CN111087365A - Crystal form of vortioxetine hydrobromide and preparation method thereof - Google Patents
Crystal form of vortioxetine hydrobromide and preparation method thereof Download PDFInfo
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- CN111087365A CN111087365A CN201911371596.5A CN201911371596A CN111087365A CN 111087365 A CN111087365 A CN 111087365A CN 201911371596 A CN201911371596 A CN 201911371596A CN 111087365 A CN111087365 A CN 111087365A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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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
Abstract
The invention provides a hydrobromic acid vortioxetine crystal form and also relates to a preparation method of the crystal form. The vortioxetine hydrobromide crystal form disclosed by the invention has good physical and chemical stability and purity, is easy to produce in a large scale, is simple to operate, and has a wide application prospect.
Description
1. Field of the invention
The invention belongs to the technical field of medicines, and particularly relates to a vortioxetine hydrobromide crystal form and a preparation method of the vortioxetine hydrobromide crystal form.
2. Background of the invention
Vortioxetine Hydrobromide (Vortioxetine Hydrobromide) with the chemical name of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine Hydrobromide has the structural formula shown in the following formula I. Vothioxetine hydrobromide was approved by the U.S. Food and Drug Administration (FDA) for treatment of adult patients with major depression for 30 days 9 months 2013 under the trade name brinellix. This approval was based on efficacy and safety data for treatment of major depressive disorder in a comprehensive clinical development program. This project consisted of 7 key studies, including 6 short-term studies with periods ranging from 6 to 8 weeks, and 1 long-term study with periods ranging from 24 to 64 weeks, which showed statistically significant improvement in major depressive symptoms in adult patients with major depressive disorder by brinellix.
The invention patent CN102317272A discloses a method for preparing 1- [2- (2, 4-dimethylphenylthio) phenyl ] piperazine. The method has the advantages that the steps for purifying the vortioxetine hydrobromide are complex, the isopropanol solvate needs to be separated, and then the product is dissolved in other solvents for precipitation, so that the operation steps are complex.
The invention patent CN105801517A discloses a crystal form delta of a vortioxetine hydrobromide compound (formula I), which is characterized in that an X-ray powder diffraction pattern of the crystal form delta comprises characteristic peaks (+/-0.2 degrees) shown by the following 2 theta angles: 4.0 °, 11.5 °, 15.5 °, 17.7 °, 19.1 °, 20.8 °, 22.9 °, 27.2 °, 28.6 °. However, the solvent used for refining the vortioxetine hydrobromide is an unconventional reagent, and has potential risk of solvent residue
The invention patent CN105367515A discloses a preparation method of vortioxetine hydrobromide α crystal form, which comprises the following steps of removing sec-butyl alcohol from vortioxetine hydrobromide-sec-butyl hydrate to obtain the vortioxetine hydrobromide α crystal form, but the yield is obviously lower.
The invention patent CN110520415A discloses a preparation method for preparing vortioxetine hydrobromide α crystal form, which comprises the following steps a) obtaining vortioxetine solution in substantially pure toluene, b) reacting said solution obtained in step a) with hydrobromic acid and C at a temperature higher than 10 DEG C1-C3Mixing carboxylic acids to obtain a mixture b); and c) collecting the precipitate obtained in step b). Wherein, the solvent used for refining the vortioxetine hydrobromide is toluene, and is a second type of solvent limited by ICH.
In summary, there is a need to develop a vortioxetine hydrobromide crystal form having good physicochemical stability and purity, easy mass production, simple operation, and more environmental protection.
3. Summary of the invention
The invention aims to solve the problems in the prior art and provides a stable vortioxetine hydrobromide crystal form and a preparation method of the vortioxetine hydrobromide crystal form. The vortioxetine hydrobromide crystal form disclosed by the invention has good physical and chemical stability and purity, is easy to produce in a large scale, is simple to operate, and has a wide application prospect.
Specifically, the invention provides a vortioxetine hydrobromide crystal form which is characterized in that an X-ray powder diffraction X-RPD diagram has characteristic peaks at the following 2 theta angle positions of 5.8 +/-0.2 degrees, 7.1 +/-0.2 degrees, 14.1 +/-0.2 degrees, 16.3 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.6 +/-0.2 degrees and 23.0 +/-0.2 degrees by using Cu-K α radiation.
