A preparation process of canagliflozin hemihydrate raw material

Abstract

The present invention applies to provide a kind of preparation process of canagliflozin hemihydrate bulk drug, belong to the field of medical technology. The preparation process of canagliflozin hemihydrate bulk drug includes: using methanol-n-propanol-water ternary mixed solvent system, canagliflozin crude product is dissolved therein to obtain a dissolved mixture; using commercially available canagliflozin hemihydrate as crystal seed first pre-treated, then filtered and dried; after dissolution, the mixture is warmed up to 50-60 DEG C, cooled to 30-35 DEG C at a rate of 2-4 DEG C / min, pre-treated hemihydrate crystal seeds are added, and stirred at a constant temperature for 1-2 hours at 30-35 DEG C, then cooled to 5-10 DEG C at a rate of 0.8-1.2 DEG C / min, stirred and crystallized for 3-5 hours; after the completion of crystallization, centrifugation is performed for solid-liquid separation, filter cake is washed, and the crystallized product is separated, washed and dried to obtain canagliflozin hemihydrate. The present invention application can improve canagliflozin hemihydrate bulk drug product purity and yield.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a preparation process of canagliflozin hemihydrate raw material. Background Art

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

[0003] Existing preparation methods primarily employ solvent evaporation or antisolvent methods using an ethanol-water system. However, these methods suffer from long crystallization cycles (20-48 hours), incomplete removal of impurities (especially the α-isomer) (residual levels ≥ 1.0%), and excessive solvent residues. Invention patent application CN103694230A discloses the purification of the API through amino acid cocrystal technology, addressing the existing issue of high α-isomer content in canagliflozin. However, this involves the introduction of a new cocrystal former, increasing the difficulty of subsequent separation.

[0004] Therefore, it is of great significance to develop a new preparation process for canagliflozin hemihydrate API to avoid the use of cocrystal formers, shorten the crystallization cycle and produce low / no impurity residues in the preparation of canagliflozin to meet the needs of industrial production. It is expected to bring breakthroughs to the research and development, production and market of canagliflozin drugs. Summary of the Invention

[0005] The present invention provides a process for preparing the raw material of canagliflozin hemihydrate, aiming to partially or completely solve the technical problems of high residual impurities, long crystallization cycle, and the use of eutectic formers in the prior art of canagliflozin preparation. The present invention avoids the use of eutectic formers and achieves efficient preparation of hemihydrate by optimizing the ternary solvent system, seed pretreatment, and staged temperature-controlled crystallization technology. In order to achieve the purpose of the present invention, the technical solution of the present invention is as follows:

[0006] In a first aspect, a process for preparing a canagliflozin hemihydrate API comprises:

[0007] Step S100: using a methanol-n-propanol-water ternary mixed solvent system, wherein n-propanol accounts for 30% by volume, dissolving the crude canagliflozin therein to obtain a dissolved mixture, and the solubility difference between canagliflozin and the α-configuration impurity is ≥15 mg / mL;

[0008] Step S200: Pre-treating the commercially available canagliflozin hemihydrate as a seed crystal, wherein the pre-treatment includes soaking the commercially available canagliflozin hemihydrate in an organic solvent, ultrasonic treatment, and then filtering and drying to make the surface hydroxyl density of the seed crystal ≥8×10 14 groups / cm 2 ;

[0009] Step S300: The dissolved mixture is heated to 50-60°C, then cooled to 30-35°C, and the hemihydrate seed crystals pretreated in step S200 are added, stirred, cooled, and crystallized;

[0010] Step S400: After the crystallization is completed, the crystallized product is separated, washed and dried to obtain canagliflozin hemihydrate.

[0011] 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, 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: heating the dissolved mixture to 50-60°C, then cooling it to 30-35°C at a rate of 2-4°C / min, adding 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 and crystallizing for 3-5 hours.

[0012] 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.

[0013] Optionally, in step S200 , the ultrasonic power is 90-150 W, the frequency is 35-50 kHz, and the time is 10-20 minutes.

[0014] Optionally, in step S200, the soaking organic solvent is selected from at least one of methanol, ethanol and n-propanol, and the commercially available canagliflozin hemihydrate seed crystals are soaked in methanol and / or ethanol at 30-70°C for 20-50 minutes; or, the commercially available canagliflozin hemihydrate seed crystals are soaked in n-propanol at 40-60°C for 25-45 minutes; or, the commercially available canagliflozin hemihydrate seed crystals are soaked in methanol and / or ethanol, n-propanol at 40-60°C for 25-45 minutes.

[0015] Optionally, in step S300, the amount of seed crystals added is 0.1-0.5% of the quality of the crude canagliflozin.

[0016] Optionally, in step S400, after crystallization is completed, centrifugation is performed to separate solid and liquid, and the filter cake is washed. 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.

[0017] Optionally, in step S400, the centrifugal speed is 3500-4000 rpm, and the centrifugal time is 10-12 minutes.

[0018] Optionally, in step S400, the filter cake is washed 2-3 times, with the amount of washing liquid used each time being 3-4 times the mass of the filter cake.

[0019] Optionally, in step S400, the drying condition is drying under vacuum conditions at 40-45°C for 8-10 hours.

[0020] In the second aspect, a canagliflozin hemihydrate API is prepared using the preparation process of a canagliflozin hemihydrate API described in any one of the first aspects above, wherein the API has a purity of ≥99.8%, a yield of ≥90%, and the crystal X-ray powder diffraction of the canagliflozin API has a DSC endothermic peak at 98.5±1°C.

[0021] Compared with the prior art, the present invention has the following advantages:

[0022] In the present application, through the overall synergy of a specific mixed solvent system and a specific seed crystal 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 purity of similar process products. The yield of canagliflozin hemihydrate is increased to more than 90%, significantly improving production efficiency and economic benefits; the entire preparation process cycle is shortened by about 40% compared with the traditional process, from the original 20 hours to less than 12 hours, greatly improving production efficiency and reducing production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a schematic diagram of the PXRD (Powder X-Ray Diffraction) spectrum of canagliflozin hemihydrate prepared in Example 1 of the present application.

[0024] Figure 2 This is a DSC schematic diagram of canagliflozin hemihydrate prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments; multiple times include once or twice or more than twice; the numerical range can at least be understood to include the endpoint values, and can also be reasonably understood based on actual conditions; based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0026] As used herein, "crude canagliflozin" refers to canagliflozin that can be obtained by any preparation method in the art.

