CN105669476A - Dobutamine hydrochloride crystal form and preparation method and application thereof - Google Patents
Dobutamine hydrochloride crystal form and preparation method and application thereof Download PDFInfo
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- CN105669476A CN105669476A CN201610099336.7A CN201610099336A CN105669476A CN 105669476 A CN105669476 A CN 105669476A CN 201610099336 A CN201610099336 A CN 201610099336A CN 105669476 A CN105669476 A CN 105669476A
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- dobutamine hydrochloride
- crystal formation
- hydrochloride crystal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—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
- 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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- 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
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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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Abstract
The invention discloses a dobutamine hydrochloride crystal form and a preparation method and application thereof. The dobutamine hydrochloride crystal form has characteristic peaks in diffraction angles 2 theta of 9.7 degrees +/- 0.2 degree, 13.5 degrees +/- 0.2 degree, 16.5 degrees +/- 0.2 degree, 17.6 degrees +/- 0.2 degree, 19.5 degrees +/- 0.2 degree, 21.5 degrees +/- 0.2 degree, 24.3 degrees +/- 0.2 degree, 24.5 degrees +/- 0.2 degree, 25.6 degrees +/- 0.2 degree, 27.9 degrees +/- 0.2 degree, 28.5 degrees +/- 0.2 degree, 29.3 degrees +/- 0.2 degree, 29.7 degrees +/- 0.2 degree, 32.6 degrees +/- 0.2 degree, 33.9 degrees +/- 0.2 degree and 35.5 degrees +/- 0.2 degree in an X-ray powder diffraction spectrum using Cu-K alpha as a radiant source. The dobutamine hydrochloride crystal form is high in purity and good in stability, the preparation method is simple and convenient, the repeatability is good, and industrial application and promotion are achieved conveniently.
Description
Technical field
The present invention relates to drug world, be specifically related to a kind of dobutamine hydrochloride crystal formation and its preparation method and application.
Background technology
Dobutamine hydrochloride, chemical name: 4-[2-[[1-methyl-3-(4-hydroxyphenyl) propyl group] amino] ethyl]-1,2-Benzodiazepines hydrochlorate, English name: DobutamineHydrochloride, molecular formula: C18H23NO3HCl, structural formula is as follows:
The United States Patent (USP) that publication number is US3987200A discloses dobutamine hydrochloride and preparation method thereof and purposes first. Dobutamine hydrochloride is dopamine homologue, is a selectivity heart β1-receptor analeptic, is clinically used for treatment organic heart disease myocardial contraction and declines the heart failure, cardiogenic shock caused by myocardial infarction and the postoperative hypotension that cause.
But, dobutamine hydrochloride amorphous article crude drug or its ejection preparation easily occur drug degradation to produce related substances within the effect phase, thus increasing adverse effect, such as arrhythmia, angina pectoris etc. It has been investigated that, its basic reason is in that the unstability defect of dobutamine hydrochloride.
Polymorph in pharmaceuticals is the common phenomenon in drug research and development, is the key factor affecting drug quality. Polymorphism, refers to same compound, by controlling its different formation condition, can form two or more molecule space arrangement mode, thus producing the phenomenon of different solid crystals. The different crystal forms of same compound, its chemical composition is identical, but microcosmic crystal structure is different, thus results in them and there are differences on mode of appearance, physicochemical property and biological activity. The different crystal forms of medicine often has different dissolubility, storage stability, water absorption, density and bioavailability. Drug crystal forms directly affects pharmaceutical preparation quality, drug absorption behavior, and finally affects the benefit ratio of medication effect and side effect. Therefore, the preparation method of drugs polytropism and different crystal forms has great importance.
At present, there is not yet the report of dobutamine hydrochloride crystal formation aspect.
