CN115872948B - Crystal form B of ritodrine, and preparation method and application thereof - Google Patents
Crystal form B of ritodrine, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of compound crystal forms, in particular to a ritodrine crystal form B and a preparation method and application thereof. According to the technical scheme, N-dimethylformamide is used as a solvent, so that the ritodrine forms the crystal form B, and the preparation method has the advantages of being good in stability, high in water solubility and good in bioavailability.
Description
Technical Field
The invention belongs to the technical field of preparation of pharmaceutical chemical crystals, and particularly relates to a crystal form B of ritodrine, and a preparation method and application of the crystal form B.
Background
The lipocalin is a typical thiazole carboxylic acid type leukopenia-increasing medicament, has a chemical name of 2- (alpha-phenyl-alpha-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid, has a proliferation promoting effect on leucocytes, and is widely applied to treatment of leucopenia caused in the process of radiotherapy and chemotherapy for treating malignant tumors. The ritodrine is a cysteine derivative which is rapidly absorbed after administration, thereby enhancing the function of the hematopoietic system of the organism, and is currently used for preventing and treating leukopenia, aplastic anemia, thrombocytopenia and the like caused by various reasons.
The general method for preparing 4-carboxylic thiazolidine and its derivative is that L-cysteine hydrochloride and corresponding aldehyde are condensed under proper condition, concretely speaking, the method is that ethyl phenylacetate reacts with ethyl formate in the presence of sodium alkoxide to produce alpha-formylphenyl ethyl acetate, then the alpha-formylphenyl ethyl acetate is cyclized with L-cysteine hydrochloride, the product is separated out under room temperature condition, and the product is basically white crystalline powder which is soluble in alkali liquor, insoluble in water and ethanol after filtration, washing and recrystallization.
Patent application No. CN200410054101.3 discloses a preparation method and a purification method of a crystal prepared by condensing, acidifying and cyclizing ethyl phenylacetate, ethyl formate, diethyl ether and metallic sodium to obtain a raw material of the Likejun, wherein the pH is controlled to be about 7 in the cyclizing step, the reactant is heated and refluxed in the presence of water and ethanol, then cooled, crystallized and filtered, the crystal is washed by distilled water and ethanol successively, and then washed by a small amount of diethyl ether.
The synthesis process disclosed in the patent application with the application number of CN200610037819.0 is to condense and acidify ethyl phenylacetate and ethyl formate under the action of condensing agent to obtain formylphenyl ethyl acetate, and cyclize the formylphenyl ethyl acetate and cysteine to obtain the crude drug of the ritodrine, wherein the preparation and purification methods of the crude drug crystal are basically the same as the methods, and the solvents used for washing and crystallizing are different from each other and are diethyl ether, ethanol and water.
In the patent application with the application number of CN201110357853.7, it is disclosed that ethyl phenylacetate and ethyl formate are subjected to condensation reaction in the presence of a specific solvent and a condensing agent, the reaction liquid is acidified after extraction and purification, then the solid intermediate alpha-formylphenyl ethyl acetate with high purity is obtained by low Wen Xijing, the reaction is carried out with L-cysteine hydrochloride in the presence of water and acetone, and after the reaction is finished, the product is obtained by cooling, suction filtration, repeated washing with water and acetone and vacuum drying.
Furthermore, fu Lin et al report a method of washing the product with water and ethanol, respectively. Wang Yanxia et al report a process in which the product obtained by the reaction in the presence of water and ethanol is filtered, the filter cake is washed with water and petroleum ether, respectively, and dried to obtain white crystalline ritodrine, the melting point of the product is 158.1-158.7 ℃. Liu Jiang and Wang Yanyan report a method in which a reaction solution containing water and ethanol is heated to reflux and then cooled to 15 to 18 ℃, water is added and stirred for 6 hours to sufficiently precipitate a product, and then the product is filtered and washed with ethanol, water (pH 3.0) and ethanol. Zhao Ling, yang Bo report a method of preparing a reaction product using water and ethanol as solvents, cooling the reaction product to crystallize, washing the crystals with diethyl ether, ethanol and water, filtering, and drying to obtain a product.
Although the ritodrine has many advantages for the prevention and treatment of diseases of the blood system such as leukopenia, thrombocytopenia, aplastic anemia and the like caused by various reasons, the following problems are still faced in practical application:
1) The existing crystal form of the ritodrine has a special smell and has a certain influence on the medication compliance of patients;
2) The bulk density of the crystal form commonly used by the ritodrine is small, and the crystal form has a certain influence on the release of the medicine;
3) The ritodrine contains methyl ester impurities, which can affect the drug effect, and the content of the methyl ester impurities exceeds 0.1% and does not meet the drug requirement.
