Dobutamine hydrochloride and injection thereof

Abstract

The invention relates to dobutamine hydrochloride and an injection thereof, wherein the dobutamine hydrochloride is a dobutamine hydrochloride having a molecular formula of C18H23NO3·HCl·3H2O. The dobutamine hydrochloride prepared by the invention has good solubility, low hygroscopicity and good stability, and the prepared pharmaceutical composition preparation has good stability and a simple preparation process, and has obvious advantages over the prior art.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and relates to dobutamine hydrochloride and an injection thereof. Background Art

[0002] Dobutamine hydrochloride, chemical name: 4-[2-[[1-methyl-3-(4-hydroxyphenyl)propyl]amino]ethyl]-1,2-benzenediol hydrochloride, English name Dobutamine Hydrochloride, molecular formula C 18 H 23 NO3·HCl is a dopamine homologue and a selective cardiac β1-receptor stimulant. It is clinically used to treat heart failure caused by decreased myocardial contractility in organic heart disease, cardiogenic shock caused by myocardial infarction, and postoperative hypotension.

[0003] Heart failure, cardiogenic shock caused by myocardial infarction and postoperative hypotension are common diseases worldwide with high mortality rates, which seriously affect human safety and health. β1-receptor stimulants with dobutamine hydrochloride as the main ingredient are widely used clinically in people with heart failure, cardiogenic shock caused by myocardial infarction and postoperative hypotension in my country, with outstanding therapeutic effects.

[0004] Because of the positive curative effect of dobutamine hydrochloride, dobutamine hydrochloride is slightly soluble in water and dissolves under acidic conditions, which limits the clinical use of dobutamine hydrochloride. The existing preparation technology generally adopts the method of hydrochloric acid dissolution to prepare dobutamine hydrochloride injection, and other auxiliary materials are added at the same time, but this increases the difficulty of preparation, and the use of auxiliary materials increases the safety risk. Therefore, studying a dobutamine hydrochloride compound with better solubility and more stability has a positive effect on the application of dobutamine hydrochloride. The inventor unexpectedly obtained a new dobutamine hydrochloride compound and a preparation method thereof during a long-term large-scale study of dobutamine hydrochloride. The dobutamine hydrochloride compound prepared by the method has extremely high quality stability and significantly improves solubility and reduces hygroscopicity. The prepared dobutamine hydrochloride is prepared into an injection, which increases the convenience of medication and preparation, and is significantly better than the prior art. Summary of the invention

[0005] The purpose of the present invention is to provide dobutamine hydrochloride and a preparation method thereof. The compound has good stability and solubility, low hygroscopicity, and is convenient for the preparation of pharmaceutical preparations; at the same time, a dobutamine hydrochloride injection with good stability, high solubility and simple preparation process is provided.

[0006] The technical solution provided by the present invention is: the dobutamine hydrochloride compound is: dobutamine hydrochloride trihydrate, and its molecular formula is: C 18 H23 NO3·HCl·3H2O.

[0007] The dobutamine hydrochloride compound is a crystal, and is measured by X-ray powder diffraction. The characteristic peaks in its spectrum at 2θ±0.2° are 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°.

[0008] The preparation method of dobutamine hydrochloride compound comprises the following steps:

[0009] (1) adding water, isopropanol, ethyl acetate and dobutamine hydrochloride into a reaction pot in sequence, starting stirring at a speed of 80 to 100 rpm, heating to 62 to 65° C., and maintaining for 30 to 35 minutes; wherein the weight ratio of dobutamine hydrochloride, water, isopropanol and ethyl acetate is: dobutamine hydrochloride: water: isopropanol: ethyl acetate = 1:25:4:0.2;

[0010] (2) cooling to 52-57° C., maintaining a stirring speed of 80-100 rpm, and slowly adding tetrahydrofuran while stirring; the weight ratio of tetrahydrofuran is: dobutamine hydrochloride: tetrahydrofuran = 1:1.5;

[0011] (3) filtering the material of step (2) into a crystallization kettle, cooling to 5-7° C., filtering to obtain a filter cake, and washing the filter cake twice with 2 times the weight of water;

[0012] (4) The filter cake obtained in step (3) is placed in a drying oven at 65-70° C., dried for 4 hours, then crushed, passed through a 40-60 mesh sieve, and flattened to a thickness not exceeding 5 mm. The filter cake is placed in a constant temperature and humidity chamber at 24-28° C. and a humidity of 70-75%. After 32-40 hours, the filter cake is taken out and dried under vacuum conditions. The drying starting temperature is 30° C., and the temperature is increased by 5° C. every hour to 60° C., and dried at 60° C. to constant weight to obtain a dobutamine hydrochloride compound.