Summary of the invention
Namely the technical problem to be solved is in that to overcome the defect that in prior art, in the dobutamine hydrochloride amorphous substance effect phase, drug quality is unstable, it is provided that a kind of dobutamine hydrochloride crystal formation and its preparation method and application. The dobutamine hydrochloride crystal form purity height of the present invention, good stability, preparation method are easy, and favorable reproducibility, it is simple to industrial application.
The present invention solves above-mentioned technical problem by the following technical programs:
The invention provides a kind of dobutamine hydrochloride crystal formation, described dobutamine hydrochloride crystal formation is in the X-ray powder diffraction using radiation source to be Cu-K α, in the angle of diffraction 2 θ=9.7 ° ± 0.2 °, 13.5 ° ± 0.2 °, 16.5 ° ± 0.2 °, 16.9 ° ± 0.2 °, 17.6 ° ± 0.2 °, 19.5 ° ± 0.2 °, 21.5 ° ± 0.2 °, 21.7 ° ± 0.2 °, 23.3 ° ± 0.2 °, 24.3 ° ± 0.2 °, 24.5 ° ± 0.2 °, 25.6 ° ± 0.2 °, 25.9 ° ± 0.2 °, 27.9 ° ± 0.2 °, 28.5 ° ± 0.2 °, 29.3 ° ± 0.2 °, 29.7 ° ± 0.2 °, 31.1 ° ± 0.2 °, 32.2 ° ± 0.2 °, 32.6 ° ± 0.2 °, 33.9 ° ± there is characteristic peak at 0.2 ° and 35.5 ° ± 0.2 ° place.
Wherein it is preferred that the relative intensity that the angle of diffraction is peak during 2 θ is as shown in the table:
In the present invention, the X-ray powder diffraction of described dobutamine hydrochloride crystal formation is as shown in Figure 1.
In the present invention, in the differential scanning calorimetry collection of illustrative plates (DSC) of described dobutamine hydrochloride crystal formation, there is maximum absorption band at 180 DEG C～200 DEG C; It is preferred that have maximum absorption band at 193.0 DEG C; More preferably, the differential scanning calorimetry collection of illustrative plates of described dobutamine hydrochloride crystal formation is as shown in Figure 2.
The preparation method that present invention also offers described dobutamine hydrochloride crystal formation, it comprises the steps: dobutamine hydrochloride solid and methanol mixed, heating for dissolving, adds polar solvent, cooling crystallization, filtration drying and get final product.
Wherein, described polar solvent is preferably the polar solvent dissolved each other with methanol, is more preferably one or more in water, ethanol and acetone.
Wherein, the temperature of described heating for dissolving is preferably 55～70 DEG C, is more preferably 60 DEG C.
Wherein, the mass ratio of described methanol and described dobutamine hydrochloride solid is preferably (0.8～2.5): 1, is more preferably 1:1.
Wherein, the mass ratio of described methanol and described polar solvent is preferably 1:1.5～3, is more preferably 1:2.
Wherein, described cooling crystallization is preferably and first naturally cools to room temperature, then is placed in 1～5 DEG C and stands crystallize.
In the present invention, room temperature generally refers to 15～30 DEG C.
Wherein, described filtration is preferably filtration under diminished pressure.
Wherein, described dry temperature is preferably 50～60 DEG C, and the described dry time is preferably 7～9 hours.
In the present invention, described dobutamine hydrochloride solid is preferably dobutamine hydrochloride amorphous article solid.
The content (HPLC purity) of the dobutamine hydrochloride crystal formation that the preparation method of the present invention obtains is up to more than 99%.
Present invention also offers above-mentioned dobutamine hydrochloride crystal formation to decline the heart failure, the cardiogenic shock caused by myocardial infarction and the application in postoperative hypotensive medicine that cause at preparation treatment organic heart disease myocardial contraction.
Invention further provides a kind of pharmaceutical composition, described pharmaceutical composition includes dobutamine hydrochloride crystal formation as above and pharmaceutically acceptable carrier.