The above drawbacks limit their further clinical popularization and use. Therefore, how to simply and effectively improve the above properties is an extremely critical factor for the further development and application of the ritodrine. However, the conventional methods for improving the properties thereof generally require changing the structure or adding auxiliary agents, which not only has high cost but also has uncertain effects. Therefore, there is a need to solve the above problems in the drug development process for ritodrine.
Disclosure of Invention
The invention aims to solve the problems of methyl ester impurity, special odor and poor water solubility in the prior art, and the technical scheme of the invention prepares the crystal form B by taking N, N-dimethylformamide as a solvent, has the advantages of high water solubility value and high water dissolution rate, and is suitable for being applied to the production process of pharmaceutical preparations. The medicines with the same chemical structure can obtain different crystals due to different crystallization conditions, and the different crystals generally have different physicochemical properties, so that more selectivity is provided for formulation development.
In order to achieve the technical purpose, the invention provides the following technical scheme: form B of ritodrine having an X-ray powder diffraction pattern with diffraction peaks at least three of the following 2Θ angles: 8.025 ° ± 0.2, 11.115 ° ± 0.2, 20.310 ° ± 0.2, 22.282 ° ± 0.2, 28.546 ° ± 0.2, 33.667 ° ± 0.2, 35.671 ° ± 0.2.
Further, the X-ray powder diffraction pattern thereof has diffraction peaks at least at four of the following 2θ angles: 8.025 ° ± 0.2, 11.115 ° ± 0.2, 20.310 ° ± 0.2, 22.282 ° ± 0.2, 28.546 ° ± 0.2, 33.667 ° ± 0.2, 35.671 ° ± 0.2.
Further, the X-ray powder diffraction pattern thereof has diffraction peaks at least five of the following 2θ angles: 8.025℃0.2, 11.115 ℃0.2, 17.662 ℃0.2, 20.310 ℃0.2, 22.282 ℃0.2, 24.115 ℃0.2, 28.546 ℃0.2, 33.667 ℃0.2, 35.671 ℃0.2.
Further, the X-ray powder diffraction pattern thereof has diffraction peaks at least seven of the following 2θ angles: 8.025℃0.2, 11.115 ℃0.2, 17.662 ℃0.2, 20.310 ℃0.2, 22.282 ℃0.2, 24.115 ℃0.2, 28.546 ℃0.2, 33.667 ℃0.2, 35.671 ℃0.2.
Further, the melting point is 159-160 ℃.
The invention also provides a preparation method of the crystal form B of the ritodrine, which comprises the steps of dissolving the ritodrine in the presence of N, N-dimethylformamide, heating and stirring, cooling, precipitating solid, filtering, washing a filter cake, and drying to obtain the crystal form B.
Further, the temperature of the dissolution and stirring is higher than 70 ℃.
Still further, the temperature of the dissolution and agitation is 80-85 ℃.
Further, the temperature is reduced to 10-30 ℃.
Further, the drying is air drying at 60-80 ℃.
Still further, the drying is forced air drying at 70 ℃.
Further, the mass-volume ratio of the ritodrine bulk drug to the N, N-dimethylformamide is 1g to 2mL.
The invention also provides a pharmaceutical composition comprising an effective amount of the crystalline form B of ritodrine as described above.
Still further, pharmaceutically acceptable excipients are included.
The invention also provides application of the ritodrine crystal form B or the pharmaceutical composition in preparing medicines for preventing and treating blood system diseases.
Further, the blood system diseases are leukopenia, thrombocytopenia, aplastic anemia caused by various causes.
By adopting the technology, compared with the prior art, the invention has the remarkable advantages that:
1) According to the technical scheme, the crystal form B of the ritodrine is prepared by taking N, N-dimethylformamide as a solvent under a heating condition, and has the advantages of high water solubility value and high water dissolution rate, particularly, the solubility in water is improved to be more than 256 mug/ml, the impurity content is greatly reduced, the method is suitable for being applied to the production process of a pharmaceutical preparation, and the inconvenience in the preparation and storage process caused by the low water solubility of the ritodrine in the prior art is solved;
2) Compared with the conventional crystal form of the original drug of the ritodrine, the crystal form B of the present invention has better biological activity, and is more suitable for being applied in pharmaceutical preparations.
Drawings
Fig. 1 is an XRPD pattern of crystalline form B of the present invention.
Fig. 2 is an XRPD pattern of crystalline form a of the present invention.
