A process for the preparation of a small particle size crystalline form a of tegoprazan

Abstract

The present application belongs to the technical field of crystalline compounds, and particularly relates to a preparation method of small-particle-size tigositabine crystal form A. The method comprises dissolving tigositabine crude product in an acidic mixed solvent (pH 2-3) containing a surfactant, removing impurities by hot filtration after constant-temperature stirring, transferring the filtrate into a crystallizer, pressurizing and cooling, slowly releasing pressure, adding an alkali solution to adjust to neutrality, and obtaining the product after low-temperature aging, filtration and drying. The present application effectively inhibits crystal grain agglomeration and growth by means of synergistic methods such as surfactant regulation, controllable nucleation by pressurizing and cooling, slow pressure release and mild alkali adjustment crystallization, and small-particle-size crystal form A with a Dv(90) of 7.46-8.97 μm is prepared. The product yield reaches 85.5%-88.0%, the dissolution rate in water is significantly better than that of the original research and the product of the comparative example, and the dissolution equilibrium can be basically reached in 30 min, thus solving the technical pain points of large crystal size and slow dissolution in the prior art, and the present application can be widely used in the research and production of tigositabine preparations.

Description

Technical Field

[0001] This invention belongs to the field of crystal compound technology, specifically relating to a method for preparing small-particle ticorla crystal form A. 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] Tegoprazan, chemically named (S)-4-[(5,7-difluorobenzodihydropyran-4-yl)oxy]-N,N,2-trimethyl-1H-benzo[d]imidazolium-6-carboxamide, is a novel potassium-competitive acid blocker (P CAB). This product can competitively and reversibly block H2O in gastric parietal cells. + / K + K of ATPase + The drug binds to specific sites, allowing for rapid onset of action without acid activation. It provides strong and long-lasting acid suppression and is unaffected by food intake or metabolic genotype. First approved in South Korea in 2018, it was launched in China in 2022. Clinically used for acid-related diseases such as gastroesophageal reflux disease, erosive esophagitis, and gastric and duodenal ulcers, it has significant clinical value and broad market prospects.

[0004] Tiggorasen belongs to the BCS Class II drugs and has extremely poor solubility, resulting in low in vivo dissolution rate and poor absorption, which has become a key technical bottleneck limiting clinical efficacy and dosage form development. It also leads to drug waste, increased medication costs, and higher prices. To improve the poor solubility and low dissolution rate of tiggorasen, existing technologies have focused on two main pathways: crystal form regulation and salt formation modification. Regarding crystal form control, patent CN119222643 describes crystal form B obtained in a mixed solvent system of ethers and esters; patent CN121293190 describes crystal form DCVI obtained in a mixed solvent system of ethers and alkanes; and patents CN120131557 and CN116715660 disclose amorphous forms and their preparation methods. Compared to crystal form A disclosed in the original patent CN107207478, these new crystal forms improve the solubility of the original crystal form; however, they also have many important shortcomings. First, changes in crystal form are subject to strict regulatory constraints and pharmaceutical risks. According to the Pharmacopoeia of the People's Republic of China and domestic and international drug regulatory regulations, drug crystal form is a critical quality attribute. New crystal forms require comprehensive pharmaceutical research, safety evaluation, and even restarting clinical trials before they can be used pharmaceutically. This not only involves a research and development cycle of several years but also requires enormous human, material, and financial resources, significantly increasing drug development costs and the difficulty of market entry. Furthermore, academic papers such as "Structure Determination of Tegoprazan ((S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-formamide) Polymorphs A and B by Laboratory X-Ray Powder Diffraction" and "Comprehensive Investigation of Polymorphic Stability and PhaseTransformation Kinetics in Both Tegoprazan and others pointed out that crystal form A is a thermodynamically stable crystal form, and other crystal forms will transform into crystal form A under normal storage conditions. Based on this, it is believed that these metastable crystal forms with strong solubility may pose storage stability risks and are difficult to obtain market approval.

