CN113121507A - Stable crystal form of tandospirone citrate and preparation method thereof - Google Patents
Stable crystal form of tandospirone citrate and preparation method thereof Download PDFInfo
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- CN113121507A CN113121507A CN201911393018.1A CN201911393018A CN113121507A CN 113121507 A CN113121507 A CN 113121507A CN 201911393018 A CN201911393018 A CN 201911393018A CN 113121507 A CN113121507 A CN 113121507A
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Abstract
The invention discloses a stable crystal form of tandospirone citrate and a preparation method thereof. The preparation method adopts a one-step salt formation method, avoids recrystallization operation in the existing preparation method, simplifies the preparation process and reduces the cost. The prepared tandospirone citrate has the characteristics of single crystal form, good crystal form stability and stable quality.
Description
Technical Field
The invention relates to the technical field of crystal forms of tandospirone citrate, and particularly relates to a stable crystal form of tandospirone citrate and a preparation method thereof.
Background
Tandospirone was first developed by sumitomo pharmaceutical corporation of japan and was approved for marketing in japan in 1996. Tandospirone belongs to azaspirone (azapirone) drugs, is a 3 rd generation anxiolytic drug, acts on 5-HT receptors, selectively binds with 5-HT1A receptors in brain, and has main action parts concentrated in the cerebral marginal systems of hippocampus, amygdala and the like of emotional center and the midriff of 5-HT-nervously projecting nerves. The medicine can inhibit 5-HT effect of action inhibition system by stimulating 5-HT1A autoreceptor, regulating 5-HT projected from suture nucleus to hippocampus, and playing anxiolytic role, and has the following structural formula:
benzodiazepine (BDZ) drugs mainly act on BDZ receptors and have the functions of muscle relaxation, sedation, hypnosis and influence on psychomotor functions. Compared with BDZ medicines, the tandospirone has the advantages that the combination parts of the tandospirone are relatively concentrated, the tandospirone can play an anxiolytic effect with higher selectivity, and basically has no sedation, no sleep induction, no anti-tic effect, no muscle relaxation effect and no dependence effect, thereby reducing the common adverse reactions of the BDZ medicines. The tandospirone citrate is mainly used for treating the anxiety symptoms of patients with generalized anxiety disorder, such as hypertension patients with anxiety, irritable bowel syndrome patients with anxiety and Chronic Obstructive Pulmonary Disease (COPD) patients in clinic, and has good market prospect.
At present, the crystal form of tandospirone citrate is not reported abroad. Domestic patent is as follows: CN 102344442A, CN 103641817A, CN 103641818A, CN 105985327A and the like perform related researches on the crystal forms. Although the above patents disclose various crystal forms of tandospirone citrate, the crystal forms are mixed crystal forms and the preparation method has the disadvantages of complex operation, high cost, environmental unfriendliness and the like.
Disclosure of Invention
In view of the above, the invention provides a novel crystal form of tandospirone citrate and a preparation method of the crystal form.
In order to achieve the purpose, the invention adopts the technical scheme that: a stable crystal form of tandospirone citrate, wherein the crystal form has an X-ray powder diffraction pattern with a 2 theta diffraction angle: characteristic diffraction peaks are at 12.3 +/-0.2 degrees, 16.5 +/-0.2 degrees, 20.2 +/-0.2 degrees and 21.0 +/-0.2 degrees.
Further, in the X-ray powder diffraction pattern of the crystal form, the 2 theta diffraction angle is also as follows: 13.6 +/-0.2 degrees, 14.8 +/-0.2 degrees, 15.3 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.6 +/-0.2 degrees, 22.6 +/-0.2 degrees, 24.7 +/-0.2 degrees, 27.7 +/-0.2 degrees, 29.2 +/-0.2 degrees and 32.2 +/-0.2 degrees.
In a further preferred embodiment of the present invention, the crystalline form of tandospirone citrate, using Cu-ka radiation, has an X-ray powder diffraction pattern substantially as shown in figure 1.
In a further preferred embodiment of the present invention, the crystalline form has a DSC profile substantially as shown in figure 2.
The invention also provides a preparation method of the stable crystal form of tandospirone citrate, which comprises the following steps: adding tandospirone free alkali and citric acid into a solvent, wherein the molar ratio of the tandospirone free alkali to the citric acid is 1: 1.0-1: 3.0; stirring at 0-80 ℃ until solid is precipitated. Can be directly separated out solid or separated out solid after cooling.
In the above preparation scheme, the preferred molar ratio is tandospirone free base: 1 part of citric acid: 1.0-1: 1.5.
in the above preparation scheme, the solvent is selected from one or a combination of more of protic solvent or aprotic polar solvent.
