CN116199590A - Dobutamine hydrochloride and injection thereof - Google Patents
Dobutamine hydrochloride and injection thereof Download PDFInfo
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- CN116199590A CN116199590A CN202211671855.8A CN202211671855A CN116199590A CN 116199590 A CN116199590 A CN 116199590A CN 202211671855 A CN202211671855 A CN 202211671855A CN 116199590 A CN116199590 A CN 116199590A
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- dobutamine hydrochloride
- dobutamine
- hydrochloride
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- 229960001654 dobutamine hydrochloride Drugs 0.000 title claims abstract description 113
- JRWZLRBJNMZMFE-UHFFFAOYSA-N Dobutamine Chemical compound C=1C=C(O)C(O)=CC=1CCNC(C)CCC1=CC=C(O)C=C1 JRWZLRBJNMZMFE-UHFFFAOYSA-N 0.000 title claims abstract description 85
- 238000002347 injection Methods 0.000 title claims abstract description 16
- 239000007924 injection Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- -1 dobutamine hydrochloride compound Chemical class 0.000 claims description 30
- 238000001035 drying Methods 0.000 claims description 25
- 239000012065 filter cake Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 6
- 238000011010 flushing procedure Methods 0.000 claims description 5
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims description 5
- 229930182555 Penicillin Natural products 0.000 claims description 3
- 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 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229940049954 penicillin Drugs 0.000 claims description 3
- 238000001228 spectrum Methods 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- CUGZEDSDRBMZMY-UHFFFAOYSA-N trihydrate;hydrochloride Chemical compound O.O.O.Cl CUGZEDSDRBMZMY-UHFFFAOYSA-N 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 11
- 239000013078 crystal Substances 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 4
- 206010019280 Heart failures Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010062300 Procedural hypotension Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000004455 differential thermal analysis Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 229960001089 dobutamine 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
- 229940079593 drug Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 206010007625 cardiogenic shock Diseases 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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Abstract
The invention relates to dobutamine hydrochloride and an injection thereof, wherein the dobutamine hydrochloride is dobutamine hydrochloride with a molecular formula of C18H223NO3.HCl.3H2O. The dobutamine hydrochloride prepared by the invention has the advantages of good solubility, low hygroscopicity, good stability of the prepared pharmaceutical composition preparation, simple preparation process and obvious advantages compared with the prior art.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to dobutamine hydrochloride and an injection thereof.
Background
Dobutamine hydrochloride, chemical name: 4- [2- [ [ 1-methyl-3- (4-hydroxyphenyl) propyl ]]Amino group]Ethyl group]-1, 2-benzenediol hydrochloride, english name is DOBUTAMINEHydrochloride, molecular formula is C 18 H 23 NO 3 HCl, which is a dopamine homolog, is a selective cardiac beta 1-receptor agonist and is clinically used for treating heart failure caused by reduced myocardial contractility of organic heart diseases, cardiogenic shock caused by myocardial infarction and postoperative hypotension.
Heart failure, heart shock caused by myocardial infarction and postoperative hypotension are common diseases worldwide, have high mortality, seriously affect the safety and health of human beings, and have wide clinical application in the population suffering from heart failure, heart shock caused by myocardial infarction and postoperative hypotension due to beta 1-receptor stimulant taking dobutamine hydrochloride as a main component and have outstanding curative effect.
Because the dobutamine hydrochloride has positive curative effect, but the dobutamine hydrochloride is slightly dissolved in water and is dissolved under an acidic condition, the clinical use of the dobutamine hydrochloride is limited, the existing preparation technology generally adopts a method of dissolving the dobutamine hydrochloride to prepare dobutamine hydrochloride injection, other auxiliary materials are added, but the difficulty of the preparation is increased, and the use of the auxiliary materials increases the safety risk, so that the research on the dobutamine hydrochloride compound with better solubility and more stability has positive effect on the application of the dobutamine hydrochloride. The inventor unexpectedly obtains a new dobutamine hydrochloride compound and a preparation method thereof in a large amount of research processes of dobutamine hydrochloride for a long time, the dobutamine hydrochloride compound prepared by the method has extremely high quality stability, remarkably improves the solubility and reduces the hygroscopicity, and the prepared dobutamine hydrochloride is prepared into injection, so that the convenience of medication and preparation is improved, and the method is obviously superior to the prior art.