[0005] Regarding salt formation modification, patent CN120923480A discloses tigorasen's monoethyl fumarate salt; patent CN119219615A discloses tigorasen's pyroglutamate salt. Both improve the solubility of tigorasen through salt formation. However, similar to the development of new crystal forms, the salt formation pathway also faces regulatory constraints: according to the current "Classification of Chemical Drug Registration and Requirements for Application Materials," new salt forms belong to Class 2 modified new drugs, and clinical trials must be completed and clinical value demonstrated before market launch, which undoubtedly brings significant time costs and R&D investment.

[0006] To address the aforementioned limitations, this invention proposes that improving the dissolution rate of ticorax crystal form A through particle size control strategies could potentially enhance tablet solubility. Numerous studies have shown that for poorly soluble drugs in BCS Class II, controlling the particle size within an ultrafine range can effectively increase the drug's specific surface area and surface energy, thereby significantly improving its dissolution rate and alleviating the challenges in clinical application and industrial production caused by insufficient solubility in the short term. Summary of the Invention

[0007] To address the problems existing in the prior art, this invention designs and adjusts the particle size of ticoraxen crystal form A to improve the solubility of the drug formulation. To achieve this objective, this invention employs a crystallization process, simultaneously achieving ultrafine particle size control during the refining of the active pharmaceutical ingredient. While obtaining ultrafine particle size products, it avoids problems such as dust pollution, material loss, and crystal form destruction caused by traditional pulverization processes. It combines process economy, environmental friendliness, and quality controllability, and has significant technical value and practical significance for improving the quality of ticoraxen active pharmaceutical ingredient, enhancing clinical efficacy, and reducing industrial production costs.

[0008] To achieve the above-mentioned technical effects, the present invention provides the following technical content: This invention provides a method for preparing small-particle ticagogue crystal form A, comprising the following steps: (1) Dissolve crude ticorlan in an organic solution of surfactant, heat and stir and adjust the pH of the system to acidic, continue stirring and filter out the insoluble matter; (2) The obtained filtrate is transferred to a crystallizer, pressurized and cooled, then depressurized to atmospheric pressure and stirred rapidly; (3) Add alkaline aqueous solution to adjust the pH of the system to neutral, continue stirring at low temperature for a period of time, filter, and retain the solid part to obtain the final product.

[0009] Since the stable crystal form of tegorasen is crystal form A, it is generally believed in the art that the tegorasen contained in the crude product is usually crystal form A. Since tegorasen is a basic nitrogen-containing heterocyclic drug, in the above step (1), the tegorasen in the crude product is dissolved as a salt under acidic conditions to ensure that the raw material completely enters the liquid phase; the organic solvent can reduce the surface tension of the system and improve wettability, which is beneficial to the subsequent formation of fine crystals; and the surfactant is adsorbed on the crystal growth surface to inhibit excessive crystal growth.

[0010] In some embodiments where step (1) has a better effect, the surfactant is one of polyvinylpyrrolidone K15, polyvinylpyrrolidone K30, PEG200, PEG400, Tween 20, and Tween 80; in the acidic mixed solution, the amount of surfactant added is 100 to 300 ppm.

[0011] The organic solution is a mixture of organic solvent and water in a volume ratio of 5~15:95~85, wherein the organic solvent is one of ketones (acetone, butanone), alcohols (methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol), acetonitrile, tetrahydrofuran, and dioxane.

[0012] Dissolve crude ticorax in an organic solution of surfactant, heat the system to 35-45°C, add acetic acid (2-5 mol / L) or hydrochloric acid (1-3 mol / L) to adjust the pH of the system to 2-3, and continue stirring at the above temperature for 30-60 min.

[0013] In step (2) above, pressurization can increase the supersaturation of the solution and compress the intermolecular distance, promoting orderly arrangement, which is beneficial to maintaining crystal form A. At this time, cooling is carried out to create a mild supersaturated system, thereby promoting the slow and uniform growth of crystals. In the depressurization stage, the supersaturation is released in a slow depressurization manner to avoid a sudden drop in pressure that causes a large amount of crystallization.

