Preparation process of canagliflozin semihydrate bulk drug

Abstract

The invention provides a preparation process of a canagliflozin semihydrate bulk drug, and belongs to the technical field of medicines. The preparation process of the canagliflozin semihydrate bulk drug comprises the following steps: dissolving a canagliflozin crude product in a methanol-normal propyl alcohol-water ternary mixed solvent system to obtain a dissolved mixture; the preparation method comprises the following steps: pre-treating commercially available canagliflozin hemihydrate as a seed crystal, filtering and drying; heating the dissolved mixture to 50-60 DEG C, cooling the mixture to 30-35 DEG C at a rate of 2-4 DEG C / min, adding pretreated semihydrate seed crystals, stirring the mixture at a constant temperature of 30-35 DEG C for 1-2 hours, cooling the mixture to 5-10 DEG C at a rate of 0.8-1.2 DEG C / min, and stirring and crystallizing the mixture for 3-5 hours; and after crystallization is completed, centrifuging for solid-liquid separation, washing a filter cake, separating a crystallized product, washing and drying to obtain the canagliflozin semihydrate. According to the invention, the purity and yield of the canagliflozin semihydrate bulk drug product can be improved.

Description

Technical Field

[0001] This invention application belongs to the field of pharmaceutical technology and relates to a preparation process of canagliflozin hemihydrate raw material drug. Background Art

[0002] As a sodium-glucose cotransporter 2 (SGLT2) inhibitor, the hemihydrate crystal form of canagliflozin (melting point 97 - 100 °C, characteristic PXRD peaks at 4.36°, 13.54°, etc.) is the core medicinal crystal form of the original research product (see invention patent application CN102675380A).

[0003] Existing preparation methods mainly adopt the solvent evaporation method or the antisolvent method in an ethanol-water system, but there are problems such as a long crystallization period (20 - 48 hours), incomplete removal of impurities (especially α-configuration isomers) (residual amount ≥ 1.0%), and excessive solvent residues. Invention patent application CN103694230A discloses that: purifying the raw material drug through an amino acid cocrystal technology solves the problem of high α-configuration impurity content in canagliflozin in the prior art, but it will introduce a new cocrystal former and increase the subsequent separation difficulty.

[0004] Therefore, developing a brand-new preparation process of canagliflozin hemihydrate raw material drug, avoiding the use of cocrystal formers, shortening the crystallization period, and having low / no residue of canagliflozin preparation impurities, is of great significance for meeting the industrial production requirements and is expected to bring a breakthrough to the research, production, and market of canagliflozin drugs. Summary of the Invention

[0005] This invention application provides a preparation process of canagliflozin hemihydrate raw material drug, aiming to partially or completely solve the technical problems in the prior art such as high residue of canagliflozin preparation impurities, long crystallization period, and the use of cocrystal formers. This invention application realizes the efficient preparation of hemihydrate by optimizing the ternary solvent system, pre-treating the seed crystal, and segmental temperature-controlled crystallization technology, and avoids the use of cocrystal formers. To achieve the purpose of this invention application, the technical solution of this invention application is as follows: In the first aspect, a preparation process of canagliflozin hemihydrate raw material drug includes: Step S100: Using a ternary mixed solvent system of methanol - n-propanol - water, where the volume ratio of n-propanol is 30%, dissolving the canagliflozin crude product therein to obtain a dissolved mixture, and the solubility difference between canagliflozin and α-configuration impurities ≥ 15 mg / mL; Step S200: Pretreating with commercially available canagliflozin hemihydrate as the seed crystal. The pretreatment includes soaking the commercially available canagliflozin hemihydrate in an organic solvent, ultrasonic treatment, then filtering and drying to make the hydroxyl density on the surface of the seed crystal ≥ 8×10 14 groups / cm2 ; Step S300: Heat the dissolved mixture to 50 - 60°C, then cool it to 30 - 35°C, add the hemihydrate seeds pretreated in Step S200, and stir while cooling to crystallize. Step S400: After crystallization is completed, separate, wash, and dry the crystallization product to obtain canagliflozin hemihydrate.

[0006] Optionally, in Step S100, the polarity gradient of the ternary solvent is methanol, n-propanol, and water, and the volume ratio of methanol - n-propanol - water is 2 - 3:3:4 - 5, such that the solubility of canagliflozin is ≥20 mg / mL and the solubility of α-impurity is ≤5 mg / mL; and / or, Step S300 includes: heating the dissolved mixture to 50 - 60°C, then cooling it at a rate of 2 - 4°C / min to 30 - 35°C, adding the hemihydrate seeds pretreated in Step S200, stirring at a constant temperature of 30 - 35°C for 1 - 2 hours, and then cooling it at a rate of 0.8 - 1.2°C / min to 5 - 10°C, and stirring to crystallize for 3 - 5 hours.

[0007] Optionally, in Step S100, the ratio of the crude canagliflozin to the ternary mixed solvent is 1:5 - 1:10 g / mL, and the dissolution temperature is 40 - 50°C.

[0008] Optionally, in Step S200, the ultrasonic power is 90 - 150 W, the frequency is 35 - 50 kHz, and the time is 10 - 20 minutes.

[0009] Optionally, in Step S200, the soaking organic solvent is selected from at least one of methanol, ethanol, and n-propanol. The commercially available canagliflozin hemihydrate seeds are soaked in methanol and / or ethanol at 30 - 70°C for 20 - 50 minutes; or, the commercially available canagliflozin hemihydrate seeds are soaked in n-propanol at 40 - 60°C for 25 - 45 minutes; or, the commercially available canagliflozin hemihydrate seeds are soaked in methanol and / or ethanol and n-propanol at 40 - 60°C for 25 - 45 minutes.

[0010] Optionally, in Step S300, the amount of seeds added is 0.1 - 0.5% of the mass of the crude canagliflozin.

[0011] Optionally, in Step S400, after crystallization is completed, perform centrifugation for solid-liquid separation, wash the filter cake, and the washing solution for the filter cake is a methanol-water mixed solution at 4 - 8°C, and the volume ratio of methanol to water in the methanol-water mixed solution is 1:2.

[0012] Optionally, in Step S400, the centrifugation speed is 3500 - 4000 rpm, and the centrifugation time is 10 - 12 minutes.

[0013] Optionally, in step S400, the filter cake is washed 2 - 3 times, and the amount of washing liquid used each time is 3 - 4 times the mass of the filter cake.

[0014] Optionally, in step S400, the drying condition is drying under vacuum at 40 - 45 °C for 8 - 10 hours.

[0015] In a second aspect, a canagliflozin hemihydrate raw material drug is prepared by using the preparation process of a canagliflozin hemihydrate raw material drug described in any one of the first aspects above. The purity of the raw material drug is ≥99.8%, the yield is ≥90%, and the crystal form of the canagliflozin raw material drug has a DSC endothermic peak at 98.5 ± 1 °C in X - ray powder diffraction.

[0016] Compared with the prior art, the beneficial effects of the present invention application are as follows: In the present invention application, through the overall coordination of a specific mixed solvent system and a specific seed pretreatment step, combined with precise crystallization control, the content of α - configuration impurities is effectively reduced. The product purity can reach more than 99.8%, far exceeding the product purity of similar processes. The yield of canagliflozin hemihydrate is increased to more than 90%, significantly improving the production efficiency and economic benefits; the entire preparation process cycle is shortened by about 40% compared with the traditional process, from about 20 hours to within 12 hours, greatly improving the production efficiency and reducing the production cost. Description of the Drawings

[0017] Figure 1 It is a schematic diagram of the PXRD (Powder X - Ray Diffraction) pattern of the canagliflozin hemihydrate prepared in Example 1 of the present invention application.

[0018] Figure 2 It is a schematic diagram of the DSC of the canagliflozin hemihydrate prepared in Example 1 of the present invention application. Detailed Embodiments

[0019] Next, the technical solutions in the embodiments of the present invention application will be clearly and completely described in conjunction with the drawings in the embodiments of the present invention application. Obviously, the described embodiments are only a part of the embodiments of the present invention application, rather than all of the embodiments; multiple times include once or twice or more than twice; the numerical range can be at least understood as including the endpoint values, and can also be reasonably understood according to the actual situation; based on the embodiments in the present invention application, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present invention application.