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
XRPD assay
XRPD test using X' Pert from PANalytical corporation 3 Type X-ray diffractometer. Appropriate amounts of samples were plated uniformly on single crystal silicon sample trays and XRPD testing was performed using the following parameters:
TABLE 1 XRPD Experimental parameters
TGA and DSC measurement method
TGA and DCS spectra were collected on a TA Discovery TGA 5500 thermogravimetric analyzer and a TA Discovery DSC 2500 differential scanning calorimeter, respectively, with the following experimental parameters:
TABLE 2 TGA and DSC test parameters
| TGA | DSC | |
| Sample tray | Aluminium dish, uncap | Aluminum plate and gland |
| Temperature range/. Degree.C | RT-～190～205 | 25-～190 |
| Scan rate/. Degree.C/min | 10 | 10 |
| Protective gas | Nitrogen gas | Nitrogen gas |
Example 1
The preparation method of the ritodrine crystal form B of the embodiment is implemented according to the following steps:
weighing 25mLN, N-dimethylformamide as a raw material of 5g of the ritodrine, adding 10mL of dimethylformamide into a three-necked flask, magnetically stirring, and heating to 80-85 ℃ in an oil bath to obtain a basic solution. Removing the oil bath for heating, cooling to 25-30 ℃, and filtering the precipitated solid. The filter cakes were each slurried 2 times with 15mL tetrahydrofuran, rinsed 1 time, and air dried at 70 ℃. About 0.3g was obtained, and no methyl ester impurity was detected (less than 0.01%). The XRPD pattern is shown in fig. 1, and specific diffraction peak data is shown in table 3. Melting point: 159-160 ℃.
TABLE 3 XRPD diffraction peak data
Example 2
The preparation method of the ritodrine crystal form C of the embodiment is implemented according to the following steps:
2g of the ritodrine raw material medicine 25mL of ethanol is weighed and dissolved in a three-mouth bottle, placed in an ice-water bath for cooling, and stirred. When the internal temperature of the reaction flask is about 10 ℃, 25mL of purified water is measured and added into the reaction flask in a dropwise manner, and the temperature is controlled to be 10+/-2 ℃. And (5) after the dripping is finished, preserving heat, stirring for 15-20 minutes, and carrying out suction filtration. The filter cakes are respectively pulped and washed for 2 times by 20mL of ice purified water, leached for 1 time, and dried by blowing at 70 ℃ to obtain 0.5g of crystal form C powder of the Likejun, wherein the content of methyl ester impurities is 0.09 percent. Melting point: 157-158 ℃.
Example 3
TGA/DCS data for form B and C of Li Kejun are shown in the table below:
TABLE 4 TGA/DCS test results for Likejun Crystal form B and C
| Sample group | DSC endothermic peak (peak temperature, DEG C) | TGA weight loss (%) |
| Crystal form B | 162.4 | 0.46(150℃) |
| Crystal form C | 95.2，107.8 | 3.54(70℃) |
The above table shows that Li Kejun form B has better thermal stability than form C.
Example 4
The water saturation solubility test data for form B and C of Li Kejun are shown in the following table:
TABLE 5 results of Water saturation solubility test of Likejun Crystal form B and C
| Sample group | Solubility (μg/ml) for 1 hour | Solubility in 2 hours (μg/ml) | Solubility at 18 hours (μg/ml) |
| Crystal form B | 161.68 | 177.41 | 256.62 |
| Crystal form C | 112.64 | 133.16 | 227.89 |
The above table shows that the dissolution performance of form Li Kejun is better than that of form C.
Example 5
Balb/C mice, males and weight ranges of 22-24 g are selected, 100 mice are randomly selected and randomly divided into 5 groups, namely a normal control group, a model control group, a Li Kejun crystal form A group, a Li Kejun crystal form B group and a Li Kejun crystal form C group, and 20 mice are selected in each group. The ritodrine A, B and the group C are co-administered by gastric lavage for 28 days, 1 time a day, 30mg/kg each time; normal control and model control were given equal volumes of physiological saline. Cyclophosphamide was intraperitoneally injected with 25mg/kg of molding (model group, ritodrine group) at day 8-14. And the stomach is irrigated for 28 days. The number of white blood cells was measured by taking the retroorbital venous sinus blood before molding, after molding, and after the end of administration (i.e., 7 th, 15 th, and 29 th days after administration). Statistical treatment of experimental data was performed using the mean square errorThe SPSS17.0 software package is used for statistical processing to obtain P<0.05 is statistically significant. The results are shown in the following table.
