Dopamine hydrochloride c crystal form, and preparation method and application thereof

Abstract

The application provides a crystal form C of dopamine hydrochloride, a preparation method and application thereof, and relates to the technical field of medicine separation. The crystal form C of dopamine hydrochloride provided by the application has more regular morphology and better hygroscopic stability compared with the original crystal form A. The crystal form C of dopamine hydrochloride is prepared by using a method of solvent-out crystallization, and the preparation process is simple, the product has high yield and high purity, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical separation technology, specifically to a dopamine hydrochloride C crystal form, its preparation method, and its application. Background Technology

[0002] Dopamine hydrochloride (CAS number: 62-31-7), chemical formula C8H 12 ClNO2, with a relative molecular mass of 189.639, is chemically named 4-(2-aminoethyl)-1,2-benzenediol hydrochloride, and its structure is shown in Formula I. Commercially available, it is a white or off-white crystalline powder, readily soluble in water, soluble in methanol and 95% hot ethanol, and sparingly soluble in most organic solvents. The solid powder and aqueous solution gradually darken in color upon exposure to air and light.

[0003]

[0004] Dopamine hydrochloride is a common dopamine receptor agonist that acts on cardiomyocytes to increase heart rate and cardiac contractility. Dopamine hydrochloride is primarily used for shock syndromes caused by various factors, such as myocardial infarction, renal failure, and cardiac surgery. Dopamine hydrochloride can also increase cardiac output, and therefore can be used to treat heart failure in certain conditions.

[0005] Currently, only one crystal form, A, is known for dopamine hydrochloride. Polymorphism is a common phenomenon in drug molecules; different crystal forms exhibit different physicochemical properties, thus affecting the drug's efficacy. Commercially available solid dopamine hydrochloride currently suffers from irregular morphology and poor hygroscopic stability. Summary of the Invention

[0006] The purpose of this invention is to provide a dopamine hydrochloride C crystal form, its preparation method, and its application. The dopamine hydrochloride C crystal form provided by this invention has a more regular morphology and better hygroscopic stability compared with the original A crystal form.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0008] This invention provides a dopamine hydrochloride C crystal form, the X-ray powder diffraction pattern of which has diffraction angles 2θ of 10.410±0.2°, 12.780±0.2°, 14.690±0.2°, 15.520±0.2°, 15.970±0.2°, 16.450±0.2°, 16.790±0.2°, 17.970±0.2°, 19.520±0.2°, 20.240±0.2°, 21.150±0.2°, 21.720±0.2°, and 22.0°. Characteristic peaks are observed at 90±0.2°, 23.210±0.2°, 23.840±0.2°, 24.640±0.2°, 25.540±0.2°, 26.091±0.2°, 27.150±0.2°, 27.690±0.2°, 29.650±0.2°, 30.140±0.2°, 31.600±0.2°, 32.180±0.2°, 32.430±0.2°, and 34.050±0.2°; the melting point of the dopamine hydrochloride C crystal form is 140.833℃.

[0009] This invention provides a method for preparing the C crystal form of dopamine hydrochloride as described in the above technical solution, comprising the following steps:

[0010] Dopamine hydrochloride solid, propionate and solvent are mixed to obtain a mixed solution;

[0011] An antisolvent was added to the mixed solution to grow crystals and obtain dopamine hydrochloride C crystal form.

[0012] Preferably, the solvent includes at least one of water and methanol.

[0013] Preferably, when the solvent is methanol, the ratio of the solid dopamine hydrochloride to methanol is 10-20 mg:1 mL; when the solvent is water, the ratio of the solid dopamine hydrochloride to water is 30-40 mg:1 mL.

[0014] Preferably, the mass of the propionate is more than 30% of the mass of the solid dopamine hydrochloride.

[0015] Preferably, the antisolvent comprises acetonitrile.

[0016] Preferably, the feeding rate of the antisolvent is 2 to 5 mL / min.

[0017] Preferably, the crystal growth temperature is 25–40°C, and the crystal growth time is 0.5–1 hour.