[0013] In order to solve the shortcomings of low solubility and low bioavailability, the dobutamine hydrochloride trihydrate prepared by the above method has good water solubility. Generally, the solubility and dissolution rate of drugs in water are in the order of hydrate < anhydrous < organic solvate. Unexpectedly, the dobutamine hydrochloride trihydrate prepared by the present invention has better solubility than dobutamine hydrochloride anhydrous compound, and has better stability, and has the same pharmaceutical activity as dobutamine hydrochloride.

[0014] It should be noted that the ratio of dobutamine hydrochloride, isopropanol, ethyl acetate, tetrahydrofuran and water, the reaction temperature, the mesh size of the sieve, the thickness of the flattened product, the temperature and humidity of the constant temperature and humidity, the time, and the rate of heating are crucial to obtaining the dobutamine hydrochloride compound of the present invention. According to a large number of experiments conducted by the applicant, the dobutamine hydrochloride compound of the present invention cannot be obtained by changing the relevant parameters of the present application.

[0015] The dobutamine hydrochloride used can be synthesized according to known techniques or purchased from the market.

[0016] Another object of the present invention is to provide a preparation containing the dobutamine hydrochloride compound according to the characteristics of the dobutamine hydrochloride compound according to the present invention.

[0017] Preferably, the dobutamine hydrochloride preparation is an injection.

[0018] Preferably, the specification of dobutamine hydrochloride injection is 0.25 g (calculated as dobutamine).

[0019] Preferably, the above-mentioned dobutamine hydrochloride injection is prepared by the following method:

[0020] The dobutamine hydrochloride compound is aseptically filled into a vial according to the specification, stoppered, and capped to obtain the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the X-ray powder diffraction pattern of the dobutamine hydrochloride compound prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0022] Study on the properties of dobutamine hydrochloride trihydrate

[0023] 1. Elemental analysis

[0024] The dobutamine hydrochloride trihydrate prepared by the method of the present invention was subjected to elemental analysis, and the results showed that the values ​​of C: 55.14%, H: 7.67%, and N: 3.60% (accurate to two decimal places), which were consistent with the theoretical values ​​of dobutamine hydrochloride trihydrate. The theoretical values ​​of dobutamine hydrochloride trihydrate were: C: 55.17%, H: 7.66%, and N: 3.58% (accurate to two decimal places).

[0025] 2. Differential thermal analysis

[0026] The dobutamine hydrochloride trihydrate prepared by the method of the present invention was subjected to differential thermal analysis and compared with dobutamine hydrochloride, the raw material for preparing dobutamine hydrochloride trihydrate. The results showed that dobutamine hydrochloride trihydrate had an absorption peak between 110 and 115°C, indicating that there was crystal water or crystallization solvent in the sample, while the reference substance had no absorption peak, indicating that there was no crystal water or crystallization solvent in the sample.

[0027] 3. Moisture analysis

[0028] The water content of the dobutamine hydrochloride trihydrate of the present invention was measured by Karl Fischer water determination method, and the result was between 13.74% and 13.81%, which was consistent with the theoretical water content of dobutamine hydrochloride trihydrate of 13.79%, and the two results were consistent, indicating that the sample contained only water and no other solvents.

[0029] Comprehensive elemental analysis, differential thermal analysis, and water analysis results can prove that the dobutamine hydrochloride of the present invention contains 3 molecules of crystal water.

[0030] 4. Experimental comparative analysis

[0031] Sample 1: the dobutamine hydrochloride compound prepared in Example 1 of the present invention;

[0032] Sample 2: dobutamine hydrochloride prepared according to Example 2 of Chinese application 201510216051.2;

[0033] Sample 3: dobutamine hydrochloride prepared according to Example 1 of Chinese application 202210381529.7;

[0034] Sample 4: dobutamine hydrochloride raw material marketed product;

[0035] 4.1 Characteristic Study:

[0036] Samples 1-4 were subjected to characteristic studies according to the test method of this application. The results are shown in Table 1

[0037] Table 1 Study results of dobutamine hydrochloride characteristics

[0038] sample characteristic Sample 1 Trihydrate Sample 2 No crystal water Sample 3 No crystal water Sample 4 No crystal water

[0039] 4.2 Stability and high humidity test:

[0040] Samples 1-4 were placed under high temperature (60°C), high humidity (RH92.5%±5%) and light (4500lx) conditions for 10 days. Samples were taken on the 10th day to examine the content and moisture content. The results were compared with those on day 0, see Table 2.