TABLE 6 Effect of different crystalline forms of Likejun on mouse leukocyte count
Note that P < 0.05 compared to model control; compared with the group C of the Likejun, the delta P is less than O.05
The upper table showsThe number of peripheral blood leucocytes of mice in each model group is obviously reduced and is less than 4.0X10 9 and/L, indicating successful molding. After treatment, the Li Kejun crystal form A, B, C group can obviously increase the content of white blood cells, and has obvious difference (P) compared with the model control group<0.05 A) is provided; wherein the group A, B of the crystalline form of the ritodrine has better effect and has significant difference (P compared with the group C of the crystalline form of the ritodrine<0.05)。
The above embodiments are only preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the protection scope of the present invention should be defined by the claims, including the technical equivalents of the technical features in the claims, as the protection scope, that is, the equivalent replacement and improvement within the protection scope of the present invention.
Claims (8)
1. Form B of ritodrine, characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2Θ angles: 8.025 ° ± 0.2, 11.115 ° ± 0.2, 20.310 ° ± 0.2, 22.282 ° ± 0.2, 28.546 ° ± 0.2, 33.667 ° ± 0.2, 35.671 ° ± 0.2; the melting point is 159-160 ℃.
2. Form B according to claim 1, characterized in that its X-ray powder diffraction pattern has diffraction peaks in the following 2Θ angles: 8.025℃0.2, 11.115 ℃0.2, 17.662 ℃0.2, 20.310 ℃0.2, 22.282 ℃0.2, 24.115 ℃0.2, 28.546 ℃0.2, 33.667 ℃0.2, 35.671 ℃0.2.
3. A process for preparing crystalline form B of ritodrine as defined in claim 1, wherein the crystalline form B is obtained by dissolving the ritodrine in N, N-dimethylformamide solvent under stirring, cooling, precipitating solid, suction filtering, washing the filter cake, and drying.
4. A method of preparation according to claim 3, wherein the temperature of dissolution and agitation is above 70 ℃;
the temperature is reduced to 10-30 ℃;
the drying is air drying at 60-80deg.C.
5. A pharmaceutical composition comprising an effective amount of the crystalline form B of ritodrine as defined in any one of claims 1 or 2 or the crystalline form B of ritodrine as prepared in any one of claims 3 or 4.
6. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable adjuvant.
7. Use of the crystalline form B of ritodrine as defined in claim 1 or of the pharmaceutical composition as defined in any one of claims 5 or 6 for the preparation of a medicament for the prevention and treatment of a disease of the blood system.
8. The use according to claim 7, wherein the blood system diseases are leukopenia, thrombocytopenia, aplastic anemia caused by various causes.
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| CN202111654303.1A CN115872948B (en) | 2021-12-30 | 2021-12-30 | Crystal form B of ritodrine, and preparation method and application thereof |
| PCT/CN2022/125692 WO2023124408A1 (en) | 2021-12-30 | 2022-10-17 | Crystalline form of leucogen and method for preparation thereof and use thereof |
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| CN1629128A (en) * | 2004-08-30 | 2005-06-22 | 俞锋 | Method for preparing leucogen materials and leucogen tablets |
| CN1810791A (en) * | 2006-01-17 | 2006-08-02 | 张宏业 | Synthesis process of medicine for treating hemopathy |
| CN1872844A (en) * | 2006-03-31 | 2006-12-06 | 张宏业 | Method for synthesizing 2 (alpha - phenyl - alpha - methoxycarbonyl - methyl) thiazolidine - 4 - carboxylic acid and mensurating limitation |
| CN103102324A (en) * | 2011-11-14 | 2013-05-15 | 南京长澳医药科技有限公司 | Preparation method of leucongen |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1629128A (en) * | 2004-08-30 | 2005-06-22 | 俞锋 | Method for preparing leucogen materials and leucogen tablets |
| CN1810791A (en) * | 2006-01-17 | 2006-08-02 | 张宏业 | Synthesis process of medicine for treating hemopathy |
| CN1872844A (en) * | 2006-03-31 | 2006-12-06 | 张宏业 | Method for synthesizing 2 (alpha - phenyl - alpha - methoxycarbonyl - methyl) thiazolidine - 4 - carboxylic acid and mensurating limitation |
| CN103102324A (en) * | 2011-11-14 | 2013-05-15 | 南京长澳医药科技有限公司 | Preparation method of leucongen |
Non-Patent Citations (3)
| Title |
|---|
| 利可君合成工艺优化;赵玲;杨博;;武汉轻工大学学报(04);第104-107页 * |
| 利血生合成工艺的改进;傅霖;郑虎;;华西药学杂志(02);第176-177页 * |
| 利血生的合成;王艳霞;;漯河职业技术学院学报(02);第100-101页 * |
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