Further, the protic solvent is selected from one or a combination of water, methanol, ethanol and isopropanol; the aprotic polar solvent is selected from one or a combination of acetone, acetonitrile and ethyl acetate.
In the above preparation scheme, the preferred solvents are: water, methanol, ethanol, isopropanol, and acetone.
In the above preparation scheme, the method further comprises the following steps: separating the solid from the suspension; drying the separated solid to obtain tandospirone citrate, wherein the drying temperature is 60-150 ℃; the drying time is 3-24 hours.
In particular, the preferred molar ratio is tandospirone free base: 1 part of citric acid: 1.2; the solvent is water, methanol or ethanol, the volume of the solvent is 5-20 times of the weight of tandospirone free alkali, and the unit is ml/g.
In the preparation scheme, the citric acid is citric acid anhydrous compound or citric acid monohydrate.
The tandospirone citrate disclosed by the invention has the characteristics of single crystal form, good crystal form stability and stable quality. The preparation method adopts a one-step salt formation method, avoids recrystallization operation in the existing preparation method, simplifies the preparation process and reduces the cost. The method has the advantages of single organic solvent, recycling of the solvent and avoidance of the defect that the mixed solvent used in the existing method is not easy to recycle. In addition, the invention also develops and uses water as a solvent, thereby achieving the purposes of economy and environmental protection. The purity of the tandospirone citrate prepared by the method can reach more than 99.8 percent.
The tandospirone citrate prepared by the invention has the advantages of convenient long-term storage and good medicinal safety in preparation of corresponding medicaments due to the characteristics of single crystal form and good crystal form stability.
Drawings
FIG. 1 is an XRPD pattern for tandospirone citrate prepared in example 1;
FIG. 2 is a DSC chart of tandospirone citrate prepared in example 1;
FIG. 3 is an XRPD pattern for tandospirone citrate prepared in example 3;
FIG. 4 is an XRPD pattern for tandospirone citrate prepared in example 5;
FIG. 5 is the XRPD pattern of tandospirone citrate for high humidity test of example 10;
FIG. 6 is the XRPD pattern of tandospirone citrate for 6 months of the accelerated test in example 10;
Detailed Description
The structural characterization of the stable crystal form of tandospirone citrate uses X-ray powder diffraction and differential scanning calorimetry. The purity of the compound was checked using Waters hplc.
X-ray powder diffraction was collected on a PANalytical X' Pert 3X-ray powder diffraction analyzer using high resolution transmission mode XRPD patterns with the following XRPD test parameters: x-ray K alpha 1
1.540598, respectively; the scanning range (2 TH) is 3-40 DEG; scanning step size (° 2TH) 0.0131; each step scans for time(s) 97.767.
The differential scanning calorimetry uses T-A differential thermal calorimetry and DSC2000, and the operation method comprises the following steps: a t-zero bottle is used, the heating range is 30-350 ℃, the heating speed is 5 ℃ per minute, and the nitrogen flow rate is 80 ml/min.
The technical scheme of the invention is further explained by combining the specific examples as follows:
example 1 preparation of stable crystalline form of tandospirone citrate
Weighing 100.0g of tandospirone free alkali and 50.1g of citric acid, adding 1500ml of methanol, stirring and heating to reflux, slowly cooling to 0-20 ℃, keeping the temperature and stirring for 2 hours, filtering, and washing a filter cake with methanol to obtain the tandospirone citrate wet product. Drying the wet product at 65 deg.C for 15 hr to obtain tandospirone citrate with yield of 88.1% and purity of 99.89%, XRPD shown in figure 1, and DSC shown in figure 2.
Example 2 preparation of stable crystalline form of tandospirone citrate
Weighing 100.0g of tandospirone free alkali and 60.1g of citric acid, adding 1500ml of methanol, stirring at room temperature until solid is separated out, stirring for 2 hours, filtering, and washing a filter cake with methanol to obtain the tandospirone citrate wet product. Drying the wet product at 65 ℃ for 15 hours to obtain the tandospirone citrate with the yield of 91.4 percent and the purity of 99.82 percent.
Example 3 preparation of stable crystalline form of tandospirone citrate
Weighing 100.0g of tandospirone free alkali and 60.1g of citric acid, adding 1500ml of ethanol, stirring and heating to reflux, slowly cooling to 0-20 ℃, keeping the temperature and stirring for 2 hours, filtering, and washing a filter cake with ethanol to obtain the tandospirone citrate wet product. Drying the wet product at 80 deg.C for 10 hr to obtain tandospirone citrate with yield of 95.8% and purity of 99.87%, and XRPD is shown in figure 3.