[0020] As used herein, "crude canagliflozin" means that it can be obtained by all preparation methods in the art.

[0021] As used herein, commercially available canagliflozin hemihydrate was purchased from Zhejiang Huayi Pharmaceutical Co., Ltd.

[0022] Preparation process of canagliflozin hemihydrate API In a first aspect, a preparation process of canagliflozin hemihydrate API includes: Step S100: Using a ternary mixed solvent system of methanol - n - propanol - water, where the volume percentage of n - propanol is 30%, dissolving the canagliflozin crude product therein to obtain a dissolved mixture, and the solubility difference between canagliflozin and α - configuration impurities ≥ 15 mg / mL; In step S100, methanol and n - propanol, as polar organic solvents, can effectively dissolve the organic part of canagliflozin, and the addition of water adjusts the overall polarity of the solvent system. This ternary combination optimizes the solubility of canagliflozin by balancing polarity and non - polarity, enabling the complete dissolution of the crude product.

[0023] In the present invention application, the hydroxyl group of n - propanol forms an intermolecular hydrogen bond with the carbonyl group of the canagliflozin molecule. Through the polar gradient synergistic effect (methanol dielectric constant 32.7 → n - propanol 20.1 → water 78.5), the co - dissolution rate of α - configuration impurities is reduced to less than 0.3%.

[0024] In the present invention application, the solubility difference between canagliflozin and α - configuration impurities in the solvent system ≥ 15 mg / mL means that canagliflozin hemihydrate is more likely to preferentially precipitate during the crystallization process, while α - configuration impurities tend to remain in the mother liquor. This difference provides favorable conditions for the crystallization of canagliflozin hemihydrate. Canagliflozin hemihydrate can slowly precipitate under suitable conditions, forming larger and uniform crystal particles, reducing the generation of fine crystals or amorphous substances, maintaining the stability and consistency of the crystal form, and thus reducing the canagliflozin residue in the mother liquor.

[0025] In the present invention application, the ternary solvent system optimizes the polarity, improves the solubility of canagliflozin, ensures the complete dissolution of the crude product, and lays a foundation for the subsequent crystallization process. Subsequently, by adjusting the proportion of the mixed solvent, the supersaturation of the crystallization solution and the crystal growth rate can be controlled, thereby affecting the crystal morphology and quality, helping to obtain an ideal crystallization product. Moreover, the appropriate solvent selection helps to separate the target product from impurities, improve the purity of the crystallization product, and reduce the burden of subsequent purification steps.

[0026] Step S200: Pretreating with commercially available canagliflozin hemihydrate as a seed crystal. The pretreatment includes soaking the commercially available canagliflozin hemihydrate in an organic solvent, ultrasonic treatment, and then filtering and drying to make the hydroxyl group density on the surface of the seed crystal ≥ 8×10 14 groups / cm 2 ; Specifically, step S200 includes: using commercially available canagliflozin hemihydrate as a seed crystal for pretreatment first. The pretreatment includes soaking the commercially available canagliflozin hemihydrate in an organic solvent, ultrasonic treatment, then filtering and drying, and then measuring the hydroxyl density on the surface of the seed crystal, so that the hydroxyl density on the surface of the seed crystal ≥ 8×10 14 groups / cm 2 ; In some embodiments, in step S200, the hydroxyl density on the surface of the seed crystal is measured by X-ray photoelectron spectroscopy.

[0027] In some embodiments, in step S200, commercially available seed crystals may adsorb impurities (such as moisture, dust or other organic substances) during storage or transportation, and these impurities will reduce the surface activity of the seed crystals.

[0028] In some embodiments, it can be soaked in organic solvents such as methanol, ethanol, and n-propanol. The solvent can dissolve or elute the impurities on the surface of the seed crystal at the corresponding temperature and time, thereby purifying the seed crystal. At the same time, the soaking in the organic solvent can activate the surface of the seed crystal, making it easier to interact with the solute molecules in the crystallization solution, and promoting the formation of crystal nuclei and crystal growth.

[0029] In some embodiments, ultrasonic treatment can generate cavitation effects and mechanical vibrations through ultrasonic waves with a power of 90 - 150 W and a frequency of 35 - 50 kHz, destroy the adsorption of impurities and seed crystals within 10 - 20 minutes, strip the impurities on the surface and in the micropores, and at the same time increase the surface roughness of the seed crystal, expose more active sites, and increase the specific surface area by 20 - 30%. The synergistic process of soaking in an organic solvent and ultrasonic treatment can increase the hydroxyl density on the surface of the seed crystal to ≥ 8×10 14 groups / cm 2 , significantly enhancing the hydrogen bond interaction with canagliflozin molecules and promoting the formation of crystal nuclei and crystal growth.

[0030] In some embodiments, the pretreatment process may remove too large or too small seed crystal particles, making the particle size of the seed crystal more uniform. A uniform particle size distribution helps to control the particle size consistency of the crystallization product. The selected organic solvent can be compatible with the crystallization system, and the soaking process allows the surface of the seed crystal to be fully in contact with the solvent, improving the dispersibility and stability of the seed crystal in the solution.

[0031] In step S200, by removing surface impurities, the pretreatment improves the purity of the seed crystal, reduces the interference of impurities on the crystallization process, thereby contributing to the production of higher purity canagliflozin hemihydrate. After pretreatment, the surface activity of the seed crystal is improved, which can effectively induce the formation of crystal nuclei, accelerate the crystallization process, and improve the crystallization efficiency. The pretreated seed crystal can control the crystal growth direction and speed. Ultimately, the pretreatment improves the purity and yield of the crystallization product, meeting the high standards required for drug preparation.

[0032] Step S300: Heat the dissolved mixture to 50 - 60°C, then cool it to 30 - 35°C, add the hemihydrate seeds pretreated in step S200, and stir while cooling to crystallize. In some embodiments, step S300 includes: heating the dissolved mixture to 50 - 60°C, then cooling it to 30 - 35°C at a rate of 2 - 4°C / min, adding the hemihydrate seeds pretreated in step S200, stirring at a constant temperature of 30 - 35°C for 1 - 2 hours, and then cooling it to 5 - 10°C at a rate of 0.8 - 1.2°C / min and stirring to crystallize for 3 - 5 hours. In some embodiments, heat the dissolved mixture to 50 - 60°C to ensure that canagliflozin is completely dissolved to form a uniform solution. In this stage, heat energy is used to overcome the interaction between the solute and the solvent, dispersing the solute molecules in the solution, laying the foundation for the subsequent formation of a supersaturated state.

[0033] In some embodiments, then cool it to 30 - 35°C. The solution temperature can be reduced to 30 - 35°C at a rate of 2 - 4°C / min to reduce the solubility of the solute, thereby forming a supersaturated solution. Supersaturation is the thermodynamic driving force for crystallization, and rapid cooling promotes initial nucleation, providing conditions for crystal formation.

[0034] In some embodiments, add the pretreated seeds at 30 - 35°C. The seeds serve as heterogeneous nucleation centers, providing a fixed surface to promote the aggregation of solute molecules on their surface to form new crystal nuclei. Stir at a constant temperature for 1 - 2 hours to ensure the stable growth of the crystal nuclei under an appropriate supersaturation, avoiding non-uniform crystals caused by spontaneous nucleation (homogeneous nucleation). Heterogeneous nucleation is a commonly used method in the pharmaceutical industry to control crystal morphology and particle size.

[0035] In some embodiments, the mixture can be cooled while stirring to 5 - 10°C at a rate of 0.8 - 1.2°C / min to increase the supersaturation and promote further crystal growth. Slow cooling helps control the crystal growth rate and avoid defects or inclusion of impurities caused by too fast crystallization. Stir and crystallize at 5 - 10°C for 3 - 5 hours. Stirring helps the solute to be evenly distributed and promotes crystal growth. At the same time, crystal ripening may occur, that is, smaller crystals dissolve and larger crystals continue to grow.