[0014] In some embodiments where step (2) has a better effect, after the filtrate is transferred to the crystallization vessel, it is pressurized to 2.0 ~ 3.0 MPa, cooled to 0 ~ 5℃, and the cooling rate is 10 ~ 15 ℃ / h; the depressurization rate is 3 ~ 6 MPa / h, and the stirring speed is increased to 450 ~ 550 rpm when depressurizing.

[0015] In step (3) above, feasible alkaline aqueous solutions include sodium carbonate, sodium hydroxide, and sodium bicarbonate aqueous solutions. According to the research of this invention, the flow rate of alkaline aqueous solutions has an important influence on the control of crystal particle size. If the flow rate is too fast, it will cause a sudden change in local pH and a large amount of crystal precipitation. If the flow rate is too slow, it will also be difficult to inhibit crystal growth. The more suitable flow time for the above alkaline solutions is 20 to 40 minutes.

[0016] In step (3), the low temperature condition is 0~5℃. After stirring at this temperature for ~2h, filter the cake, rinse it with purified water and dry it to obtain the final product.

[0017] Compared with the prior art, the beneficial effects of the present invention are: 1. The tigorasine prepared by this invention achieves a small particle size (D) without altering its pharmaceutical crystal form (crystal form A). 50 <5 μm, D 90 <10 μm), uniform particle size distribution, faster dissolution rate, and avoids many problems caused by secondary crushing in traditional processes; 2. This crystallization method is simple to operate, highly controllable, and has the advantages of low cost, short working time, high yield, no scale-up effect, and good reproducibility, making it suitable for industrial production. Attached Figure Description

[0018] 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.

[0019] Figure 1 The particle size distribution diagram of ticoraxen prepared in Example 1; Figure 2 Micrograph of ticoraxan prepared in Example 1; Figure 3 X-ray powder diffraction pattern of ticoraxan prepared in Example 1; Figure 4 The X-ray powder diffraction pattern of ticorax crystal form A obtained according to the original process in Comparative Example 4 is shown. Detailed Implementation

[0020] 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.

[0021] 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 invention, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0022] In the context of this invention, the word "comprising" is considered to mean "particularly including". It should not be interpreted as "consisting of only".

[0023] In the description of this invention, it should be understood that the term "and / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A existing alone, A and B existing simultaneously, and B existing alone. The symbol " / " in this document indicates that the related objects are in an "or" relationship; for example, A / B means A or B.

[0024] In the description of embodiments of the present invention, the words "exemplary" or "for example" are used to indicate that they are examples, illustrations, or descriptions. Any embodiment or design that is described as "exemplary" or "for example" in the embodiments of the present invention should not be construed as being more preferred or advantageous than other embodiments or design. Specifically, the use of the words "exemplary" or "for example" is intended to present the relevant concepts in a specific manner.

[0025] In the description of the embodiments of the present invention, unless otherwise stated, "a plurality of" means two or more.

[0026] To enable those skilled in the art to more clearly 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 comparative examples. The crude ticorax used in the following embodiments and comparative examples are all from the same batch, all of crystal form A, with an HPLC purity of 98.55%.

[0027] Example 1 In this embodiment, a method for preparing small-particle-size ticagogue crystal form A is provided, and the specific steps are as follows: (1) Dissolve 10g of crude ticoraxate in an aqueous solution of 150g acetone (10%). v / v Add 100 ppm of polyvinylpyrrolidone K15 to the mixture and heat the system to 35°C. Adjust the pH to 2.5 with 1 mol / L hydrochloric acid, maintain the temperature at 35°C and stir continuously for 45 min. Filter while hot to remove insoluble matter and obtain the filtrate.

[0028] (2) Transfer the above filtrate into a crystallizer and pressurize it to 2.0 MPa; cool it down to 2 ℃ at a rate of 12 ℃ / h; depressurize it to atmospheric pressure at a rate of 3 MPa / h, and increase the stirring speed to 500 rpm during the depressurization process.

[0029] (3) Add sodium carbonate aqueous solution to the system obtained in step (2) for 25 min and adjust the pH to 8. Continue stirring at 2 °C for 1.5 h, filter, rinse the filter cake with 1 part purified water, collect the filter cake, and vacuum dry at 45 °C to constant weight to obtain ticorax product.

