CN116239525A - Milrinone-baicalein co-crystal - Google Patents
Milrinone-baicalein co-crystal Download PDFInfo
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- CN116239525A CN116239525A CN202111486050.1A CN202111486050A CN116239525A CN 116239525 A CN116239525 A CN 116239525A CN 202111486050 A CN202111486050 A CN 202111486050A CN 116239525 A CN116239525 A CN 116239525A
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- milrinone
- baicalein
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- 229940015301 baicalein Drugs 0.000 title claims abstract description 54
- 239000013078 crystal Substances 0.000 title claims abstract description 46
- 230000005855 radiation Effects 0.000 claims abstract description 7
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 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 29
- 229960003574 milrinone Drugs 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- FXNFHKRTJBSTCS-UHFFFAOYSA-N Baicalein Natural products C=1C(=O)C=2C(O)=C(O)C(O)=CC=2OC=1C1=CC=CC=C1 FXNFHKRTJBSTCS-UHFFFAOYSA-N 0.000 claims description 17
- UDFLTIRFTXWNJO-UHFFFAOYSA-N baicalein Chemical compound O1C2=CC(=O)C(O)=C(O)C2=C(O)C=C1C1=CC=CC=C1 UDFLTIRFTXWNJO-UHFFFAOYSA-N 0.000 claims description 17
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- 238000001914 filtration Methods 0.000 claims description 15
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- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
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- 229910017488 Cu K Inorganic materials 0.000 abstract description 5
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- 238000001228 spectrum Methods 0.000 abstract description 2
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- 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
- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical class N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 238000002447 crystallographic data Methods 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
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- 229910052739 hydrogen Inorganic materials 0.000 description 2
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
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- 229940049954 penicillin Drugs 0.000 description 2
- 239000002510 pyrogen Substances 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
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- 102000004190 Enzymes Human genes 0.000 description 1
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- IPQKDIRUZHOIOM-UHFFFAOYSA-N Oroxin A Natural products OC1C(O)C(O)C(CO)OC1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 IPQKDIRUZHOIOM-UHFFFAOYSA-N 0.000 description 1
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- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
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- 229960002105 amrinone Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- IKIIZLYTISPENI-ZFORQUDYSA-N baicalin Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 IKIIZLYTISPENI-ZFORQUDYSA-N 0.000 description 1
- 229960003321 baicalin Drugs 0.000 description 1
- AQHDANHUMGXSJZ-UHFFFAOYSA-N baicalin Natural products OC1C(O)C(C(O)CO)OC1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 AQHDANHUMGXSJZ-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 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
- 230000003727 cerebral blood flow Effects 0.000 description 1
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- 238000012790 confirmation Methods 0.000 description 1
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- 238000011161 development Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
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- 229960003638 dopamine Drugs 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- -1 flavonoid compound Chemical class 0.000 description 1
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- 238000005984 hydrogenation reaction Methods 0.000 description 1
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- 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
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- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
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- 230000024883 vasodilation Effects 0.000 description 1
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Images
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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
- C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C31/02—Monohydroxylic acyclic alcohols
- C07C31/08—Ethanol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/40—Separation, e.g. from natural material; Purification
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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
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a milrinone-baicalein co-crystal. The milrinone-baicalein co-crystal uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at least at 4.7+/-0.2 degrees, 7.3+/-0.2 degrees, 7.6+/-0.2 degrees, 9.4+/-0.2 degrees, 14.2+/-0.2 degrees and 28.6+/-0.2 degrees.
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 co-crystal of milrinone and baicalein, 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 amirinone, and has better tolerance and less adverse reaction. 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 cannot be thoroughly solved, for example, inorganic acid is used as a cosolvent, the Cl-carried by hydrochloric acid is likely to cause hyperchlorhydria, and the cosolvent effects of phosphoric acid, sulfuric acid and the like are poor; among organic acids, lactic acid has a good dissolution assisting effect, but 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 a human body and the metabolism capacity are limited, if excessive D-lactic acid is taken in, metabolic disorder and even acidosis can be caused.
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.
Baicalein is flavonoid compound and has various pharmacological effects. For example, has effects in reducing cerebrovascular resistance, improving cerebral blood circulation, increasing cerebral blood flow, and resisting platelet aggregation. The traditional Chinese medicine composition is clinically used for treating paralysis after cerebrovascular diseases. Baicalein is an effective component in vivo, and is rapidly converted into baicalin and other metabolites in blood after entering animal body. However, baicalein is insoluble in water and has poor hydrophilicity, so that the baicalein is difficult to be absorbed and has poor oral absorption, so that the clinical application of the baicalein is limited to a great extent. Thus, the preparation development of baicalein is difficult.
Based on the problems, the problems of the dissolubility and the stability of milrinone are solved only by means of a preparation technology, and the potential safety hazard of clinical medication caused by overlarge dosage of auxiliary materials and auxiliary agents is unavoidable. Therefore, providing a new crystal form of milrinone with good solubility, high stability and high safety becomes a problem to be solved by those skilled in the art.
