A method for preparing a high-stability crystalline form alpha of vortioxetine hydrobromide

Abstract

The application belongs to the technical field of crystal form drug preparation, and particularly relates to a preparation method of high-stability vortioxetine hydrobromide crystal form alpha. Vortioxetine hydrobromide is an antidepressant widely used at present, and the crystal form alpha thereof has higher solubility and better bioavailability, but is unstable and is easy to be transformed into the crystal form beta. The preparation method comprises the following steps: adding vortioxetine hydrobromide into an alcohol-water mixed solution to fully dissolve, applying a direct current electric field to induce the formation of the crystal form alpha, and controlling the cooling rate to crystallize for 1-2 hours, so that the crystal form alpha with high purity and good stability is prepared, and the crystal form alpha will not be transformed for a long time, and has better safety when applied to clinical preparations.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of crystal form of drug preparation, and particularly relates to a preparation method of high-stability vortioxetine hydrobromide crystal form alpha. BACKGROUND

[0002] The information disclosed in this Background section is for the purpose of providing an understanding of the general context of the present application, and is not necessarily recognized as prior art by the present application.

[0003] Vortioxetine hydrobromide is a multi-modal 5-hydroxytryptamine (5-HT) drug for major depressive disorder and generalized anxiety disorder, and its chemical name is (2S)-2-(2,4-dimethylphenylsulfanyl)-N-(2-pyridyl)piperidine-1-acetamide hydrobromide, CAS No. 960203-27-4, and its trade name is Brintellix. The chemical structure of vortioxetine hydrobromide is shown in the following formula:

[0004] .

[0005] Vortioxetine hydrobromide has a synergistic effect through two mechanisms of action, modulation of receptor activity and inhibition of reuptake. Studies have shown that vortioxetine hydrobromide is an antagonist of 5-HT3 and 5-HT7 receptors, an inhibitor of serotonin transporter (SERT), an agonist of 5-HT1A receptor, and a partial agonist of 5-HT1B receptor. The multi-modal action characteristics of vortioxetine are expected to bring new hope to patients with severe depression who have not been effectively controlled by existing drugs.

[0006] At present, one of the main problems of vortioxetine hydrobromide is poor solubility and poor bioavailability. It is known that different crystal forms of the same compound have different solubilities, and the regulation of crystal forms to improve the dissolution rate of drugs is a novel idea and has practical significance. At present, it is known that vortioxetine hydrobromide exists in multiple crystal forms and solvates, WO2007144005 discloses vortioxetine hydrobromide crystal form alpha, crystal form beta, crystal form gamma, hemihydrate and ethyl acetate solvate; WO2010094285 discloses an isopropanol solvate of vortioxetine hydrobromide; and WO2014044721 discloses a solvated crystal form delta of vortioxetine hydrobromide. Among these crystal forms, crystal form beta is the current pharmaceutical crystal form, which is a stable crystal form, but its bioavailability is poor, which restricts the exertion of drug efficacy. Solvated crystal forms are usually used for impurity removal or purification, and cannot be directly used for drug preparation. Patent WO2007144005 points out that the solubility of crystal form alpha is higher than that of crystal form beta, which is more conducive to the absorption of the preparation in the human body.

[0007] However, as a metastable crystal form of hydrobromide vortioxetine, crystal form alpha also has many defects. For example, patents CN109928941 and CN104736526 indicate that crystal form alpha has the risk of transforming into crystal form beta and is prone to mixed crystals; patents WO2007144005 and CN105017176 indicate that the yield of crystal form alpha of the current process is too low, etc. The reports on the preparation method of crystal form alpha, such as patents CN109503517 and CN105367515, etc., have not effectively solved the above defects, which is not conducive to drug preparation processing.

[0008] In summary, it is of great significance to seek a preparation process of hydrobromide vortioxetine crystal form alpha which is stable in crystal form and simple to operate. SUMMARY

[0009] Through scientific and reasonable system design, the present application can stably prepare crystal form alpha by using simple process operation, and achieve the goals of high purity, high crystal stability and high yield. Based on the technical effects achieved, the present application provides the following solutions:

[0010] The present application provides a preparation method of high-stability hydrobromide vortioxetine crystal form alpha, comprising the following steps:

[0011] The hydrobromide vortioxetine is added into an alcohol-water mixed solution, heated to 30-70 ℃, fully dissolved, retained the supernatant, once cooled to 0-30 ℃, applied a direct current electric field to induce crystallization for 5-9 h, the electric field strength is 100-300 kV / m, twice cooled to-5-0 ℃, crystal growth for 1-2 h, retained the solid part and dried to obtain the product.