[0030] The yield of the product was 87.4%. The particle size Dv(90) was 8.03 μm.

[0031] Example 2 In this embodiment, another method for preparing small-particle ticorla crystal form A is provided, and the specific steps are as follows: (1) Dissolve 10 g of crude tegopramine in 225 g of an aqueous solution of tert-butanol (15%). v / v Add 300 ppm of Tween 80 to the mixture and heat the system to 40°C. Adjust the pH to 2 with 5 mol / L acetic acid, maintain the temperature at 40°C and stir continuously for 30 min. Filter while hot to remove insoluble matter and retain the filtrate.

[0032] (2) Transfer the above filtrate into a crystallizer and pressurize it to 2.5 MPa; cool it down to 5 ℃ at a rate of 10 ℃ / h; depressurize it to atmospheric pressure at a rate of 4.5 MPa / h, and increase the stirring speed to 500 rpm during the depressurization process.

[0033] (3) Add sodium hydroxide aqueous solution to the system obtained in step (2) for 30 min and adjust the pH to 7. Continue stirring at 5 °C for 1 h, filter, rinse the filter cake with twice the amount of purified water, collect the filter cake, and vacuum dry it at 45 °C to constant weight to obtain ticorax product.

[0034] The yield of the product was 85.5%. The particle size Dv(90) was 7.96 μm.

[0035] Example 3 In this embodiment, another method for preparing small-particle ticorla crystal form A is provided, and the specific steps are as follows: (1) Dissolve 10g of crude tigorapa in an aqueous solution of 300g of butanone (5%). ,v / v Add 200 ppm of PEG400 to the mixture and heat the system to 45 °C. Adjust the pH to 3 with 3 mol / L acetic acid, maintain the temperature at 45 °C and stir continuously for 60 min. Filter while hot to remove insoluble matter and obtain the filtrate.

[0036] (2) Transfer the above filtrate into a crystallizer and pressurize it to 3.0 MPa; cool it down to 0℃ at a rate of 15℃ / h; depressurize it to atmospheric pressure at a rate of 6MPa / h, and increase the stirring speed to 500 rpm during the depressurization process.

[0037] (3) Add sodium bicarbonate aqueous solution to the system obtained in step (2) for 40 min and adjust the pH to 8. Continue stirring at 0℃ for 2 h, filter, rinse the filter cake with 3 times the amount of purified water, collect the filter cake, and vacuum dry it at 45℃ to constant weight to obtain ticorax product.

[0038] The yield of the product was 85.7%. The particle size Dv(90) was 8.97 μm.

[0039] Example 4 In this embodiment, another method for preparing small-particle ticorla crystal form A is provided, and the specific steps are as follows: (1) Dissolve 10g of crude ticoraxate in 180g of an aqueous solution of acetonitrile (8%). v / v Add 150 ppm of PEG200 to the mixture and heat the system to 38°C. Adjust the pH to 2.8 with 2 mol / L hydrochloric acid, maintain the temperature at 38°C and stir continuously for 50 min. Filter while hot to remove insoluble matter and obtain the filtrate.

[0040] (2) Transfer the above filtrate into a crystallizer and pressurize it to 2.2 MPa; cool it down to 4℃ at a rate of 11℃ / h; depressurize it to atmospheric pressure at a rate of 3.5MPa / h, and increase the stirring speed to 500 rpm during the depressurization process.

[0041] (3) Add sodium carbonate aqueous solution to the system obtained in step (2) for 25 min and adjust the pH to 7.2. Continue stirring at 4℃ for 1.8 h, filter, rinse the filter cake with 1.5 times the amount of purified water, collect the filter cake, and vacuum dry it at 45℃ to constant weight to obtain ticorax product.

[0042] The yield of the product was 87.7%. The particle size Dv(90) was 7.46 μm.