Disclosure of Invention
The invention aims to provide the dobutamine hydrochloride and the preparation method thereof, and the compound has better stability and solubility and lower hygroscopicity, and is convenient for preparing a pharmaceutical preparation; meanwhile, the dobutamine hydrochloride injection with good stability, high dissolution rate and simple preparation process is provided.
The technical scheme provided by the invention is as follows: the dobutamine hydrochloride compound is: dobutamine hydrochloride trihydrate having the formula: c (C) 18 H 23 NO 3 ·HCl·3H 2 O。
The dobutamine hydrochloride compound is a crystal, and is determined by adopting X-ray powder diffraction, wherein characteristic peaks in a map are shown at 11.5 degrees, 12.1 degrees, 15.8 degrees, 18.3 degrees, 21.2 degrees, 21.8 degrees, 22.3 degrees, 24.4 degrees, 25.0 degrees, 26.3 degrees, 27.1 degrees and 28.4 degrees in 2 theta + -0.2 degrees.
The preparation method of the dobutamine hydrochloride compound comprises the following steps: the method comprises the following steps:
(1) Sequentially adding water, isopropanol, ethyl acetate and dobutamine hydrochloride into a reaction kettle, starting stirring, heating to 62-65 ℃ at a stirring speed of 80-100 rpm, and keeping for 30-35 minutes; wherein the weight ratio of the dobutamine hydrochloride to the water to the isopropanol to the ethyl acetate is as follows: dobutamine hydrochloride: water: isopropyl alcohol: ethyl acetate = 1:25:4:0.2;
(2) Cooling to 52-57 ℃, maintaining the stirring speed of 80-100 rpm, and slowly adding tetrahydrofuran while stirring; the weight ratio of the tetrahydrofuran is as follows: dobutamine hydrochloride: tetrahydrofuran=1:1.5;
(3) Filtering the material in the step (2) to a crystallization kettle, cooling to 5-7 ℃, filtering to obtain a filter cake, and flushing the filter cake with 2 times of water by weight for 2 times;
(4) Placing the filter cake obtained in the step (3) in a drying box, drying for 4 hours at 65-70 ℃, crushing the filter cake, sieving with a 40-60 mesh sieve until the thickness is not more than 5mm, placing in a constant temperature and humidity box with the temperature of 24-28 ℃ and the humidity of 70-75% for 32-40 hours, taking out, drying under vacuum condition, adjusting the drying initial temperature to 30 ℃ at 5 ℃ per hour to 60 ℃, and drying at 60 ℃ to constant weight to obtain the dobutamine hydrochloride compound.
In order to solve the defects of low dissolution and low bioavailability, the dobutamine hydrochloride trihydrate prepared by the method has better water solubility, and generally, the solubility and the dissolution rate of the medicine in water are in sequence of hydrate < anhydrate < organic solvate, and the dobutamine hydrochloride trihydrate prepared by the method has better solubility than dobutamine hydrochloride anhydrate, has better stability and has the same pharmaceutical activity as dobutamine hydrochloride.
The ratio of the dobutamine hydrochloride, the isopropanol, the ethyl acetate, the tetrahydrofuran and the water is important to the preparation of the dobutamine hydrochloride compound according to the invention, and the dobutamine hydrochloride compound according to the invention can not be obtained by changing the relevant parameters according to a large number of experiments of the applicant, wherein the reaction temperature, the sieving mesh number, the flattened thickness, the temperature and humidity of constant temperature and constant humidity, the time and the heating speed are important to the preparation of the dobutamine hydrochloride compound according to the invention.
The dobutamine hydrochloride can be synthesized according to the known technology, and can also be purchased from commercial products.
According to another object of the present invention, there is provided a formulation comprising the dobutamine hydrochloride compound of the present invention according to the characteristics of the dobutamine hydrochloride compound of the present invention.
Preferably, the dobutamine hydrochloride preparation is an injection.
Preferably, the specification of the dobutamine hydrochloride injection is 0.25g (calculated as dobutamine).