[0018] Preferably, the crystal growth process further includes: performing solid-liquid separation on the obtained crystal growth system to obtain crystals; and drying the crystals to obtain dopamine hydrochloride C crystal form.

[0019] This invention provides the application of the dopamine hydrochloride C crystal form described in the above-described technical solution or the dopamine hydrochloride C crystal form prepared by the preparation method described in the above-described technical solution in the preparation of dopamine receptor agonist drugs.

[0020] This invention provides a dopamine hydrochloride C crystal form, which, compared to the original A crystal form, exhibits a more regular morphology and better hygroscopic stability. Example results show that, during storage at 25±5℃ and 40±5%RH for 30 days, the color and morphology of the dopamine hydrochloride C crystal form provided by this invention remained unchanged, and the purity remained essentially unchanged, indicating good chemical stability. Furthermore, its hygroscopic stability at 25℃ and 0–70%RH is significantly better than that of the original A crystal form.

[0021] This invention provides a method for preparing the dopamine hydrochloride C crystal form described in the above-mentioned technical solution. This invention uses a solution-crystallization method to prepare the dopamine hydrochloride C crystal form, which is simple in process, yields high product, has high purity, and is suitable for industrial production. Example results show that the yield of the dopamine hydrochloride C crystal form is above 81%, and the purity is 99.8%. Attached Figure Description

[0022] Figure 1 X-ray powder diffraction pattern of the C crystal form of dopamine hydrochloride prepared in Example 1;

[0023] Figure 2 The image shows the DSC-TG analysis of the C crystal form of dopamine hydrochloride prepared in Example 1.

[0024] Figure 3 The dvs curves of the C crystal form and the original A crystal form of dopamine hydrochloride prepared in Example 1 are shown.

[0025] Figure 4 Microscopic image of the dopamine hydrochloride C crystal form prepared in Example 1. Detailed Implementation

[0026] This invention provides a dopamine hydrochloride C crystal form, the X-ray powder diffraction pattern of which has diffraction angles 2θ of 10.410±0.2°, 12.780±0.2°, 14.690±0.2°, 15.520±0.2°, 15.970±0.2°, 16.450±0.2°, 16.790±0.2°, 17.970±0.2°, 19.520±0.2°, 20.240±0.2°, 21.150±0.2°, 21.720±0.2°, and 22.0°. Characteristic peaks are observed at 90±0.2°, 23.210±0.2°, 23.840±0.2°, 24.640±0.2°, 25.540±0.2°, 26.091±0.2°, 27.150±0.2°, 27.690±0.2°, 29.650±0.2°, 30.140±0.2°, 31.600±0.2°, 32.180±0.2°, 32.430±0.2°, and 34.050±0.2°; the melting point of the dopamine hydrochloride C crystal form is 140.833℃.

[0027] The dopamine hydrochloride C crystal form provided by this invention has a needle-like crystal structure and appears as a light yellow powder.

[0028] This invention provides a method for preparing the C crystal form of dopamine hydrochloride as described in the above technical solution, comprising the following steps:

[0029] Dopamine hydrochloride solid, propionate and solvent are mixed to obtain a mixed solution;

[0030] An antisolvent was added to the mixed solution to grow crystals and obtain dopamine hydrochloride C crystal form.

[0031] This invention involves mixing dopamine hydrochloride solid, propionate, and a solvent to obtain a mixed solution. The source of the dopamine hydrochloride solid is not particularly limited; any commercially available product well-known to those skilled in the art can be used. In a specific embodiment of this invention, the dopamine hydrochloride solid is preferably purchased from Hainan Lingkang Pharmaceutical Co., Ltd.

[0032] In this invention, the solvent preferably includes at least one of water and methanol, more preferably methanol. When the solvent is methanol, the ratio of the solid dopamine hydrochloride to methanol is preferably 10-20 mg:1 mL, more preferably 17-19 mg:1 mL, specifically preferably 17 mg:1 mL, 18 mg:1 mL, or 19 mg:1 mL; when the solvent is water, the ratio of the solid dopamine hydrochloride to water is preferably 30-40 mg:1 mL, more preferably 33-34 mg:1 mL, specifically preferably 33 mg:1 mL or 34 mg:1 mL.