[0043] Example 5 In this embodiment, another method for preparing small-particle ticorla crystal form A is provided, and the specific steps are as follows: (1) Dissolve 10g of crude ticoraxate in 250g of an aqueous solution of dioxane (12%). v / v Add 250 ppm of Tween 20 to the mixture and heat the system to 42°C. Adjust the pH to 2.2 with 4 mol / L acetic acid, maintain the temperature at 42°C and stir continuously for 35 min. Filter while hot to remove insoluble matter and obtain the filtrate.

[0044] (2) Transfer the above filtrate into a crystallizer and pressurize it to 2.8 MPa; cool it down to 1℃ at a rate of 14℃ / h; depressurize it to atmospheric pressure at a rate of 5.5MPa / h, and increase the stirring speed to 500 rpm during the depressurization process.

[0045] (3) Add sodium hydroxide aqueous solution to the system obtained in step (2) for 35 min and adjust the pH to 7.8. Continue stirring at 1℃ for 1.2 h, filter, rinse the filter cake with 2.5 times the amount of purified water, collect the filter cake, and vacuum dry it at 45℃ to constant weight to obtain ticorax product.

[0046] The yield of the product was 88.0%. The particle size Dv(90) was 7.95 μm.

[0047] Example 6 In this embodiment, another method for preparing small-particle ticorla crystal form A is provided, and the specific steps are as follows: (1) Dissolve 10g of crude ticoraxate in 200g of an aqueous solution of isopropanol (6%). v / v Add 180 ppm of polyvinylpyrrolidone K30 to the mixture and heat the system to 36 °C. Adjust the pH to 2.7 with 2.5 mol / L hydrochloric acid, maintain the temperature at 36 °C and stir continuously for 40 min. Filter while hot to remove insoluble matter and obtain the filtrate.

[0048] (2) Transfer the above filtrate into a crystallizer and pressurize it to 2.3 MPa; cool it down to 3℃ at a rate of 12℃ / h; depressurize it to atmospheric pressure at a rate of 4MPa / h, and increase the stirring speed to 500 rpm during the depressurization process.

[0049] (3) Add sodium bicarbonate aqueous solution to the system obtained in step (2) for 28 min and adjust the pH to 7.3. Continue stirring at 3℃ for 1.3 h, filter, wash the filter cake with 1.8 times the amount of purified water, collect the filter cake, and vacuum dry it at 45℃ to constant weight to obtain ticorax product.

[0050] The yield of the product was 86.3%. The particle size Dv(90) was 7.78 μm.

[0051] Example 7 In this embodiment, a method for preparing small-particle-size ticagogue crystal form A is provided, and the specific steps are as follows: (1) Dissolve 10g of crude ticoraxate in an aqueous solution of 280g of n-butanol (14%). v / v Add 200 ppm of PEG200 to the mixture and heat the system to 44°C. Adjust the pH to 2.3 with 3.5 mol / L acetic acid, maintain the temperature at 44°C and stir continuously for 55 min. Filter while hot to remove insoluble matter and obtain the filtrate.

[0052] (2) Transfer the above filtrate into a crystallizer and pressurize it to 2.7 MPa; cool it down to 2.5℃ at a rate of 13℃ / h; depressurize it to atmospheric pressure at a rate of 5MPa / h, and increase the stirring speed to 500 rpm during the depressurization process.

[0053] (3) Add sodium carbonate aqueous solution to the system obtained in step (2) for 32 min and adjust the pH to 7.7. Continue stirring at 2.5℃ for 1.6 h, filter, rinse the filter cake with 2.2 times the amount of purified water, collect the filter cake, and vacuum dry it at 45℃ to constant weight to obtain ticorax product.

[0054] The yield of the product was 85.9%. The particle size Dv(90) was 8.45 μm.

[0055] Comparative Example 1 This comparative example provides a crystallization method for ticoraxen, which differs from Example 1 in that the depressurization rate in step (2) exceeds the range of the technical solution and is 10 MPa / h. The specific operation is as follows: depressurize to atmospheric pressure at a rate of 10 MPa / h, and increase the stirring speed to 500 rpm during the depressurization process. The remaining settings are the same as in Example 1.