[0027] As used herein, commercially available canagliflozin hemihydrate was purchased from Zhejiang Huayi Pharmaceutical Co., Ltd.

[0028] A preparation process of canagliflozin hemihydrate raw material

[0029] In a first aspect, a process for preparing a canagliflozin hemihydrate API comprises:

[0030] Step S100: using a methanol-n-propanol-water ternary mixed solvent system, wherein n-propanol accounts for 30% by volume, dissolving the crude canagliflozin therein to obtain a dissolved mixture, and the solubility difference between canagliflozin and the α-configuration impurity is ≥15 mg / mL;

[0031] In step S100, methanol and n-propanol, as polar organic solvents, effectively dissolve the organic portion of canagliflozin, while 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, allowing the crude product to be completely dissolved.

[0032] In the present application, the hydroxyl group of n-propanol forms an intermolecular hydrogen bond with the carbonyl group of the canagliflozin molecule, and through the polarity gradient synergistic effect (methanol dielectric constant 32.7 → n-propanol 20.1 → water 78.5), the co-solubility rate of α-configuration impurities is reduced to below 0.3%.

[0033] In the present application, the solubility difference between canagliflozin and α-configuration impurities in the solvent system is ≥15 mg / mL, which means that canagliflozin hemihydrate is more likely to precipitate preferentially 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 to form larger and uniform crystal particles, reduce the formation of fine crystals or amorphous matter, maintain the stability and consistency of the crystal form, and thus reduce the canagliflozin residue in the mother liquor.

[0034] In the present application, the ternary solvent system improves the solubility of canagliflozin by optimizing polarity, ensuring that the crude product can be completely dissolved, laying the foundation for the subsequent crystallization process. By subsequently adjusting the ratio of the mixed solvent, the supersaturation of the crystallization solution and the crystal growth rate can be controlled, thereby affecting the morphology and quality of the crystals, which helps to obtain the ideal crystalline product. In addition, the appropriate solvent selection helps to separate the target product from impurities, improve the purity of the crystalline product, and reduce the burden of subsequent purification steps.

[0035] Step S200: Pre-treating the commercially available canagliflozin hemihydrate as a seed crystal, wherein the pre-treatment includes soaking the commercially available canagliflozin hemihydrate in an organic solvent, ultrasonic treatment, and then filtering and drying to make the surface hydroxyl density of the seed crystal ≥8×10 14 groups / cm 2 ;

[0036] Specifically, step S200 includes: pre-treating the commercially available canagliflozin hemihydrate as a seed crystal, wherein the pre-treatment includes soaking the commercially available canagliflozin hemihydrate in an organic solvent, ultrasonic treatment, filtering, drying, and then measuring the surface hydroxyl density of the seed crystal to ensure that the surface hydroxyl density of the seed crystal is ≥8×10 14 groups / cm 2 ;

[0037] In some embodiments, in step S200 , the hydroxyl density on the surface of the seed crystal is measured by X-ray photoelectron spectroscopy.

[0038] In some embodiments, in step S200 , commercially available seed crystals may absorb impurities (such as moisture, dust, or other organic matter) during storage or transportation, and these impurities may reduce the surface activity of the seed crystals.

[0039] In some embodiments, the seed crystals can be purified by soaking them in an organic solvent such as methanol, ethanol, or n-propanol. The solvent can dissolve or elute impurities on the surface of the seed crystals at a corresponding temperature and time. At the same time, soaking in the organic solvent can activate the surface of the seed crystals, making it easier for them to interact with the solute molecules in the crystallization solution, thereby promoting nucleation and crystal growth.

[0040] In some embodiments, ultrasonic treatment can generate cavitation effect and mechanical vibration through ultrasonic waves with a power of 90-150W and a frequency of 35-50kHz, destroying the adsorption of impurities on the seed crystal within 10-20 minutes, stripping impurities on the surface and in the micropores, and increasing the surface roughness of the seed crystal, exposing more active sites, and increasing the specific surface area by 20-30%. The synergistic process of organic solvent immersion and ultrasonic treatment can increase the hydroxyl density on the seed crystal surface to ≥8×10 14 groups / cm 2 , significantly enhancing the hydrogen bonding interaction with canagliflozin molecules, promoting nucleation and crystal growth.

[0041] In some embodiments, the pretreatment process may remove oversized or undersized seed crystals, resulting in a more uniform seed crystal size. A uniform particle size distribution helps control the particle size consistency of the crystallized product. The selected organic solvent should be compatible with the crystallization system, and the soaking process ensures sufficient contact between the seed crystal surface and the solvent, improving the dispersibility and stability of the seed crystals in the solution.

[0042] In step S200, pretreatment improves the purity of the seed crystals by removing surface impurities and reduces the interference of impurities in the crystallization process, thereby helping to produce higher-purity canagliflozin hemihydrate. The surface activity of the seed crystals is improved after pretreatment, which can effectively induce crystal nucleation, accelerate the crystallization process, and improve crystallization efficiency. The pretreated seed crystals can regulate the direction and speed of crystal growth. The pretreatment ultimately improves the purity and yield of the crystalline product, meeting the high standards for drug preparation.

[0043] Step S300: The dissolved mixture is heated to 50-60°C, then cooled to 30-35°C, and the hemihydrate seed crystals pretreated in step S200 are added, stirred, cooled, and crystallized;

[0044] In some embodiments, step S300 comprises: 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 seed crystals pretreated in step S200, stirring at a constant temperature of 30-35° C. for 1-2 hours, then cooling it to 5-10° C. at a rate of 0.8-1.2° C. / min, and stirring for crystallization for 3-5 hours;

[0045] In some embodiments, the dissolved mixture is heated to 50-60°C to ensure complete dissolution of canagliflozin and form a homogeneous solution. This stage uses thermal energy to overcome solute-solvent interactions, dispersing the solute molecules throughout the solution and paving the way for the subsequent formation of a supersaturated state.

[0046] In some embodiments, the solution is then cooled to 30-35°C at a rate of 2-4°C / min to reduce the solution temperature and solubility, thereby forming a supersaturated solution. Supersaturation is the thermodynamic driving force for crystallization, and rapid cooling promotes initial nucleation, providing conditions for crystal formation.