[0033] In this invention, the propionate preferably comprises one or more of sodium propionate, potassium propionate, and calcium propionate. In this invention, the mass of the propionate is preferably 30% or more of the mass of dopamine hydrochloride solids, more preferably 34-51%. In this invention, the propionate serves to promote crystal transformation.

[0034] In this invention, the mixing of dopamine hydrochloride solid, propionate, and solvent preferably comprises: dissolving dopamine hydrochloride solid in a solvent, and then adding propionate. In this invention, the mixing temperature is preferably 25–40°C, more preferably 30–35°C.

[0035] After obtaining the mixed solution, the present invention adds an antisolvent to the mixed solution to perform crystal growth, thereby obtaining dopamine hydrochloride C crystal form. In the present invention, the antisolvent preferably includes acetonitrile, and more specifically, acetonitrile. In the present invention, when the solvent is methanol, the volume ratio of the antisolvent to the solvent is preferably 2-5:1, more preferably 3-4:1; when the solvent is water, the volume ratio of the antisolvent to the solvent is preferably 15-25:1, more preferably 18-20:1. In the present invention, the feeding rate of the antisolvent is preferably 2-5 mL / min, more preferably 3-4 mL / min.

[0036] In this invention, the crystal growth temperature is preferably 25-40°C, more preferably 30-35°C; and the crystal growth time is preferably 0.5-1h.

[0037] In this invention, the crystal growth process preferably further includes: performing solid-liquid separation on the obtained crystal growth system to obtain crystals; and drying the crystals to obtain dopamine hydrochloride C crystal form. In this invention, the solid-liquid separation is preferably filtration, more preferably vacuum filtration. In this invention, the drying temperature is preferably 40–50°C; the drying time is preferably 3–4 hours, more preferably 3–3.5 hours. In this invention, the drying conditions are preferably a vacuum or a nitrogen atmosphere, more preferably a nitrogen atmosphere.

[0038] This invention provides the application of the dopamine hydrochloride C crystal form described in the above-described technical solution or the dopamine hydrochloride C crystal form prepared by the preparation method described in the above-described technical solution in the preparation of dopamine receptor agonist drugs.

[0039] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0040] Example 1

[0041] 0.0683 g of solid dopamine hydrochloride was dissolved in 4.5 mL of methanol at 30 °C and stirred magnetically for 5 min at a constant temperature. 0.0345 g of sodium propionate was then added and stirred magnetically for another 5 min at a constant temperature. 20 mL of the antisolvent acetonitrile was added at a feeding rate of 2 mL / min, and the mixture was allowed to crystallize at 30 °C for 1 h. The resulting crystallization system was then vacuum filtered. The resulting crystals were dried in a nitrogen drying oven at 50 °C for 3 h to obtain dopamine hydrochloride C crystal form.

[0042] Figure 1 The image shows the X-ray powder diffraction pattern of the dopamine hydrochloride C crystal form prepared in Example 1. The dopamine hydrochloride C crystal form prepared in this example has diffraction angles of 2θ = 10.410 ± 0.2°, 12.780 ± 0.2°, 14.690 ± 0.2°, 15.520 ± 0.2°, 15.970 ± 0.2°, 16.450 ± 0.2°, 16.790 ± 0.2°, 17.970 ± 0.2°, 19.520 ± 0.2°, 20.240 ± 0.2°, 21.150 ± 0.2°, and 21. Characteristic peaks are observed at 0.720±0.2°, 22.090±0.2°, 23.210±0.2°, 23.840±0.2°, 24.640±0.2°, 25.540±0.2°, 26.091±0.2°, 27.150±0.2°, 27.690±0.2°, 29.650±0.2°, 30.140±0.2°, 31.600±0.2°, 32.180±0.2°, 32.430±0.2°, and 34.050±0.2°. DSC-TG results indicate a melting temperature of 140.833℃.