[0012] In the above preparation method, the application of a direct current electric field plays a key role in the induction formation of crystal form alpha. Under the same preparation process, only crystal form beta can be obtained without applying an electric field. The use of an electric field induction can effectively change the crystal face energy, induce the highly ordered growth of crystal form alpha, and does not require crystal nucleus induction; and the electric field application operation is simple, only needs to place the electrode in the solution. In the above electric field induction process, the electric field strength has an important influence on the crystal lattice arrangement, and the range of 100-300 kV / m is beneficial to the rapid and stable growth of crystal form alpha, and the preferred electrode material is platinum gold.

[0013] Secondly, the rate of cooling will directly affect the stability of crystal form alpha, especially in the process of secondary cooling. If the cooling speed is too fast, the transformation of crystal form alpha to crystal form beta will occur. In the preferred embodiment, the above first cooling speed is 0.2-0.5 ℃ / min, and the second cooling speed is 0.05-0.1 ℃ / min.

[0014] The above preparation method also has the following preferred embodiments:

[0015] The vortioxetine hydrobromide as a raw material can be in a molecular structure or a crystal form, and the crystal is not limited to a crystal form, and can be any one of crystal form alpha, crystal form beta, crystal form gamma, or a mixture of two or more of the amorphous state.

[0016] In the alcohol-water mixed solution, the ratio of alcohol to water is 1:0.5-3, v / v. The alcohol is a low-carbon-number alcohol, including linear alcohol and branched alcohol; further, the carbon atom number is 1-4, and examples are methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol or sec-butanol.

[0017] The solid-liquid ratio of vortioxetine hydrobromide to the alcohol-water mixed solution is 1 g: 10-60 mL.

[0018] After the crystal growth is completed, the solid part in the product can be separated by filtration, and dried to constant weight to obtain the above-mentioned high-stability vortioxetine hydrobromide crystal form alpha, and the drying temperature is 40-50 ℃.

[0019] Compared with the prior art, the present application has the following beneficial effects:

[0020] The preparation method of vortioxetine hydrobromide crystal form alpha reported in the prior art is still mainly solvent evaporation method, and the crystal form alpha prepared by this method still has the defect of insufficient long-term stability, and cannot meet the requirements of preparation processing. The present application finds that a direct current field with appropriate intensity can induce the growth of the alpha crystal surface of vortioxetine hydrobromide, and the crystal form alpha can be prepared by combining slow cooling. This method is simple in process operation, suitable for industrial production, and the obtained crystal form alpha has the characteristics of high purity, high stability and high yield. BRIEF DESCRIPTION OF DRAWINGS

[0021] The drawings accompanying the specification of the present application serve to provide further understanding of the present application, and the illustrative embodiments of the present application and their descriptions serve to explain the present application, and do not constitute an improper limitation on the present application.

[0022] Figure 1 The X-ray powder diffraction (PXRD) pattern of the crystal form alpha prepared in Example 1 is shown in the following figure:

[0023] Figure 2 The differential scanning calorimetry (DSC) pattern of the crystal form alpha prepared in Example 1 is shown in the following figure. DETAILED DESCRIPTION

[0024] It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs.

[0025] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, components, and / or groups thereof, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof.

[0026] In the context of this specification, the word "comprise" is to be construed as meaning "comprise, but not limited to." It should not be interpreted as "consist only of."

[0027] As introduced in the background, the existing vortioxetine hydrobromide α crystal form has the disadvantages of poor stability and easy crystal transformation. In order to solve the above technical problems, the present application provides a preparation method of high-stability vortioxetine hydrobromide crystal form α.

[0028] In order for those skilled in the art to have a clearer understanding of the technical solutions of the present application, the technical solutions of the present application will be described in detail below in combination with specific examples and comparative examples.

[0029] Example 1

[0030] In this embodiment, a preparation method of high-stability vortioxetine hydrobromide crystal form α is provided, and the steps are as follows:

[0031] 10 g of vortioxetine hydrobromide, 50 mL of methanol, and 50 mL of water were put into a crystallizer, stirred and dissolved at 60 ℃ for 30 min, and the insoluble substances were filtered out. The filtrate was collected and incubated at 60 ℃. The system was cooled to 30 ℃ at a rate of 0.2 ℃ / min, and then a platinum-gold electrode was used to apply a direct current field of 200 kV / m to the solution to induce crystallization for 6 h. Then the system was cooled to 0 ℃ at a rate of 0.05 ℃ / min, and the crystal was incubated for 1 h. The filter cake was dried at 40 ℃ to constant weight. The vortioxetine hydrobromide obtained in this example had a purity of 100% detected by HPLC, and its X-ray powder diffraction (PXRD) was as shown in Figure 1 , and the differential scanning calorimetry (DSC) graph was as shown in Figure 2 , which was confirmed as crystal form α, and the overall yield was 94.3%.

