CN116239522A - Milrinone-succinic acid co-crystal - Google Patents
Milrinone-succinic acid co-crystal Download PDFInfo
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- CN116239522A CN116239522A CN202111512375.2A CN202111512375A CN116239522A CN 116239522 A CN116239522 A CN 116239522A CN 202111512375 A CN202111512375 A CN 202111512375A CN 116239522 A CN116239522 A CN 116239522A
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- milrinone
- succinic acid
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- 239000013078 crystal Substances 0.000 title claims abstract description 46
- 239000001384 succinic acid Substances 0.000 title claims abstract description 39
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229960003574 milrinone Drugs 0.000 claims abstract description 35
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 25
- 230000005855 radiation Effects 0.000 claims abstract description 7
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000005496 eutectics Effects 0.000 claims description 8
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 13
- 229910017488 Cu K Inorganic materials 0.000 abstract description 5
- 229910017541 Cu-K Inorganic materials 0.000 abstract description 5
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 abstract description 3
- 229960005137 succinic acid Drugs 0.000 description 32
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 206010019280 Heart failures Diseases 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 206010007559 Cardiac failure congestive Diseases 0.000 description 3
- 239000012752 auxiliary agent Substances 0.000 description 3
- 238000002447 crystallographic data Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- 229930182843 D-Lactic acid Natural products 0.000 description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 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
- 230000006838 adverse reaction Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 229940022769 d- lactic acid Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229940082795 milrinone injection Drugs 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000002510 pyrogen Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000010444 Acidosis Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010020601 Hyperchlorhydria Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 229960002105 amrinone Drugs 0.000 description 1
- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical compound N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- 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
-
- 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
-
- 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
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
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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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a novel crystal form of milrinone, in particular to a co-crystal of milrinone and succinic acid, and a preparation method and application thereof. The milrinone-succinic acid co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 5.2+/-0.2 degrees, 20.0+/-0.2 degrees, 20.7+/-0.2 degrees, 24.1+/-0.2 degrees, 24.2+/-0.2 degrees, 26.1+/-0.2 degrees and 27.1+/-0.2 degrees.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a novel crystal form of milrinone, in particular to a co-crystal of milrinone and succinic acid, and a preparation method and application 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:
milrinone was first developed by Sterling corporation in the united states to successfully produce an anti-heart failure drug, which was first approved by the FDA in the united states in 1987, formally marketed in the united states in 1992, and subsequently marketed in the united kingdom, france, germany, the netherlands, belgium, etc.
Milrinone is a phosphodiesterase inhibitor, is a derivative of amirinone, and has the same action mechanism as amirinone. It is effective for oral administration and intravenous injection, and has positive muscle strength and vasodilatation effects. Is suitable for short-term treatment of patients with severe congestive heart failure, the curative effect of which is 10-30 times stronger than that of amrinone, the tolerance is better, and the adverse reaction is less. The positive inotropic effect of the product is mainly to increase the concentration of Cyclic Adenosine Monophosphate (CAMP) in myocardial cells, increase intracellular calcium, strengthen myocardial contractility and increase heart blood discharge by inhibiting phosphodiesterase. It is considered to be a high-efficiency, low-toxicity, non-digitalis and non-sympathomimetic cardiotonic, and has remarkable effects on severe heart failure and pulmonary edema caused by ischemic heart disease, dilated cardiomyopathy, etc., and is superior to dopamine, less in adverse reaction and not increasing heart rate. Therefore, the medicine plays an increasingly important role in treating Congestive Heart Failure (CHF), peripheral vascular dilation and the like.