[0047] In some embodiments, pretreated seed crystals are added at 30-35°C. These seed crystals act as heterogeneous nucleation centers, providing a fixed surface for solute molecules to aggregate and form new nuclei. Stirring is performed at this temperature for 1-2 hours to ensure stable nucleation at an appropriate supersaturation level and to avoid heterogeneous crystals caused by spontaneous nucleation (homogeneous nucleation). Heterogeneous nucleation is a common method in the pharmaceutical industry that can control crystal morphology and particle size.

[0048] In some embodiments, the temperature can be lowered to 5-10°C with stirring at a rate of 0.8-1.2°C / min to increase supersaturation and promote further crystal growth. Slow cooling helps control the crystal growth rate and avoid defects or impurity entrapment caused by excessive crystallization. Crystallization is stirred at 5-10°C for 3-5 hours. Stirring helps evenly distribute the solute and promotes crystal growth. At the same time, crystal ripening may occur, that is, smaller crystals dissolve and larger crystals continue to grow.

[0049] In some embodiments, canagliflozin hemihydrate is a hydrated crystal, and its crystallization process involves not only solute molecules but also the orderly arrangement of water molecules. Temperature control and the introduction of seed crystals ensure that the water molecules are properly integrated into the crystal lattice in the form of hemihydrate.

[0050] In step S300, seed induction and staged cooling are used to ensure uniform crystal growth and a narrow particle size distribution, which are suitable for tableting and flowability of pharmaceutical preparations. The use of seed crystals reduces the spontaneous nucleation time, accelerates the crystallization process, and improves yield and production efficiency. The process conditions and seed crystal selection ensure the formation of the target hemihydrate and reduce the risk of other polymorphs. The crystallization process effectively separates impurities. Seed induction promotes the growth of pure crystals and improves the purity of the final product. Temperature control (3°C / min and 1°C / min cooling rates) and the use of standardized seed crystals ensure process stability and repeatability, making it suitable for industrial production.

[0051] Step S400: After the crystallization is completed, the crystallized product is separated, washed and dried to obtain canagliflozin hemihydrate.

[0052] In some embodiments, step S400 comprises: after crystallization is completed, centrifuging to separate the solid and liquid, washing the filter cake, separating, washing and drying the crystallized product to obtain canagliflozin hemihydrate.

[0053] In some embodiments, in step S400, the centrifugation speed is 3500-4000 rpm, and the centrifugation time is 10-12 minutes.

[0054] 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.

[0055] 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.

[0056] In some embodiments, in step S400 , the drying condition is drying under vacuum conditions at 40-45° C. for 8-10 hours.

[0057] In some embodiments, centrifugation utilizes centrifugal force to cause the denser solid crystals to settle to the bottom, leaving the liquid (solvent) on top. This achieves solid-liquid separation, accelerates the settling of the solid particles, and shortens the separation time. A speed of 3500-4000 rpm and a separation time of 10-12 minutes are used to ensure efficient separation without disrupting the crystal structure.

[0058] In some embodiments, washing involves rinsing with solvent to remove impurities and residual solvent from the crystal surface. Using a methanol-water mixture cooled to 4-8°C can reduce dissolution losses of canagliflozin hemihydrate. As the temperature decreases, the solubility of the solute decreases. Low-temperature washing effectively preserves the crystals while removing soluble impurities. The amount of washing solution used (3-4 times the mass of the filter cake) ensures sufficient washing without wasting solvent.

[0059] In some embodiments, drying can remove residual solvent and moisture, ensuring product stability and purity. Drying is typically performed in a vacuum or temperature-controlled oven to prevent high-temperature degradation. The stability of hydrate crystals is closely related to their moisture content, and the drying process must be controlled under appropriate conditions to avoid dehydration or moisture absorption.

[0060] In step S400, centrifugation is rapid and efficient, suitable for large-scale production and reducing product loss. Low-temperature washing removes impurities without dissolving the product, ensuring high purity. Parameters such as centrifugation speed, time, washing temperature, and dosage are controllable, ensuring process stability and repeatability. Centrifugation and washing are easily scalable, suitable for the transition from laboratory to industrial production. Low-temperature washing and optimized washing volume reduce product dissolution loss and improve yield. Low-temperature washing and optimized volume reduce dissolution loss and improve yield. Through centrifugation, washing, and drying, efficient separation and purification of canagliflozin hemihydrate are ensured, combining efficiency, purity, and scalability.

[0061] 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, so that the solubility of canagliflozin is ≥20 mg / mL and the solubility of α-impurity is ≤5 mg / mL.

[0062] In some embodiments, the polarity differences between 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, highly polarity)—form a gradient. This gradient enables the solvent to effectively dissolve substances with both polar and non-polar components. For example, the polar groups in the canagliflozin molecule interact with water, while the non-polar portion interacts with n-propanol. Methanol acts as a bridge to balance the two, thereby enhancing overall solubility.

[0063] In some embodiments, the mixed solvent ratio is adjusted to control the supersaturation of the solution, a key driving force for crystallization. In a 2-3:3:4-5 ratio (n-propanol accounts for 30%), the higher proportion of water makes it easier for the solution to reach supersaturation upon cooling, promoting crystal nucleation. Simultaneously, 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 solubility of water, lowers the surface tension of the solution, reduces agglomeration during crystallization, and promotes more uniform crystal growth. In a 30% ratio of n-propanol, the hydroxyl group of n-propanol forms an intermolecular hydrogen bond (bond length 2.0±0.1Å) with the carbonyl group of the canagliflozin molecule. This polarity gradient synergy (dielectric constant of methanol 32.7 → n-propanol 20.1 → water 78.5) reduces the co-solubility of α-configured impurities to below 0.3%.

[0064] 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.

[0065] In some embodiments, the mass-to-volume ratio of crude canagliflozin to the ternary mixed solvent (methanol-n-propanol-water) is 1:5 to 1:10, meaning that 5-10 mL of solvent is used per gram of crude canagliflozin. This ratio ensures that canagliflozin is fully dissolved in the solvent while avoiding excessive solvent that may cause difficulty in subsequent crystallization or insufficient solvent that may cause incomplete dissolution.

[0066] In some embodiments, dissolution is performed at 40-50°C, with moderate heating 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 create an appropriate solvent polarity, optimizing dissolution efficiency. By adjusting polarity and solubility, the ternary solvent system provides suitable supersaturation conditions for subsequent cooling crystallization.