[0032] Example 2

[0033] In this embodiment, a preparation method of high-stability vortioxetine hydrobromide crystal form α is provided, and the steps are as follows:

[0034] Into a crystallizer, 10 g of vortioxetine hydrobromide, 125 mL of ethanol, 375 mL of water were put, and stirred to dissolve at 40 °C for 30 min. The undissolved substances were filtered off, and the filtrate was collected and kept at 40 °C. The system was cooled to 10 °C at a rate of 0.3 °C / min, and then a direct current electric field of 100 kV / m was applied to the solution using a platinum-gold electrode to induce crystallization for 9 h. Subsequently, the system was cooled to -5 °C at a rate of 0.1 °C / min, and the crystals were kept for 2 h. Filtration was performed, and the filter cake was dried at 45 °C to constant weight to obtain vortioxetine hydrobromide. The purity of vortioxetine hydrobromide obtained in this example was 100% as detected by HPLC, and the crystal form was alpha as detected by PXRD, and the overall yield was 92.6%.

[0035] Example 3

[0036] In this example, another method for preparing vortioxetine hydrobromide crystal form alpha with high stability is provided, and the steps are as follows:

[0037] Into a crystallizer, 10 g of vortioxetine hydrobromide, 200 mL of isopropanol, 400 mL of water were put, and stirred to dissolve at 40 °C for 30 min. The undissolved substances were filtered off, and the filtrate was collected and kept at 40 °C. The system was cooled to 0 °C at a rate of 0.5 °C / min, and then a direct current electric field of 150 kV / m was applied to the solution using a platinum-gold electrode to induce crystallization for 9 h. Subsequently, the system was cooled to 0 °C at a rate of 0.05 °C / min, and the crystals were kept for 2 h. Filtration was performed, and the filter cake was dried at 50 °C to constant weight to obtain vortioxetine hydrobromide. The purity of vortioxetine hydrobromide obtained in this example was 100% as detected by HPLC, and the crystal form was alpha as detected by PXRD, and the overall yield was 94.4%.

[0038] Example 4

[0039] In this example, another method for preparing vortioxetine hydrobromide crystal form alpha with high stability is provided, and the steps are as follows:

[0040] Into a crystallizer, 10 g of vortioxetine hydrobromide, 125 mL of n-propanol, 75 mL of water were put, and stirred to dissolve at 30 °C for 30 min. The undissolved substances were filtered off, and the filtrate was collected and kept at 30 °C. The system was cooled to 10 °C at a rate of 0.4 °C / min, and then a direct current electric field of 300 kV / m was applied to the solution using a platinum-gold electrode to induce crystallization for 5 h. Subsequently, the system was cooled to 0 °C at a rate of 0.05 °C / min, and the crystals were kept for 1 h. Filtration was performed, and the filter cake was dried at 50 °C to constant weight to obtain vortioxetine hydrobromide. The purity of vortioxetine hydrobromide obtained in this example was 100% as detected by HPLC, and the crystal form was alpha as detected by PXRD, and the overall yield was 93.1%.

[0041] Example 5

[0042] In this embodiment, another method for preparing the high-stability vortioxetine hydrobromide crystal form α is provided, and the steps are as follows:

[0043] The 10 g of vortioxetine hydrobromide, 200 mL of n-butanol, and 100 mL of water were put into a crystallizer, stirred and dissolved at 50 ℃ for 30 min, and the undissolved substances were filtered out. The filtrate was collected and kept at 50 ℃. The system was cooled to 20 ℃ at a rate of 0.3 ℃ / min, and then a direct current field of 250 kV / m was applied to the solution using a platinum-gold electrode to induce crystallization for 7 h. Subsequently, the system was cooled to -5 ℃ at a rate of 0.1 ℃ / min, and the crystal was kept for 2 h. Filtration was performed, and the filter cake was dried at 40 ℃ to a constant weight. The vortioxetine hydrobromide obtained in this embodiment had a purity of 100% detected by HPLC, was in crystal form α detected by PXRD, and the overall yield was 95.3%.