Furthermore, the vortioxetine hydrobromide crystal form disclosed by the invention has characteristic peaks at the following 2 theta angle positions in an X-ray powder diffraction X-RPD diagram by using Cu-K α radiation, wherein the characteristic peaks are 5.8 +/-0.2 degrees, 7.1 +/-0.2 degrees, 9.3 +/-0.2 degrees, 12.9 +/-0.2 degrees, 14.1 +/-0.2 degrees, 16.3 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.4 +/-0.2 degrees, 21.1 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.1 +/-0.2 degrees, 28.0 +/-0.2 degrees and 29.5 +/-0.2 degrees.
Furthermore, the vortioxetine hydrobromide crystal form disclosed by the invention has characteristic peaks at the following 2 theta angle positions of 5.8 +/-0.2 °, 7.1 +/-0.2 °, 9.3 +/-0.2 °, 12.9 +/-0.2 °, 14.1 +/-0.2 °, 16.3 +/-0.2 °, 17.5 +/-0.2 °, 18.2 +/-0.2 °, 18.6 +/-0.2 °, 19.4 +/-0.2 °, 20.4 +/-0.2 °, 21.1 +/-0.2 °, 21.6 +/-0.2 °, 22.2 +/-0.2 °, 23.0 +/-0.2 °, 23.7 +/-0.2 °, 24.1 +/-0.2 °, 24.6 +/-0.2 °, 25.8 +/-0.2 °, 27.0 +/-0 ± 0.2 °, 28.0 +/-0.2 °, 28.8 +/-0.2 °, 30.0.7 +/-0.0.0.5 ± 0.2 °, 30.0 ± 0 ± 0.5 ± 0.2 °, 30.5 ± 0 ± 0.2 °, 30.7 +/-0.2 °, 3 ± 0.2 ° 2.2.2 ° 0.2 ° and 31 ± 0.7 ± 0.2 ° 2 ° 2.2 ° 0.2 ° 0.7 +/-0.2.2 ° 0.2 ° by using Cu-K α radiation.
The crystal form of vortioxetine hydrobromide provided by the invention has characteristic X-ray powder diffraction peak data as shown in Table 1.
TABLE 1 characteristic peak data of X-ray powder diffraction of vortioxetine hydrobromide crystal form
In a preferred embodiment of the invention, the crystalline form of vortioxetine hydrobromide has a characteristic X-ray powder diffraction pattern as shown in figure 1.
Through Differential Scanning Calorimetry (DSC) determination, the vortioxetine hydrobromide crystal form disclosed by the invention has DSC endothermic peaks at 225-230 ℃ and 230-235 ℃. Preferably, the compound has a Differential Scanning Calorimetry (DSC) endothermic peak at two positions of 226.2 +/-2 ℃ and 233.3 +/-2 ℃; wherein 233.3 +/-2 ℃ is a main endothermic peak.
In a preferred embodiment of the invention, the crystalline form of vortioxetine hydrobromide has a DSC profile as shown in figure 2.
The crystal form of the vortioxetine hydrobromide in the first aspect of the present invention has almost no weight loss before 230 ℃ as shown by TGA thermogravimetric analysis, and is decomposed by heating to 280 ℃ +/-5 ℃.
In a preferred embodiment of the invention, the crystalline form of vortioxetine hydrobromide has a TGA profile as shown in figure 3.
In another aspect of the present invention, a method for preparing the vortioxetine hydrobromide crystal form according to the first aspect is further provided, which comprises the following steps: adding the vortioxetine hydrobromide into sec-butyl alcohol, heating, adding water, dissolving clearly, maintaining for 0.5h, cooling to 0 ℃, separating out solids in the cooling process, keeping the temperature at 0 ℃ for crystal growing, and drying at high temperature to obtain the target crystal form product of the vortioxetine hydrobromide.
Preferably, the volume mass ratio of sec-butyl alcohol to vortioxetine hydrobromide is 10:1 to 12:1, more preferably 10: 1.
preferably, the volume mass ratio of the water to the vortioxetine hydrobromide is 0.3: 1 to 1: 1, more preferably 0.5: 1.
preferably, the volume ratio of the sec-butyl alcohol to the water is 10: 1-30: 1, and more preferably 20: 1-30: 1.