[0067] In this application, a solid-liquid ratio of 1:5-1:10 ensures complete dissolution of the crude canagliflozin product, while maintaining a moderate solvent dosage to reduce waste and facilitate subsequent crystallization control. A dissolution temperature of 40-50°C both increases the dissolution rate and avoids the effects of high temperatures on canagliflozin's stability, making it suitable for industrial operations. The methanol-n-propanol-water combination provides balanced polarity and solubility, aiding in the dissolution of canagliflozin and the separation of impurities, enhancing crude product purification. The solid-liquid ratio range (1:5-1:10) provides operational flexibility, allowing the solvent dosage to be adjusted based on the crude product's characteristics to accommodate varying batch requirements.

[0068] Optionally, in step S200, the soaking organic solvent is selected from at least one of methanol, ethanol and n-propanol, and the commercially available canagliflozin hemihydrate seed crystals are soaked in methanol and / or ethanol at 30-70°C for 20-50 minutes; or, the commercially available canagliflozin hemihydrate seed crystals are soaked in n-propanol at 40-60°C for 25-45 minutes; or, the commercially available canagliflozin hemihydrate seed crystals are soaked in methanol and / or ethanol, n-propanol at 40-60°C for 25-45 minutes.

[0069] 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 with good solubility and volatility. These solvents can dissolve organic impurities, residues, or adsorbates that may be present on the surface of the canagliflozin seed crystals, and are compatible with the chemical properties of canagliflozin hemihydrate without destroying the crystal structure. Methanol and n-propanol have the same or similar composition to the ternary solvent system (methanol-n-propanol-water) in step S100, ensuring that the pretreatment process does not introduce incompatible substances, maintaining the chemical consistency of the process, and avoiding the introduction of exogenous impurities, ensuring the stability of the subsequent crystallization process.

[0070] 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; alternatively, commercially available canagliflozin hemihydrate seed crystals are soaked in methanol and / or ethanol, or 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 activate the seed crystal surface (e.g., through micro-dissolution or surface reconstruction), thereby improving the seed crystal's inductive ability during subsequent crystallization. The seed crystals are separated from the solvent by filtration, and the residual solvent and water are dried to obtain pure, dry seed crystals, which facilitate the induction of uniform crystallization in step S300 and improve the crystal morphology and particle size distribution of canagliflozin hemihydrate.

[0071] In the present invention, methanol and n-propanol are both common solvents with low cost and easy access, excellent cleaning effect, and are suitable for large-scale production. The pretreated seed crystal surface is cleaner and more active.

[0072] Optionally, in step S300, the amount of seed crystals added is 0.1-0.5% of the quality of the crude canagliflozin.

[0073] In some embodiments, the amount of seed crystals added is 0.1-0.5% of the quality of the crude canagliflozin, that is, 0.1-0.5g of seed crystals are added for every 100g of crude product. This low ratio of seed crystals is sufficient to induce crystal nucleation, avoiding excessive seed crystals that cause crystals to grow too fast or the crystal size to be too small. The seed crystals provide initial crystal nuclei, reduce the nucleation energy barrier, and promote orderly crystallization of the solution under supersaturated conditions; the pretreated canagliflozin hemihydrate seed crystals have the same structure as the target crystal form, and after addition, they induce crystal growth through surface adsorption molecules, controlling the consistency of the crystal form and the quality of the crystal. The seed crystal amount of 0.1-0.5% balances the nucleation rate and the crystal growth rate, avoiding excessive seed crystals that cause the crystal particles to be too fine or insufficient to effectively induce crystallization.

[0074] In the present application, the seed amount of 0.1-0.5% is moderate, which can effectively induce the formation of the canagliflozin hemihydrate crystal form, ensure the consistency of the crystal structure, and meet the pharmaceutical requirements. The low seed amount avoids excessive crystal growth. Combined with slow cooling (1°C / min) and long-term stirring (3 hours), it promotes uniform crystal growth, reduces crystal defects, and 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 amount range (0.1-0.5%) provides operational flexibility. The seed amount can be adjusted according to the crude product quality or the target crystal size to adapt to different production needs. The low seed amount reduces pretreatment costs while ensuring efficient crystallization and reducing overall production costs.

[0075] 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.

[0076] In this application, methanol (boiling point 64.7°C) has a strong dissolving power, effectively removing organic impurities remaining on the filter cake surface. Water (boiling point 100°C) reduces the solubility of the solution, minimizing dissolution losses of canagliflozin hemihydrate during the washing process. The 1:2 volume ratio balances cleaning effectiveness with crystal protection, ensuring impurity removal while preserving as much crystal as possible. Furthermore, the cold solution helps maintain the stability of the crystal structure and prevent polymorphic transformations.

[0077] Optionally, in step S400, the drying condition is drying under vacuum conditions at 40-45°C for 8-10 hours.

[0078] In this application, vacuum drying reduces the boiling point of the solvents (methanol and water) by lowering the ambient pressure, accelerating the volatilization of residual solvents while preventing high temperatures from damaging the canagliflozin hemihydrate crystal form. A moderate temperature of 40-45°C effectively removes solvent and water while preventing excessive temperatures from causing crystal degradation or crystal transformation (e.g., hemihydrate dehydration to anhydrous). A drying time of 8-10 hours ensures sufficient removal of residual solvent and water without excessively extending the process time, achieving a balance between efficiency and quality.

[0079] In the second aspect, a canagliflozin hemihydrate API is prepared using the preparation process of a canagliflozin hemihydrate API described in any one of the first aspects above, wherein the API has a purity of ≥99.8%, a yield of ≥90%, and the crystal X-ray powder diffraction of the canagliflozin API has a DSC endothermic peak at 98.5±1°C.

[0080] In the present application, the preparation process of canagliflozin hemihydrate API (the ternary solvent system in step S100 optimizes the solubility, the solvent polarity is moderate, ensures the complete dissolution of the crude product, and facilitates the separation of impurities, the pretreatment in step S200 removes impurities on the surface of the seed crystal, the gradual cooling in step S300 controls the supersaturation, the seed crystal induces orderly nucleation, the slow cooling and long-term stirring promote the uniform growth of the crystal, a small amount of seed crystals (0.1-0.5%) balances the nucleation and growth rate to ensure the quality of the crystal, step S4 00 solid-liquid separation and washing and drying), systematically removing organic and inorganic impurities and non-target crystal forms to ensure that the API meets pharmaceutical standards (such as ICHQ3C residual solvent requirements). Based on ternary solvent dissolution, seed crystal induced crystallization, temperature-controlled growth and efficient purification, the preparation of canagliflozin hemihydrate API with high purity, high yield, stable crystal form, controllable process, safety and economy was completed. The canagliflozin hemihydrate API with purity ≥99.8% and yield ≥90% was synergistically obtained, which is suitable for industrial production and pharmaceutical requirements.

