Preparation method of high-fluidity vortioxetine hydrobromide alpha crystal form

Abstract

The application relates to a preparation method of a high-fluidity alpha crystal form of vortioxetine hydrobromide. The technical scheme of the application is that vortioxetine hydrobromide is dissolved in 5-10 times the volume of an organic solvent, and after the insoluble substances are filtered out, 1-2.5 times the mass of polyvinylpyrrolidone is added to the filtrate. The above solution is flowed into pre-cooled purified water containing crystal seeds to crystallize, is filtered, and is dried to constant weight to obtain vortioxetine hydrobromide. 2 The vortioxetine hydrobromide obtained by the method is in an alpha crystal form, is spherical in shape, has a particle size less than 15 mu m, a specific surface area higher than 1600 m 2 / g, a fast dissolution rate, good fluidity, high yield, and is easy to realize industrialization.

Description

Technical Field

[0001] This invention belongs to the field of crystal drug preparation technology, and in particular relates to a method for preparing the highly fluid α-crystal form of vortioxetine hydrobromide. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Vortioxetine Hydrobromide, chemically named (2S)-2-(2,4-dimethylphenylthio)-N-(2-pyridyl)piperidine-1-acetamide hydrobromide, CAS number 960203-27-4, has the following chemical structural formula:

[0004] .

[0005] Vortioxetine hydrobromide has low solubility, resulting in poor bioavailability. To address this, the dosage usually needs to be increased, which not only raises the cost of medication but may also reduce patient compliance and increase the risk of side effects. Since the course of treatment with vortioxetine hydrobromide typically lasts from several months to several years, effectively improving its solubility and enhancing bioavailability would undoubtedly bring significant benefits to patients.

[0006] Improving drug solubility through crystal form regulation is a recognized feasible strategy. The original patent for this drug, WO2007144005 (CN101472906), discloses the existence of three non-solventizable crystal forms: α, β, and γ. Among these, β is a stable crystal form, currently used in pharmaceutical applications, with a melting point of 231 °C and high stability, but suffers from poor solubility. Patent WO2015035802 indicates that crystal form α is a metastable crystal form with a melting point of 226 °C, exhibiting higher solubility than β and better stability than γ. Overall, the α crystal form shows greater potential for pharmaceutical applications.

[0007] The main reports on the preparation methods of vortioxetine hydrobromide α-crystal form are as follows:

[0008] Patent CN105367515 obtains the α-crystalline form by preparing a sec-butanol solvate and then continuously heating for 24-32 hours to remove the solvent. This method is complex, and prolonged heating inevitably leads to high energy consumption and labor costs. Furthermore, the vapors generated by the solvent during heating can easily cause safety accidents. More importantly, the solvation method can easily lead to excessive residual solvent levels. Patent CN108069924A uses highly toxic solvents such as chloroform, posing significant challenges to industrial production and potential risks of residual toxicity. Patent CN109928941 provides a process for preparing the α-crystalline form, but this technology uses highly toxic and volatile hydrobromic acid, making industrial production difficult and incompatible with the safety and cleanliness requirements of refining workshops. In addition, there are several problems that urgently need to be solved regarding the α-crystalline form of vortioxetine hydrobromide, which have become key obstacles to its widespread pharmaceutical use. These problems are as follows:

[0009] Patent CN109928941 points out that the crystalline form α prepared according to the original patent WO2007144005 (CN101472906) exhibits a flocculent structure, extremely poor flowability, and difficulty in sieving, thus affecting the uniform distribution of the active ingredient in the formulation. Patent CN115160258 points out that the crystalline form α prepared according to the original patent WO2007144005 (CN101472906) has improved solubility compared to the pharmaceutical crystalline form β, but it still has insufficient dissolution rate, which limits further improvement in the pharmacokinetic properties of this poorly soluble drug formulation. Summary of the Invention

[0010] To address the shortcomings of the existing technology, the present invention aims to provide a vortioxetine hydrobromide α-crystalline raw material with improved solubility and processing performance, thereby enhancing the bioavailability and processing performance of the drug. To achieve this objective, the present invention improves the solvent system for vortioxetine hydrobromide crystallization, resulting in spherical crystals of the small-particle vortioxetine hydrobromide α-crystalline form, with a particle size less than 15 μm and a specific surface area greater than 1600 m². 2 The α-crystal form of vortioxetine hydrobromide, at a yield of [value missing] / kg, exhibits faster dissolution compared to other α-crystal forms. Its spherical crystals demonstrate excellent flowability, which is beneficial for downstream formulation processing, especially tablets. Furthermore, it boasts high yield and a simple, easily industrialized process. This discovery reinforces the advantages of the α-crystal form of vortioxetine hydrobromide and compensates for its shortcomings, demonstrating significant potential for pharmaceutical applications.