[0043] The dopamine hydrochloride C crystal form prepared in this embodiment appears as a light yellow needle-like crystalline powder with a product purity of 99.8% and a process yield of 86%.

[0044] Example 2

[0045] 0.0846 g of solid dopamine hydrochloride was dissolved in 7.6 mL of methanol at 25 °C and stirred magnetically for 5 min at a constant temperature. 0.0427 g of sodium propionate was then added and stirred magnetically for another 5 min at a constant temperature. 30 mL of the antisolvent acetonitrile was added at a feeding rate of 5 mL / min, and crystallization was carried out at 30 °C for 1 h. The resulting crystallization system was then vacuum filtered. The resulting crystals were dried in a nitrogen drying oven at 50 °C for 3.5 h to obtain dopamine hydrochloride C crystal form.

[0046] The X-ray powder diffraction patterns of the dopamine hydrochloride C crystal form prepared in this embodiment are as follows: diffraction angles 2θ = 10.410 ± 0.2°, 12.780 ± 0.2°, 14.690 ± 0.2°, 15.520 ± 0.2°, 15.970 ± 0.2°, 16.450 ± 0.2°, 16.790 ± 0.2°, 17.970 ± 0.2°, 19.520 ± 0.2°, 20.240 ± 0.2°, 21.150 ± 0.2°, and 21.720 ± 0.2°. Characteristic peaks were observed at 22.090±0.2°, 23.210±0.2°, 23.840±0.2°, 24.640±0.2°, 25.540±0.2°, 26.091±0.2°, 27.150±0.2°, 27.690±0.2°, 29.650±0.2°, 30.140±0.2°, 31.600±0.2°, 32.180±0.2°, 32.430±0.2°, and 34.050±0.2°. DSC-TG results showed a melting temperature of 140.833℃.

[0047] The dopamine hydrochloride C crystal form prepared in this embodiment appears as a light yellow needle-like crystalline powder with a product purity of 99.8% and a process yield of 83%.

[0048] Example 3

[0049] 0.0402 g of solid dopamine hydrochloride was dissolved in 4.0 mL of methanol at 40 °C and stirred magnetically for 5 min at a constant temperature. 0.0163 g of sodium propionate was then added and stirred magnetically for another 5 min at a constant temperature. 20 mL of the antisolvent acetonitrile was added at a feeding rate of 2 mL / min, and the mixture was then grown into crystals at 35 °C for 1 h. The resulting crystal growth system was then vacuum filtered. The resulting crystals were dried in a nitrogen drying oven at 50 °C for 3 h to obtain the C crystal form of dopamine hydrochloride.

[0050] The X-ray powder diffraction patterns of the dopamine hydrochloride C crystal form prepared in this embodiment are as follows: diffraction angles 2θ = 10.410 ± 0.2°, 12.780 ± 0.2°, 14.690 ± 0.2°, 15.520 ± 0.2°, 15.970 ± 0.2°, 16.450 ± 0.2°, 16.790 ± 0.2°, 17.970 ± 0.2°, 19.520 ± 0.2°, 20.240 ± 0.2°, 21.150 ± 0.2°, and 21.720 ± 0.2°. Characteristic peaks were observed at 22.090±0.2°, 23.210±0.2°, 23.840±0.2°, 24.640±0.2°, 25.540±0.2°, 26.091±0.2°, 27.150±0.2°, 27.690±0.2°, 29.650±0.2°, 30.140±0.2°, 31.600±0.2°, 32.180±0.2°, 32.430±0.2°, and 34.050±0.2°. DSC-TG results showed a melting temperature of 140.833℃.

[0051] The dopamine hydrochloride C crystal form prepared in this embodiment appears as a light yellow needle-like crystalline powder with a product purity of 99.8% and a process yield of 82%.