[0044] Example 6

[0045] In this embodiment, another method for preparing the high-stability vortioxetine hydrobromide crystal form α is provided, and the steps are as follows:

[0046] The 10 g of vortioxetine hydrobromide, 250 mL of tert-butanol, and 150 mL of water were put into a crystallizer, stirred and dissolved at 50 ℃ for 30 min, and the undissolved substances were filtered out. The filtrate was collected and kept at 50 ℃. The system was cooled to 20 ℃ at a rate of 0.2 ℃ / min, and then a direct current field of 300 kV / m was applied to the solution using a platinum-gold electrode to induce crystallization for 8 h. Subsequently, the system was cooled to 0 ℃ at a rate of 0.1 ℃ / min, and the crystal was kept for 1 h. Filtration was performed, and the filter cake was dried at 45 ℃ to a constant weight. The vortioxetine hydrobromide obtained in this embodiment had a purity of 100% detected by HPLC, was in crystal form α detected by PXRD, and the overall yield was 94.6%.

[0047] Example 7

[0048] In this embodiment, another method for preparing the high-stability vortioxetine hydrobromide crystal form α is provided, and the steps are as follows:

[0049] The 10 g of vortioxetine hydrobromide, 80 mL of methanol, and 120 mL of water were put into a crystallizer, stirred and dissolved at 70 ℃ for 30 min, and the undissolved substances were filtered out. The filtrate was collected and kept at 50 ℃. The system was cooled to 30 ℃ at a rate of 0.5 ℃ / min, and then a direct current field of 100 kV / m was applied to the solution using a platinum-gold electrode to induce crystallization for 6 h. Subsequently, the system was cooled to -5 ℃ at a rate of 0.1 ℃ / min, and the crystal was kept for 2 h. Filtration was performed, and the filter cake was dried at 45 ℃ to a constant weight. The vortioxetine hydrobromide obtained in this embodiment had a purity of 100% detected by HPLC, was in crystal form α detected by PXRD, and the overall yield was 92.8%.

[0050] Comparative Example 1

[0051] In this comparative example, another method for preparing vortioxetine hydrobromide is provided, in which instead of using direct current field-induced crystallization, stirring crystallization is used, and the rest of the settings are the same as in Example 1, and the specific steps are as follows:

[0052] 10 g of vortioxetine hydrobromide, 50 mL of methanol, and 50 mL of water were put into the crystallizer, and the temperature was raised to 60°C and stirred for 30 min to dissolve, and the undissolved substances were filtered out, and the filtrate was collected and kept at 60°C. The system was cooled to 30°C at a rate of 0.2°C / min, and stirring crystallization was carried out for 6 h. Then the system was cooled to 0°C at a rate of 0.05°C / min, and the crystal was kept for 1 h. Filtration was carried out, and the filter cake was dried at 40°C to constant weight to obtain vortioxetine hydrobromide. The vortioxetine hydrobromide obtained in this example was detected by PXRD to be crystal form β.

[0053] Comparative Example 2: Too fast cooling rate

[0054] In this comparative example, another method for preparing vortioxetine hydrobromide is provided, in which after direct current field-induced crystallization, the temperature is quickly lowered (2°C / min) to 0°C for crystal keeping, and the rest of the settings are the same as in Example 1, and the specific steps are as follows:

[0055] 10 g of vortioxetine hydrobromide, 50 mL of methanol, and 50 mL of water were put into the crystallizer, and the temperature was raised to 60°C and stirred for 30 min to dissolve, and the undissolved substances were filtered out, and the filtrate was collected and kept at 60°C. The system was cooled to 30°C at a rate of 0.2°C / min, and then a direct current field of 200 kV / m was applied to the solution using a platinum-gold electrode to induce crystallization for 6 h. Then the system was cooled to 0°C at a rate of 2°C / min, and the crystal was kept for 1 h. Filtration was carried out, and the filter cake was dried at 40°C to constant weight to obtain vortioxetine hydrobromide. The vortioxetine hydrobromide obtained in this example was detected by HPLC to have a purity of 98.74%, and by PXRD to be a mixed crystal of crystal form α and crystal form β.

[0056] Performance verification

[0057] 1. Crystal form confirmation

[0058] Vortioxetine hydrobromide crystal form α was obtained by referring to the preparation method of Example 4a in the patent WO2007144005 (referred to as Test Example 1), and the sample had a purity of 99.15% detected by HPLC, and was confirmed by PXRD to be consistent with the crystal form α of Examples 1-7 above.

[0059] 2. Test Example 2

[0060] Referring to the preparation method of Example 6 in the patent CN105367515, the hydrobromide vortioxetine crystal form α was obtained, the purity of the sample was 99.54% detected by HPLC, and it was confirmed by PXRD that the crystal form α was consistent with the crystal form α of Examples 1-7 above.