Preferably, the temperature of the heating after the addition of sec-butyl alcohol in the present invention is 80 ℃ or higher, more preferably 85 ℃ or higher.
Preferably, the holding time after the temperature is reduced to 0 ℃ is 1-2h, and more preferably 2 h.
Preferably, the high temperature drying temperature in the present invention is 90-110 deg.C, more preferably 90 deg.C.
Preferably, the high-temperature drying time in the present invention is 2 hours or more, more preferably 4 hours or more.
The crystal form of the vortioxetine hydrobromide provided by the present invention is prepared, and the initial charge of the vortioxetine hydrobromide includes, but is not limited to, known crystal forms or amorphous forms, and can be any form of vortioxetine hydrobromide.
In another aspect of the present invention, a method for preparing the vortioxetine hydrobromide crystal form according to the first aspect is further provided, which comprises the following steps: heating the hydrobromic acid vortioxetine and sec-butyl alcohol to 84 ℃, adding water, dissolving, filtering while the solution is hot, cooling the filtrate to 58 ℃, separating out a large amount of solids, and continuously cooling to 0 ℃. Keeping the temperature and growing the crystals for 2h, carrying out suction filtration to obtain a white solid, and carrying out forced air drying at 90 ℃ for 5h to obtain a target crystal form product of the vortioxetine hydrobromide; wherein the volume ratio of the sec-butyl alcohol to the water is 20: 1.
Compared with the prior art, the invention has the beneficial effects that due to the adoption of the technical scheme:
(1) provides a hydrobromic acid vortioxetine crystal form, which is confirmed to be a single crystal form by X-ray powder diffraction, differential scanning calorimetry analysis and thermogravimetric analysis;
(2) the crystal form of the vortioxetine hydrobromide is stable, and the stability test results of the vortioxetine hydrobromide placed at 40 +/-2 ℃ and RH75 +/-5% for 1 month, 2 months and 3 months prove that the vortioxetine hydrobromide is stable and does not generate crystal form change and chemical degradation;
(3) the preparation method of the vortioxetine hydrobromide crystal form has high yield of 87% -96%;
(4) the purity of the crystal form obtained by the preparation method of the vortioxetine hydrobromide crystal form is high and is 99.9%;
(5) the preparation method of the vortioxetine hydrobromide crystal form has short preparation time and complete crystallization within 2 h;
(6) in the preparation method of the crystal form of vortioxetine hydrobromide, the usage amount of the organic solvent is low, and the sec-butyl alcohol: the volume-mass ratio of the vortioxetine hydrobromide to the vortioxetine hydrobromide is 8: 1-12: 1, so that the vortioxetine hydrobromide is more environment-friendly.
4. Description of the drawings
Figure 1 is an XRPD pattern of the crystalline form of vortioxetine hydrobromide according to the invention described in example 1.
Figure 2 is a DSC profile of the crystalline form of vortioxetine hydrobromide according to the invention described in example 1.
Figure 3 is a TGA profile of the crystalline form of vortioxetine hydrobromide according to the invention described in example 1.
Figure 4 is an XRPD pattern of the crystalline form of vortioxetine hydrobromide according to example 6 of the present invention.
Figure 5 is an XRPD pattern of vortioxetine hydrobromide form accelerated stability test of 1 month according to the present invention.
Figure 6 is an XRPD pattern of vortioxetine hydrobromide form accelerated stability test of 2 months according to the present invention.
Figure 7 is an XRPD pattern of vortioxetine hydrobromide form accelerated stability test of 3 months according to the present invention.
5. Detailed description of the preferred embodiments
The following detailed description of specific embodiments of the present invention is provided for illustrative purposes only and is not intended to limit the scope of the present invention.
Example 1
5g of vortioxetine hydrobromide and 50ml of sec-butyl alcohol are taken and added into a 100ml round-bottom flask. Heating to 80 deg.C, adding 5ml water, dissolving, and maintaining for 0.5 h. Cooling to 15 deg.c to separate out great amount of solid, and further cooling to 0 deg.c. Keeping the temperature and growing the crystal for 2 hours. And (5) carrying out suction filtration to obtain a white solid. Air-blast drying at 90 deg.C for 2h, and weighing 4.33 g. The yield was 86.6% and the purity was 99.9%. The XRPD pattern remained consistent with that of figure 1.
