CN117105858A - Milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form - Google Patents
Milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form Download PDFInfo
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- CN117105858A CN117105858A CN202211064068.7A CN202211064068A CN117105858A CN 117105858 A CN117105858 A CN 117105858A CN 202211064068 A CN202211064068 A CN 202211064068A CN 117105858 A CN117105858 A CN 117105858A
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- Prior art keywords
- milrinone
- acid hydrate
- mixed solvent
- dicarboxylic acid
- pyridine dicarboxylic
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- 239000013078 crystal Substances 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 18
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- 238000002360 preparation method Methods 0.000 claims abstract description 8
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 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 45
- 229960003574 milrinone Drugs 0.000 claims description 44
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 37
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- 239000012046 mixed solvent Substances 0.000 claims description 27
- MPFLRYZEEAQMLQ-UHFFFAOYSA-N dinicotinic acid Chemical compound OC(=O)C1=CN=CC(C(O)=O)=C1 MPFLRYZEEAQMLQ-UHFFFAOYSA-N 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
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- 238000001035 drying Methods 0.000 claims description 7
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 4
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- 238000012360 testing method Methods 0.000 description 6
- 206010019280 Heart failures Diseases 0.000 description 5
- 230000000052 comparative effect Effects 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
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- 238000010586 diagram Methods 0.000 description 4
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 206010067484 Adverse reaction Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000006838 adverse reaction Effects 0.000 description 3
- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical class N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
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- 238000002447 crystallographic data Methods 0.000 description 3
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- 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
- 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229960002105 amrinone Drugs 0.000 description 2
- 229940022769 d- lactic acid Drugs 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 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
- 238000001727 in vivo Methods 0.000 description 2
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- 239000004310 lactic acid Substances 0.000 description 2
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- 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
- 108010024636 Glutathione Proteins 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
- 229930003427 Vitamin E Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 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
- 229960003180 glutathione Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940082795 milrinone injection Drugs 0.000 description 1
- -1 milrinone sodium salt Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 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
- 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
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001020 rhythmical effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 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
-
- 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
- C07D213/79—Acids; Esters
-
- 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
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form, which uses Cu-K alpha radiation, and has an X-ray diffraction pattern expressed by 2 theta with characteristic peaks at least at 9.3+/-0.2 degrees, 12.3+/-0.2 degrees, 15.4+/-0.2 degrees, 24.3+/-0.2 degrees and 25.7+/-0.2 degrees, belonging to monoclinic crystal system and having a space group of P2 1 And/n, the unit cell parameters are: α=90 °, β= 95.6650 (10) °, γ=90°, unit cell volume
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a novel milrinone crystal form, in particular to a milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form, and a preparation method and application thereof.
Background
Milrinone (formula I) with chemical name of 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 amrinone, and has the same action mechanism as amrinone. 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 almost insoluble in water, has poor water solubility and poor in vivo absorption effect, and has heavier adverse reaction when being taken orally; the existing milrinone injection has the problems of poor stability and easy degradation, and various auxiliary materials are required to be added. As disclosed in patent CN106361710a, crystals are precipitated in a solvent of ethanol + acetone + water, lactic acid is used as a cosolvent, and a certain amount of vitamin E and glutathione are added as antioxidants to improve the stability of the injection, but the new crystal form itself is not used to overcome the problem of poor solubility of milrinone, and lactic acid is a racemate and consists of L-lactic acid and D-lactic acid, and since only enzymes for metabolizing L-lactic acid in human body have limited metabolic capacity, metabolic disorder and even acidosis can be caused if excessive D-lactic acid is taken in. For another example, patent CN19151919a discloses a method of preparing a lyophilized preparation after salifying with milrinone using hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, sodium hydroxide, potassium hydroxide, but the solubility and stability of milrinone salt itself are still poor.
Besides, besides low solubility, the prior art purification/crystallization method of milrinone crystals has low yield. For example, patent CN104387320a crystallizes crude milrinone in an ethanol-water system, the purity of the obtained white milrinone crystals is 99.7%, and the yield is 83.8%; the patent CN102558044A adopts mixed solvent (DMF plus water with a certain temperature) for crystallization, dimethylformamide (DMF) is firstly used for heating and dissolving, then hot water is added under the condition of stirring, crystallization is slowly carried out, white crystals with uniform size can be separated out, the purity is 99.98%, and the yield is 82.6%; the patent CN104744357A adopts a mixed solvent consisting of water, ethanol and DMF for purification, the purity can reach 99.90 percent, but the yield is lower as well; the patent CN103965101B is dissolved by 50vt percent ethanol under reflux, filtered, and the filtrate is stirred and crystallized at the temperature of between 5 ℃ below zero and 10 ℃ below zero to obtain white solid milrinone with the purity of 99.97 percent and the yield of 82.8 percent.