[0041] Table 2 Test results of factors affecting dobutamine hydrochloride trihydrate

[0042]

[0043] The test results in Table 2 show that dobutamine hydrochloride trihydrate has good stability and low hygroscopicity. The same test was also carried out in other embodiments of the present invention, and similar results were obtained.

[0044] 4.3 Solubility analysis

[0045] The solubility of samples 1-4 in water (25°C ± 2°C) is compared, and the results are shown in Table 3:

[0046] Table 3 Solubility comparison

[0047] sample Solubility (mg / ml) Sample 1 75.4 Sample 2 28.5 Sample 3 27.9 Sample 4 28.2

[0048] The test results in Table 3 show that the solubility of the dobutamine hydrochloride compound prepared by the present invention is significantly improved. The same test was also carried out in other embodiments of the present invention, and similar results were obtained.

[0049] Example

[0050] Example 1 Preparation of dobutamine hydrochloride compound

[0051] (1) Add water, isopropanol, ethyl acetate and dobutamine hydrochloride into a reaction pot in sequence, start stirring at a speed of 80 rpm, heat to 62° C., and maintain for 30 minutes; wherein the weight ratio of dobutamine hydrochloride, water, isopropanol and ethyl acetate is: dobutamine hydrochloride: water: isopropanol: ethyl acetate = 1:25:4:0.2;

[0052] (2) Cooling to 52° C., maintaining a stirring speed of 80 rpm, and slowly adding tetrahydrofuran while stirring; the weight ratio of tetrahydrofuran is: dobutamine hydrochloride: tetrahydrofuran = 1:1.5;

[0053] (3) filtering the material of step (2) into a crystallization kettle, cooling to 5° C., filtering to obtain a filter cake, and washing the filter cake twice with 2 times the weight of water;

[0054] (4) The filter cake obtained in step (3) is placed in a drying oven and dried at 65° C. for 4 hours. The filter cake is then crushed, passed through a 40-mesh sieve and flattened to a thickness not exceeding 5 mm. The filter cake is placed in a constant temperature and humidity chamber at 24° C. and 70% humidity for 32 hours. The filter cake is then taken out and dried under vacuum conditions. The drying starting temperature is 30° C. and the temperature is increased by 5° C. every hour to 60° C. The filter cake is dried at 60° C. to constant weight to obtain a dobutamine hydrochloride compound.

[0055] X-ray powder diffraction pattern is attached Figure 1The characteristic peaks in its spectrum are shown at 2θ 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°, with a content of 99.96%.

[0056] Example 2 Preparation of dobutamine hydrochloride compound

[0057] (1) Add water, isopropanol, ethyl acetate and dobutamine hydrochloride into a reaction pot in sequence, start stirring at a speed of 100 rpm, heat to 65° C., and maintain for 35 minutes; wherein the weight ratio of dobutamine hydrochloride, water, isopropanol and ethyl acetate is: dobutamine hydrochloride: water: isopropanol: ethyl acetate = 1:25:4:0.2;

[0058] (2) cooling to 57° C., maintaining a stirring speed of 100 rpm, and slowly adding tetrahydrofuran while stirring; the weight ratio of tetrahydrofuran is: dobutamine hydrochloride: tetrahydrofuran = 1:1.5;

[0059] (3) filtering the material of step (2) into a crystallization kettle, cooling to 7° C., filtering to obtain a filter cake, and washing the filter cake twice with 2 times the weight of water;

[0060] (4) The filter cake obtained in step (3) is placed in a drying oven and dried at 70° C. for 4 hours. The filter cake is then crushed, passed through a 60-mesh sieve and flattened to a thickness not exceeding 5 mm. The filter cake is placed in a constant temperature and humidity chamber at 28° C. and 75% humidity for 40 hours. The filter cake is then taken out and dried under vacuum conditions. The drying starting temperature is 30° C. and the temperature is increased by 5° C. every hour to 60° C. The filter cake is dried at 60° C. to constant weight to obtain a dobutamine hydrochloride compound.

[0061] The X-ray powder diffraction pattern is consistent with that of Example 1, and the content is 99.95%.