[0011] Based on the above-mentioned technical effects, the present invention provides the following technical solution:

[0012] A method for preparing the highly fluid α-crystal form of vortioxetine hydrobromide includes the following steps: adding vortioxetine hydrobromide to 5-10 times its volume of organic solvent and stirring at 40-60°C to dissolve it into a saturated solution and keeping it at that temperature; then adding 1-2.5 times its mass of polyvinylpyrrolidone (PVP) to obtain an organic phase solution of vortioxetine hydrobromide.

[0013] Add seed crystals to pre-cooled water and disperse evenly. While stirring, add the above organic phase solution of vortioxetine hydrobromide and let it stand to grow crystals. Filter to obtain the final product.

[0014] The above preparation method does not use toxic or harmful reagents, the preparation conditions are mild, the process is simple, and it is easy to scale up for industrial production. Compared with the samples prepared by the original patented process, the α-crystal form prepared by the above method has higher solubility, faster dissolution rate, and better powder flowability. The core of this improvement lies in the synergistic effect of PVP-induced crystal morphology regulation and low-temperature antisolvent crystallization process. The long-chain molecules of PVP are adsorbed on the surface of drug molecules through van der Waals forces / hydrogen bonds, forming a steric hindrance layer, which prevents excessive particle aggregation during crystallization, thereby reducing crystal size and increasing specific surface area. Furthermore, PVP has a stronger affinity for specific crystal faces of the α-crystal form (such as hydrophobic faces), guiding the preferential formation and stable existence of the α-crystal form. In addition, during the preparation process of this invention, an organic phase solution of vortioxetine hydrobromide (40~60℃) at a relatively high temperature is added to pre-cooled water (5~10℃). Due to the large temperature gradient, the solubility of vortioxetine hydrobromide in the cold water drops sharply, instantly reaching a high supersaturation, thereby achieving explosive nucleation. Thus, under the guidance of seed crystals and the encapsulation of PVP, this smaller α-crystal form of vortioxetine hydrobromide is stably generated.

[0015] Furthermore, the present invention also provides the following preferred embodiments:

[0016] The organic solvents mentioned above are preferably reagents that can fully dissolve vortioxetine hydrobromide, including but not limited to one of dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). To improve the dissolution effect, the stirring time can be appropriately extended, such as 25~35 min.

[0017] The PVPs mentioned above are preferably of high molecular weight type, defined by K value, with preferred models such as 29 K, 40 K or 54 K.

[0018] The aforementioned seed crystals are the α-crystal form of vortioxetine hydrobromide, made from pure micro powder with a particle size of less than 15 μm, and added at 0.5% to 1% (mass fraction) of vortioxetine hydrobromide.

[0019] The temperature of the precooling water is 5~10℃, and the volume of the precooling water is 2~10 times that of the organic solvent.

[0020] The above-mentioned flow addition is carried out at a constant rate and can be completed within 1 to 3 hours.

[0021] The crystal growth period is 1-2 hours. After crystal growth, the solid portion is filtered, washed with water, and dried under vacuum until constant weight is obtained.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] 1. In view of the shortcomings of existing methods for preparing vortioxetine hydrobromide α crystal form, which use toxic and highly volatile reagents, the optimized preparation method of this invention does not introduce highly irritating reagents, has mild preparation conditions, is simpler in process, and achieves a yield of 91% or more, making it very suitable for industrial scale-up production.

[0024] 2. To address the shortcomings of existing vortioxetine hydrobromide α-crystals, such as insufficient solubility and poor processing performance, the α-crystals prepared by the method of this invention have a particle size of less than 15 μm and a specific surface area higher than 1600 m². 2 The α-crystal form, at a concentration of / kg, offers the advantage of faster dissolution compared to other α-crystal forms produced by different processes. The spherical crystals exhibit good flowability, which is more beneficial for downstream formulation processing. Since the commercially available dosage forms of vortioxetine hydrobromide are currently mainly tablets, this α-crystal form provided by the present invention effectively compensates for the shortcomings of existing active pharmaceutical ingredients and has promising application prospects. Attached Figure Description

[0025] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0026] Figure 1 The image shows the X-ray powder diffraction (PXRD) pattern of the α-crystal form of vortioxetine hydrobromide obtained in Example 1.