In summary, the milrinone crystal form which has good solubility, good stability and good prospect of patent medicine is provided, and the milrinone crystal form becomes a problem to be solved urgently by the person skilled in the art.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention aims to provide a novel milrinone crystal form with higher solubility and good stability, namely a milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form. In addition, the invention provides a method for preparing the milrinone-3, 5-pyridine dicarboxylic acid hydrate, which is simple, convenient, high in yield and suitable for industrial production.
The specific technical content of the invention is as follows:
in one aspect, the present invention provides a crystalline form of milrinone-3, 5-pyridinedicarboxylic acid hydrate, having characteristic peaks in an X-ray diffraction pattern expressed in 2θ of at least 9.3±0.2°, 12.3±0.2°, 15.4±0.2°, 24.3±0.2°, 25.7±0.2° using Cu-kα radiation.
Preferably, the milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 6.0+/-0.2 degrees, 9.3+/-0.2 degrees, 11.1+/-0.2 degrees, 12.3+/-0.2 degrees, 13.1+/-0.2 degrees, 15.4+/-0.2 degrees, 20.8+/-0.2 degrees, 21.1+/-0.2 degrees, 24.1+/-0.2 degrees, 24.3+/-0.2 degrees, 25.7+/-0.2 degrees, 26.5+/-0.2 degrees and 35.9+/-0.2 degrees.
Preferably, the milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form has a molecular formula of C 38 H 32 N 8 O 12 The crystallographic parameters were: monoclinic crystal system with space group P2 1 And/n, the unit cell parameters are: α=90 °, β= 95.6650 (10) °, γ=90°, unit cell volume +.>
In another aspect, the present invention provides a method for preparing milrinone-3, 5-pyridinedicarboxylic acid hydrate, comprising the steps of:
and dissolving milrinone and 3, 5-pyridine dicarboxylic acid in a mixed solvent, heating and stirring, filtering, cooling for crystallization, filtering and drying to obtain the crystalline form of the milrinone-3, 5-pyridine dicarboxylic acid hydrate.
Preferably, the mixed solvent is a mixed solvent of methanol, water and trifluoroethanol or a mixed solvent of methanol, water and acetone.
Preferably, the volume ratio of methanol, water and trifluoroethanol or acetone in the mixed solvent is 1:0.01 to 0.125:1 to 2; further preferably 1:0.01 to 0.125:1.25 to 1.5; further preferably 1:0.05 to 0.0625:1.25 to 1.5.
Preferably, the mass volume ratio of the milrinone to the mixed solvent is 5-12: 1, a step of; wherein the mass of milrinone is calculated in mg, and the volume of the mixed solvent is calculated in ml.
Preferably, the molar ratio of milrinone to 3, 5-pyridine dicarboxylic acid is 1:0.8 to 1.2, preferably 1:1.
Preferably, the heating temperature is 50 to 70 ℃, preferably 60 ℃.
The temperature-reducing crystallization temperature is 0-30 ℃, preferably 10-15 ℃.
The crystallization time is 10-62 hours.
The drying temperature is 50-65 ℃ and the drying time is 8-15 hours.
The raw material milrinone used in the preparation method may be prepared according to any method in the prior art or purchased from commercial products.
Finally, the invention provides an oral pharmaceutical composition, which contains the milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form and other pharmaceutically feasible 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-3, 5-pyridine dicarboxylic acid hydrate crystal form test, X-ray crystal data are collected on a Japanese 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 corrected by Lp. 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.
Testing and resolving the crystallographic data (as Table 1) of the crystalline form of milrinone-3, 5-pyridine dicarboxylic acid hydrate prepared according to the invention is a monoclinic crystal system with a space group of P2 1 And/n, the unit cell parameters are: α=90 °, β= 95.6650 (10) °, γ=90°, unit cell volume +.>
TABLE 1 major crystallographic data for the crystalline form of milrinone-3, 5-pyridinedicarboxylic acid hydrate
ORTEP diagram of the hydrate crystal form of milrinone-3, 5-pyridine dicarboxylic acid shows that the crystal form contains two molecules of milrinone, two molecules of 3, 5-pyridine dicarboxylic acid and two molecules of water, and is shown in figure 2. The stacking diagram of the milrinone-3, 5-pyridine dicarboxylic acid hydrate 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 crystalline form of milrinone-3, 5-pyridinedicarboxylic acid hydrate
Compared with the prior art, the invention has the technical effects that:
the invention provides a novel milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form, and the preparation method is simple to operate, easy to control the crystallization process and good in reproducibility. The crystal form of the milrinone-3, 5-pyridine dicarboxylic acid hydrate has good stability and solubility, can obviously improve the oral bioavailability of milrinone, and has strong patent medicine value.