[0062] Example 3 Preparation of dobutamine hydrochloride compound

[0063] (1) Add water, isopropanol, ethyl acetate and dobutamine hydrochloride into a reaction pot in sequence, start stirring at a speed of 90 rpm, heat to 64° C. and maintain for 32 minutes; wherein the weight ratio of dobutamine hydrochloride, water, isopropanol and ethyl acetate is: dobutamine hydrochloride: water: isopropanol: ethyl acetate = 1:25:4:0.2;

[0064] (2) cooling to 54° C., maintaining a stirring speed of 90 rpm, and slowly adding tetrahydrofuran while stirring; the weight ratio of tetrahydrofuran is: dobutamine hydrochloride: tetrahydrofuran = 1:1.5;

[0065] (3) filtering the material of step (2) into a crystallization kettle, cooling to 6° C., filtering to obtain a filter cake, and washing the filter cake twice with 2 times the weight of water;

[0066] (4) The filter cake obtained in step (3) is placed in a drying oven and dried at 67° C. for 4 hours. The filter cake is then crushed, passed through a 50-mesh sieve and flattened to a thickness not exceeding 5 mm. The filter cake is placed in a constant temperature and humidity chamber at 26° C. and a humidity of 72% for 36 hours. The filter cake is then taken out and dried under vacuum conditions. The drying starting temperature is 30° C. and the temperature is increased by 5° C. every hour to 60° C. The filter cake is dried at 60° C. to constant weight to obtain a dobutamine hydrochloride compound.

[0067] The X-ray powder diffraction pattern is consistent with that of Example 1, and the content is 99.98%.

[0068] Example 4 Preparation of dobutamine hydrochloride injection (0.25 g)

[0069] prescription:

[0070] Dobutamine hydrochloride compound (calculated as dobutamine): 250 g;

[0071] Produced 1000 bottles

[0072] Process:

[0073] The dobutamine hydrochloride compound is aseptically filled into a vial according to the specification, stoppered, and capped to obtain the product.

[0074] Test Example 1:

[0075] The accelerated test was carried out on Examples 1-4 of the present invention in the following manner: the samples were placed in a stability test box (40°C ± 2°C, RH 75% ± 5%), and samples were taken at 1, 2, 3, and 6 months, respectively, and the results are shown in Table 4.

[0076] Table 4 Dobutamine hydrochloride accelerated test results

[0077]

[0078] It can be seen from the results in Table 4 that the dobutamine hydrochloride compound and dobutamine hydrochloride injection prepared by the present invention have good stability under accelerated conditions.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A dobutamine hydrochloride, characterized in that The dobutamine hydrochloride is: dobutamine hydrochloride trihydrate, whose molecular formula is C 18 H 23 NO3·HCl·3H2O, the dobutamine hydrochloride is crystalline, and is measured by X-ray powder diffraction. The characteristic peaks in its spectrum are 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° at 2θ±0.2°.

2. The method for preparing dobutamine hydrochloride according to claim 1, comprising the steps of: (1) adding water, isopropanol, ethyl acetate and dobutamine hydrochloride into a reaction pot in sequence, starting stirring at a speed of 80 to 100 rpm, heating to 62 to 65° C., and maintaining for 30 to 35 minutes; wherein the weight ratio of dobutamine hydrochloride, water, isopropanol and ethyl acetate is: dobutamine hydrochloride: water: isopropanol: ethyl acetate = 1:25:4:0.2; (2) cooling to 52-57° C., maintaining a stirring speed of 80-100 rpm, and slowly adding tetrahydrofuran while stirring; the weight ratio of tetrahydrofuran is: dobutamine hydrochloride: tetrahydrofuran = 1:1.5; (3) filtering the material of step (2) into a crystallization kettle, cooling to 5-7° C., filtering to obtain a filter cake, and washing the filter cake twice with 2 times the weight of water; (4) The filter cake obtained in step (3) is placed in a drying oven at 65-70° C., dried for 4 hours, then crushed, passed through a 40-60 mesh sieve, and flattened to a thickness not exceeding 5 mm. The filter cake is placed in a constant temperature and humidity chamber at 24-28° C. and a humidity of 70-75%. After 32-40 hours, the filter cake is taken out and dried under vacuum conditions. The drying starting temperature is 30° C., and the temperature is increased by 5° C. every hour to 60° C., and dried at 60° C. to constant weight to obtain a dobutamine hydrochloride compound.

3. Dobutamine hydrochloride injection, characterized in that: Contains the dobutamine hydrochloride according to claim 1.

4. The dobutamine hydrochloride injection according to claim 3, characterized in that: The specification of the dobutamine hydrochloride injection is 0.25g.

5. The method for preparing the dobutamine hydrochloride injection according to claim 4, comprising the steps of aseptically filling the dobutamine hydrochloride compound into a vial according to the specification, adding a stopper, and rolling the cap to obtain the vial.

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