[0027] Figure 2 The image shows the morphology of the α-crystal form of vortioxetine hydrobromide obtained in Example 1.

[0028] Figure 3 This is an electron microscope image of the α-crystal form of vortioxetine hydrobromide obtained in Example 1. Detailed Implementation

[0029] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. 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 this invention pertains.

[0030] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0031] In the context of this specification, the word "including" is considered to mean "particularly including". It should not be interpreted as "consisting of only".

[0032] Terminology Explanation:

[0033] 1. Dv90 (90% volume average particle size): refers to the diameter of the particles that occupy 90% of the volume when the additive particles are arranged in ascending order of diameter.

[0034] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and experimental examples.

[0035] Example 1

[0036] 10 g of vortioxetine hydrobromide and 50 mL of DMAC were added to a crystallizer and stirred at 50 °C for 30 min to dissolve. The insoluble matter was filtered off, and the filtrate was collected and kept at 50 °C to obtain a vortioxetine hydrobromide DMAC solution. 15 g of PVP (29 K) was added to the solution, and then the mixture was stirred at a constant temperature for 0.5 h to obtain an organic phase solution of vortioxetine hydrobromide.

[0037] In another crystallizer, pre-cool 200 mL of purified water to 5 °C, add 0.05 g of α-crystal form as seed crystals, and stir to disperse. The organic phase solution of vortioxetine hydrobromide is then uniformly added to the pre-cooled purified water over 2 h with continuous stirring. After the addition is complete, crystallization continues for another 2 h. The mixture is filtered, and the filter cake is washed with 5 mL of purified water. The filter cake is then vacuum-dried at 45 °C to constant weight.

[0038] The product obtained in this embodiment weighed 9.33 g, with a yield of 93.3%. PXRD analysis showed it to be α-crystalline with a Dv(90) of 10.97 μm and a specific surface area of ​​1892 m². 2 / kg.

[0039] Example 2

[0040] 10 g of vortioxetine hydrobromide and 70 mL of DMAC were added to a crystallizer and stirred at 45 °C for 30 min to dissolve. The insoluble matter was filtered off, and the filtrate was collected and kept at 45 °C to obtain a vortioxetine hydrobromide DMAC solution. 10 g of PVP (40 K) was added to the solution, and then the mixture was stirred at a constant temperature for 1 h to obtain an organic phase solution of vortioxetine hydrobromide.

[0041] In another crystallizer, 400 mL of purified water was pre-cooled to 10 °C, and 0.1 g of α-crystal form was added as seed crystals and stirred to disperse. The organic phase solution of vortioxetine hydrobromide was added to the pre-cooled purified water at a uniform rate over 1 h, with continuous stirring during the addition. After the addition was completed, crystallization continued for 2 h. The mixture was filtered, and the filter cake was washed with 10 mL of purified water. The filter cake was then vacuum dried at 40 °C to constant weight.

[0042] The product obtained in this embodiment weighed 9.12 g, with a yield of 91.2%. PXRD analysis showed it to be α-crystalline, with a Dv(90) of 10.02 μm and a specific surface area of ​​2013 m². 2 / kg.

[0043] Example 3

[0044] 10 g of vortioxetine hydrobromide and 60 mL of DMSO were added to a crystallizer and stirred at 55 °C for 30 min to dissolve. The insoluble matter was filtered off, and the filtrate was collected and kept at 55 °C to obtain a vortioxetine hydrobromide DMAC solution. 20 g of PVP (54 K) was added to the solution, and then the mixture was stirred at a constant temperature for 0.5 h to obtain an organic phase solution of vortioxetine hydrobromide.

[0045] In another crystallizer, pre-cool 300 mL of purified water to 5 °C, add 0.1 g of α-form as seed crystals, and stir to disperse. The organic phase solution of vortioxetine hydrobromide is then uniformly added to the pre-cooled purified water over 3 h with continuous stirring. After the addition is complete, crystallization continues for 2 h. The mixture is filtered, the filter cake is washed with 5 mL of purified water, and then vacuum-dried at 50 °C to constant weight.

[0046] The product obtained in this embodiment weighed 9.35 g, with a yield of 93.5%. PXRD analysis showed it to be α-crystalline with a Dv(90) of 9.53 μm and a specific surface area of ​​2115 m². 2 / kg.