Preferably, the dobutamine hydrochloride injection is prepared by the following method:
aseptically filling the dobutamine hydrochloride compound into a penicillin bottle according to the specification, adding a plug, and capping to obtain the dobutamine hydrochloride compound.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of dobutamine hydrochloride compound prepared in example 1 of the present invention.
Detailed Description
Characterization of dobutamine hydrochloride trihydrate
1. Elemental analysis
The dobutamine hydrochloride trihydrate prepared by the method is taken for elemental analysis, and the result is that: c:55.14 % H:7.67%, N:3.60% (to the two positions after the decimal point) which is consistent with the theoretical value of dobutamine hydrochloride trihydrate: c:55.17%, H:7.66%, N3.58% (to the two decimal places).
2. Differential thermal analysis
The dobutamine hydrochloride trihydrate prepared by the method is taken for differential thermal analysis, and the dobutamine hydrochloride trihydrate is used as a reference with dobutamine hydrochloride serving as a raw material for preparing the dobutamine hydrochloride. The results show that: the dobutamine hydrochloride trihydrate has an absorption peak between 110 and 115 ℃ to indicate that the sample has crystallization water or crystallization solvent, and the reference substance has no absorption peak to indicate that the sample has no crystallization water or crystallization solvent.
3. Moisture analysis
The water content in the dobutamine hydrochloride trihydrate is measured according to a Karl Fischer water content measuring method, the result is between 13.74 and 13.81 percent, the theoretical water content of the dobutamine hydrochloride trihydrate is 13.79 percent, and the two results are consistent. This indicates that the sample contained only water and no other solvents.
The results of elemental analysis, differential thermal analysis and moisture analysis are combined, so that the dobutamine hydrochloride of the invention can be proved to contain 3 molecules of crystal water.
4. Test comparative analysis
Sample 1: the dobutamine hydrochloride compound prepared in the embodiment 1 of the invention;
sample 2: dobutamine hydrochloride prepared according to example 2 of chinese application 201510216051.2;
sample 3: dobutamine hydrochloride prepared according to example 1 of chinese application 202210381529.7;
sample 4: the dobutamine hydrochloride raw material is marketed;
4.1 characterization study:
samples 1-4 were subjected to characterization studies by reference to the test methods of the present application, the results of which are shown in Table 1
TABLE 1 results of characterization studies on dobutamine hydrochloride
| Sample of | Characteristics of |
| Sample 1 | Trihydrate of |
| Sample 2 | Does not contain crystal water |
| Sample 3 | Does not contain crystal water |
| Sample 4 | Does not contain crystal water |
4.2 stability and high moisture drainage test:
samples 1-4 were subjected to a factor test and examined and placed under conditions of high temperature (60 ℃) and high humidity (92.5% + -5%) and light irradiation (4500 lx) for 10 days, and samples were taken on day 10, and the results of the content and moisture examination were compared with those on day 0, and are shown in Table 2.
TABLE 2 results of dobutamine hydrochloride trihydrate influencing factor tests
Table 2 test results show that: the dobutamine hydrochloride trihydrate has better stability and lower hygroscopicity, and other embodiments of the invention also carry out the same test, and similar results are obtained.
4.3 solubility analysis
Samples 1-4 were compared for solubility in water (25 ℃.+ -. 2 ℃), the results are shown in Table 3:
table 3 solubility comparison
| Sample of | Solubility (mg/ml) |
| Sample 1 | 75.4 |
| Sample 2 | 28.5 |
| Sample 3 | 27.9 |
| Sample 4 | 28.2 |
Table 3 test results show that: the solubility of the dobutamine hydrochloride compound prepared by the invention is obviously improved, and other embodiments of the invention also carry out the same test, thus obtaining similar results.