[0061] 3. Stability study

[0062] Referring to the Guiding Principles for Stability Test of Raw Materials in Chinese Pharmacopoeia 2020 Edition 9001, the most severe influencing factor experiment method was selected to evaluate the stability of the hydrobromide vortioxetine crystal form α obtained in the examples of the application, and the crystal form α sample prepared according to the original research process in Test Example 1 and the crystal form α prepared according to the process in patent CN105367515A in Test Example 2 were compared, and the results were as follows:

[0063] A. High temperature experiment: 50℃±2.0℃ for 6 months, sampling at 0th day, 5th day, 10th day, 30th day, 3rd month, 6th month, and the crystal form stability results and chemical purity stability results were shown in Table 1 and Table 2 respectively:

[0064] Table 1 High temperature crystal form stability test results of crystal form α in Examples 1-7 and Test Examples 1-2

[0065]

[0066] Table 2 High temperature chemical stability test results of crystal form α in Examples 1-7 and Test Examples 1-2

[0067]

[0068] The high temperature stability test results showed that the crystal form α obtained in the examples of the application had higher crystal form stability and chemical stability under high temperature environment, and had more stability advantages than the products prepared by the original research process and other existing processes.

[0069] B. High humidity experiment: placed in 90%±5% environment for 6 months, sampling at 0th day, 5th day, 10th day, 30th day, 3rd month, 6th month, and the crystal form stability results and chemical purity stability results were shown in Table 3 and Table 4 respectively:

[0070] Table 3 High humidity crystal form stability test results of crystal form α in Examples 1-7 and Test Examples 1-2

[0071]

[0072] Table 4 High humidity chemical stability test results of crystal form α in Examples 1-7 and Test Examples 1-2

[0073]

[0074] The high humidity stability test results show that the crystal form alpha obtained in the embodiment has higher crystal form stability and chemical stability under high humidity conditions, and has a stability advantage compared with the product of the original research process and other existing processes.

[0075] C. Light experiment: 4500Lx±500Lx for 6 months, sampling at 0th day, 5th day, 10th day, 30th day, 3rd month and 6th month, the crystal form stability results and the chemical purity stability results are shown in Tables 5 and 6 respectively:

[0076] Table 5: Light crystal form stability test results of crystal form alpha in Examples 1-7 and Test Examples 1-2

[0077]

[0078] Table 6: Light chemical stability test results of crystal form alpha in Examples 1-7 and Test Examples 1-2

[0079]

[0080] The light stability test results show that the crystal form alpha obtained in the embodiment has higher crystal form stability and chemical stability under light conditions, and has a stability advantage compared with the product of the original research process and other existing processes.

[0081] The CN105367515A above dissolves vortioxetine hydrobromide in an organic solvent, and prepares crystal form alpha by controlling the solution cooling rate, according to Tables 1-6, the crystal form alpha prepared by the above method will also be converted under extreme conditions, and the chemical purity will also decrease slightly. The crystal alpha provided in the above Examples 1-7 has higher chemical stability and crystal form stability under high temperature, high humidity and strong light conditions, and has obvious advantages compared with the product of the original research process and other reported processes.

[0082] The above only describes the preferred embodiments of the present application and is not used to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing a highly stable vortioxetine hydrobromide crystal form α, characterized in that: The steps include: Vortioxetine hydrobromide is added to an alcohol-water mixed solution and heated to 30-70°C to fully dissolve, the supernatant is retained and cooled to 0-30°C once, a DC electric field is applied for inducing crystallization for 5-9 hours with an electric field strength of 100-300 kV / m, the temperature is then lowered to -5-0°C for a second time to grow the crystals for 1-2 hours, and the solid portion is retained and dried to obtain the product; The primary cooling rate is 0.2-0.5°C / min, and the secondary cooling rate is 0.05-0.1°C / min.

2. The method for preparing the highly stable vortioxetine hydrobromide crystal form α according to claim 1, wherein: The vortioxetine hydrobromide is in a molecular structure or crystal form, and the crystal form is any one of crystal form α, crystal form β, crystal form γ, and an amorphous state, or a mixture of several of them.

3. The method for preparing the highly stable vortioxetine hydrobromide crystal form α according to claim 1, wherein: In the alcohol-water mixed solution, the volume ratio of alcohol to water is 1:0.5-3; the alcohol is methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol or sec-butanol.

4. The method for preparing the highly stable vortioxetine hydrobromide crystal form α according to claim 1, wherein: The solid-to-liquid ratio of the vortioxetine hydrobromide to the alcohol-water mixed solution is 1 g:10-60 mL.

5. The method for preparing the highly stable vortioxetine hydrobromide crystal form α according to claim 1, wherein: The drying temperature is 40-50°C.

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