Drawings
FIG. 1 PXRD spectra of milrinone-3, 5-pyridinedicarboxylic acid hydrate crystalline form.
FIG. 2 ORTEP diagram of the crystalline form of milrinone-3, 5-pyridinedicarboxylic acid hydrate.
FIG. 3 is a diagram showing the stacking of the crystalline form of milrinone-3, 5-pyridinedicarboxylic acid hydrate.
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
211.2mg of milrinone and 167.1mg of 3, 5-pyridine dicarboxylic acid are dissolved in a mixed solvent of 8mL of methanol and 10mL of trifluoroethanol, 0.5mL of water is added, 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 cooled, kept stand and volatilized for crystallization for 48 hours at 10-15 ℃, then the mixture is filtered, and the mixture is dried for 12 hours at 50 ℃ to obtain milrinone-3, 5-pyridine dicarboxylic acid hydrate with the yield: 96.5%, purity: 99.92%.
Example 2
211.2mg milrinone and 200.5mg 3, 5-pyridine dicarboxylic acid are dissolved in a mixed solvent of 16mL methanol and 22mL acetone, 1mL water is added, 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 cooled, kept stand and volatilized for crystallization at 10-15 ℃ for 60 hours, the mixture is filtered, and the mixture is dried at 60 ℃ for 8 hours to obtain milrinone-3, 5-pyridine dicarboxylic acid hydrate, and the yield is: 93.8%, purity: 99.95%.
Example 3
211.2mg of milrinone and 133.7mg of 3, 5-pyridine dicarboxylic acid are dissolved in a mixed solvent of 10mL of methanol and 15mL of acetone, 0.5mL of water is added, 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 cooled, kept stand and volatilized for crystallization for 36h at 10-15 ℃, the mixture is filtered, and the mixture is dried for 10h at 55 ℃ to obtain milrinone-3, 5-pyridine dicarboxylic acid hydrate, and the yield is: 92.5%, purity: 99.91%.
Example 4
211.2mg of milrinone and 167.1mg of 3, 5-pyridine dicarboxylic acid are dissolved in a mixed solvent of 8mL of methanol and 8mL of trifluoroethanol, 0.5mL of water is added, the mixture is heated and stirred in a water bath at the temperature of 60 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is cooled, kept stand and volatilized for crystallization for 48 hours at the temperature of 10-15 ℃, the mixture is filtered, and the mixture is dried for 8 hours at the temperature of 60 ℃ to obtain milrinone-3, 5-pyridine dicarboxylic acid hydrate with the yield: 88.3% of purity: 99.92%.
Example 5
211.2mg milrinone and 200.5mg 3, 5-pyridine dicarboxylic acid are dissolved in a mixed solvent of 16mL methanol and 32mL acetone, 1mL water is added, 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 cooled, kept stand and volatilized for crystallization at 10-15 ℃ for 60 hours, the mixture is filtered, and the mixture is dried at 60 ℃ for 8 hours to obtain milrinone-3, 5-pyridine dicarboxylic acid hydrate, and the yield is: 87.5%, purity: 99.93%.
Example 6
211.2mg of milrinone and 133.7mg of 3, 5-pyridine dicarboxylic acid are dissolved in a mixed solvent of 10mL of methanol and 15mL of acetone, heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, kept stand at 25 ℃ for volatilization and crystallization for 36 hours, filtered and dried at 55 ℃ for 10 hours to obtain milrinone-3, 5-pyridine dicarboxylic acid hydrate, and the yield is: 83.7% of purity: 99.91%.
Example 7
211.2mg milrinone and 250.6mg 3, 5-pyridine dicarboxylic acid are dissolved in a mixed solvent of 8mL methanol and 10mL acetonitrile, 2mL water is added, 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 cooled, kept stand and volatilized for crystallization for 48 hours at 10-15 ℃, then the mixture is filtered, and the mixture is dried for 12 hours at 50 ℃ to obtain milrinone-3, 5-pyridine dicarboxylic acid hydrate, and the yield is: 80.1%, purity: 99.92%.
Comparative example 1 milrinone recrystallisation
Adding a mixed solvent (volume ratio, ethanol: water: dimethylformamide=4:4:1) with the mass of 20 times of the crude product into the milrinone crude product, slowly heating to 60 ℃, adding active carbon with the mass of 15% of the crude product for decoloring for 1 hour when the crude product is hot, and filtering to remove the active carbon; cooling the filtrate obtained by suction filtration to room temperature under slow stirring, crystallizing, suction filtering again, washing the filter cake obtained by suction filtering again with ethanol, and drying at 60 ℃ to obtain white-like crystals; adding the mixed solvent with the mass of 20 times of that of the white crystals into the white crystals, slowly heating to 60 ℃, cooling to room temperature under slow stirring until the white crystals are completely dissolved, and crystallizing to obtain white milrinone crystals with the purity: 99.90% and 80.5% yield.