Examples
EXAMPLE 1 preparation of dobutamine hydrochloride Compound
(1) Sequentially adding water, isopropanol, ethyl acetate and dobutamine hydrochloride into a reaction kettle, starting stirring, heating to 62 ℃ at a stirring speed of 80 revolutions per minute, and keeping for 30 minutes; wherein the weight ratio of the dobutamine hydrochloride to the water to the isopropanol to the ethyl acetate is as follows: dobutamine hydrochloride: water: isopropyl alcohol: ethyl acetate = 1:25:4:0.2;
(2) Cooling to 52 ℃, keeping the stirring speed of 80 revolutions per minute, and slowly adding tetrahydrofuran while stirring; the weight ratio of the tetrahydrofuran is as follows: dobutamine hydrochloride: tetrahydrofuran=1:1.5;
(3) Filtering the material in the step (2) to a crystallization kettle, cooling to 5 ℃, filtering to obtain a filter cake, and flushing the filter cake with 2 times of water by weight for 2 times;
(4) And (3) placing the filter cake obtained in the step (3) in a drying oven, drying at 65 ℃ for 4 hours, crushing the filter cake, sieving with a 40-mesh sieve, flattening until the thickness is not more than 5mm, placing in a constant temperature and humidity oven with the temperature of 24 ℃ and the humidity of 70% for 32 hours, taking out, drying under vacuum condition, adjusting the drying initial temperature to 30 ℃ at 5 ℃ per hour to 60 ℃, and drying at 60 ℃ to constant weight to obtain the dobutamine hydrochloride compound.
The X-ray powder diffraction chart is shown in figure 1, wherein characteristic peaks in the chart are shown in the angles of 11.5 degrees, 12.1 degrees, 15.8 degrees, 18.3 degrees, 21.2 degrees, 21.8 degrees, 22.3 degrees, 24.4 degrees, 25.0 degrees, 26.3 degrees, 27.1 degrees and 28.4 degrees of 2 theta, and the content is as follows: 99.96%.
EXAMPLE 2 preparation of dobutamine hydrochloride Compound
(1) Sequentially adding water, isopropanol, ethyl acetate and dobutamine hydrochloride into a reaction kettle, starting stirring at a stirring speed of 100 revolutions per minute, heating to 65 ℃, and keeping for 35 minutes; wherein the weight ratio of the dobutamine hydrochloride to the water to the isopropanol to the ethyl acetate is as follows: dobutamine hydrochloride: water: isopropyl alcohol: ethyl acetate = 1:25:4:0.2;
(2) Cooling to 57 ℃, maintaining the stirring speed of 100 revolutions per minute, and slowly adding tetrahydrofuran while stirring; the weight ratio of the tetrahydrofuran is as follows: dobutamine hydrochloride: tetrahydrofuran=1:1.5;
(3) Filtering the material in the step (2) to a crystallization kettle, cooling to 7 ℃, filtering to obtain a filter cake, and flushing the filter cake with 2 times of water by weight for 2 times;
(4) And (3) placing the filter cake obtained in the step (3) in a drying box, drying at 70 ℃ for 4 hours, crushing the filter cake, sieving with a 60-mesh sieve, flattening until the thickness is not more than 5mm, placing in a constant temperature and humidity box with the temperature of 28 ℃ and the humidity of 75% for 40 hours, taking out, drying under vacuum, adjusting the drying initial temperature to 30 ℃, adjusting the temperature to 60 ℃ with the temperature of 5 ℃ per hour, and drying to constant weight at 60 ℃ to obtain the dobutamine hydrochloride compound.
The X-ray powder diffraction pattern was identical to example 1, content: 99.95%.
EXAMPLE 3 preparation of dobutamine hydrochloride Compound
(1) Sequentially adding water, isopropanol, ethyl acetate and dobutamine hydrochloride into a reaction kettle, starting stirring at a stirring speed of 90 revolutions per minute, heating to 64 ℃, and keeping for 32 minutes; wherein the weight ratio of the dobutamine hydrochloride to the water to the isopropanol to the ethyl acetate is as follows: dobutamine hydrochloride: water: isopropyl alcohol: ethyl acetate = 1:25:4:0.2;
(2) Cooling to 54 ℃, keeping the stirring speed of 90 revolutions per minute, and slowly adding tetrahydrofuran while stirring; the weight ratio of the tetrahydrofuran is as follows: dobutamine hydrochloride: tetrahydrofuran=1:1.5;
(3) Filtering the material in the step (2) to a crystallization kettle, cooling to 6 ℃, filtering to obtain a filter cake, and flushing the filter cake with 2 times of water by weight for 2 times;
(4) And (3) placing the filter cake obtained in the step (3) in a drying box, drying at 67 ℃ for 4 hours, crushing the filter cake, sieving with a 50-mesh sieve, flattening until the thickness is not more than 5mm, placing in a constant temperature and humidity box with the temperature of 26 ℃ and the humidity of 72% for 36 hours, taking out, drying under vacuum, adjusting the drying initial temperature to 30 ℃, adjusting the temperature to 60 ℃ with the temperature of 5 ℃ per hour, and drying to constant weight at 60 ℃ to obtain the dobutamine hydrochloride compound.