However, milrinone is hardly soluble in water, so that it is necessary to add special auxiliary materials to improve the solubility of milrinone in the preparation of the formulation product. The existing preparation method generally adopts the addition of a cosolvent and a pH regulator to improve the water solubility, and the dosage is larger. Therefore, the safety and the dissolution assisting effect of the cosolvent are particularly important. For example, patent CN9151919a discloses a method of preparing a freeze-dried preparation after salifying with inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, etc.; patent CN106361710a discloses a method of preparing a formulation by first precipitating crystals in a solvent of ethanol + acetone + water and then using lactic acid as a pH adjuster. However, the problems of poor solubility and poor stability of milrinone per se, such as Cl brought by hydrochloric acid, are not thoroughly solved - It is possible to cause hyperchlorhydria, and the dissolution assisting effects of phosphoric acid, sulfuric acid and the like are poor; among organic acids, lactic acid has good dissolution-assisting effect, but lactic acid is a racemate, and consists of L-lactic acid and D-lactic acid, and can cause substitution if excessive D-lactic acid is taken because only enzymes for metabolizing L-lactic acid are in human body and the metabolism capacity is limitedXie Wenluan even acidosis.
Furthermore, as is known from the disclosure of patent CN105663034a, since milrinone is hardly soluble in water, there are problems that dissolution time is long, dissolution is incomplete, and insoluble fine particles exceed the standard in a mass production process. The existing preparation technology of milrinone injection adopts an active carbon adsorption method to remove pyrogen, the adsorption quantity of active carbon to milrinone is large, the use amount of active carbon is 0.05%, the adsorption of milrinone can reach about 14%, and excessive feeding is needed to ensure that the content of milrinone injection meets the regulation. The excessive feeding causes a great increase in production cost, and the active carbon can introduce excessive unknown substances while adsorbing pyrogen, thereby affecting the product quality.
Based on the problems, the problems of poor solubility and poor stability of milrinone are solved by only relying on a preparation technology, and the clinical medication potential safety hazard caused by excessive dosage of auxiliary materials and auxiliary agents is unavoidable. Therefore, providing a new crystal form of milrinone with good solubility, good stability and high safety becomes a problem to be solved urgently by those skilled in the art.
Disclosure of Invention
Aiming at the potential safety hazard of medicine taking caused by the fact that a large amount of auxiliary agents and pH regulators are needed for improving the solubility of milrinone in the prior art, the invention aims to provide the milrinone-succinic acid eutectic with higher solubility and safety, which fundamentally solves the problem of the solubility of milrinone, can reduce the use of auxiliary materials in the preparation process of a preparation product and improves the safety of medicine taking.
The specific technical content of the invention is as follows:
in one aspect, the invention provides a milrinone-succinic acid co-crystal, wherein the molar ratio of milrinone to succinic acid in the co-crystal unit structure is 2:1.
preferably, the milrinone-succinic acid co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 5.2+/-0.2 DEG, 20.0+/-0.2 DEG, 20.7+/-0.2 DEG, 24.1+/-0.2 DEG, 24.2+/-0.2 DEG, 26.1+/-0.2 DEG and 27.1+/-0.2 deg.
Preferably, the milrinone-succinic acid co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 5.2+/-0.2 DEG 2 DEG, 9.8+/-0.2 DEG, 10.4+/-0.2 DEG, 16.0+/-0.2 DEG, 18.1+/-0.2 DEG, 20.0+/-0.2 DEG, 20.7+/-0.2 DEG, 24.1+/-0.2 DEG, 25.4+/-0.2 DEG, 26.1+/-0.2 DEG, 26.6+/-0.2 DEG, 27.1+/-0.2 DEG, 31.3+/-0.2 DEG and 31.4+/-0.2 deg.
Preferably, the milrinone-succinic acid co-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-succinic acid co-crystal has a molecular formula of C 28 H 24 N 6 O 6 The crystallographic parameters were: the triclinic system has a space group of P-1 and unit cell parameters of:
α= 72.656 (6) °, β= 73.157 (4) °, γ= 86.534 (4) °, unit cell volume +.>
In another aspect, the invention provides a method for preparing a milrinone-succinic acid co-crystal, comprising the steps of:
and (3) dissolving milrinone and succinic acid in the mixed solvent, heating and stirring, filtering, cooling, standing, volatilizing, crystallizing, filtering and drying to obtain milrinone-succinic acid crystals.
Preferably, the mixed solvent is a mixture of methanol and solvent A; wherein the solvent A is selected from one or more of ethanol, acetonitrile, water, acetone or trifluoroethanol; solvent a is particularly preferably one of trifluoroethanol, water or acetonitrile.