[0036] In some embodiments, canagliflozin hemihydrate is a hydrated crystal, and its crystallization process involves not only solute molecules but also the ordered arrangement of water molecules. Temperature control and the introduction of seeds ensure that water molecules are correctly incorporated into the crystal lattice in the form of hemihydrate.

[0037] In step S300, through seed induction and stepwise cooling, uniform crystal growth is ensured, with a narrow particle size distribution, suitable for the tableting property and fluidity of pharmaceutical preparations. The use of seeds reduces the spontaneous nucleation time, accelerates the crystallization process, improves the yield and production efficiency. The process conditions and seed selection ensure the formation of the target hemihydrate, reducing the risk of other polymorphs. The crystallization process effectively separates impurities, and seed induction promotes the growth of pure crystals, enhancing the purity of the final product. Temperature control (cooling rates of 3°C / min and 1°C / min) and standardized seed use ensure process stability and repeatability, suitable for industrial production.

[0038] Step S400: After crystallization is completed, the crystallization product is separated, washed, and dried to obtain canagliflozin hemihydrate.

[0039] In some embodiments, step S400 includes: after crystallization is completed, centrifugation is performed for solid-liquid separation, the filter cake is washed, and the crystallization product is separated, washed, and dried to obtain canagliflozin hemihydrate.

[0040] In some embodiments, in step S400, the centrifugation speed is 3500 - 4000 rpm, and the centrifugation time is 10 - 12 minutes.

[0041] In some embodiments, in step S400, the washing solution for washing the filter cake is a methanol-water mixed solution at 4 - 8°C, and the volume ratio of methanol to water in the methanol-water mixed solution is 1:2.

[0042] In some embodiments, in step S400, the filter cake is washed 2 - 3 times, and the amount of washing liquid used each time is 3 - 4 times the mass of the filter cake.

[0043] In some embodiments, in step S400, the drying conditions are drying under vacuum at 40 - 45°C for 8 - 10 hours.

[0044] In some embodiments, centrifugation uses centrifugal force to make the solid crystals (with a larger density) settle to the bottom, and the liquid (solvent) remains on the upper layer, achieving solid-liquid separation, accelerating the sedimentation of solid particles, and shortening the separation time. The settings of a speed of 3500 - 4000 rpm and a time of 10 - 12 minutes ensure efficient separation as much as possible without damaging the crystal structure.

[0045] In some embodiments, washing removes impurities and residual solvent on the crystal surface through solvent rinsing. Using a methanol-water mixture cooled to 4 - 8°C can reduce the dissolution loss of canagliflozin hemihydrate. When the temperature decreases, the solubility of the solute decreases. Low-temperature washing can effectively retain the crystals while removing soluble impurities. The amount of washing liquid (3 - 4 times the mass of the filter cake) ensures sufficient washing without wasting solvent.

[0046] In some embodiments, drying can remove residual solvents and moisture, ensuring the stability and purity of the product. The drying method is usually vacuum drying or a temperature-controlled oven to prevent high-temperature degradation. The stability of the hydrate crystals is closely related to the moisture content, and the drying process needs to be controlled under suitable conditions to avoid dehydration or moisture absorption.

[0047] In step S400, centrifugal separation is rapid and effective, suitable for large-scale production, reducing product loss. Low-temperature washing removes impurities without dissolving the product, ensuring high purity. Parameters such as the centrifugal speed, time, washing temperature, and dosage are controllable, ensuring process stability and repeatability. Centrifugation and washing are easy to scale up, suitable for the transition from laboratory to industrial production. Low-temperature washing and optimized washing volume reduce the dissolution loss of the product, increasing the yield. Low-temperature washing and optimized volume reduce dissolution loss and increase the yield. Through centrifugation, washing, and drying, efficient separation and purification of canagliflozin hemihydrate are ensured, with high efficiency, purity, and scalability.

[0048] Optionally, in step S100, the polarity gradient of the ternary solvent is methanol, n-propanol, and water, and the volume ratio of methanol - n-propanol - water is 2 - 3:3:4 - 5, such that the solubility of canagliflozin ≥ 20 mg / mL and the solubility of α-impurity ≤ 5 mg / mL.

[0049] In some embodiments, the polarity differences among the three solvents, methanol (dielectric constant 32.7, relatively strong polarity), n-propanol (dielectric constant 20.1, relatively weak polarity), and water (dielectric constant 78.5, strong polarity), form a gradient. This gradient enables the solvent to effectively dissolve substances with both polar and non-polar parts. For example, the polar groups in the canagliflozin molecule can interact with water, and the non-polar part interacts with n-propanol. Methanol acts as a bridge to balance the two, thereby increasing the overall solubility.

[0050] In some embodiments, the mixed solvent controls the supersaturation of the solution by adjusting the ratio, which is the key driving force for crystallization. In the ratio of 2 - 3:3:4 - 5 (n-propanol accounts for 30%), the proportion of water is relatively high, making it easier for the solution to reach the supersaturated state during cooling, promoting the formation of crystal nuclei. At the same time, methanol and n-propanol regulate the solubility of the solute, controlling the crystallization rate and crystal quality. The addition of methanol and n-propanol improves the dissolution characteristics of water, reduces the surface tension of the solution, and reduces the agglomeration phenomenon during crystallization, making the crystal growth more uniform. With n-propanol accounting for 30%, the hydroxyl group of n-propanol forms an intermolecular hydrogen bond (bond length 2.0 ± 0.1 Å) with the carbonyl group of the canagliflozin molecule. Through the synergistic effect of the polarity gradient (methanol dielectric constant 32.7 → n-propanol 20.1 → water 78.5), the co-solubility rate of the α-configuration impurity is reduced to less than 0.3%.

[0051] Optionally, in step S100, the material-liquid ratio of the crude canagliflozin to the ternary mixed solvent is 1:5 - 1:10 g / mL, and the dissolution temperature is 40 - 50 °C.

[0052] In some embodiments, the mass-volume ratio of the crude canagliflozin to the ternary mixed solvent (methanol - n-propanol - water) is 1:5 to 1:10, meaning 5 - 10 mL of the solvent is used per gram of the crude canagliflozin. This ratio ensures that canagliflozin can be fully dissolved in the solvent, while avoiding difficulties in subsequent crystallization due to excessive solvent or incomplete dissolution due to too little solvent.

[0053] In some embodiments, dissolution is carried out at 40 - 50 °C. Moderate heating is used to increase the solubility of canagliflozin and accelerate the dissolution process, while avoiding degradation or side reactions that may be caused by high temperatures. The low boiling points of methanol and n-propanol (64.7 °C and 97.2 °C respectively) combined with water form an appropriate solvent polarity, optimizing the dissolution efficiency. The ternary solvent system provides suitable supersaturation conditions for subsequent cooling crystallization by adjusting the polarity and dissolution ability.

[0054] In the present invention application, the material-liquid ratio of 1:5 - 1:10 ensures the complete dissolution of the crude canagliflozin. At the same time, the solvent usage is moderate, reducing waste and facilitating subsequent crystallization control. The dissolution temperature of 40 - 50 °C can not only increase the dissolution rate but also avoid the influence of high temperature on the stability of canagliflozin, which is suitable for industrial operation. The combination of methanol - n-propanol - water provides balanced polarity and dissolution ability, helping to dissolve canagliflozin and separate impurities, improving the purification effect of the crude product. The material-liquid ratio range (1:5 - 1:10) provides operational flexibility, allowing the solvent amount to be adjusted according to the characteristics of the crude product to meet the requirements of different batches.

[0055] Optionally, in step S200, the soaking organic solvent is selected from at least one of methanol, ethanol, and n-propanol. The commercially available canagliflozin hemihydrate seeds are soaked in methanol and / or ethanol at 30 - 70 °C for 20 - 50 minutes; or, the commercially available canagliflozin hemihydrate seeds are soaked in n-propanol at 40 - 60 °C for 25 - 45 minutes; or, the commercially available canagliflozin hemihydrate seeds are soaked in methanol and / or ethanol and n-propanol at 40 - 60 °C for 25 - 45 minutes.