Example 2
5g of vortioxetine hydrobromide and 50ml of sec-butyl alcohol are taken and added into a 100ml round-bottom flask. Heating to 81 deg.C, adding 2.5ml water, dissolving, and maintaining for 0.5 h. Cooling to 45 deg.c to separate out great amount of solid, and further cooling to 0 deg.c. Keeping the temperature and growing the crystal for 2 hours. And (5) carrying out suction filtration to obtain a white solid. Air-blast drying at 90 deg.C for 2h, and weighing 4.73 g. The yield is 94.6 percent, and the purity is 99.9 percent. The XRPD pattern remained consistent with that of figure 1.
Practice ofExample 3
5g of vortioxetine hydrobromide and 50ml of sec-butyl alcohol are taken and added into a 100ml round-bottom flask. Heating to 82 deg.C, adding 1.7ml of water, dissolving, and maintaining for 0.5 h. Cooling to 47 deg.C to separate out a large amount of solid, and further cooling to 0 deg.C. Keeping the temperature and growing the crystal for 2 hours. And (5) carrying out suction filtration to obtain a white solid. Air-blast drying at 90 deg.C for 2h, and weighing 4.78 g. The yield is 95.6 percent, and the purity is 99.9 percent. The XRPD pattern remained consistent with that of figure 1.
Example 4
5g of vortioxetine hydrobromide and 55ml of sec-butyl alcohol are taken and added into a 100ml round-bottom flask. Heating to 80 deg.C, adding 1.85ml of water, dissolving, and maintaining for 0.5 h. Cooling to 64 deg.c to separate out solid, and further cooling to 0 deg.c. Keeping the temperature and growing the crystal for 2 hours. And (5) carrying out suction filtration to obtain a white solid. Air-blast drying at 90 deg.C for 2h, and weighing 4.68 g. The yield was 93.6% and the purity was 99.9%. The XRPD pattern remained consistent with that of figure 1.
Example 5
5g of vortioxetine hydrobromide and 60ml of sec-butanol are taken and added into a 100ml round-bottom flask. Heating to 81 deg.C, adding 2ml water, dissolving, and maintaining for 0.5 h. Cooling to 60 deg.c to separate out solid, and further cooling to 0 deg.c. Keeping the temperature and growing the crystal for 2 hours. And (5) carrying out suction filtration to obtain a white solid. Air-blast drying at 90 deg.C for 2h, and weighing 4.57 g. The yield was 91.4% and the purity was 99.9%. The XRPD pattern remained consistent with that of figure 1.
Example 6
130g of vortioxetine hydrobromide and 1.3L of sec-butanol are added into a 2L three-neck round-bottom flask. The temperature is raised to 81 ℃, water 43.3ml is added into the mixture and the mixture is dissolved clearly. The hot solution is filtered, and the bottle wall is rinsed with sec-butanol/water (65ml/2.2 ml). The temperature of the filtrate is returned to 85 ℃ again, and the filtrate is maintained for 0.5h and still is not dissolved. Cooling to 68 deg.c to separate out great amount of solid, and further cooling to 0 deg.c. Keeping the temperature and growing the crystal for 2 hours. And (5) carrying out suction filtration to obtain a white solid. The dried product was dried by blowing at 90 ℃ for 3.5 hours and weighed 122.8 g. The yield is 94.5 percent, and the purity is 99.9 percent. The XRPD pattern is shown in FIG. 4, which is consistent with FIG. 1.
Example 7
8g of vortioxetine hydrobromide and 80ml of sec-butyl alcohol are taken and added into a 250ml three-neck round-bottom flask. The temperature is raised to 85 ℃, and 4ml of water is added to dissolve the undissolved solution. Cooling to 0 deg.C for 0.5h, and keeping the temperature for crystal growth for 2 h. And (5) carrying out suction filtration to obtain a white solid. Air-blast drying at 90 deg.C for 2h, and weighing 7.40 g. The yield is 92.5 percent, and the purity is 99.9 percent. The XRPD pattern remained consistent with that of figure 1.