Preferably, the volume ratio of the methanol to the solvent A in the mixed solvent is 1-4: 1.
preferably, the mass volume ratio of the milrinone to the mixed solvent is 21.1:1-3, mg/ml; preferably 21.1:1.5-2.5 mg/ml.
Preferably, the molar ratio of milrinone to succinic acid is 1:0.6 to 2.0; preferably 1:1.0 to 1.2.
Preferably, the heating temperature is 50-70 ℃; preferably 60 ℃.
Preferably, the crystallization time is 8-72 hours.
Preferably, the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
Finally, the invention provides a pharmaceutical composition which contains the milrinone-succinic acid eutectic crystal and other pharmaceutically acceptable components.
Preferably, the other pharmaceutically acceptable components may be pharmaceutically active ingredients that may be used in combination and/or pharmaceutically acceptable auxiliary ingredients.
Confirmation of Crystal Structure
In the milrinone-succinic acid co-crystal test, X-ray crystal data are collected on a Japan-science XtaLAB synergy model instrument, the test temperature 293 (2) K is irradiated by Cu-Ka, and the 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 test and analysis of the crystallographic data (as shown in Table 1) of the crystalline form of milrinone-succinic acid co-crystal prepared by the invention is that the triclinic system, the space group is P-1, and the unit cell parameters are as follows:
α= 72.656 (6) °, β= 73.157 (4) °, γ= 86.534 (4) °, unit cell volume +.>
TABLE 1 Milrinon-succinic acid eutectic primary crystallographic data
The ORTEP diagram of the milrinone-succinic acid co-crystal of the invention shows that the crystal form contains two molecules of milrinone and one molecule of succinic acid, as shown in figure 2. The hydrogen bond diagram of the milrinone-succinic acid eutectic of the invention is shown in figure 3. According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in FIG. 1 and Table 2.
TABLE 2 PXRD peak of milrinone-succinic acid co-crystals
Compared with the prior art, the invention has the technical effects that:
firstly, the invention provides a milrinone-succinic acid eutectic, which has the characteristics of high solubility and good stability; the preparation method provides ideal raw materials for milrinone preparation products, and the use of the eutectic preparation products can avoid the use of a large amount of auxiliary materials and auxiliary agents in the prior art, thereby reducing the production cost and reducing the potential safety hazard of clinical medication.
Secondly, the invention provides a preparation method of the milrinone-succinic acid eutectic, which is simple to operate, easy to control the crystallization process and good in reproducibility.
Drawings
FIG. 1 PXRD spectra of milrinone-succinic acid co-crystals.
FIG. 2 ORTEP diagram of milrinone-succinic acid co-crystal.
FIG. 3 is a diagram of hydrogen bonding of milrinone-succinic acid co-crystals.
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.
The materials used in the examples may be prepared according to any of the methods known in the art or purchased from commercial products, wherein milrinone crystals are prepared with reference to patent CN106361710a, milrinone hydrochloride, milrinone mesylate with reference to CN1951919 a.
Example 1
211mg of milrinone and 129mg of succinic acid are dissolved in a mixed solvent of 10mL of methanol and 10mL of trifluoroethanol, the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at room temperature for volatilization and crystallization for 24 hours, the mixture is filtered, and the mixture is dried at 60 ℃ for 10 hours to obtain crystals, and the yield is: 93%, purity: 99.92%.
Example 2
168.8mg milrinone and 94.4mg succinic acid are dissolved in a mixed solvent of 15mL methanol and 5mL water, heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, stood at room temperature for volatilization and crystallization for 30h, filtered, dried at 60 ℃ for 12h to obtain crystals, and the yield is: 92%, purity: 99.93%.
Example 3
211mg of milrinone and 129mg of succinic acid are dissolved in a mixed solvent of 10mL of methanol and 5mL of trifluoroethanol, the mixture is heated and stirred in a water bath at 55 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at room temperature for volatilization and crystallization for 36h, the mixture is filtered, and the mixture is dried at 65 ℃ for 16h to obtain crystals, and the yield is: 93%, purity: 99.91%.