Meeting on the basis of this area general knowledge, above-mentioned each optimum condition, can combination in any, obtain the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
The actively progressive effect of the present invention is in that: the dobutamine hydrochloride crystal form purity height of the present invention, good stability, preparation method are easy, and favorable reproducibility, it is simple to industrial application.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of the dobutamine hydrochloride crystal formation that the present invention prepares.
Fig. 2 is the differential scanning calorimetry collection of illustrative plates (DSC) of the dobutamine hydrochloride crystal formation that the present invention prepares.
Fig. 3 is the thermogravimetric analysis figure (TGA) of the dobutamine hydrochloride crystal formation that the present invention prepares.
Detailed description of the invention
Mode by the examples below further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments. The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
In following embodiment, room temperature refers to 15～30 DEG C.
Embodiment 1: the preparation of dobutamine hydrochloride crystal formation
Unformed for 50g dobutamine hydrochloride solid is added in 50g methanol, heat to 60 DEG C of stirring and dissolving, it is slow added into 100g purified water, stop heating, naturally cool to room temperature, put into 4 DEG C of refrigerators and stand 12h, filtration under diminished pressure, 55 DEG C of dry 8h of vacuum drying oven put into by filter cake, obtain 42g dobutamine hydrochloride crystal formation, HPLC content 99.4%.The X-ray powder diffraction pattern of this crystal formation and differential scanning collection of illustrative plates are as shown in Figure 1 and Figure 2.
Embodiment 2: the preparation of dobutamine hydrochloride crystal formation
Unformed for 50g dobutamine hydrochloride solid is added in 50g methanol, heat to 60 DEG C of stirring and dissolving, it is slow added into 100g ethanol, stop heating, naturally cool to room temperature, put into 4 DEG C of refrigerators and stand 12h, filtration under diminished pressure, 55 DEG C of dry 8h of vacuum drying oven put into by filter cake, obtain 42.6g dobutamine hydrochloride crystal formation, HPLC content 99.2%. The X-ray powder diffraction pattern of this crystal formation and differential scanning collection of illustrative plates are as shown in Figure 1 and Figure 2.
Embodiment 3: the preparation of dobutamine hydrochloride crystal formation
Unformed for 50g dobutamine hydrochloride solid is added in 50g methanol, heat to 60 DEG C of stirring and dissolving, it is slow added into 100g acetone, stop heating, naturally cool to room temperature, put into 4 DEG C of refrigerators and stand 12h, filtration under diminished pressure, 55 DEG C of dry 8h of vacuum drying oven put into by filter cake, obtain 41.3g dobutamine hydrochloride crystal formation, HPLC content 99.2%. The X-ray powder diffraction pattern of this crystal formation and differential scanning collection of illustrative plates are as shown in Figure 1 and Figure 2.
Effect example 1: the X-ray powder diffraction of dobutamine hydrochloride crystal formation is analyzed
Instrument and equipment: D/MAX-1200 type X-ray powder diffractometer.
Condition determination and method: Cu/K-alpha1 (target), 40KV-40mA (running voltage and electric current), I (max)=2244,2 θ=5～60 degree (sweep limits), 0.005/0.06sec. (scanning speed), λ=1.54056.
As it is shown in figure 1, wherein, the parameter of the relative intensity of the angle of diffraction 2 θ value of each characteristic peak, interplanar distance and characteristic peak is as shown in the table for the X-ray powder diffraction of the dobutamine hydrochloride crystal formation that embodiment 1～3 prepares:
Effect example 2: the differential scanning calorimetric analysis of dobutamine hydrochloride crystal formation
Differential scanning calorimetry (DSC) is adopted to carry out research sign the dobutamine hydrochloride crystal formation of embodiment 1～3 preparation. Differential scanning calorimetric analysis test condition: instrument: DSC204F1 (Germany) differential scanning calorimeter; Example weight is 4.1mg; Heating rate: 2 DEG C/min; The highest temperature 250 DEG C; Nitrogen flow rate: 20mL/min. Result is as shown in Figure 2.