Example 8
165g of vortioxetine hydrobromide and 1.38L of sec-butanol are added into a 2L three-neck round-bottom flask. The temperature is raised to 85 ℃, water 69ml is added into the mixture without dissolving the mixture clearly. The hot solution is filtered, and the bottle wall is rinsed with sec-butanol/water (70ml/3.5 ml). Cooling the filtrate to 57 deg.C, separating out a large amount of solid, and continuously cooling to 0 deg.C. Keeping the temperature and growing the crystal for 2 hours. And (4) carrying out suction filtration, and leaching a filter cake by using 138ml of sec-butyl alcohol to obtain a white solid. Dried by blowing at 90 ℃ for 4.5h and weighed 128.1 g. The yield is 92.8 percent, and the purity is 99.9 percent. The XRPD pattern remained consistent with that of figure 1.
Example 9
180g of vortioxetine hydrobromide and 1.5L of sec-butanol are added into a 2L three-neck round-bottom flask. The temperature is increased to 84 ℃, water of 75ml is added into the mixture without dissolving the mixture, and the mixture is dissolved clearly. Filtering while the solution is hot, cooling the filtrate to 58 ℃ to separate out a large amount of solid, and continuously cooling to 0 ℃. Keeping the temperature and growing the crystal for 2 hours. And (5) carrying out suction filtration to obtain a white solid. Dried by blowing at 90 ℃ for 5h and weighed 140.0 g. The yield is 92.9 percent, and the purity is 99.9 percent. The XRPD pattern remained consistent with that of figure 1.
Example 10 stability study of vortioxetine hydrobromide crystalline form
Samples of the vortioxetine hydrobromide prepared in example 6 were taken and placed at 40 ℃ ± 2 ℃ and RH 75% ± 5% to examine the stability of the samples after being placed for 1 month, 2 months and 3 months, and the test results are shown in table 2.
The specific stability investigation is carried out according to an accelerated test method in a standardized process technical guide principle established by a chemical drug quality standard and a 2015-year standard convention of Chinese pharmacopoeia 9001 raw material drug and preparation stability test guide principle.
Table 2 accelerated stability test results for vortioxetine hydrobromide crystal form of example 6
Test results show that the vortioxetine hydrobromide crystal form is stable for 1 month, 2 months and 3 months under the conditions of 40 +/-2 ℃ and RH75 +/-5%, and does not generate crystal form change and chemical degradation.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention; those skilled in the art can make various changes, modifications and alterations without departing from the scope of the invention, and all equivalent changes, modifications and alterations to the disclosed technology are equivalent embodiments of the present invention; meanwhile, any changes, modifications, and evolutions of the equivalent changes of the above embodiments according to the actual techniques of the present invention are still within the protection scope of the technical solution of the present invention.
Claims (10)
1. A crystalline form of vortioxetine hydrobromide characterized by having characteristic peaks at the following 2 theta angular positions of 5.8 + -0.2 °, 7.1 + -0.2 °, 14.1 + -0.2 °, 16.3 + -0.2 °, 18.2 + -0.2 °, 18.6 + -0.2 ° and 23.0 + -0.2 ° with irradiation with Cu-K α.
2. The crystalline form of vortioxetine hydrobromide of claim 1 having characteristic peaks at the following 2 Θ angular positions: 5.8 +/-0.2 degrees, 7.1 +/-0.2 degrees, 9.3 +/-0.2 degrees, 12.9 +/-0.2 degrees, 14.1 +/-0.2 degrees, 16.3 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.4 +/-0.2 degrees, 21.1 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.1 +/-0.2 degrees, 28.0 +/-0.2 degrees and 29.5 +/-0.2 degrees.