[0047] Example 4

[0048] 10 g of vortioxetine hydrobromide and 100 mL of DMF were added to a crystallizer and stirred at 40 °C for 30 min to dissolve. The insoluble matter was filtered off, and the filtrate was collected and kept at 40 °C to obtain a vortioxetine hydrobromide DMAC solution. 25 g of PVP (40 K) was added to the solution, and then the mixture was stirred at a constant temperature for 1 h to obtain an organic phase solution of vortioxetine hydrobromide.

[0049] In another crystallizer, pre-cool 500 mL of purified water to 10 °C, add 0.05 g of α-crystal form as seed crystals, and stir to disperse. The organic phase solution of vortioxetine hydrobromide is then uniformly added to the pre-cooled purified water over 2 h with continuous stirring. After the addition is complete, crystallization continues for another 2 h. The mixture is filtered, the filter cake is washed with 10 mL of purified water, and then vacuum-dried at 50 °C to constant weight.

[0050] The product obtained in this embodiment weighed 9.28 g, with a yield of 92.8%. PXRD analysis showed it to be α-crystalline with a Dv(90) of 11.65 μm and a specific surface area of ​​1855 m². 2 / kg.

[0051] Example 5

[0052] 10 g of vortioxetine hydrobromide and 50 mL of DMF were added to a crystallizer and stirred at 50 °C for 30 min to dissolve. The insoluble matter was filtered off, and the filtrate was collected and kept at 50 °C to obtain a vortioxetine hydrobromide DMAC solution. 15 g of PVP (54 K) was added to the solution, and then the mixture was stirred at a constant temperature for 1 h to obtain an organic phase solution of vortioxetine hydrobromide.

[0053] In another crystallizer, pre-cool 500 mL of purified water to 10 °C, add 0.1 g of α-crystal form as seed crystals, and stir to disperse. The organic phase solution of vortioxetine hydrobromide is then uniformly added to the pre-cooled purified water over 3 h with continuous stirring. After the addition is complete, crystallization continues for 1 h. The mixture is filtered, the filter cake is washed with 5 mL of purified water, and then vacuum-dried at 45 °C to constant weight.

[0054] The product obtained in this embodiment weighed 9.47 g, with a yield of 94.7%. PXRD analysis showed it to be α-crystalline with a Dv(90) of 14.29 μm and a specific surface area of ​​1656 m². 2 / kg.

[0055] Example 6

[0056] 10 g of vortioxetine hydrobromide and 50 mL of DMSO were added to a crystallizer and stirred at 60 °C for 30 min to dissolve. The insoluble matter was filtered off, and the filtrate was collected and kept at 60 °C to obtain a vortioxetine hydrobromide DMAC solution. 15 g of PVP (29 K) was added to the solution, and then the mixture was stirred at a constant temperature for 0.5 h to obtain an organic phase solution of vortioxetine hydrobromide.

[0057] In another crystallizer, pre-cool 300 mL of purified water to 5 °C, add 0.05 g of α-crystal form as seed crystals, and stir to disperse. The organic phase solution of vortioxetine hydrobromide is then uniformly added to the pre-cooled purified water over 1 h with continuous stirring. After the addition is complete, crystallization continues for another 1 h. The mixture is filtered, and the filter cake is washed with 5 mL of purified water. The filter cake is then vacuum-dried at 40 °C to constant weight.

[0058] The product obtained in this embodiment weighed 9.19 g, with a yield of 91.9%. PXRD analysis showed it to be α-crystalline with a Dv(90) of 12.63 μm and a specific surface area of ​​1773 m². 2 / kg.

[0059] Example 7

[0060] 10 g of vortioxetine hydrobromide and 90 mL of DMAC were added to a crystallizer and stirred at 450 °C for 30 min to dissolve. The insoluble matter was filtered off, and the filtrate was collected and kept at 50 °C to obtain a vortioxetine hydrobromide DMAC solution. 20 g of PVP (29 K) was added to the solution, and then the mixture was stirred at a constant temperature for 0.5 h to obtain an organic phase solution of vortioxetine hydrobromide.

[0061] In another crystallizer, pre-cool 200 mL of purified water to 10 °C, add 0.1 g of α-crystal form as seed crystals, and stir to disperse. The organic phase solution of vortioxetine hydrobromide is then uniformly added to the pre-cooled purified water over 2 h with continuous stirring. After the addition is complete, crystallization continues for another 2 h. The mixture is filtered, the filter cake is washed with 10 mL of purified water, and then vacuum-dried at 40 °C to constant weight.