[0056] The yield of the product was 87.2%. The particle size Dv(90) was 31.15 μm.

[0057] Comparative Example 2 This comparative example provides a method for crystallizing ticoraxen, which differs from Example 1 in that no surfactant is added in step (1). The specific operation is as follows: 10g of crude ticoraxen is dissolved in an aqueous solution of 150g of acetone (10%). v / v In this case, the temperature of the system is raised to 35°C. The remaining settings are the same as in Example 1.

[0058] The yield of the product was 88.4%. The particle size Dv(90) was 30.92 μm.

[0059] Comparative Example 3 This comparative example provides a method for crystallizing ticoraxane, which differs from Example 1 in that step (3) uses a slow-flowing alkaline aqueous solution. The specific operation is as follows: add sodium carbonate aqueous solution, the flow time is 120 min, and adjust the pH to 8. The remaining settings are the same as in Example 1.

[0060] The yield of the product was 87.5%. The particle size Dv(90) was 37.94 μm.

[0061] Comparative Example 4 This comparative example uses the original preparation method for crystal form A: referring to the method in Example 2 of patent CN107207478, 50 g of ticoraxan was dissolved in 100 mL of methanol. After complete dissolution, the solution was slowly added dropwise to 900 mL of purified water, and stirred continuously at room temperature for 12 h. After filtration, the filter cake was collected and dried under vacuum at 40 °C to constant weight.

[0062] The product particle size Dv(90) is 102.30 μm.

[0063] Performance testing 1. Dissolution rate test Under constant temperature of 25 °C, the dissolution rate of ticoraxan obtained in Examples 1-7 and Comparative Examples 1-4 in 100 mL of water was determined.

[0064] Table 1. Solubility of ticoraxan obtained in the examples and comparative examples As shown in Table 1, the product yield in Comparative Example 1 was 87.2%, which was basically the same as that in Example 1 (87.4%). However, the particle size Dv(90) soared to 31.15 μm, much higher than the 8.03 μm in Example 1. The dissolution rate decreased significantly, with only 0.8 mg dissolved in 15 minutes and 1.2 mg dissolved in 30 minutes, and the time to reach dissolution equilibrium was extended to 2 hours. This comparison shows that the depressurization rate is one of the key parameters for controlling the particle size of the product. Comparative Example 1 used a rapid depressurization of 10 MPa / h. The sudden pressure drop caused an instantaneous burst of supersaturation in the system, resulting in the rapid generation and aggregation of a large number of crystal nuclei, forming large-particle crystals. As the particle size increases, the specific surface area of ​​the crystal decreases, and the dissolution rate decreases accordingly, ultimately leading to its dissolution performance being far inferior to that of the product in the examples.

[0065] The product yield of Comparative Example 2 was 88.4%, slightly higher than that of Example 1 (87.4%), but the particle size Dv(90) reached 30.92 μm, far exceeding that of Example 1; the dissolution rate decreased significantly, with a dissolution amount of 0.9 mg in 15 min and 1.3 mg in 30 min, requiring 2 h to reach dissolution equilibrium, indicating significantly inferior dissolution performance compared to the product of the examples. Since no surfactant was added to Comparative Example 2, the above comparative results demonstrate that surfactants have a good auxiliary dispersing effect and can inhibit crystal growth.

[0066] In Comparative Example 3, the particle size Dv(90) reached 37.94 μm, which is 4.7 times that of Example 1. It exhibited the worst dissolution rate, with only 0.7 mg dissolved in 15 minutes, 1.0 mg in 30 minutes, and 1.6 mg in 1 hour. Reaching dissolution equilibrium required more than 2 hours, indicating significantly lower solubility than all other examples. This demonstrates that the flow rate of the alkaline aqueous solution directly affects the uniformity of crystal precipitation and crystal size. The present invention employs a reasonable addition time of 25 minutes, allowing the system pH to rise slowly and uniformly, avoiding localized pH jumps and achieving stable precipitation of crystal form A, while also preventing crystal agglomeration. In contrast, Comparative Example 3 used a slow addition time of 120 minutes, resulting in an excessively slow pH rise and release of supersaturation. This allowed sufficient time for crystal growth, leading to continuous coarsening of the crystals and ultimately the formation of large-particle crystals. Furthermore, the slow addition also resulted in uneven crystal growth, with some crystals becoming excessively large, further reducing the dissolution rate. The results confirm that "appropriate alkaline aqueous solution addition time" is an important parameter for controlling product particle size and ensuring solubility. Too slow addition will lead to rapid crystal growth and excessively large particle size.