[0052] Example 4

[0053] 0.0531 g of solid dopamine hydrochloride was dissolved in 4.66 mL of methanol at 30 °C and stirred magnetically for 5 min at a constant temperature. Then, 0.0167 g of sodium propionate was added and stirred magnetically for another 5 min at a constant temperature. 20 mL of the antisolvent acetonitrile was added at a feeding rate of 3 mL / min, and the mixture was then kept at 30 °C for 1 h to grow crystals. The resulting crystal growth system was then vacuum filtered. The crystals were dried in a nitrogen drying oven at 50 °C for 3 h to obtain the C crystal form of dopamine hydrochloride.

[0054] The X-ray powder diffraction patterns of the dopamine hydrochloride C crystal form prepared in this embodiment are as follows: diffraction angles 2θ = 10.410 ± 0.2°, 12.780 ± 0.2°, 14.690 ± 0.2°, 15.520 ± 0.2°, 15.970 ± 0.2°, 16.450 ± 0.2°, 16.790 ± 0.2°, 17.970 ± 0.2°, 19.520 ± 0.2°, 20.240 ± 0.2°, 21.150 ± 0.2°, and 21.720 ± 0.2°. Characteristic peaks were observed at 22.090±0.2°, 23.210±0.2°, 23.840±0.2°, 24.640±0.2°, 25.540±0.2°, 26.091±0.2°, 27.150±0.2°, 27.690±0.2°, 29.650±0.2°, 30.140±0.2°, 31.600±0.2°, 32.180±0.2°, 32.430±0.2°, and 34.050±0.2°. DSC-TG results showed a melting temperature of 140.833℃.

[0055] The dopamine hydrochloride C crystal form prepared in this embodiment appears as a light yellow needle-like crystalline powder with a product purity of 99.8% and a process yield of 81%.

[0056] Example 5

[0057] 0.0331 g of solid dopamine hydrochloride was dissolved in 1.01 mL of water at 25 °C and stirred magnetically for 5 min at a constant temperature. 0.0167 g of sodium propionate was added and stirred magnetically for another 5 min at a constant temperature. 20 mL of the antisolvent acetonitrile was added at a feeding rate of 3 mL / min, and crystallization was carried out at 30 °C for 1 h. The resulting crystallization system was vacuum filtered. The obtained crystals were dried in a nitrogen drying oven at 50 °C for 3.5 h to obtain dopamine hydrochloride C crystal form.

[0058] The X-ray powder diffraction patterns of the dopamine hydrochloride C crystal form prepared in this embodiment are as follows: diffraction angles 2θ = 10.410 ± 0.2°, 12.780 ± 0.2°, 14.690 ± 0.2°, 15.520 ± 0.2°, 15.970 ± 0.2°, 16.450 ± 0.2°, 16.790 ± 0.2°, 17.970 ± 0.2°, 19.520 ± 0.2°, 20.240 ± 0.2°, 21.150 ± 0.2°, 21.720 ± 0.2°, and 22.090 ± 0.2°. The characteristic peaks are located at 23.210±0.2°, 23.840±0.2°, 24.640±0.2°, 25.540±0.2°, 26.091±0.2°, 27.150±0.2°, 27.690±0.2°, 29.650±0.2°, 30.140±0.2°, 31.600±0.2°, 32.180±0.2°, 32.430±0.2°, and 34.050±0.2°. The DSC-TG results show that its melting temperature is 140.833℃.

[0059] The dopamine hydrochloride C crystal form prepared in this embodiment appears as a light yellow needle-like crystalline powder with a product purity of 99.8% and a process yield of 83%.

[0060] Test case

[0061] The chemical properties of the dopamine hydrochloride C crystals prepared in Examples 1-5 were tested.

[0062] (1) The chemical stability of the dopamine hydrochloride C crystal form prepared in this invention was tested. During storage at 25℃±5℃ and 40±5%RH for 30 days, the color and morphology of the product did not change, and the purity remained basically unchanged, indicating that the crystal form has good chemical stability. The test results are shown in Table 1.