Example 4
211mg of milrinone and 129mg of succinic acid are dissolved in a mixed solvent of 10mL of methanol and 10mL of acetonitrile, the mixture is heated and stirred in a water bath at 55 ℃ until the mixture is completely dissolved, the mixture is filtered, and the mixture is stood at room temperature for volatilization and crystallization for 48 hours, is filtered, and is dried at 65 ℃ for 24 hours to obtain crystals, and the yield is: 90%, purity: 99.92%.
Example 5
211mg of milrinone and 129mg of succinic acid are dissolved in a mixed solvent of 20mL of methanol and 15mL of trifluoroethanol, the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at room temperature for volatilization and crystallization for 48 hours, the mixture is filtered, and the mixture is dried at 65 ℃ for 24 hours to obtain crystals, so that the yield is: 83%, purity: 99.89%.
Example 6
211mg of milrinone and 129mg of succinic acid are dissolved in a mixed solvent of 15mL of methanol and 20mL of trifluoroethanol, the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at room temperature for volatilization and crystallization for 48 hours, the mixture is filtered, and the mixture is dried at 65 ℃ for 24 hours to obtain crystals, so that the yield is: 79%, purity: 99.86%.
Stability test
The specific stability test method is carried out by referring to the guidance method related to stability investigation in the fourth section of Chinese pharmacopoeia, the purity detection is carried out by using an HPLC method, and the specific detection result is shown in Table 3.
TABLE 3 stability test results of milrinone-succinic acid co-crystals
Solubility experiment
The method comprises the following steps: respectively weighing 10ml of medium (water, 0.01mol/LHCl 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; HPLC detection, calculation according to external standard method and concentration of solution.
TABLE 4 solubility of milrinone-butanedioic acid co-crystals (mg/mL)
Claims (9)
1. The milrinone-succinic acid co-crystal is characterized in that the molar ratio of milrinone to succinic acid in the co-crystal unit structure is 2:1.
2. the co-crystal of claim 1, wherein the X-ray diffraction pattern expressed in 2Θ has characteristic peaks at least at 5.2 ± 0.2 °, 20.0 ± 0.2 °, 20.7 ± 0.2 °, 24.1 ± 0.2 °, 24.2 ± 0.2 °, 26.1 ± 0.2 °, 27.1 ± 0.2 ° using Cu-ka radiation.
3. The co-crystal of claim 1, wherein the X-ray diffraction pattern expressed in 2Θ has characteristic peaks at least at 5.2±0.2° 2 °, 9.8±0.2°, 10.4±0.2°, 16.0±0.2°, 18.1±0.2°, 20.0±0.2°, 20.7±0.2°, 24.1±0.2°, 25.4±0.2°, 26.1±0.2°, 26.6±0.2°, 27.1±0.2°, 31.3±0.2°, 31.4±0.2° using Cu-ka radiation.
4. Co-crystal 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 shown in figure 1.
5. The co-crystal of claim 1 wherein said milrinone-succinic acid co-crystal has a formula of C 28 H 24 N 6 O 6 The crystallographic parameters were: the triclinic system has a space group of P-1 and unit cell parameters of:
α= 72.656 (6) °, β= 73.157 (4) °, γ= 86.534 (4) °, unit cell volume +.>
6. The method for preparing a co-crystal according to any one of claims 1 to 5, wherein milrinone and succinic acid are dissolved in a mixed solvent, heated and stirred, filtered, cooled, stood still, volatilized and crystallized, and filtered and dried to obtain milrinone-succinic acid crystals.
7. The method according to claim 6, wherein the mixed solvent is a mixture of methanol and solvent A; wherein the solvent A is selected from one or more of ethanol, acetonitrile, water, acetone or trifluoroethanol.
8. The pharmaceutical composition is characterized by comprising milrinone-succinic acid eutectic and other pharmaceutically acceptable components.
9. The pharmaceutical composition of claim 8, wherein the other pharmaceutically acceptable component is a combinable pharmaceutically active ingredient and/or a pharmaceutically acceptable adjuvant ingredient.
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