Disclosure of Invention
In view of the above problems, the present invention has found through studies that milrinone and baicalein having low water solubility can form co-crystals which exist stably, and the crystals formed by the two have significantly improved solubility, significantly improved stability, and the like. In addition, the invention provides a method for preparing the milrinone-baicalein eutectic, which is simple, convenient and suitable for industrial production.
The specific technical content of the invention is as follows:
in one aspect, the invention provides a milrinone-baicalein co-crystal, wherein the crystal unit of the co-crystal comprises the following components in a molar ratio of 2:2:1, milrinone-baicalein-ethanol molecules.
Preferably, the milrinone-baicalein co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed in terms of 2 theta has characteristic peaks at least at 4.7+/-0.2 degrees, 7.3+/-0.2 degrees, 7.6+/-0.2 degrees, 9.4+/-0.2 degrees, 14.2+/-0.2 degrees and 28.6+/-0.2 degrees.
Preferably, the milrinone-baicalein co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 4.7+/-0.2 degrees, 6.9+/-0.2 degrees, 7.3+/-0.2 degrees, 7.6+/-0.2 degrees, 9.4+/-0.2 degrees, 12.5+/-0.2 degrees, 14.2+/-0.2 degrees, 18.9+/-0.2 degrees, 23.7+/-0.2 degrees, 26.1+/-0.2 degrees and 28.6+/-0.2 degrees.
Preferably, the milrinone-baicalein 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-baicalein co-crystal has a molecular formula of C 56 H 44 N 6 O 13 The crystallographic parameters were: the triclinic system has a space group of P-1 and unit cell parameters of:
α= 78.0950 (10) °, β= 89.8300 (10) °, γ= 86.0040 (10) °, unit cell volume +.>
In another aspect, the present invention provides a method for preparing a milrinone-baicalein co-crystal, comprising the steps of:
adding milrinone and baicalein into solvent, adding ethanol, heating and stirring, filtering, cooling, standing for crystallization, filtering, and drying to obtain milrinone-baicalein eutectic.
Preferably, the solvent is selected from one or a combination of several of methanol, acetonitrile, acetone and trifluoroethanol; particularly preferred is one or a combination of methanol and acetone.
Preferably, the mass volume ratio of milrinone to solvent is 5-30: 1, mg/ml; preferably 10 to 20:1, mg/ml.
Preferably, the volume ratio of the ethanol to the solvent is 1:1 to 2.
Preferably, the molar ratio of milrinone to baicalein is 1:0.8 to 2.0; preferably 1:1.
preferably, the heating temperature is 50-70 ℃; preferably 60 ℃.
Preferably, the heating and stirring time is 6-24 hours.
Preferably, the temperature reduction crystallization temperature is 0-30 ℃; preferably, the temperature of the cooling crystallization is 5-15 ℃.
Preferably, the crystallization time is 12-72 hours.
Preferably, the drying temperature is 45-65 ℃ and the drying time is 8-24 hours.
Preferably, the starting material milrinone used in the preparation process may be prepared according to any method known in the art or purchased from commercial products.
Finally, the invention provides a pharmaceutical composition which contains the milrinone-baicalein eutectic crystal and other pharmaceutically feasible components.
Preferably, the other pharmaceutically acceptable components may be pharmaceutically active ingredients that may be combined and/or pharmaceutically acceptable auxiliary ingredients.
Confirmation of Crystal Structure
In the milrinone-baicalein co-crystal test, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is radiated 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 crystallography data (as shown in Table 1) of the milrinone-baicalein co-crystal form prepared by the invention is that the triclinic system is a space groupP-1, unit cell parameters are:
α= 78.0950 (10) °, β= 89.8300 (10) °, γ= 86.0040 (10) °, unit cell volume +.>
TABLE 1 Milrinon-baicalein co-crystal primary crystallographic data
The ORTEP diagram of the milrinone-baicalein co-crystal of the invention shows that the crystal form contains two molecules of milrinone, two molecules of baicalein and one molecule of ethanol, as shown in figure 2. The hydrogen bond diagram of the milrinone-baicalein co-crystal 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-baicalein co-crystal
Compared with the prior art, the invention has the technical effects that:
the invention provides the milrinone-baicalein eutectic for the first time, the preparation method is simple to operate, the crystallization process is easy to control, and the repeatability is good. After the two are formed into eutectic, the dissolubility of milrinone can be obviously enhanced, the oral bioavailability can be improved, and the pharmaceutical value is very high.
Drawings
FIG. 1 PXRD spectra of milrinone-baicalein co-crystals.
FIG. 2 ORTEP diagram of milrinone-baicalein co-crystal.
FIG. 3 shows hydrogen bonding diagram of milrinone-baicalein co-crystal.
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.