Example 4 preparation of stable crystalline form of tandospirone citrate
Weighing 100.0g of tandospirone free alkali and 75.1g of citric acid, adding 500ml of purified water, stirring and heating to 60-80 ℃, cooling to 0-20 ℃, keeping the temperature and stirring for 2 hours, filtering, and washing a filter cake with water to obtain the tandospirone citrate wet product. Drying the wet product at 90 ℃ for 12 hours to obtain the tandospirone citrate with the yield of 92.3 percent and the purity of 99.82 percent.
Example 5 preparation of stable crystalline form of tandospirone citrate
Weighing 100.0g of tandospirone free alkali and 75.1g of citric acid, adding 500ml of purified water, stirring at room temperature until solid is separated out, stirring for 2 hours, filtering, and washing a filter cake with water to obtain the tandospirone citrate wet product. Drying the wet product at 90 deg.C for 12 hr to obtain tandospirone citrate with yield of 90.6% and purity of 99.86%, and XRPD is shown in figure 4.
Example 6 preparation of stable crystalline form of tandospirone citrate
Weighing 100.0g of tandospirone free alkali and 100.2g of citric acid, adding 2000ml of acetone, stirring and heating to reflux, cooling to 0-20 ℃, keeping the temperature and stirring for 2 hours, filtering, and washing a filter cake with acetone to obtain the tandospirone citrate wet product. And drying the wet product at 65 ℃ for 15 hours to obtain the tandospirone citrate with the yield of 96.2 percent and the purity of 99.84 percent.
Example 7 preparation of stable crystalline form of tandospirone citrate
Weighing 100.0g of tandospirone free alkali and 60.1g of citric acid, adding 2000ml of acetonitrile, stirring and heating to reflux, cooling to 0-20 ℃, keeping the temperature and stirring for 2 hours, filtering, and washing a filter cake with acetonitrile to obtain the tandospirone citrate wet product. And drying the wet product at 75 ℃ for 12 hours to obtain the tandospirone citrate with the yield of 93.0 percent and the purity of 99.81 percent.
Example 8 preparation of stable crystalline form of tandospirone citrate
Weighing 100.0g of tandospirone free alkali and 65.1g of citric acid, adding 1500ml of isopropanol, stirring at room temperature until solid is separated out, stirring for 2 hours, filtering, and washing a filter cake with the isopropanol to obtain the tandospirone citrate wet product. Drying the wet product at 85 ℃ for 8 hours to obtain the tandospirone citrate with the yield of 94.8 percent and the purity of 99.83 percent.
Example 9 preparation of stable crystalline form of tandospirone citrate
Weighing 100.0g of tandospirone free alkali and 75.1g of citric acid, adding 1500ml of ethyl acetate, stirring at room temperature until solid is separated out, stirring for 2 hours, filtering, and washing a filter cake with ethyl acetate to obtain the tandospirone citrate wet product. Drying the wet product at 80 ℃ for 10 hours to obtain the tandospirone citrate with the yield of 95.5 percent and the purity of 99.84 percent.
Example 10 evaluation of Crystal form stability of Tandospirone citrate
The prepared tandospirone citrate crystal is used for carrying out influence factor tests and accelerated stability tests, and the test method is shown in the second appendix XIXC of Chinese pharmacopoeia (2015) of the stability test guidance principle of bulk drugs and pharmaceutical preparations.
(I) influence factor test:
1. high-temperature test: tandospirone citrate prepared in the above example is placed at 60 ℃ for 10 days, samples are taken on the 5 th day and the 10 th day, each index is measured and compared with the 0 th day, and the test results are shown in Table 1.
2. High humidity test: tandospirone citrate prepared in the above example is placed under humidity of 75% for 10 days, samples are taken on the 5 th day and the 10 th day, each index is measured and compared with the 0 th day, and the test results are shown in Table 1.
3. Strong light irradiation test: tandospirone citrate prepared in the above example is placed under the condition of illumination intensity of (4500 +/-500) Lux for 10 days, samples are taken on the 5 th day and the 10 th day, each index is measured and compared with the 0 th day, and the test result is shown in Table 1. The selected partial XRPD patterns are shown in figure 5.
TABLE 1 Tandospirone citrate influencing factor test
(II) accelerated stability test:
the tandospirone citrate prepared in the above examples was subjected to an accelerated stability test in a constant temperature and humidity chamber for 6 months. Test conditions were wet: samples were taken at 40 ℃/75% Relative Humidity (RH) at 0, 1, 2, 3, 6 months respectively for purity, related substances and XRPD assay, and the results are shown in table 2. The selected partial XRPD patterns are shown in figure 6.