[0063] Table 1 Chemical stability of dopamine hydrochloride C crystal form

[0064]

[0065]

[0066] (2) The dopamine hydrochloride C crystal form prepared in Example 1 of this invention was subjected to DSC-TG analysis. The specific method of DSC-TG analysis is a conventional method in the prior art. The dopamine hydrochloride C crystal form prepared in Example 1 was detected, and the DSC-TG analysis chromatogram of the dopamine hydrochloride C crystal form is shown below. Figure 2 As shown in the figure, the DSC-TG results show that its melting temperature is 140.833℃. The information in the figure confirms that the dopamine hydrochloride C crystal form prepared in the example has a stable form.

[0067] (3) The original A crystal form of dopamine hydrochloride (purchased from Hainan Lingkang Pharmaceutical Co., Ltd.) Figure 3 A) and the dopamine hydrochloride C crystal form prepared in Example 1 ( Figure 3 C) The hygroscopicity of different crystal forms was tested at 25℃ and 0-70% RH, and the results are as follows: Figure 3 As shown, the original A crystal form begins to increase rapidly at 25% RH, while the new crystal form C prepared by this invention does not begin to increase rapidly until 70% RH. This shows that the hygroscopic stability of the dopamine hydrochloride C crystal form prepared by this invention is much better than that of the original A crystal form.

[0068] (4) Figure 4 Microscopic image of the dopamine hydrochloride C crystal form prepared in Example 1. Figure 4 It can be seen that the crystal form of dopamine hydrochloride C is needle-shaped crystal, indicating that the crystal form of dopamine hydrochloride C prepared by this invention has a regular morphology.

[0069] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a crystalline form C of dopamine hydrochloride, wherein the crystalline form C of dopamine hydrochloride has an X-ray powder diffraction pattern characterized by peaks at diffraction angles 2θ of 10.410±0.2°, 12.780±0.2°, 14.690±0.2°, 15.520±0.2°, 15.970±0.2°, 16.450±0.2°, 16.790±0.2°, 17.970±0.2°, 19.520±0.2°, 20.240±0.2°, 21.150±0.2°, 21.720±0.2°, 22.090±0.2°, 23.210±0.2°, 23.840±0.2°, 24.640±0.2°, 25.540±0.2°, 26.091±0.2°, 27.150±0.2°, 27.690±0.2°, 29.650±0.2°, 30.140±0.2°, 31.600±0.2°, 32.180±0.2°, 32.430±0.2°, and 34.050±0.2°; and the crystalline form C of dopamine hydrochloride has a melting point of 140.833℃. The method for preparing the crystalline form C of dopamine hydrochloride comprises the following steps: mixing a solid of dopamine hydrochloride, a propionate salt, and a solvent to obtain a mixed solution; adding an anti-solvent to the mixed solution to perform crystallization to obtain the crystalline form C of dopamine hydrochloride. The solvent comprises at least one of water and methanol; and the anti-solvent comprises acetonitrile. When the solvent is methanol, the ratio by amount of the solid of dopamine hydrochloride to methanol is 10-20 mg:1 mL; and when the solvent is water, the ratio by amount of the solid of dopamine hydrochloride to water is 30-40 mg:1 mL. When the solvent is methanol, the volume ratio of the anti-solvent to the solvent is 2-5:1; and when the solvent is water, the volume ratio of the anti-solvent to the solvent is 15-25:

1. The mass of the propionate salt is 34%-51% of the mass of the solid of dopamine hydrochloride. The temperature of the crystallization is 25-40℃, and the time of the crystallization is 0.5-1 h.

2. The production method according to claim 1, characterized by, The feeding rate of the anti-solvent is 2-5 mL / min.

3. The method of claim 1, wherein, The method further comprises, after the crystallization, performing solid-liquid separation on the obtained crystallization system to obtain crystals, and drying the crystals to obtain the crystalline form C of dopamine hydrochloride. 4.The crystalline form C of dopamine hydrochloride prepared by the method of claim 1 is used for preparing a dopamine receptor agonist drug.

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