Milrinone crystals used in the stability and solubility experiments were prepared with reference to patent CN106361710 a.
Example 1
200mg milrinone and 256mg baicalein are dissolved in 10mL methanol, then 10mL ethanol is added, water bath heating and stirring are carried out at 60 ℃ for 12 hours, filtration is carried out, the filtrate is kept stand and crystallized for 36 hours at 5-10 ℃, filtration is carried out, drying is carried out at 50 ℃ for 12 hours, and the milrinone-baicalein eutectic is obtained, the yield is: 94%, purity: 99.92%.
Example 2
100mg milrinone and 128mg baicalein are dissolved in 10mL acetone, then 10mL ethanol is added, water bath heating and stirring are carried out for 12h at 50 ℃, filtration is carried out, the filtrate is kept stand and crystallized for 48h at 5-10 ℃, filtration is carried out, drying is carried out at 50 ℃ for 12h, and the milrinone-baicalein eutectic is obtained, the yield is: 90%, purity: 99.92%.
Example 3
200mg milrinone and 256mg baicalein are dissolved in 20mL methanol, then 10mL ethanol is added, water bath heating and stirring are carried out at 65 ℃ for 12h, filtration is carried out, filtrate is stood for crystallization for 48h at 10-15 ℃, filtration is carried out, drying is carried out at 55 ℃ for 12h, and milrinone-baicalein eutectic is obtained, the yield is: 89%, purity: 99.91%.
Example 4
300mg milrinone and 383.9mg baicalein are dissolved in 10mL methanol, then 10mL ethanol is added, water bath heating and stirring are carried out for 24 hours at 65 ℃, filtration is carried out, filtrate is stood and crystallized for 12 hours at 10-15 ℃, filtration is carried out, drying is carried out at 50 ℃ for 24 hours, and milrinone-baicalein eutectic is obtained, and the yield is: 86%, purity: 99.89%.
Example 5
Dissolving 50mg milrinone and 64mg baicalein in 10mL methanol, adding 15mL ethanol, heating in 65 ℃ water bath, stirring for 24h, filtering, standing filtrate at 10-15 ℃ for crystallization for 10h, filtering, and drying at 60 ℃ for 8h to obtain milrinone-baicalein eutectic, wherein 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 results of stability test of milrinone-baicalein 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 and calculation of the concentration of saturated solution according to external standard method.
TABLE 4 solubility of milrinone-baicalein co-crystals (mg/mL)
Claims (10)
1. A milrinone-baicalein co-crystal, characterized in that the crystal unit of the co-crystal comprises the components with a molar ratio of 2:2:1, milrinone-baicalein-ethanol molecules.
2. The co-crystal of claim 1, wherein the milrinone-baicalein co-crystal has characteristic peaks in X-ray diffraction patterns expressed in 2Θ of at least 4.7 ± 0.2 °, 7.3 ± 0.2 °, 7.6 ± 0.2 °, 9.4 ± 0.2 °, 14.2 ± 0.2 °, 28.6 ± 0.2 ° using Cu-ka radiation.
3. The co-crystal of claim 1, wherein the milrinone-baicalein co-crystal has characteristic peaks in an X-ray diffraction pattern expressed in 2Θ of at least 4.7 ± 0.2 °, 6.9 ± 0.2 °, 7.3 ± 0.2 °, 7.6 ± 0.2 °, 9.4 ± 0.2 °, 12.5 ± 0.2 °, 14.2 ± 0.2 °, 18.9 ± 0.2 °, 23.7 ± 0.2 °, 26.1 ± 0.2 °, 28.6 ± 0.2 ° using Cu-ka radiation.
4. The co-crystal of claim 1, wherein the milrinone-baicalein co-crystal uses Cu-ka radiation and has a characteristic peak corresponding to the X-ray powder diffraction pattern shown in figure 1.
5. The co-crystal of claim 1 wherein said milrinone-baicalein co-crystal has a formula of C 56 H 44 N 6 O 13 The crystallographic parameters were: the triclinic system has a space group of P-1 and unit cell parameters of:
α= 78.0950 (10) °, β= 89.8300 (10) °, γ= 86.0040 (10) °, unit cell volume +.>
6. A method of preparing the milrinone-baicalein co-crystal of any one of claims 1-5, comprising the steps of:
adding milrinone and baicalein into solvent, adding ethanol, heating and stirring, filtering, cooling, standing for crystallization, filtering, and drying to obtain milrinone-baicalein eutectic.
7. The method according to claim 6, wherein the solvent is one or a combination of methanol, acetonitrile, acetone, and trifluoroethanol.
8. The preparation method of claim 6, wherein the mass-to-volume ratio of milrinone to solvent is 5-30: 1, mg/ml.
9. The method of claim 6, wherein the volume ratio of ethanol to solvent is 1:1 to 2.
10. The method of claim 6, wherein the heating and stirring time is 6 to 24 hours.
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