[0056] In some embodiments, the organic solvent can be selected from methanol, ethanol, and n-propanol. Methanol (boiling point 64.7 °C), ethanol (boiling point 78.4 °C), and n-propanol (boiling point 97.2 °C) are all low-molecular-weight alcohol solvents, which have good solubility and volatility. These solvents can dissolve the organic impurities, residues, or adsorbates that may exist on the surface of the canagliflozin seed crystals, and are chemically compatible with the canagliflozin hemihydrate without destroying the crystal structure. Methanol and n-propanol are consistent or similar in composition to the ternary solvent system (methanol - n-propanol - water) in step S100, ensuring that no incompatible substances are introduced during the pretreatment process, maintaining the chemical consistency of the process, and also avoiding the introduction of exogenous impurities to ensure the stability of the subsequent crystallization process.

[0057] In some embodiments, commercially available canagliflozin hemihydrate seed crystals are soaked in methanol and / or ethanol at 30 - 70 °C for 20 - 50 minutes; alternatively, commercially available canagliflozin hemihydrate seed crystals can be soaked in n-propanol at 40 - 60 °C for 25 - 45 minutes; or, commercially available canagliflozin hemihydrate seed crystals are soaked in methanol and / or ethanol and n-propanol at 40 - 60 °C for 25 - 45 minutes. Moderate heating can be used to enhance the cleaning ability of the solvent, promote the dissolution of impurities, and simultaneously activate the surface of the seed crystals (such as by slight dissolution or surface reconstruction), improving the induction ability of the seed crystals in the subsequent crystallization process. The seed crystals are separated from the solvent by filtration, and the residual solvent and moisture are removed by drying to obtain pure and dry seed crystals, which are convenient for inducing uniform crystallization in step S300 and improving the crystal morphology and particle size distribution of canagliflozin hemihydrate.

[0058] In the present invention application, both methanol and n-propanol are common solvents, with low costs and easy availability, and excellent cleaning effects, making them suitable for large-scale production. The surface of the pretreated seed crystals is cleaner and more active.

[0059] Optionally, in step S300, the amount of seed crystals added is 0.1 - 0.5% of the mass of the canagliflozin crude product.

[0060] In some embodiments, the amount of seed crystals added is 0.1 - 0.5% of the mass of the canagliflozin crude product, that is, 0.1 - 0.5 g of seed crystals are added per 100 g of crude product. This low proportion of seed crystals is sufficient to induce the formation of crystal nuclei and avoid excessive seed crystals from causing too fast crystal growth or too small crystal size. The seed crystals provide initial crystal nuclei, reduce the nucleation energy barrier, and promote the orderly crystallization of the solution in the supersaturated state; the pretreated canagliflozin hemihydrate seed crystals have the same structure as the target crystal form, and after addition, they induce crystal growth by surface adsorption of molecules, controlling the crystal form consistency and crystal quality. The amount of 0.1 - 0.5% of seed crystals balances the nucleation rate and crystal growth rate, avoiding excessive seed crystals from resulting in overly fine crystal particles or insufficient effective induction of crystallization.

[0061] In the application of the present invention, a seed crystal amount of 0.1-0.5% is appropriate, which can effectively induce the formation of the canagliflozin hemihydrate crystal form, ensure the consistency of the crystal structure, meet the pharmaceutical requirements. A low seed crystal amount avoids excessive crystal growth. Combining slow cooling (1°C / min) and long-term stirring (3 hours) promotes uniform crystal growth, reduces crystal defects, improves crystal purity and stability. A small amount of seed crystals (0.1-0.5%) can significantly reduce the nucleation energy barrier, accelerate the crystallization process, shorten the process time, and improve production efficiency. The seed crystal amount range (0.1-0.5%) provides operation flexibility, and the seed crystal dosage can be adjusted according to the quality of the crude product or the target crystal size to adapt to different production requirements. The low seed crystal dosage reduces the pretreatment cost, while ensuring efficient crystallization and reducing the overall production cost.

[0062] Optionally, in step S400, the washing solvent is a methanol-water mixed solution at 4-8°C, and the volume ratio of methanol to water in the methanol-water mixed solution is 1:2.

[0063] In the application of the present invention, methanol (boiling point 64.7°C) has strong dissolving ability and can effectively remove the organic impurities remaining on the surface of the filter cake, while water (boiling point 100°C) reduces the dissolving ability of the solution and reduces the dissolution loss of canagliflozin hemihydrate during washing. The volume ratio of 1:2 balances the cleaning effect and crystal protection, ensures the removal of impurities while retaining the crystals as much as possible. At the same time, the cold solution helps to maintain the stability of the crystal structure and prevent crystal form transformation.

[0064] Optionally, in step S400, the drying condition is drying under vacuum at 40-45°C for 8-10 hours.

[0065] In the application of the present invention, vacuum drying reduces the boiling point of the solvent (methanol, water) by reducing the environmental pressure, accelerates the volatilization of the residual solvent, and at the same time avoids the destruction of the canagliflozin hemihydrate crystal form by high temperature. The temperature of 40-45°C is appropriate, which can effectively remove the solvent and moisture, and avoid excessive temperature causing crystal degradation or crystal form transformation (such as the hemihydrate losing water to become the anhydrous form). The drying time of 8-10 hours ensures that the residual solvent and moisture are fully removed, while not overly extending the process time, balancing efficiency and quality.

[0066] In a second aspect, a canagliflozin hemihydrate raw material drug is prepared by using the preparation process of any one of the canagliflozin hemihydrate raw material drugs in the first aspect above. The purity of the raw material drug is ≥99.8%, the yield is ≥90%, and the canagliflozin raw material drug has a DSC endothermic peak at 98.5±1°C in X-ray powder diffraction of the crystal form. In the present invention application, through the preparation process of canagliflozin hemihydrate bulk drug (optimizing the solubility in the ternary solvent system in step S100, with moderate solvent polarity to ensure complete dissolution of the crude product and facilitate the separation of impurities, pretreating to remove impurities on the surface of the seed crystal in step S200, gradually cooling in step S300 to control the supersaturation, inducing ordered nucleation with the seed crystal, slowly cooling and long-time stirring to promote uniform crystal growth, using a small amount of seed crystal (0.1 - 0.5%) to balance the nucleation and growth rates and ensure crystal quality, solid-liquid separation and washing / drying in step S400), organic, inorganic impurities and non-target crystal forms are systematically removed to ensure that the bulk drug meets the pharmaceutical standards (such as the ICH Q3C residual solvent requirements). Based on ternary solvent dissolution, seed crystal-induced crystallization, temperature-controlled growth and high-efficiency purification, the preparation of canagliflozin hemihydrate bulk drug with high purity, high yield, stable crystal form, controllable process, safety and economy is completed, and canagliflozin hemihydrate bulk drug with a purity ≥ 99.8% and a yield ≥ 90% is obtained synergistically, which is suitable for industrial production and pharmaceutical requirements.

[0067] In the following experiments of the present invention application, unless otherwise specified, the raw materials or reagents used are all conventional commercially available products or reagents prepared by conventional methods, and the methods used in the experiments are all conventional experimental methods unless otherwise specified. The instruments used in the experiments can be obtained through commercial channels unless otherwise specified.

[0068] Example 1 (1) Dissolution: Weigh 10 g of canagliflozin crude product and add it to a mixed solvent containing 20 mL of methanol, 30 mL of n-propanol and 50 mL of water, and stir at 50 °C for 30 minutes until canagliflozin is completely dissolved.

[0069] (2) Seed crystal pretreatment: Take 0.05 g of commercially available seed crystal, soak it in a methanol solution at 50 °C for 30 minutes, and perform ultrasonic treatment. Ultrasonic treatment conditions: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic for 15 minutes, filter and dry, and the surface hydroxyl density is 8.5×10 14 groups / cm 2 , for standby.