[0081] Unless otherwise specified, the raw materials and reagents used in the following experiments are commercially available or prepared according to conventional methods. Unless otherwise specified, the methods used in the experiments are conventional experimental methods. Unless otherwise specified, the instruments used in the experiments are commercially available.

[0082] Example 1

[0083] (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.

[0084] (2) Seed pretreatment: 0.05 g of commercially available seed was soaked in a methanol solution at 50 °C for 30 minutes and then ultrasonically treated. The ultrasonic treatment conditions were as follows: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic treatment for 15 minutes, filtration, and drying. The surface hydroxyl density was 8.5 × 10 14 groups / cm 2 ,spare.

[0085] (3) Crystallization: After dissolution, the mixture was heated to 50°C, cooled to 35°C at a rate of 3°C / min, and the pretreated seed crystals were added. The mixture was stirred at 35°C for 1 hour. Subsequently, the mixture was cooled to 10°C at a rate of 1°C / min and crystallization was continued with stirring for 3 hours.

[0086] (4) Separation, washing, and drying: The crystallized solution was centrifuged at 3500 rpm for 10 minutes to collect the filter cake. The filter cake was washed twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5°C, with the amount of washing liquid being 4 times the mass of the filter cake. The washed filter cake was dried under vacuum at 40°C for 8 hours to obtain the canagliflozin hemihydrate product.

[0087] Example 2

[0088] (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.

[0089] (2) Seed pretreatment: 0.25 g of commercially available seed was taken and the seed treatment method was the same as in Example 1. The hydroxyl density was 8.2 × 10 14 groups / cm 2 .

[0090] (3) Crystallization: The cooling and seeding steps were the same as in Example 1, and the constant temperature stirring and crystallization time were extended to 1.5 hours and 4 hours, respectively.

[0091] (4) Separation, washing, and drying: The crystallized solution was centrifuged at 4000 rpm for 12 minutes, and the filter cake was washed twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5°C. The amount of washing liquid was 4 times the mass of the filter cake, and dried under vacuum conditions at 45°C for 10 hours.

[0092] Comparative Example 1

[0093] The preparation was carried out using the ethanol-water binary solvent system (volume ratio 3:1) and the traditional crystallization process described in invention patent application CN102675380A.

[0094] (1) Dissolution: Add 10 g of crude canagliflozin to 40 mL of ethanol-water mixed solvent and stir to dissolve at 45°C.

[0095] (2) Crystallization: The temperature was directly lowered to 10°C at a rate of 3°C / min for crystallization without using pretreated seed crystals. The crystallization cycle was 20 hours.

[0096] (3) Separation, washing, and drying: conventional centrifugal separation and ethanol washing at room temperature, followed by drying at 50°C under normal pressure for 12 hours.

[0097] Comparative Example 2

[0098] (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.

[0099] (2) Seed pretreatment: 0.05 g of commercially available seed was soaked in a methanol solution at 50 °C for 30 minutes and then ultrasonically treated. The ultrasonic treatment conditions were as follows: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic treatment for 15 minutes, filtration, and drying. The surface hydroxyl density was 8.5 × 10 14 groups / cm 2 ,spare.

[0100] (3) Crystallization: After dissolution, the mixture was heated to 50°C, cooled to 35°C at a rate of 3°C / min, and the pretreated seed crystals were added. The mixture was stirred at 35°C for 1 hour. Subsequently, the mixture was cooled to 10°C at a rate of 1°C / min and crystallization was continued with stirring for 3 hours.

[0101] (4) Separation, washing, and drying: The crystallized solution was centrifuged at 3500 rpm for 10 minutes to collect the filter cake. The filter cake was washed twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5°C, with the amount of washing liquid being 4 times the mass of the filter cake. The washed filter cake was dried under vacuum at 40°C for 8 hours to obtain the canagliflozin hemihydrate product.

[0102] Comparative Example 3

[0103] (1) Dissolution: Weigh 10 g of crude canagliflozin 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.

[0104] (2) Seed pretreatment: 0.05 g of commercially available seed was soaked in a methanol solution at 50 °C for 30 minutes and then ultrasonically treated. The ultrasonic treatment conditions were as follows: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic treatment for 15 minutes, filtration, and drying. The surface hydroxyl density was 8.5 × 1014 groups / cm 2 ,spare.

[0105] (3) Crystallization: After dissolution, the mixture was heated to 50°C, cooled to 35°C at a rate of 3°C / min, and the pretreated seed crystals were added. The mixture was stirred at 35°C for 1 hour. Subsequently, the mixture was cooled to 10°C at a rate of 1°C / min and crystallization was continued with stirring for 3 hours.

[0106] (4) Separation, washing, and drying: The crystallized solution was centrifuged at 3500 rpm for 10 minutes to collect the filter cake. The filter cake was washed twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5°C, with the amount of washing liquid being 4 times the mass of the filter cake. The washed filter cake was dried under vacuum at 40°C for 8 hours to obtain the canagliflozin hemihydrate product.

[0107] Comparative Example 4

[0108] (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.

[0109] (2) Seed pretreatment: 0.05 g of commercially available seed was soaked in a methanol solution at 50 °C for 30 minutes, filtered, and dried. The surface hydroxyl density was 5.2 × 10 14 groups / cm 2 ,spare.

[0110] (3) Crystallization: After dissolution, the mixture was heated to 50°C, cooled to 35°C at a rate of 3°C / min, and the pretreated seed crystals were added. The mixture was stirred at 35°C for 1 hour. Subsequently, the mixture was cooled to 10°C at a rate of 1°C / min and crystallization was continued with stirring for 3 hours.

[0111] (4) Separation, washing, and drying: The crystallized solution was centrifuged at 3500 rpm for 10 minutes to collect the filter cake. The filter cake was washed twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5°C, with the amount of washing liquid being 4 times the mass of the filter cake. The washed filter cake was dried under vacuum at 40°C for 8 hours to obtain the canagliflozin hemihydrate product.

[0112] Comparative Example 5

[0113] (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.

