken on days 5 and 10, and the purity was measured by HPLC.
TABLE 3 stability test results of milrinone-sulfamic acid crystals
Experimental results show that the milrinone-sulfamic acid crystal prepared by the embodiment of the invention has high purity, small sample purity change under high temperature, high humidity and strong light conditions and good stability.
Solubility test
The method comprises the following steps: respectively weighing 10ml of medium (water and 0.01mol/L HCl solution) in a penicillin bottle, adding excessive sample to be tested, sealing the penicillin bottle, placing in a constant-temperature water bath at 25 ℃ for stirring for 1 hour, filtering by a filter membrane, and taking filtrate; the absorbance was measured at a wavelength of 270nm, and the solubility was calculated by measuring the absorbance of the standard control.
TABLE 4 solubility test results of milrinone-sulfamic acid crystals
Test results show that the solubility of the milrinone-sulfamic acid crystal provided by the invention in 0.01mol/L HCl and water is obviously improved compared with other crystal forms of milrinone, and the milrinone-sulfamic acid crystal is beneficial to the application of the milrinone-sulfamic acid crystal in oral preparations.
Pharmacokinetic studies
The method comprises the following steps: in vivo PK test was carried out by single dose oral administration, male SD rats (220-260 g) were fed in a quiet atmosphere of 0% -60% constant humidity at 25+ -1deg.C, with rhythmic light from 7 in the morning to 7 in the evening. PK experiments were strictly performed according to the laboratory management guidelines issued by the chinese institute of technology. Prior to the experiment, the rats tested were randomly divided into three groups (n=5 per group) and allowed to drink water freely, and fasted overnight. All samples tested were suspended in vegetable oil and then orally administered in a single dose of 10mg/kg milrinone or its equivalent. After administration, 0.5mL blood samples were collected at the designed time points according to the administration conditions, and the concentration of milrinone in blood was measured according to the literature method.
TABLE 5 pharmacokinetic experiment results of milrinone-sulfamic acid crystals
Test results show that compared with other milrinone crystal forms, the milrinone-sulfamic acid crystal form provided by the invention has higher peak concentration, has the same dissolution trend as that of the milrinone-sulfamic acid crystal form, and provides conditions for rapid absorption of the milrinone and a large amount of medicines into blood. The longer residence time of the drug in the body is provided by the prolonged half-life of the milrinone-sulfamic acid crystal form compared with other milrinone crystal forms, thereby providing possibility for obtaining long-term therapeutic effect.
Claims (10)
1. A milrinone-sulfamic acid crystal, characterized in that Cu-ka radiation is used, and the X-ray diffraction pattern expressed in 2Θ has characteristic peaks at least at 6.8±0.2°, 10.2±0.2°, 10.4±0.2°, 21.4±0.2°, 24.2±0.2°, 31.1±0.2°, 38.3±0.2°.
2. Milrinone-sulfamic acid crystal according to claim 1, characterized in that the X-ray diffraction pattern expressed in terms of 2Θ has characteristic peaks at least at 6.8 ± 0.2 °, 10.2 ± 0.2 °, 10.4 ± 0.2 °, 17.3 ± 0.2 °, 17.7 ± 0.2 °, 21.4 ± 0.2 °, 24.2 ± 0.2 °, 24.8 ± 0.2 °, 25.5 ± 0.2 °, 25.6 ± 0.2 °, 25.9 ± 0.2 °, 28.7 ± 0.2 °, 31.1 ± 0.2 °, 38.3 ± 0.2 ° using Cu-ka radiation.
3. Milrinone-sulfamic acid crystals according to claim 1, characterized in that Cu-ka radiation is used, the characteristic peaks of which correspond to the X-ray powder diffraction pattern as shown in figure 1.
4. The preparation method of the milrinone-sulfamic acid crystal is characterized by comprising the following specific preparation steps: and (3) dissolving milrinone and sulfamic acid in a mixed solvent, heating, stirring, reacting at a constant temperature, cooling for crystallization, filtering, washing and drying to obtain milrinone-sulfamic acid crystals.
5. The method for preparing milrinone-sulfamic acid crystals according to claim 4, wherein the mixed solvent is selected from the group consisting of mixed solvents of DMSO and methanol, ethanol, acetone or acetonitrile, preferably mixed solvents of DMSO and ethanol or methanol.
6. The method for preparing milrinone-sulfamic acid crystal according to claim 4, wherein the mass-volume ratio of the milrinone to the mixed solvent is 10:0.9-1.8; preferably 10:1 to 1.5, wherein the mass is in mg and the volume is in mL.
7. The process for the preparation of milrinone-sulfamic acid crystals according to claim 4, wherein the molar ratio of milrinone to sulfamic acid is 1:0.9-1.5, preferably 1:0.95-1.2.
8. The method for preparing milrinone-sulfamic acid crystals according to claim 4, wherein the temperature of the cooling crystallization is 10-30 ℃, preferably 15-20 ℃.
9. The method for preparing milrinone-sulfamic acid crystals according to claim 4, wherein the drying temperature is 55-65 ℃ and the drying time is 8-10 hours.
10. A pharmaceutical composition comprising milrinone-sulfamic acid crystals according to any one of claims 1-4 in combination with other components.
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