[0070] (3) Crystallization: After dissolution, heat the mixture to 50 °C, cool the solution to 35 °C at a rate of 3 °C / min, add the pretreated seed crystal, and stir at a constant temperature of 35 °C for 1 hour. Subsequently, cool it to 10 °C at a rate of 1 °C / min and continue to stir for crystal precipitation for 3 hours.

[0071] (4) Separation, washing and drying: Centrifuge the crystallized solution at a speed of 3500 rpm for 10 minutes to collect the filter cake. Wash the filter cake twice with 30 mL of a pre-cooled methanol-water (volume ratio 1:2) mixed solution at 5°C, with the washing solution dosage being 4 times the mass of the filter cake. Dry the washed filter cake under vacuum at 40°C for 8 hours to obtain the canagliflozin hemihydrate product.

[0072] Example 2 (1) Dissolution: Weigh 50 g of crude canagliflozin and add it to a mixed solvent containing 100 mL of methanol, 150 mL of n-propanol and 250 mL of water. Stir at 50°C for 40 minutes to achieve complete dissolution.

[0073] (2) Seed pretreatment: Take 0.25 g of commercially available seeds. The seed treatment method is the same as in Example 1, and the hydroxyl density is 8.2×10 14 groups / cm 2 .

[0074] (3) Crystallization: The steps of cooling and adding seeds are the same as in Example 1, and the constant temperature stirring and crystal precipitation time are extended to 1.5 hours and 4 hours respectively.

[0075] (4) Separation, washing and drying: Centrifuge the crystallized solution at a speed of 4000 rpm for 12 minutes, wash the filter cake twice with 30 mL of a pre-cooled methanol-water (volume ratio 1:2) mixed solution at 5°C, with the washing solution dosage being 4 times the mass of the filter cake, and dry it under vacuum at 45°C for 10 hours.

[0076] Comparative Example 1 The ethanol-water binary solvent system (volume ratio 3:1) in the invention patent application CN102675380A and the traditional crystallization process are used for preparation.

[0077] (1) Dissolution: Add 10 g of crude canagliflozin to 40 mL of an ethanol-water mixed solvent and stir to dissolve at 45°C.

[0078] (2) Crystallization: Directly cool at a rate of 3°C / min to 10°C for crystallization, without using pretreated seeds, and the crystallization period is 20 hours.

[0079] (3) Separation, washing and drying: Conventional centrifugal separation and ethanol washing at room temperature, and drying at 50°C under normal pressure for 12 hours.

[0080] Comparative Example 2 (1) Dissolution: Weigh 10 g of crude canagliflozin and add it to a mixed solvent containing 20 mL of methanol, 35 mL of n-propanol and 45 mL of water. Stir at 50°C for 30 minutes until canagliflozin is completely dissolved.

[0081] (2) Seed pretreatment: Take 0.05 g of commercially available seeds, soak them in a methanol solution at 50 °C for 30 minutes, and perform ultrasonic treatment. Ultrasonic treatment conditions: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic for 15 minutes, filter and dry. The surface hydroxyl density is 8.5×10 14 groups / cm 2 , and set aside for later use.

[0082] (3) Crystallization: After dissolution, the mixture is heated to 50 °C, and the solution is cooled to 35 °C at a rate of 3 °C / min. Add the pretreated seeds and stir at a constant temperature of 35 °C for 1 hour. Subsequently, cool it to 10 °C at a rate of 1 °C / min and continue stirring for crystallization for 3 hours.

[0083] (4) Separation, washing, and drying: Centrifuge the crystallized solution at 3500 rpm for 10 minutes to collect the filter cake. Wash the filter cake twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5 °C. The amount of washing solution used is 4 times the mass of the filter cake. Dry the washed filter cake under vacuum at 40 °C for 8 hours to obtain the canagliflozin hemihydrate product.

[0084] Comparative Example 3 (1) Dissolution: Weigh 10 g of canagliflozin crude product and add it to a mixed solvent containing 20 mL of methanol, 25 mL of n-propanol, and 55 mL of water. Stir at 50 °C for 30 minutes until canagliflozin is completely dissolved.

[0085] (2) Seed pretreatment: Take 0.05 g of commercially available seeds, soak them in a methanol solution at 50 °C for 30 minutes, and perform ultrasonic treatment. Ultrasonic treatment conditions: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic for 15 minutes, filter and dry. The surface hydroxyl density is 8.5×10 14 groups / cm 2 , and set aside for later use.

[0086] (3) Crystallization: After dissolution, the mixture is heated to 50 °C, and the solution is cooled to 35 °C at a rate of 3 °C / min. Add the pretreated seeds and stir at a constant temperature of 35 °C for 1 hour. Subsequently, cool it to 10 °C at a rate of 1 °C / min and continue stirring for crystallization for 3 hours.

[0087] (4) Separation, washing, and drying: Centrifuge the crystallized solution at 3500 rpm for 10 minutes to collect the filter cake. Wash the filter cake twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5 °C. The amount of washing solution used is 4 times the mass of the filter cake. Dry the washed filter cake under vacuum at 40 °C for 8 hours to obtain the canagliflozin hemihydrate product.

[0088] Comparative Example 4 (1) Dissolution: Weigh 10 g of crude canagliflozin and add it to a mixed solvent containing 20 mL of methanol, 30 mL of n-propanol, and 50 mL of water. Stir at 50 °C for 30 minutes until canagliflozin is completely dissolved.

[0089] (2) Seed pretreatment: Take 0.05 g of commercially available seeds and soak them in a methanol solution at 50 °C for 30 minutes. Filter and dry them. The surface hydroxyl density is 5.2×10 14 groups / cm 2 , and set aside for later use.

[0090] (3) Crystallization: After dissolution, heat the mixture to 50 °C and cool the solution to 35 °C at a rate of 3 °C / min. Add the pretreated seeds and stir at a constant temperature of 35 °C for 1 hour. Subsequently, cool the temperature to 10 °C at a rate of 1 °C / min and continue stirring for crystallization for 3 hours.

[0091] (4) Separation, washing, and drying: Centrifuge the crystallized solution at 3500 rpm for 10 minutes to collect the filter cake. Wash the filter cake twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5 °C. The amount of washing solution used is 4 times the mass of the filter cake. Dry the washed filter cake under vacuum at 40 °C for 8 hours to obtain canagliflozin hemihydrate product.

[0092] Comparative Example 5 (1) Dissolution: Weigh 10 g of crude canagliflozin and add it to a mixed solvent containing 20 mL of methanol, 30 mL of n-propanol, and 50 mL of water. Stir at 50 °C for 30 minutes until canagliflozin is completely dissolved.

[0093] (2) Seed pretreatment: Take 0.05 g of commercially available seeds and perform ultrasonic treatment. Ultrasonic treatment conditions: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic treatment for 15 minutes. Filter and dry them. The surface hydroxyl density is 4.8×10 14 groups / cm 2 , and set aside for later use.

[0094] (3) Crystallization: After dissolution, heat the mixture to 50 °C and cool the solution to 35 °C at a rate of 3 °C / min. Add the pretreated seeds and stir at a constant temperature of 35 °C for 1 hour. Subsequently, cool the temperature to 10 °C at a rate of 1 °C / min and continue stirring for crystallization for 3 hours.

[0095] (4) Separation, washing, and drying: Centrifuge the crystallized solution at 3500 rpm for 10 minutes to collect the filter cake. Wash the filter cake twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5 °C. The amount of washing solution used is 4 times the mass of the filter cake. Dry the washed filter cake under vacuum at 40 °C for 8 hours to obtain canagliflozin hemihydrate product.

[0096] Comparative Example 6 (1)Dissolution: Weigh 10 g of canagliflozin crude product and add it to a mixed solvent containing 20 mL of methanol, 30 mL of n-propanol and 50 mL of water. Stir at 50 °C for 30 minutes until canagliflozin is completely dissolved.