3. The crystalline form of vortioxetine hydrobromide according to claim 2 having characteristic peaks at the following 2 Θ angular positions: 5.8 +/-0.2 °, 7.1 +/-0.2 °, 9.3 +/-0.2 °, 12.9 +/-0.2 °, 14.1 +/-0.2 °, 16.3 +/-0.2 °, 17.5 +/-0.2 °, 18.2 +/-0.2 °, 18.6 +/-0.2 °, 19.4 +/-0.2 °, 20.4 +/-0.2 °, 21.1 +/-0.2 °, 21.6 +/-0.2 °, 22.2 +/-0.2 °, 23.0 +/-0.2 °, 23.7 +/-0.2 °, 24.1 +/-0.2 °, 24.6 +/-0.2 °, 25.8 +/-0.2 °, 27.0 +/-0.2 °, 28.0 +/-0.2 °, 28.8 +/-0.2 °, 29.5 +/-0.2 °, 30.7 +/-0.2 °, 31.5 +/-0.2 °, 33.0 +/-0.2 °, 37.7 +/-0.2 °, 40.0.2 °, 40 +/-0.2 ° 0.5 ± 0.2 ° and 40.2 °.
4. The crystalline form of vortioxetine hydrobromide of claim 3, having the characteristic X-ray powder diffraction pattern shown in figure 1.
5. The crystalline form of vortioxetine hydrobromide according to claim 1, having a Differential Scanning Calorimetry (DSC) endotherm at both 225-230 ℃ and 230-235 ℃.
6. The crystalline form of vortioxetine hydrobromide according to claim 1, having a Differential Scanning Calorimetry (DSC) endotherm at both 226.2 ± 2 ℃, 233.3 ± 2 ℃; wherein 233.3 +/-2 ℃ is a main endothermic peak.
7. A process for preparing the crystalline form of vortioxetine hydrobromide according to any of claims 1 to 6, comprising the steps of: adding the vortioxetine hydrobromide into sec-butyl alcohol, heating, adding water, dissolving clearly, maintaining for 0.5h, cooling to 0 ℃, separating out solids in the cooling process, keeping the temperature at 0 ℃ for crystal growing, and drying at high temperature to obtain the target crystal form product of the vortioxetine hydrobromide.
8. The method for preparing the vortioxetine hydrobromide crystal form according to claim 7, wherein the volume ratio of sec-butanol to water is 10: 1-30: 1.
9. The method for preparing the vortioxetine hydrobromide crystal form according to claim 8, wherein the volume ratio of sec-butanol to water is 20: 1-30: 1.
10. The process for the preparation of the crystalline form of vortioxetine hydrobromide according to claim 7, comprising the steps of:
heating the hydrobromic acid vortioxetine and sec-butyl alcohol to 84 ℃, adding water, dissolving, filtering while the solution is hot, cooling the filtrate to 58 ℃, separating out a large amount of solids, and continuously cooling to 0 ℃. Keeping the temperature and growing the crystals for 2h, carrying out suction filtration to obtain a white solid, and carrying out forced air drying at 90 ℃ for 5h to obtain a target crystal form product of the vortioxetine hydrobromide;
wherein the volume ratio of the sec-butyl alcohol to the water is 20: 1.
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| CN112125868A (en) * | 2020-09-25 | 2020-12-25 | 中山万远新药研发有限公司 | Crystal form of vortioxetine hydrobromide, preparation method, composition and application thereof |
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| CN105367515A (en) * | 2015-05-08 | 2016-03-02 | 北京北陆药业股份有限公司 | Preparing method for vortioxetine hydrobromide alpha crystal form |
| CN110372635A (en) * | 2018-04-12 | 2019-10-25 | 浙江京新药业股份有限公司 | The preparation method of hydrobromic acid Vortioxetine alpha-crystal form |
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| CN105367515A (en) * | 2015-05-08 | 2016-03-02 | 北京北陆药业股份有限公司 | Preparing method for vortioxetine hydrobromide alpha crystal form |
| CN110372635A (en) * | 2018-04-12 | 2019-10-25 | 浙江京新药业股份有限公司 | The preparation method of hydrobromic acid Vortioxetine alpha-crystal form |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112125868A (en) * | 2020-09-25 | 2020-12-25 | 中山万远新药研发有限公司 | Crystal form of vortioxetine hydrobromide, preparation method, composition and application thereof |
| CN112125868B (en) * | 2020-09-25 | 2021-08-03 | 中山万远新药研发有限公司 | Crystal form of vortioxetine hydrobromide, preparation method, composition and application thereof |
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