[0114] (2) Seed pretreatment: 0.05 g of commercially available seed was ultrasonically treated. Ultrasonic treatment conditions: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic for 15 minutes, filtered, and dried. The surface hydroxyl density was 4.8 × 10 14 groups / cm 2 ,spare.

[0115] (3) Crystallization: After dissolution, the mixture was heated to 50°C, cooled to 35°C at a rate of 3°C / min, and the pretreated seed crystals were added. The mixture was stirred at 35°C for 1 hour. Subsequently, the mixture was cooled to 10°C at a rate of 1°C / min and crystallization was continued with stirring for 3 hours.

[0116] (4) Separation, washing, and drying: The crystallized solution was centrifuged at 3500 rpm for 10 minutes to collect the filter cake. The filter cake was washed twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5°C, with the amount of washing liquid being 4 times the mass of the filter cake. The washed filter cake was dried under vacuum at 40°C for 8 hours to obtain the canagliflozin hemihydrate product.

[0117] Comparative Example 6

[0118] (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.

[0119] (2) Seed pretreatment: 0.05 g of commercially available seed was soaked in ethyl acetate solution at 50 °C for 30 minutes and then ultrasonically treated. The ultrasonic treatment conditions were as follows: ultrasonic power / frequency: 50 W / 30 kHz, ultrasonic treatment for 10 minutes, filtration, and drying. The surface hydroxyl density was 5.8 × 10 14 groups / cm 2 ,spare.

[0120] (3) Crystallization: After dissolution, the mixture was heated to 50°C, cooled to 35°C at a rate of 3°C / min, and the pretreated seed crystals were added. The mixture was stirred at 35°C for 1 hour. Subsequently, the mixture was cooled to 10°C at a rate of 1°C / min and crystallization was continued with stirring for 3 hours.

[0121] (4) Separation, washing, and drying: The crystallized solution was centrifuged at 3500 rpm for 10 minutes to collect the filter cake. The filter cake was washed twice with 30 mL of a methanol-water (volume ratio 1:2) mixed solution pre-cooled to 5°C, with the amount of washing liquid being 4 times the mass of the filter cake. The washed filter cake was dried under vacuum at 40°C for 8 hours to obtain the canagliflozin hemihydrate product.

[0122] The product purity and yield of the canagliflozin hemihydrate raw material 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 tested. The product purity was determined by HPLC (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 precipitate amount to the crude quality.

[0123] The product purity and yield determination results of the canagliflozin hemihydrate raw materials prepared in Example 1 and Example 2 and the canagliflozin hemihydrate prepared in Comparative Example 1 are as follows:

[0124]

[0125] It can be seen that the purity of the canagliflozin product obtained by the canagliflozin preparation process applied for in the present invention can reach more than 99.8%, and the yield can reach more than 90%, which meets the requirements of industrial production.

[0126] (1) PXRD pattern analysis of canagliflozin hemihydrate in Example 1

[0127] 1-PXRD pattern results of canagliflozin hemihydrate:

[0128] like Figure 1 As 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 structure of canagliflozin hemihydrate and the significance of the peaks.

[0129] 1) Diffraction peak

[0130] There are multiple obvious 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°, and 16.25°. The peak intensity at 15.49° is the highest (nearly 60 CPS), indicating that this is the strongest reflection surface in the structure of canagliflozin hemihydrate. There are multiple smaller peaks in the low-angle (4°-9°) and medium-angle (10°-13°) regions, indicating that canagliflozin hemihydrate has a certain complex structure or polycrystalline phase.

[0131] 2) Crystal properties

[0132] The PXRD pattern displays multiple sharp diffraction peaks, indicating that canagliflozin hemihydrate has a well-defined crystalline structure consistent with the characteristics of a hemihydrate crystalline form. The peak with the highest intensity, 15.49°, likely corresponds to a major crystal plane (such as

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

[0133] 3) Sample purity and yield

[0134] There were no obvious impurity peaks or amorphous background in the PXRD pattern, indicating that the impurity content of canagliflozin hemihydrate was low. Figure 2 The DSC results are shown. Analysis shows that there is a single endothermic peak at 98.5±1°C, corresponding to the removal of hemihydrate crystal water (theoretical weight loss rate 8.5%, measured 8.6%), proving the purity of the crystal form.

[0135] Analysis of the PXRD pattern of 2-canagliflozin hemihydrate:

[0136] 1) Process optimization and crystal form control:

[0137] Ternary solvent system (step S100): Methanol-n-propanol-water (volume ratio 2:3:5) was used to dissolve the crude product. The solid-liquid ratio (1:10 g / mL) was moderate and the dissolution temperature was 50°C to ensure complete dissolution. Water was added to adjust the polarity of the solvent and promote the formation of the hemihydrate crystal form. Seed induction (step S200 and step S300): pre-treated seed crystals (0.05 g) were immersed in 50°C methanol to remove impurities and subjected to ultrasonic treatment. The ultrasonic treatment conditions were as follows: ultrasonic power / frequency: 100 W / 40 kHz, ultrasonic treatment for 15 minutes to activate the surface of the seed crystals; 0.5% seed crystals were added and the temperature was lowered step by step (3°C / min to 35°C, 1°C / min to 10°C) to induce ordered crystallization and generate a consistent hemihydrate crystal form, resulting in the appearance of sharp peaks in the PXRD pattern. Seeding and precise temperature control (constant temperature stirring for 1 hour, crystallization for 3 hours) reduced the amorphous phase or non-target crystal form and formed a highly ordered crystal structure, which was reflected in the clear peaks in the PXRD pattern.

[0138] 2) Crystallization conditions

[0139] Cooling the sample to 10°C at a rate of 1°C / min and stirring for a long time to control supersaturation promotes slow crystal growth, reduces crystal defects and lattice strain, and results in sharp peaks with uniform intensity. This slow crystallization process optimizes crystal face development, particularly the high-intensity peaks (14°-15°) corresponding to the primary crystal faces, indicating high crystal orientation and quality.

[0140] 3) Washing and drying optimization

[0141] The filter cake was washed with 5°C methanol-water (1:2 volume ratio) to reduce solubility, minimize surface impurities, and reduce mother liquor residue, ensuring pure crystals. Vacuum drying was performed to remove the solvent and preserve the hemihydrate crystal form (stable due to the coordination of water molecules) to avoid high-temperature-induced crystal transformations. The pure crystals and stable hemihydrate structure enhance the diffraction intensity and peak clarity of the PXRD pattern and reduce background noise.