[0097] (2)Seed pretreatment: Take 0.05 g of commercially available seeds, soak them in ethyl acetate solution at 50 °C for 30 minutes, and perform ultrasonic treatment. Ultrasonic treatment conditions: ultrasonic power / frequency: 50 W / 30 kHz, ultrasonic for 10 minutes, filter and dry. The surface hydroxyl density is 5.8×10 14 groups / cm 2 , and set aside.

[0098] (3)Crystallization: After dissolution, heat the mixture to 50 °C, cool the solution to 35 °C at a rate of 3 °C / min, add the pretreated seeds, and stir at a constant temperature of 35 °C for 1 hour. Subsequently, cool to 10 °C at a rate of 1 °C / min and continue to stir for crystallization for 3 hours.

[0099] (4)Separation, washing and drying: Centrifuge the crystallized solution at 3500 rpm for 10 minutes to collect the filter cake. Wash the filter cake twice with 30 mL of methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5 °C. The amount of washing solution is 4 times the mass of the filter cake. Dry the washed filter cake under vacuum at 40 °C for 8 hours to obtain canagliflozin hemihydrate product.

[0100] The product purity and yield of the canagliflozin hemihydrate API prepared in Example 1, Example 2, Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4, Comparative Example 5 and Comparative Example 6 were detected. The product purity was determined by HPLC method (C18, acetonitrile-water (60:40, v / v), flow rate 1.0 mL / min, detection wavelength 220 nm), and the yield was calculated as the percentage of the actual precipitation amount to the mass of the crude product.

[0101] The results of the product purity and yield determination of the canagliflozin hemihydrate API prepared in Example 1 and Example 2 and the canagliflozin hemihydrate in Comparative Example 1 are as follows:

[0102] It can be seen that the purity of the canagliflozin product obtained by the canagliflozin preparation process of the present invention application can reach more than 99.8%, and the yield reaches more than 90%, meeting the requirements of industrial production.

[0103] (1)Analysis of the PXRD pattern of canagliflozin hemihydrate in Example 1 1 - Results of the PXRD pattern of canagliflozin hemihydrate: As Figure 1 shown, in the PXRD pattern of canagliflozin hemihydrate, the horizontal axis (2θ angle): ranges from about 7° to 16.5°, covering the low-angle region of the PXRD pattern, which is usually used to characterize the main diffraction peaks of canagliflozin hemihydrate. The vertical axis (CPS, Counts Per Second): represents the X-ray diffraction intensity, reflecting the orderliness of the canagliflozin hemihydrate structure and the significance of the peaks.

[0104] 1) Diffraction peaks There are multiple distinct diffraction peaks, especially near 2θ = 3.87°, 7.73°, 7.95°, 8.63°, 9.66°, 10.65°, 10.92°, 11.17°, 12.38°, 13.04°, 13.59°, 13.94°, 14.27°, 15.18°, 15.49°, 15.96°, 16.25°. Among them, the peak at 15.49° has the highest intensity (close to 60 CPS), indicating that this is the strongest reflecting plane in the canagliflozin hemihydrate structure. There are multiple smaller peaks in the low-angle (4° - 9°) and medium-angle (10° - 13°) regions, showing that canagliflozin hemihydrate has a certain complex structure or polymorphic phase.

[0105] 2) Crystal characteristics The PXRD pattern shows multiple sharp diffraction peaks, indicating that canagliflozin hemihydrate has a good crystal structure, conforming to the characteristics of the hemihydrate crystal form. The peak with the highest intensity at 15.49° may correspond to the main crystal plane in the lattice (such as

[001] or a similar high-density plane), while other peaks reflect secondary crystal planes or two-dimensional or three-dimensional arrangements of the lattice.

[0106] 3) Sample purity and yield There are no obvious impurity peaks or amorphous background in the PXRD pattern, indicating a low impurity content in canagliflozin hemihydrate. Figure 2 The DSC results are shown as follows. The analysis shows that there is a single endothermic peak at 98.5 ± 1 °C, corresponding to the removal of the hemihydrate crystal water (theoretical weight loss rate 8.5%, measured 8.6%), proving the crystal form purity.

[0107] Analysis of the reasons for the PXRD pattern of 2-canagliflozin hemihydrate: 1) Process optimization and crystal form control: Ternary Solvent System (Step S100): Methanol - n - propanol - water (volume ratio 2:3:5) is used to dissolve the crude product. The solid - liquid ratio (1:10 g / mL) is moderate. The dissolution temperature of 50°C ensures complete dissolution. Meanwhile, the addition of water adjusts the solvent polarity, promoting the formation of the hemihydrate crystal form. Seed Induction (Steps S200 and S300): The pretreated seed (0.05 g) is soaked in methanol at 50°C to remove impurities and then subjected to ultrasonic treatment. Ultrasonic treatment conditions: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic treatment for 15 minutes to activate the seed surface; 0.5% seed is added and the temperature is decreased step - by - step (3°C / min to 35°C, 1°C / min to 10°C) to induce ordered crystallization, generating a consistent hemihydrate crystal form, resulting in the appearance of sharp peaks in the PXRD pattern. The seed and precise temperature control (constant - temperature stirring for 1 hour, crystal precipitation for 3 hours) reduce the amorphous phase or non - target crystal forms, forming a highly ordered crystal structure, which is reflected in the clear peaks of the PXRD pattern.

[0108] 2) Crystallization Conditions Cooling to 10°C at 1°C / min and long - time stirring control the supersaturation, promoting slow crystal growth, reducing crystal defects and lattice strain, resulting in sharp and uniformly intense peaks. The slow crystallization process optimizes the development of crystal planes, especially the high - intensity peaks (14° - 15°) corresponding to the main crystal planes, indicating higher crystal orientation and quality.

[0109] 3) Washing and Drying Optimization The filter cake is washed with methanol - water (volume ratio 1:2) at 5°C to reduce solubility, remove surface impurities and mother liquor residues, ensuring crystal purity. Vacuum drying is used to remove the solvent, protecting the hemihydrate crystal form (stable water molecule coordination), avoiding crystal form transformation caused by high temperature. The pure crystals and stable hemihydrate structure enhance the diffraction intensity and peak clarity of the PXRD pattern, reducing background noise.

[0110] (2) Product Purity Analysis Product purity results: The purity of both Example 1 and Example 2 is greater than 99.8%, higher than that of Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4, Comparative Example 5, and Comparative Example 6, indicating that the ternary solvent system and the optimized process are superior to the ethanol - water binary solvent system and the traditional process in terms of purity improvement.

[0111] Reasons for product purity: 1) Differences in solvent systems Examples 1 and 2: The methanol - n - propanol - water ternary solvent system is adopted. The ternary system optimizes the dissolution of canagliflozin and impurity separation by combining the strong solubility of methanol and n - propanol with the polarity regulation of water. The addition of water reduces the solubility of canagliflozin, which helps to preferentially precipitate the target crystal form during crystallization and reduces impurity incorporation.

[0112] 2) Seed pretreatment and addition Examples 1 and 2: Pretreated canagliflozin hemihydrate seed crystals (0.05g and 0.25g, representing 0.5% of the crude mass) were soaked in 50°C methanol to remove surface impurities and then ultrasonically treated for 15 minutes at 100W / 40kHz power to activate the seed crystal surface. This seeding process induced ordered crystallization, ensuring the consistency of the target hemihydrate crystal form and minimizing the formation of non-target crystal forms or amorphous material, thereby improving purity.

[0113] 3) Crystallization condition control Examples 1 and 2 employed stepwise cooling (3°C / min to 35°C, followed by constant temperature stirring for 1 or 1.5 hours after seed crystal addition, followed by cooling to 10°C at 1°C / min, and crystallization for 3 or 4 hours). Precise temperature control and seed induction optimized supersaturation and crystal growth, reducing crystal defects and impurity inclusions. Example 2 extended the constant temperature stirring (1.5 hours) and crystallization time (4 hours) to further optimize crystal growth, resulting in slightly higher purity than Example 1.