TABLE 2 accelerated stability test of tandospirone citrate
According to the influence factor test and the accelerated test, the impurities of the tandospirone citrate prepared by the invention are not obviously increased under the conditions of high temperature, high humidity and illumination, the purity is not obviously changed, and the crystal form is not transformed; accelerated stability tests prove that the product has good quality stability.
In conclusion, the tandospirone citrate crystal form disclosed by the invention has high and stable purity and good quality stability, is favorable for transportation, storage and development and use of pharmaceutical preparations, and improves the medicinal safety of products. The preparation method of the tandospirone citrate crystal form disclosed by the invention has the advantages of simplicity in operation, economy, environmental friendliness, low cost, suitability for industrial production and the like.
The tandospirone citrate crystal form prepared by the invention can be used for developing tandospirone citrate solid preparations, including tandospirone citrate related medicines.
It should be understood that the above-mentioned embodiments are only preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, and any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A stable crystal form of tandospirone citrate is characterized in that: in the X-ray powder diffraction pattern of the crystal form, the 2 theta diffraction angle is as follows: characteristic diffraction peaks are at 12.3 +/-0.2 degrees, 16.5 +/-0.2 degrees, 20.2 +/-0.2 degrees and 21.0 +/-0.2 degrees.
2. The stable crystalline form of tandospirone citrate according to claim 1, characterized in that: the X-ray powder diffraction pattern and the 2 theta diffraction angle of the crystal form are as follows: 13.6 +/-0.2 degrees, 14.8 +/-0.2 degrees, 15.3 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.6 +/-0.2 degrees, 22.6 +/-0.2 degrees, 24.7 +/-0.2 degrees, 27.7 +/-0.2 degrees, 29.2 +/-0.2 degrees and 32.2 +/-0.2 degrees.
3. The stable crystalline form of tandospirone citrate according to claim 1 or 2, characterized in that: the crystal form has an X-ray powder diffraction pattern shown in figure 1.
4. The stable crystalline form of tandospirone citrate according to claim 1 or 2, characterized in that: the preparation method comprises the following steps: adding tandospirone free alkali and citric acid into a solvent, wherein the molar ratio of the tandospirone free alkali to the citric acid is 1: 1.0-1: 3.0; stirring at 0-80 ℃ until solid is precipitated.
5. The process for preparing the stable crystal form of tandospirone citrate of any one of claims 1 to 4, characterized by comprising the following steps: adding tandospirone free alkali and citric acid into a solvent, wherein the molar ratio of the tandospirone free alkali to the citric acid is 1: 1.0-1: 3.0; stirring at 0-80 ℃ until solid is precipitated.
6. The preparation method of the stable crystal form of tandospirone citrate according to claim 5, characterized in that: the solvent is selected from one or a combination of more of a protic solvent and an aprotic polar solvent.
7. The preparation method of the stable crystal form of tandospirone citrate of claim 6, characterized in that: the protic solvent is selected from one or a combination of more of water, methanol, ethanol and isopropanol; the aprotic polar solvent is selected from one or a combination of acetone, acetonitrile and ethyl acetate.
8. The preparation method of the stable crystal form of tandospirone citrate according to claim 5, characterized in that: the molar ratio of tandospirone free alkali to citric acid is 1: 1.0-1: 1.5.
9. the process for preparing the stable crystalline form of tandospirone citrate according to any one of claims 5-8, characterized in that: the molar ratio of tandospirone free alkali to citric acid is 1: 1.2.
10. the method for preparing the stable crystal form of tandospirone citrate of claim 9, characterized in that: also comprises the following steps: separating the solid from the suspension; drying the separated solid to obtain tandospirone citrate, wherein the drying temperature is 60-150 ℃; the drying time is 3-24 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101880274A (en) * | 2010-06-28 | 2010-11-10 | 北大国际医院集团西南合成制药股份有限公司 | Method for preparing tandospirone and analogues of tandospirone |
| CN102344442A (en) * | 2011-08-04 | 2012-02-08 | 成都科瑞德医药投资有限责任公司 | Novel crystal form of tandospirone citrate and preparation method and application thereof |
| CN105985327A (en) * | 2014-12-17 | 2016-10-05 | 四川科瑞德制药股份有限公司 | Tandospirone citrate compound |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101880274A (en) * | 2010-06-28 | 2010-11-10 | 北大国际医院集团西南合成制药股份有限公司 | Method for preparing tandospirone and analogues of tandospirone |
| CN102344442A (en) * | 2011-08-04 | 2012-02-08 | 成都科瑞德医药投资有限责任公司 | Novel crystal form of tandospirone citrate and preparation method and application thereof |
| CN105985327A (en) * | 2014-12-17 | 2016-10-05 | 四川科瑞德制药股份有限公司 | Tandospirone citrate compound |
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