From Fig. 2 result, when temperature reaches 193.0 DEG C, significant temperature absorption is had to react. The solvent of dobutamine hydrochloride crystal formation of the present invention is low boiling point solvent, therefore 193.0 DEG C of endothermic reactions that should be crystal conversion.
Effect example 3: the thermogravimetric analysis of dobutamine hydrochloride crystal formation
Thermogravimetry (TGA) is adopted to carry out research sign the dobutamine hydrochloride crystal formation of embodiment 1～3 preparation. Thermogravimetric analysis test condition: instrument: U.S.'s Pyris1TGA thermogravimetric analyzer; Sample size is 2.204mg; Under nitrogen protection, programming rate is 10 DEG C/min; Temperature range 30 DEG C to 600 DEG C; Nitrogen flow rate: 20mL/min. Result is as shown in Figure 3.
From Fig. 3 result, when temperature reaches 300 DEG C, occurring continuing weightlessness, weightless ratio improves rapidly afterwards. Analyze result and think that 300 DEG C of weightlessness should be that sample starts to decompose. Result shows that dobutamine hydrochloride crystal formation of the present invention just decomposes at 300 DEG C, and good stability is suitable for long term storage.
Effect example 4: accelerated test and room temperature keep sample study on the stability for a long time
1, accelerated test: the dobutamine hydrochloride crystal formation thing prepared by embodiment 1 and unformed dobutamine hydrochloride solid totally 4 batch sample (being purchased from Shanghai Ziyuan Pharmaceutical Co., Ltd.) are packed (filling with medicinal Low Density Polyethylene bag pack) by crude drug, be placed in 30 DEG C, relative humidity be 75 ± 5% constant temperature and humidity incubator in, place 6 months, test the 1st, 2,3, separately sampled detection in 6 months have related substance (detection of HPLC detection method), and the result with 0 month compares, result is shown in shown in following table.
The damp and hot accelerated test result of dobutamine hydrochloride crystal formation thing and unformed dobutamine hydrochloride solid
2, keep sample stability test for a long time: the dobutamine hydrochloride crystal formation thing prepared by embodiment 1 and unformed dobutamine hydrochloride solid totally 4 batch sample (being purchased from Shanghai Ziyuan Pharmaceutical Co., Ltd.) is packed (filling with medicinal Low Density Polyethylene bag pack) totally 4 batch sample by crude drug and packs (filling with medicinal Low Density Polyethylene bag pack) by crude drug, it is placed in 16 DEG C, relative humidity is in the constant temperature and humidity incubator of 60 ± 5%, place 12 months, in test the 3rd, 6, 9, separately sampled detection in 12 months has related substance (detection of HPLC detection method), and the result with 0 month compares, result is shown in shown in following table.
The long-term stable experiment result of dobutamine hydrochloride crystal formation and unformed dobutamine hydrochloride solid
The stability of the dobutamine hydrochloride crystal formation thing that embodiment 2～3 prepares is with embodiment 1.
Claims (10)
1. a dobutamine hydrochloride crystal formation, it is characterized in that, described dobutamine hydrochloride crystal formation is in the X-ray powder diffraction using radiation source to be Cu-K α, in the angle of diffraction 2 θ=9.7 ° ± 0.2 °, 13.5 ° ± 0.2 °, 16.5 ° ± 0.2 °, 16.9 ° ± 0.2 °, 17.6 ° ± 0.2 °, 19.5 ° ± 0.2 °, 21.5 ° ± 0.2 °, 21.7 ° ± 0.2 °, 23.3 ° ± 0.2 °, 24.3 ° ± 0.2 °, 24.5 ° ± 0.2 °, 25.6 ° ± 0.2 °, 25.9 ° ± 0.2 °, 27.9 ° ± 0.2 °, 28.5 ° ± 0.2 °, 29.3 ° ± 0.2 °, 29.7 ° ± 0.2 °, 31.1 ° ± 0.2 °, 32.2 ° ± 0.2 °, 32.6 ° ± 0.2 °, 33.9 ° ± there is characteristic peak at 0.2 ° and 35.5 ° ± 0.2 ° place.