[0114] 4) Washing and drying Examples 1 and 2: The filter cake was washed with a methanol-water mixture (volume ratio 1:2) cooled to 5°C. Cooling reduced the solubility of canagliflozin, minimizing crystal loss and effectively removing surface impurities. Vacuum drying at 40-45°C gently removed the solvent, protected the crystal form, and ensured high purity.

[0115] Comparative Example 1: Using an ethanol-water binary solvent system (3:1 volume ratio). This system has a relatively monopolar polarity and strong solubility, but weak selective separation capabilities for impurities, which may result in some impurities being entrapped during crystallization, reducing purity. No seed crystals were used, and direct cooling was used for crystallization. The lack of seed crystal induction can lead to spontaneous nucleation, poor crystal form control, and the formation of impurity crystal forms or amorphous materials, reducing purity to 98.5%. Direct cooling to 10°C at a rate of 3°C / min resulted in a crystallization cycle of up to 20 hours. Rapid cooling and prolonged crystallization can lead to uneven supersaturation and crystal growth, increasing the risk of impurity incorporation and resulting in lower purity. Washing with room-temperature ethanol, however, can result in some crystal loss due to its high solubility, resulting in limited cleaning effectiveness. Conventional drying may not completely remove the solvent or impurities, affecting purity.

[0116] Comparative Example 2: The amount of n-propanol increased and the amount of water decreased. The excess n-propanol caused an imbalance in the solvent polarity gradient, reduced the overall polarity of the solvent, weakened the hydrogen bonds between canagliflozin molecules, increased the co-solubility rate of impurities, and decreased the purity. Non-polar impurities may be difficult to separate by crystallization and co-precipitate with canagliflozin, thereby reducing the purity, resulting in a purity of 98.90%.

[0117] Comparative Example 3: The amount of n-propanol decreased while the amount of water increased, enhancing the solvent polarity. Excessive polarity reduced the solubility of canagliflozin, potentially leading to a decline in the dissolution selectivity of the solvent system for α-impurities. The excessive solvent polarity made the crystallization process unsatisfactory, and the purity decreased to 98.20%.

[0118] Comparative Example 4: Without ultrasonic treatment, single immersion could not effectively open the micropores of the seeds, and the surface impurities were not thoroughly desorbed, resulting in a relatively low surface hydroxyl density (5.2×10 14 groups / cm 2 ). The impurities on the seed surface were not fully removed, and the active sites were insufficiently exposed, reducing the nucleation efficiency. The crystal growth was uneven, and impurities were easily encapsulated. Insufficient pretreatment of the seeds was the main reason for the purity to drop to 98.50%.

[0119] Comparative Example 5: Only ultrasonic treatment without solvent immersion resulted in the lowest surface hydroxyl density (4.8×10 14 groups / cm 2 ). Ultrasonic treatment only physically removed some impurities and could not repair the hydroxyl sites through chemical action. The surface activity of the seeds was limitedly enhanced, and there was a lack of solvent chemical activation, leading to a serious deficiency in nucleation ability. The crystal growth was disordered, and a large amount of impurities were incorporated. The low activity of the seeds caused the crystallization process to get out of control, and the purity decreased to 97.80%.

[0120] Comparative Example 6: Immersion in ethyl acetate at 50°C for 30 minutes + ultrasonic treatment (50W / 30kHz, 10 minutes) resulted in a surface hydroxyl density of 5.8×10 14 groups / cm 2 . Using ethyl acetate for immersion and with relatively weak ultrasonic parameters (50W / 30kHz) led to a relatively low surface hydroxyl density (5.8×10 14 groups / cm 2 ). The synergistic effect of immersion and ultrasonic treatment was insufficient, and the activation of the seeds was inadequate. The nucleation efficiency decreased, the crystal form stability was poor, and the incorporation of impurities increased. Poor pretreatment conditions of the seeds led to ineffective impurity control, and the purity was 98.10%.

[0121] The above analysis shows that the polarity change of the solvent system and the insufficiency of seed pretreatment are the main factors leading to the lower purity in Comparative Examples 2 to 6 compared to Example 1. A reasonable solvent ratio and efficient activation of seed pretreatment are crucial for improving the purity of canagliflozin hemihydrate.

[0122] (3) Yield analysis Yield results: The yields of Examples 1 and 2 were both greater than 90%, significantly higher than those of Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4, Comparative Example 5, and Comparative Example 6, indicating that the canagliflozin preparation process has obvious advantages in reducing crystal loss and improving production efficiency.

[0123] Reasons for yield: 1) Solvent system and feed liquid ratio Examples 1 and 2: The ternary solvent system (methanol:n-propanol:water) dissolves the crude product at a feed liquid ratio of 1:10 g / mL. The amount of solvent is appropriate, ensuring complete dissolution without excessive dilution, facilitating the control of supersaturation, and reducing the residue of crystals in the mother liquor. Example 2 processes 50 g of crude product, and the yield is slightly higher than that of Example 1.

[0124] 2) Seed induction and crystallization control Examples 1 and 2: Seed addition (0.5% by mass), and seed pretreatment is carried out by soaking in methanol at 50 °C to remove impurities, and ultrasonic treatment is performed. The ultrasonic treatment conditions are: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic treatment for 15 minutes, and stepwise cooling (3 °C / min to 35 °C, 1 °C / min to 10 °C) to promote ordered nucleation and uniform growth, reducing the formation of overly fine crystal particles or amorphous substances, and maximizing crystal precipitation. Example 2 extends the constant-temperature stirring (1.5 hours) and crystal precipitation time (4 hours), allowing for more sufficient crystal growth, reducing the solute residue in the mother liquor, and having a slightly higher yield.

[0125] 3) Solid-liquid separation and washing Examples 1 and 2: Centrifugation (3500 - 4000 rpm, 10 - 12 minutes) efficiently separates the crystals. The methanol-water washing solution (1:2) cooled to 5 °C reduces the solubility and decreases the dissolution loss of crystals during washing. The amount of washing solution (3 - 4 times the mass of the filter cake) is appropriate, ensuring the cleaning effect while protecting the crystals. Example 2 increases the amount of washing solution (4 times) and the centrifugation speed (4000 rpm) to optimize the separation efficiency and reduce crystal loss.

[0126] 4) Drying conditions Examples 1 and 2: Vacuum drying at 40 - 45 °C gently removes the solvent, protects the crystal structure, and reduces crystal loss caused by high temperature or improper drying. The drying time in Example 2 is extended to 10 hours, which can more thoroughly remove the solvent, reduce the residual impact, and slightly increase the yield.

[0127] Comparative Example 1: The ethanol-water system (3:1, feed liquid ratio 1:4 g / mL) has a higher solubility, which may cause part of canagliflozin to remain in the mother liquor during crystallization, reducing the yield; without seed induction, directly cooling rapidly to 10 °C, the crystallization period is long (20 hours), which may lead to uneven nucleation, different crystal particle sizes, and part of canagliflozin not being effectively precipitated and remaining in the mother liquor, with a yield of only 75%; conventional centrifugation and washing with ethanol at room temperature, ethanol has a higher solubility, which may cause partial dissolution loss of the crystals, reducing the yield; conventional drying may not optimize the temperature or time, resulting in solvent residue or slight crystal degradation, affecting the yield.

[0128] Comparative Example 2: With an increase in n-propanol and a decrease in water, the solvent polarity decreases, and the solubility of canagliflozin slightly increases, resulting in increased difficulty in controlling supersaturation. Some canagliflozin may remain in the mother liquor during the crystallization process, reducing the precipitation efficiency; the change in solvent polarity causes incomplete crystal precipitation, and some canagliflozin remains in the mother liquor, with the yield dropping to 85%.

[0129] Comparative Example 3: With a decrease in n-propanol and an increase in water, the solvent polarity increases, and the solubility of canagliflozin decreases, which may lead to premature crystallization. The excessively high supersaturation causes insufficient crystal growth, generating more fine crystals that are easily lost with the mother liquor, reducing the yield; the solvent system with too high polarity results in low crystal precipitation efficiency and significant loss of fine crystals, with the yield dropping to 82%.