[0067] XRD diffraction patterns of ticoraxen obtained in Comparative Example 1 and Comparative Example 4 ( Figure 3 and Figure 4 The locations of characteristic diffraction peaks in the two images (2) θ The values ​​are completely consistent, indicating that the ticoraxate crystal form A prepared in the embodiments of the present invention is the same as the original crystal form A, proving that the process of the present invention has not changed the target crystal form. However, the particle size of the product in Comparative Example 4 is as high as 102.30 μm, which is 12.7 times that of Example 1, and is the largest particle size among all comparative examples; the dissolution rate is the worst, with a dissolution amount of only 0.5 mg in 15 min, 0.7 mg in 30 min, 1.3 mg in 1 h, 1.9 mg in 2 h, and basically reaching dissolution equilibrium in 3 h. The dissolution performance is far inferior to that of the embodiments of the present invention and other comparative examples.

[0068] 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 small-particle-size ticorlan crystal form A, characterized in that, Includes the following steps: (1) Dissolve crude tegorane in an organic solution of surfactant, heat and stir and adjust the pH of the system to acidic, continue stirring and filter out insoluble matter. The surfactant is one of polyvinylpyrrolidone K15, polyvinylpyrrolidone K30, PEG200, PEG400, Tween 20 and Tween 80. (2) The obtained filtrate is transferred to a crystallizer, pressurized and cooled, then depressurized to atmospheric pressure and stirred rapidly at a rate of 3 to 6 MPa / h; (3) Add alkaline aqueous solution to adjust the pH of the system to neutral, continue stirring at low temperature for a period of time, filter, and retain the solid part to obtain the product; the time for adding alkaline aqueous solution is 20 ~ 40 min.

2. The method for preparing small-particle-size ticorlan crystal form A as described in claim 1, characterized in that, In step (1), the amount of surfactant added to the organic solution of the surfactant is 100 to 300 ppm.

3. The method for preparing small-particle-size ticorlan crystal form A as described in claim 1, characterized in that, In step (1), the organic solution is a mixture of organic solvent and water in a volume ratio of 5~15:95~85, wherein the organic solvent is one of acetone, butanone, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, acetonitrile, tetrahydrofuran, and dioxane.

4. The method for preparing small-particle-size ticorlan crystal form A as described in claim 1, characterized in that, In step (1), the crude ticoraxate is dissolved in an organic solution of surfactant, the system is heated to 35-45°C, 2-5 mol / L acetic acid or 1-3 mol / L hydrochloric acid is added to adjust the pH of the system to 2-3, and the temperature is maintained and stirring is continued for 30-60 min.

5. The method for preparing small-particle ticorlan crystal form A as described in claim 1, characterized in that, In step (2), after the filtrate is transferred to the crystallization vessel, it is pressurized to 2.0 ~ 3.0 MPa and cooled to 0 ~ 5℃ at a rate of 10 ~ 15℃ / h.

6. The method for preparing small-particle-size ticorlan crystal form A as described in claim 1, characterized in that, In step (2), the stirring speed is increased to 450~550 rpm when depressurizing.

7. The method for preparing small-particle ticorlan crystal form A as described in claim 1, characterized in that, In step (3), the alkaline aqueous solution is selected from aqueous solutions of sodium carbonate, sodium hydroxide or sodium bicarbonate.

8. The method for preparing small-particle-size ticorlan crystal form A as described in claim 1, characterized in that, In step (3), the low temperature condition is 0~5℃. After stirring at this temperature for ~2h, filter the cake, rinse it with purified water and dry it to obtain the final product.

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