2. dobutamine hydrochloride crystal formation as claimed in claim 1, it is characterised in that the X-ray powder diffraction of described dobutamine hydrochloride crystal formation is as shown in Figure 1.
3. dobutamine hydrochloride crystal formation as claimed in claim 1, it is characterised in that in the differential scanning calorimetry collection of illustrative plates of described dobutamine hydrochloride crystal formation, have maximum absorption band at 180 DEG C～200 DEG C; It is preferred that have maximum absorption band at 193.0 DEG C.
4. dobutamine hydrochloride crystal formation as claimed in claim 1, it is characterised in that the differential scanning calorimetry collection of illustrative plates of described dobutamine hydrochloride crystal formation is as shown in Figure 2.
5. the preparation method of the dobutamine hydrochloride crystal formation as according to any one of Claims 1 to 4, it comprises the steps: dobutamine hydrochloride solid and methanol mixed, heating for dissolving, adds polar solvent, cooling crystallization, filtration drying and get final product.
6. preparation method as claimed in claim 5, it is characterised in that described polar solvent is the polar solvent dissolved each other with methanol, it is preferred that for one or more in water, ethanol and acetone;
And/or, the temperature of described heating for dissolving is 55～70 DEG C, it is preferred that be 60 DEG C;
And/or, the mass ratio of described methanol and described dobutamine hydrochloride solid is (0.8～2.5): 1, it is preferred that for 1:1;
And/or, the mass ratio of described methanol and described polar solvent is 1:1.5～3, it is preferred that for 1:2.
7. preparation method as claimed in claim 5, it is characterised in that described cooling crystallization is for first naturally cooling to room temperature, then is placed in 1～5 DEG C and stands crystallize.
8. preparation method as claimed in claim 5, it is characterised in that described is filtered into filtration under diminished pressure;
And/or, described dry temperature is 50～60 DEG C, and the described dry time is 7～9 hours;
And/or, described dobutamine hydrochloride solid is dobutamine hydrochloride amorphous article solid.
9. the dobutamine hydrochloride crystal formation as according to any one of Claims 1 to 4 declines the heart failure, the cardiogenic shock caused by myocardial infarction and the application in postoperative hypotensive medicine that cause at preparation treatment organic heart disease myocardial contraction.
10. a pharmaceutical composition, described pharmaceutical composition comprises just like the dobutamine hydrochloride crystal formation according to any one of Claims 1 to 4 and pharmaceutically acceptable carrier.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114702398A (en) * | 2022-04-12 | 2022-07-05 | 安徽普利药业有限公司 | Preparation method of dobutamine hydrochloride |
| CN116199590A (en) * | 2022-12-26 | 2023-06-02 | 湖北美林药业有限公司 | Dobutamine hydrochloride and injection thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860833A (en) * | 2015-04-30 | 2015-08-26 | 上海紫源制药有限公司 | Purification method of dobutamine hydrochloride |
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- 2016-02-23 CN CN201610099336.7A patent/CN105669476A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860833A (en) * | 2015-04-30 | 2015-08-26 | 上海紫源制药有限公司 | Purification method of dobutamine hydrochloride |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114702398A (en) * | 2022-04-12 | 2022-07-05 | 安徽普利药业有限公司 | Preparation method of dobutamine hydrochloride |
| CN114702398B (en) * | 2022-04-12 | 2023-12-26 | 安徽普利药业有限公司 | Preparation method of dobutamine hydrochloride |
| CN116199590A (en) * | 2022-12-26 | 2023-06-02 | 湖北美林药业有限公司 | Dobutamine hydrochloride and injection thereof |
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Application publication date: 20160615 |