[0130] Comparative Example 4: The seed crystals were not ultrasonically treated, and the surface hydroxyl density was relatively low (5.2×10 14 groups / cm 2 ), resulting in insufficient nucleation efficiency. The crystal growth is uneven, and some fine crystals or amorphous substances may form, increasing the canagliflozin residue in the mother liquor and reducing the precipitation efficiency. Insufficient pretreatment of the seed crystals leads to reduced nucleation and crystal growth efficiency, and some canagliflozin fails to precipitate effectively, with the yield dropping to 88%.

[0131] Comparative Example 5: Only ultrasonically treated without soaking, the surface hydroxyl density is the lowest (4.8×10 14 groups / cm 2 ), and the nucleation ability of the seed crystals is severely insufficient, resulting in disordered crystal growth, generating more fine crystals or amorphous substances. These fine particles are easily lost with the mother liquor, significantly reducing the precipitation efficiency. The extremely low activity of the seed crystals leads to a substantial decrease in the crystal precipitation efficiency and serious loss of fine crystals, with the yield dropping to 83%.

[0132] Comparative Example 6: Soaked with ethyl acetate and with relatively weak ultrasonic parameters (50W / 30kHz, 10 minutes), the surface hydroxyl density is relatively low (5.8×10 14 groups / cm 2 ), insufficient activation of the seed crystals, reduced nucleation efficiency, uneven crystal growth, and some canagliflozin fails to precipitate effectively and remains in the mother liquor. Poor pretreatment conditions of the seed crystals reduce the nucleation efficiency, and the crystal precipitation is incomplete, with the yield dropping to 86%.

[0133] Therefore, in the present invention application, through the overall cooperation of a specific mixed solvent system and a specific seed pretreatment step, combined with precise crystallization control, the content of α-configuration impurities is effectively reduced, and the product purity can reach more than 99.8%, far exceeding the product purity of similar processes. The yield of canagliflozin hemihydrate is increased to more than 90%, significantly improving the production efficiency and economic benefits; the entire preparation process cycle is shortened by about 40% compared with the traditional process, from about 20 hours to within 12 hours, greatly improving the production efficiency and reducing the production cost.

[0134] Those skilled in the art can understand that the steps, measures, and solutions in various operations, methods, and processes discussed in the present invention application can be alternated, changed, combined, or deleted; further, other steps, measures, and solutions in various operations, methods, and processes discussed in the present invention application can also be alternated, changed, rearranged, decomposed, combined, or deleted; further, those in the prior art having steps, measures, and solutions in various operations, methods, and processes disclosed in the present invention application can also be alternated, changed, rearranged, decomposed, combined, or deleted. The technical features of the above embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification; The above-described embodiments merely represent several implementation manners of the present disclosure embodiments. The description is relatively specific and detailed, but it should not be construed as a limitation on the patent scope of the present disclosure embodiments; it should be noted that for those of ordinary skill in the art, without departing from the concept of the present disclosure embodiments, several modifications and improvements can be made, and these all belong to the protection scope of the present disclosure embodiments; therefore, the protection scope of the present disclosure embodiments should be subject to the appended claims. As described above, although the present invention application has been represented and described with reference to specific preferred embodiments, it should not be construed as a limitation on the present invention application itself. Various changes can be made to it in form and detail without departing from the spirit and scope of the present invention application defined by the appended claims.

[0135] The above describes the present invention application and its implementation manners. Such description is not restrictive, and what is shown in the drawings is only one of the implementation manners of the present invention application, and the actual structure is not limited thereto. Generally speaking, if those of ordinary skill in the art are inspired by it and design a structural manner and an embodiment similar to the technical solution without creative efforts without departing from the purpose of the present invention application, they should all belong to the protection scope of the present invention application.

Claims

1. A preparation process of canagliflozin hemihydrate raw material drug, characterized in that, Including: Step S100: Use a ternary mixed solvent system of methanol - n - propanol - water, where the volume percentage of n - propanol is 30%. Dissolve the crude canagliflozin in it to obtain a dissolved mixture, and the solubility difference between canagliflozin and α - configuration impurities is ≥15 mg / mL. Step S200: Pretreatment is first carried out using commercially available canagliflozin hemihydrate as a seed crystal. The pretreatment includes soaking the commercially available canagliflozin hemihydrate in an organic solvent, ultrasonic treatment, followed by filtration and drying to make the hydroxyl density on the surface of the seed crystal ≥ 8×10 14 groups / cm 2 ; Step S300: Heat the dissolved mixture to 50 - 60 °C, then cool it to 30 - 35 °C, add the semi - hydrate crystal seeds pretreated by step S200, and stir while cooling to crystallize. Step S400: After crystallization is completed, separate, wash, and dry the crystallization product to obtain canagliflozin semi - hydrate.

2. The preparation process of canagliflozin hemihydrate bulk drug according to claim 1, characterized in that, In step S100, the polarity gradient of the ternary solvent is methanol, n - propanol, water, and the volume ratio of methanol - n - propanol - water is 2 - 3:3:4 - 5, so that the solubility of canagliflozin is ≥20 mg / mL and the solubility of α - impurity is ≤5 mg / mL; and / or, step S300 includes: Heat the dissolved mixture to 50 - 60 °C, then cool it at a rate of 2 - 4 °C / min to 30 - 35 °C, add the semi - hydrate crystal seeds pretreated by step S200, stir at a constant temperature of 30 - 35 °C for 1 - 2 hours, and then cool it at a rate of 0.8 - 1.2 °C / min to 5 - 10 °C, and stir for crystallization for 3 - 5 hours.

3. The preparation process of canagliflozin hemihydrate API according to claim 2, wherein, In step S100, the feed ratio of the crude canagliflozin to the ternary mixed solvent is 1:5 - 1:10 g / mL, and the dissolution temperature is 40 - 50 °C.

4. The preparation process of canagliflozin hemihydrate bulk drug according to claim 2, wherein, In step S200, the ultrasonic power is 90 - 150 W, the frequency is 35 - 50 kHz, and the time is 10 - 20 minutes.

5. The preparation process of canagliflozin hemihydrate bulk drug according to claim 4, wherein, In step S200, the soaking organic solvent is selected from at least one of methanol, ethanol, and n - propanol. The commercially available canagliflozin semi - hydrate crystal seeds are soaked in methanol and / or ethanol at 30 - 70 °C for 20 - 50 minutes; or, the commercially available canagliflozin semi - hydrate crystal seeds are soaked in n - propanol at 40 - 60 °C for 25 - 45 minutes; or, the commercially available canagliflozin semi - hydrate crystal seeds are soaked in methanol and / or ethanol and n - propanol at 40 - 60 °C for 25 - 45 minutes.

6. The preparation process of a canagliflozin hemihydrate raw material drug according to claim 5, wherein, In step S300, the amount of crystal seeds added is 0.1 - 0.5% of the mass of the crude canagliflozin.

7. The preparation process of canagliflozin hemihydrate bulk drug according to claim 2, characterized in that, In step S400, after crystallization is completed, centrifuge for solid - liquid separation, wash the filter cake, and the washing solvent is a methanol - water mixed solution at 4 - 8 °C, and the volume ratio of methanol to water in the methanol - water mixed solution is 1:

2.

8. The preparation process of canagliflozin hemihydrate raw material drug according to claim 7, characterized in that, In step S400, the drying conditions are drying under vacuum at 40 - 45 °C for 8 - 10 hours.

9. A canagliflozin semi - hydrate raw material drug, which is prepared by using the preparation process of a canagliflozin semi - hydrate raw material drug according to any one of claims 1 - 8 above.

10. According to a canagliflozin semi - hydrate raw material drug described in claim 9, the purity of the raw material drug is ≥99.8%, the yield is ≥90%, and the canagliflozin raw material drug has a DSC endothermic peak at 98.5 ± 1 °C in X - ray powder diffraction of the crystal form.

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