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, airing, and then drying at 105 ℃ for 2 hours to obtain milrinone sodium salt. The yield was 90.2% and the purity was 99.89%.
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. Yield 91.0% and purity 99.91%.
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 the mixed solvent of O, the volume ratio of methanol, acetonitrile and water is 2:1:1, and the mixed solvent is rapidly and vigorously stirred for about 3 hours at 60 ℃. 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. Yield 83.5% and purity 99.90%.
Verification embodiment
1. 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 results are shown in Table 3.
TABLE 3 stability investigation results of different milrinone crystals under light, high temperature and high humidity conditions
Note that: the stability results of milrinone-3, 5-pyridinedicarboxylic acid hydrates prepared in examples 1 to 7 of the present invention, which are shown in Table 3, were tested using the crystalline form prepared in example 1, as examples.
2. Solubility experiment
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, and the results are shown in Table 4.
TABLE 4 solubility of different milrinone crystals in different media (mg/mL)
Note that: the milrinone-3, 5-pyridinedicarboxylic acid hydrates prepared in examples 1 to 7 of the present invention all had similar solubilities, and the solubilities of the milrinone-3, 5-pyridinedicarboxylic acid hydrates in Table 4 were tested using the crystalline form prepared in example 1 as an example.
3. Pharmacokinetic test
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 blood concentration of milrinone was measured, and the results are shown in table 5.
TABLE 5 pharmacokinetic study results for different milrinone crystals
Note that: compared with the crystals of comparative example 1, P <0.05, the difference was statistically significant.
Test results show that compared with other crystal forms of milrinone, the milrinone-3, 5-pyridine dicarboxylic acid hydrate provided by the invention has the advantages of faster onset of action and higher oral bioavailability.
Claims (10)
1. A crystalline form of milrinone-3, 5-pyridinedicarboxylic acid hydrate, characterized in that it has characteristic peaks in the X-ray diffraction pattern expressed in 2Θ at least at 9.3 ± 0.2 °, 12.3 ± 0.2 °, 15.4 ± 0.2 °, 24.3 ± 0.2 °, 25.7 ± 0.2 ° using Cu-ka radiation.
2. The crystalline milrinone-3, 5-pyridinedicarboxylic acid hydrate form according to claim 1, characterized in that the X-ray diffraction pattern expressed in 2Θ has characteristic peaks at least at 6.0±0.2°, 9.3±0.2°, 11.1±0.2°, 12.3±0.2°, 13.1±0.2°, 15.4±0.2°, 20.8±0.2°, 21.1±0.2°, 24.1±0.2°, 24.3±0.2°, 25.7±0.2°, 26.5±0.2°, 35.9±0.2° using Cu-ka radiation.
3. The crystalline form of milrinone-3, 5-pyridinedicarboxylic acid hydrate 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.
4. According toThe crystalline form of milrinone-3, 5-pyridinedicarboxylic acid hydrate according to claim 1, characterized in that the crystallographic parameters of the crystalline form are: monoclinic crystal system with space group P2 1 And/n, the unit cell parameters are: α=90 °, β= 95.6650 (10) °, γ=90°, unit cell volume +.>
5. A process for the preparation of a crystalline form of milrinone-3, 5-pyridinedicarboxylic acid hydrate according to any one of claims 1 to 4, comprising the steps of: and (3) dissolving milrinone and 3, 5-pyridine dicarboxylic acid in a mixed solvent, heating and stirring, filtering, cooling and crystallizing, filtering, and drying to obtain the crystalline form of the milrinone-3, 5-pyridine dicarboxylic acid hydrate.
6. The method according to claim 5, wherein the mixed solvent is a mixed solvent of methanol, water, trifluoroethanol or a mixed solvent of methanol, water, acetone.
7. The preparation method according to claim 6, wherein the volume ratio of methanol, water, and trifluoroethanol or acetone in the mixed solvent is 1:0.01 to 0.125:1 to 2.
8. The preparation method of claim 5, wherein the mass-to-volume ratio of milrinone to the mixed solvent is 5-12: 1, a step of; wherein the mass of milrinone is calculated in mg, and the volume of the mixed solvent is calculated in ml.
9. The method according to claim 5, wherein the temperature of the reduced crystallization is 0-30 ℃, preferably 10-15 ℃.
10. An oral pharmaceutical composition comprising milrinone-3, 5-pyridinedicarboxylic acid hydrate and other pharmaceutically acceptable components.
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