The X-ray powder diffraction pattern was identical to example 1, content: 99.98%.
EXAMPLE 4 preparation of dobutamine hydrochloride injection (0.25 g)
Prescription:
dobutamine hydrochloride compound (calculated as dobutamine): 250g;
1000 bottles were made
The process comprises the following steps:
aseptically filling the dobutamine hydrochloride compound into a penicillin bottle according to the specification, adding a plug, and capping to obtain the dobutamine hydrochloride compound.
Test example 1:
the acceleration test was performed on inventive examples 1-4 as follows: samples were taken in stability test chambers (40 ℃ + -2 ℃ C., 75% + -5% RH) at 1,2, 3, 6 months, respectively, and examined, with the results shown in Table 4.
TABLE 4 results of accelerated test of dobutamine hydrochloride
As can be seen from the results in Table 4, the dobutamine hydrochloride compound and dobutamine hydrochloride injection prepared by the invention have good stability under the acceleration condition.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention.
Claims (7)
1. The dobutamine hydrochloride is characterized in that the dobutamine hydrochloride is: dobutamine hydrochloride trihydrate having the molecular formula C 18 H 23 NO 3 ·HCl·3H 2 O。
2. The dobutamine hydrochloride according to claim 1, wherein the dobutamine hydrochloride is crystalline and has characteristic peaks in a spectrum of 11.5 °, 12.1 °, 15.8 °, 18.3 °, 21.2 °, 21.8 °, 22.3 °, 24.4 °, 25.0 °, 26.3 °, 27.1 ° and 28.4 ° as measured by X-ray powder diffraction.
3. A process for the preparation of dobutamine hydrochloride according to claim 1 or 2 comprising the steps of:
(1) Sequentially adding water, isopropanol, ethyl acetate and dobutamine hydrochloride into a reaction kettle, starting stirring, heating to 62-65 ℃ at a stirring speed of 80-100 rpm, and keeping for 30-35 minutes; wherein the weight ratio of the dobutamine hydrochloride to the water to the isopropanol to the ethyl acetate is as follows: dobutamine hydrochloride: water: isopropyl alcohol: ethyl acetate = 1:25:4:0.2;
(2) Cooling to 52-57 ℃, maintaining the stirring speed of 80-100 rpm, and slowly adding tetrahydrofuran while stirring; the weight ratio of the tetrahydrofuran is as follows: dobutamine hydrochloride: tetrahydrofuran=1:1.5;
(3) Filtering the material in the step (2) to a crystallization kettle, cooling to 5-7 ℃, filtering to obtain a filter cake, and flushing the filter cake with 2 times of water by weight for 2 times;
(4) Placing the filter cake obtained in the step (3) in a drying box, drying for 4 hours at 65-70 ℃, crushing the filter cake, sieving with a 40-60 mesh sieve until the thickness is not more than 5mm, placing in a constant temperature and humidity box with the temperature of 24-28 ℃ and the humidity of 70-75% for 32-40 hours, taking out, drying under vacuum condition, adjusting the drying initial temperature to 30 ℃ at 5 ℃ per hour to 60 ℃, and drying at 60 ℃ to constant weight to obtain the dobutamine hydrochloride compound.
4. The dobutamine hydrochloride preparation is characterized in that: comprising dobutamine hydrochloride according to claim 1 or 2.
5. The dobutamine hydrochloride formulation of claim 4, wherein the dobutamine hydrochloride formulation is an injection.
6. The dobutamine hydrochloride injection as defined in claim 5, wherein the dobutamine hydrochloride injection is 0.25g in size.
7. The preparation method of the dobutamine hydrochloride injection as claimed in claim 6, comprising the following steps: aseptically filling the dobutamine hydrochloride compound into a penicillin bottle according to the specification, adding a plug, and capping to obtain the dobutamine hydrochloride compound.
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