[0142] (2) Product purity analysis

[0143] Product purity results: The purities of Example 1 and Example 2 are both greater than 99.8%, which are higher than 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 optimized process are superior to the ethanol-water binary solvent system and traditional process in terms of purity improvement.

[0144] Product purity reasons:

[0145] 1) Differences in solvent systems

[0146] Examples 1 and 2 employed a methanol-n-propanol-water ternary solvent system. This ternary system optimizes canagliflozin dissolution and impurity separation by combining the strong solubility of methanol and n-propanol with the polarity regulation of water. The addition of water reduces canagliflozin's solubility, favoring the preferred crystal form during crystallization and reducing impurity incorporation.

[0147] 2) Seed pretreatment and addition

[0148] 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.

[0149] 3) Crystallization condition control

[0150] 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.

[0151] 4) Washing and drying

[0152] 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.

[0153] 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.

[0154] 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%.

[0155] Comparative Example 3: The amount of n-propanol was reduced, the amount of water was increased, and the polarity of the solvent was enhanced. Excessively high polarity reduced the solubility of canagliflozin, which may lead to a decrease in the solubility selectivity of the solvent system for α-impurities. Excessively high solvent polarity made the crystallization process unsatisfactory, and the purity dropped to 98.20%.

[0156] Comparative Example 4: No ultrasonic treatment was performed. Single immersion could not effectively open the seed crystal micropores, and the surface impurities were not completely desorbed, resulting in a low surface hydroxyl density (5.2×10 14 groups / cm 2 ), impurities on the seed crystal surface were not fully removed, active sites were not exposed enough, the nucleation efficiency was reduced, the crystal growth was uneven, impurities were easily encapsulated, and insufficient seed crystal pretreatment was the main reason for the purity to drop to 98.50%.

[0157] Comparative Example 5: Ultrasonic treatment only without solvent immersion, the surface hydroxyl density is the lowest (4.8×10 14 groups / cm 2Ultrasound only physically removed some impurities and could not repair hydroxyl sites through chemical action. The surface activity of the seed crystals was limited, and the lack of solvent chemical activation led to a serious lack of nucleation ability, disordered crystal growth, a large amount of impurities, and low seed crystal activity, resulting in an uncontrolled crystallization process and a purity drop to 97.80%.

[0158] Comparative Example 6: Soaked in ethyl acetate at 50°C for 30 minutes + ultrasonic treatment (50W / 30kHz, 10 minutes), the surface hydroxyl density was 5.8×10 14 groups / cm 2 , ethyl acetate was used for immersion, and the ultrasonic parameters were weak (50W / 30kHz), resulting in a low surface hydroxyl density (5.8×10 14 groups / cm 2 ), the synergistic effect of soaking and ultrasound is insufficient, the seed activation is insufficient, the nucleation efficiency is reduced, the crystal stability is poor, the impurity incorporation increases, and the poor seed pretreatment conditions lead to poor impurity control, with a purity of 98.10%.

[0159] The above analysis shows that the polarity change of the solvent system and the inadequate seed pretreatment are the main factors that lead to the lower purity of Comparative Examples 2 to 6 than that of Example 1. Reasonable solvent ratio and efficient seed pretreatment activation are crucial to improving the purity of canagliflozin hemihydrate.

[0160] (3) Yield analysis

[0161] Yield results: The yields of Examples 1 and 2 were both greater than 90%, which were 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 preparation process of canagliflozin has obvious advantages in reducing crystal loss and improving output efficiency.

[0162] Yield reasons:

[0163] 1) Solvent system and material-liquid ratio

[0164] Examples 1 and 2: The crude product was dissolved in a ternary solvent system (methanol:n-propanol:water) at a solid-liquid ratio of 1:10 g / mL. The appropriate amount of solvent was used to ensure complete dissolution without excessive dilution, thereby controlling supersaturation and reducing residual crystals in the mother liquor. Example 2 treated 50 g of the crude product, achieving a slightly higher yield than Example 1.

[0165] 2) Seed induction and crystallization control

[0166] Examples 1 and 2: Seed crystals (0.5% by weight) were added and pretreated. The crystals were immersed in 50°C methanol to remove impurities and then sonicated. Ultrasonication conditions included: ultrasonic power / frequency: 100W / 40kHz, 15 minutes of sonication, and stepwise cooling (3°C / min to 35°C, 1°C / min to 10°C). This promoted orderly nucleation and uniform growth, reduced the formation of excessively fine crystals or amorphous material, and maximized crystal precipitation. Example 2 extended the constant temperature stirring (1.5 hours) and crystallization time (4 hours), allowing for more complete crystal growth, reducing residual solute in the mother liquor, and resulting in a slightly higher yield.

[0167] 3) Solid-liquid separation and washing

[0168] Examples 1 and 2: Centrifugation (3500-4000 rpm, 10-12 minutes) efficiently separated the crystals. A methanol-water washing solution (1:2) cooled to 5°C reduced solubility and minimized crystal dissolution loss during the washing process. A moderate amount of washing solution (3-4 times the filter cake mass) ensured effective cleaning while protecting the crystals. Example 2 increased the amount of washing solution (4 times) and the centrifugal speed (4000 rpm) to optimize separation efficiency and minimize crystal loss.

[0169] 4) Drying conditions

[0170] Examples 1 and 2: Vacuum drying at 40-45°C gently removes the solvent, protects the crystal structure, and reduces crystal loss due to high temperatures or improper drying. In Example 2, the drying time was extended to 10 hours, which allowed for more thorough solvent removal, reduced residual effects, and slightly improved yield.

[0171] Comparative Example 1: The ethanol-water system (3:1, solid-liquid ratio 1:4 g / mL) has a high solubility, which may cause some canagliflozin to remain in the mother liquor during the crystallization process, reducing the yield; there is no seed induction, and the temperature is directly and rapidly lowered to 10°C. The crystallization cycle is long (20 hours), which may lead to uneven nucleation and different crystal particle sizes. Some canagliflozin is not effectively precipitated and remains in the mother liquor, with a yield of only 75%; conventional centrifugation and room temperature ethanol washing, the ethanol solubility is high, which may cause partial dissolution loss of crystals and reduce the yield; conventional drying may not optimize the temperature or time, resulting in solvent residue or slight degradation of crystals, affecting the yield.