[0062] The product obtained in this embodiment weighed 9.29 g, with a yield of 92.9%. PXRD analysis showed it to be α-crystalline with a Dv(90) of 8.99 μm and a specific surface area of ​​2184 m². 2 / kg.

[0063] Performance verification

[0064] 1. Crystal form confirmation

[0065] It has been confirmed that the characteristic peaks in the PXRD of the crystalline compounds obtained in Examples 1-7 above are consistent with the α-crystalline form prepared in Example 4a of the original patent WO2007144005.

[0066] 2. Solubility performance test

[0067] The solubility of the α-crystal form of vortioxetine hydrobromide obtained in Examples 1-7 above compared with the sample obtained by the process of the original patent WO2007144005 is shown in Table 1 below:

[0068] Table 1

[0069]

[0070] As shown in Table 1, the α-crystalline phases obtained in Examples 1-7 exhibited significantly better solubility than the original sample (Experimental Example 1) within 15 minutes, with a solubility exceeding that of the original sample by more than double. At 3 hours, both Examples 1-7 and Experimental Example 1 reached their maximum solubility; however, at this point, the solubility of Examples 1-7 remained superior to that of Experimental Example 1.

[0071] 3. Liquidity Test

[0072] Based on the static angle of repose determination method in the "Guidelines for Determination of Powder Flowability" issued by the National Pharmacopoeia Commission, the vortioxetine hydrobromide samples obtained in Examples 1-7 of this invention were compared with the sample obtained in Test Example 1 according to the original research process. The results are shown in Table 2 below:

[0073] Table 2

[0074]

[0075] As shown in Table 2, the angle of repose of the α-phase obtained in Examples 1-7 is significantly smaller than that in Example 1, almost half that of Example 1. This indicates that the internal frictional resistance between powder particles prepared by the method of the present invention is reduced, energy loss during flow is decreased, and flowability is significantly improved. Generally, it is considered in the art that a repose angle ≤30° indicates excellent flowability. In scenarios such as dispensing and conveying, powders with a small angle of repose are less likely to clog equipment, resulting in higher dosage accuracy. Therefore, the α-phase of vortioxetine hydrobromide provided by the present invention has better processing performance.

[0076] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing the α-crystal form of vortioxetine hydrobromide with high fluidity, characterized in that, The process includes the following steps: adding vortioxetine hydrobromide to 5-10 times its volume of organic solvent and stirring at 40-60°C to dissolve it into a saturated solution and keeping it warm; then adding 1-2.5 times its mass of PVP to vortioxetine hydrobromide to obtain an organic phase solution of vortioxetine hydrobromide. Add seed crystals to pre-cooled water and disperse evenly. While stirring, add the above organic phase solution of vortioxetine hydrobromide and let it stand to grow crystals. Filter to obtain the final product.

2. The method for preparing the highly fluid α-crystal form of vortioxetine hydrobromide as described in claim 1, characterized in that, The organic solvent is, but is not limited to, one of DMAC, DMF, and DMSO.

3. The method for preparing the highly fluid α-crystal form of vortioxetine hydrobromide as described in claim 2, characterized in that, The organic solvent is DMAC.

4. The method for preparing the highly fluid α-crystal form of vortioxetine hydrobromide as described in claim 1, characterized in that, Add vortioxetine hydrobromide to 5-10 times its volume of organic solvent and stir at 40-60°C for 25-35 minutes.

5. The method for preparing the highly fluid α-crystal form of vortioxetine hydrobromide as described in claim 1, characterized in that, The PVP is selected from 29 K, 40 K, or 54 K.

6. The method for preparing the highly fluid α-crystal form of vortioxetine hydrobromide as described in claim 1, characterized in that, The seed crystal is the α-crystal form of vortioxetine hydrobromide, and the amount added is 0.5% to 1% of the mass of vortioxetine hydrobromide.

7. The method for preparing the highly fluid α-crystal form of vortioxetine hydrobromide as described in claim 1, characterized in that, The temperature of the precooling water is 5~10℃, and the volume of the precooling water is 2~6 times that of the organic solvent.

8. The method for preparing the highly fluid α-crystal form of vortioxetine hydrobromide as described in claim 1, characterized in that, The feeding process is carried out at a constant rate and is completed within 1 to 3 hours.

9. The method for preparing the highly fluid α-crystal form of vortioxetine hydrobromide as described in claim 1, characterized in that, The time for static crystal growth is 1-2 hours. After crystal growth is completed, the solid part is filtered out, washed with water, and dried under vacuum until constant weight is obtained.

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