[0172] Comparative Example 2: Increased n-propanol and reduced water decreased the solvent polarity, slightly increasing the solubility of canagliflozin and making supersaturation control more difficult. Some canagliflozin may have remained in the mother liquor during crystallization, reducing precipitation efficiency. The change in solvent polarity resulted in incomplete crystal precipitation, with some canagliflozin remaining in the mother liquor, reducing the yield to 85%.

[0173] Comparative Example 3: Reducing n-propanol and increasing water increased solvent polarity, reducing canagliflozin solubility and potentially leading to premature crystallization. Excessive supersaturation resulted in inadequate crystal growth, resulting in a large number of fine crystals that were easily lost with the mother liquor, reducing yield. Excessively polar solvent systems led to low crystallization efficiency, significant loss of fine crystals, and a yield drop of 82%.

[0174] Comparative Example 4: The seed crystals were not ultrasonically treated, and the surface hydroxyl density was low (5.2×10 14 groups / cm 2 ), insufficient nucleation efficiency. Crystal growth was uneven, and some small crystals or amorphous materials may have formed, increasing the residual canagliflozin in the mother liquor and reducing precipitation efficiency. Insufficient seed pretreatment led to reduced nucleation and crystal growth efficiency, resulting in some canagliflozin failing to precipitate effectively, reducing the yield to 88%.

[0175] Comparative Example 5: Ultrasonic treatment only without immersion, the surface hydroxyl density is the lowest (4.8×10 14 groups / cm 2 ), the nucleation ability of the seed crystal is seriously insufficient, resulting in disordered crystal growth and the generation of a large number of fine crystals or amorphous materials. These fine particles are easily lost with the mother liquor, significantly reducing the precipitation efficiency. The extremely low activity of the seed crystal leads to a significant decrease in the crystal precipitation efficiency, severe loss of fine crystals, and the yield drops to 83%.

[0176] Comparative Example 6: Using ethyl acetate for immersion and weak ultrasonic parameters (50W / 30kHz, 10 minutes), the surface hydroxyl density was low (5.8×10 14 groups / cm 2 ), insufficient seed activation, reduced nucleation efficiency, uneven crystal growth, part of canagliflozin failed to precipitate effectively and remained in the mother liquor, poor seed pretreatment conditions reduced nucleation efficiency, incomplete crystal precipitation, and the yield dropped to 86%.

[0177] Therefore, in the present application, through the overall synergy of a specific mixed solvent system and a specific seed crystal 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 purity of similar process products. The yield of canagliflozin hemihydrate is increased to more than 90%, significantly improving production efficiency and economic benefits; the entire preparation process cycle is shortened by about 40% compared with the traditional process, from the original 20 hours to less than 12 hours, greatly improving production efficiency and reducing production costs.

[0178] Those skilled in the art can understand that the various operations, methods, steps in the process, measures, and schemes discussed in the present invention application can be interchanged, changed, combined, or deleted; further, the various operations, methods, and other steps, measures, and schemes in the process discussed in the present invention application can also be interchanged, changed, rearranged, decomposed, combined, or deleted; further, the various operations, methods, and steps in the process disclosed in the present invention application in the prior art can also be interchanged, changed, rearranged, decomposed, combined, or deleted. The various technical features of the above embodiments can be arbitrarily combined. To make the description concise, not all possible combinations of the various technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification;

[0179] The embodiments described above only express several implementation methods of the embodiments of the present disclosure, and their descriptions are relatively specific and detailed, but they cannot be understood as limiting the patent scope of the embodiments of the present disclosure; it should be pointed out that for ordinary technicians in this field, without departing from the concept of the embodiments of the present disclosure, several variations and improvements can be made, which all fall within the protection scope of the embodiments of the present disclosure; therefore, the protection scope of the embodiments of the present disclosure should be based on the attached claims. As mentioned above, although the present invention application has been expressed and described with reference to specific preferred embodiments, it shall not be interpreted as limiting 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 in the attached claims.

[0180] The above description of the present invention and its embodiments is non-limiting. The drawings show only one embodiment of the present invention, and the actual structure is not limited thereto. In short, if a person skilled in the art is inspired by this and, without departing from the inventive purpose of the present invention, designs structures and embodiments similar to the technical solution without inventiveness, they shall fall within the scope of protection of the present invention.

Claims

1. A process for preparing canagliflozin hemihydrate raw material, characterized in that: include: Step S100: using a methanol-n-propanol-water ternary mixed solvent system, wherein n-propanol accounts for 30% by volume, dissolving the crude canagliflozin therein to obtain a dissolved mixture, and the solubility difference between canagliflozin and the α-configuration impurity is ≥15 mg / mL; Step S200: Pre-treating the commercially available canagliflozin hemihydrate as a seed crystal, wherein the pre-treatment includes soaking the commercially available canagliflozin hemihydrate in an organic solvent, ultrasonic treatment, and then filtering and drying to make the surface hydroxyl density of the seed crystal ≥8×10 14 groups / cm 2 ; Step S300: The dissolved mixture is heated to 50-60°C, then cooled to 30-35°C, and the hemihydrate seed crystals pretreated in step S200 are added, stirred, cooled, and crystallized; Step S400: After crystallization is completed, the crystalline product is separated, washed and dried to obtain canagliflozin hemihydrate; In step S100, the polarity gradient of the ternary mixed solvent is methanol, n-propanol, and 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; the material-liquid ratio of crude canagliflozin to the ternary mixed solvent is 1:5-1:10 g / mL, and the dissolution temperature is 40-50°C; In step S200, the ultrasonic power is 90-150 W, the frequency is 35-50 kHz, and the time is 10-20 minutes; the soaking organic solvent is selected from methanol, and the commercially available canagliflozin hemihydrate seed crystals are soaked in methanol at 30-70° C. for 20-50 minutes; In step S300, the amount of seed crystals added is 0.1-0.5% of the quality of the crude canagliflozin; In the step S400, the drying condition is to dry under vacuum conditions at 40-45° C. for 8-10 hours.

2. The process for preparing the canagliflozin hemihydrate bulk drug according to claim 1, wherein: 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 seed crystals pretreated in step S200, stirring at a constant temperature of 30-35°C for 1-2 hours, 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.

3. The process for preparing the canagliflozin hemihydrate bulk drug according to claim 1, wherein: In step S400, after the crystallization is completed, the solid-liquid separation is performed by centrifugation, and the filter cake is washed. 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.

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