Process for the preparation of amorphous tegoprazan and products thereof

Abstract

The application discloses a preparation method of amorphous tegoprazan and a product thereof, belongs to the field of synthesis of crude drugs, and particularly relates to a method for preparing amorphous tegoprazan by a fast crystallization method of a poor solvent at low temperature, and specifically comprises the following steps: dissolving tegoprazan in tetrahydrofuran, quickly adding the tegoprazan in the tetrahydrofuran into pre-cooled normal heptane, uniformly stirring, crystallizing, filtering and drying to obtain amorphous tegoprazan. The application has the advantages of low cost, good process stability, simple operation and the like.

Description

Technical Field

[0001] This invention relates to the field of active pharmaceutical ingredient synthesis, specifically to a method for preparing amorphous tegorazan and its product. Background Technology

[0002] Tegoprazan, also known as ticoraxone (CAS No. 942195-55-3), is a potassium-competitive acid blocker. Originally developed by Pfizer, it was licensed to Raqualia Pharma for collaborative development in 2008. In 2014, Raqualia Pharma licensed it to CJ Healthcare, which ultimately developed it in South Korea. In July 2018, it was approved for marketing by the Korean Ministry of Food and Drug Safety (MFDS) for the treatment of gastroesophageal reflux disease and erosive esophagitis.

[0003] Currently, five crystalline forms of tagorazan have been reported: crystalline form A (patent CN111187259B), crystalline form B (patent CN117222643A), crystalline form DCVI (patent CN121293190A), amorphous solid (CN119409687A), and maleate (KR20250066641A). Among these, crystalline forms A, B, and DCVI exhibit low solubility, resulting in low bioavailability per unit weight. Furthermore, crystalline forms B and DCVI, as well as the amorphous solid, have poor stability and are susceptible to crystal transformation. In contrast, the amorphous form of tagorazan has high solubility, thus offering advantages such as increased drug efficacy and rapid solubility.

[0004] Common methods for preparing amorphous solids include spray drying, burst precipitation, melt extrusion, freeze drying, and vacuum distillation to remove solvents. However, melt extrusion, freeze drying, and vacuum distillation are often limited by equipment constraints and cannot be applied on a large scale in production. Chinese invention patent CN120693332A reports a method for preparing amorphous tegorazan solids via spray drying; however, this method has high requirements for spray dryer equipment and related process parameters, and the spray drying process often requires high temperatures, which may lead to mixed crystals in the resulting tegorazan solids. Therefore, burst precipitation has become the preferred method for preparing amorphous tegorazan.

[0005] Chinese invention patent CN116715660A reports a method for preparing amorphous tegorazan through crystallization with a single organic solvent or a mixed solvent. However, practical verification revealed that tegorazan solids obtained by crystallization with a single solvent were all in the A-phase crystal form. Tegorazan solids obtained by dissolving tegorazan in a good solvent, with water as a poor solvent, were mostly mixed crystals or in the A-phase crystal form, failing to yield pure amorphous solids. Chinese invention patent CN121342808A reports a method for preparing amorphous tegorazan through crystallization using a dioxane / n-heptane system. Practical verification showed that this method requires a large amount of n-heptane, resulting in high production costs, and the dropping rate significantly affects the solid state; excessively fast dropping causes the solid to adhere to the wall. Repeated experimental studies revealed that the tegorazan solids prepared by this method exhibited mixed crystal formation, indicating an unstable process.

[0006] Therefore, it is of great significance to develop a method for preparing tegorazan amorphous with low production cost, simple operation, stable and controllable quality, and good process repeatability. Summary of the Invention

[0007] Therefore, one objective of the present invention is to provide a method for preparing amorphous tegorazan; another objective of the present invention is to provide an amorphous tegorazan product prepared by the method.

[0008] To achieve the above objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides a method for preparing amorphous tegorazan, comprising the following steps: Step 1: Dissolve tegorazan in tetrahydrofuran to obtain a tetrahydrofuran solution of tegorazan; Step 2: Add the tetrahydrofuran solution of tagorazan obtained in Step 1 dropwise into cooled n-heptane to crystallize, and then filter and dry to obtain amorphous tagorazan.

[0009] In some embodiments, the mass ratio of tegorazan, tetrahydrofuran, and n-heptane is 1:1 to 5: 3 to 50; preferably, the mass ratio of tegorazan, tetrahydrofuran, and n-heptane is 1:2 to 3:5 to 20; more preferably, the mass ratio of tegorazan, tetrahydrofuran, and n-heptane is 1:2:5.

[0010] In some embodiments, in step 2, the cooling temperature of the n-heptane is -20°C to 10°C; preferably, the cooling temperature of the n-heptane is -10°C to -5°C.

[0011] In some embodiments, in step 2, the dropping rate of the tegorazan tetrahydrofuran solution is from 2 mL / min to 100 mL / min.

[0012] In some embodiments, step 2, the drying is vacuum drying.

[0013] In some preferred embodiments, the temperature of the vacuum drying is 50°C to 60°C; preferably, it is 55°C.

[0014] Secondly, the present invention provides an amorphous tegolazan product prepared by the method described above.

[0015] The beneficial effects of this invention are as follows: This invention provides a low-cost, simple-to-operate, stable and controllable quality, and good process repeatability preparation process for amorphous tegorazan. Amorphous tegorazan is prepared by crystallization using a tetrahydrofuran / n-heptane system. The preparation cost is low, the process stability is good, and it solves the problems of poor stability and easy crystal transformation of amorphous tegorazan prepared by other processes. Attached Figure Description

[0016] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the following figures are provided for illustration: Figure 1 XRPD image of amorphous tegorazan prepared in Example 1; Figure 2 XRPD image of tagorasan for crystal form A prepared in Comparative Example 1; Figure 3 XRPD image of the mixed amorphous and A-type tesserae prepared for Comparative Example 2. Detailed Implementation

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0018] The "Tegorazan solid" described in this application can be prepared with reference to Chinese Patent CN120829393A, or it can be prepared by other methods.

[0019] All ranges described in this application include the endpoints of the range between two values, and whether or not indicated, all values ​​listed in this invention include the degree of expected experimental error, technical error, and instrument error of the given technique used to measure that value. When the degree of error is not stated, all values ​​listed in this invention encompass a range of ±10% of the stated value.

[0020] In the embodiments and comparative examples of this application, the tegorazan crystal form was detected by X-ray powder diffraction (XRPD) under the following conditions: Sample preparation: Weigh the sample directly and perform X-ray powder diffraction test.

[0021] 2) Experimental instrument: Empyrean X-ray diffractometer (source CuKα) 3) Experimental conditions: CuKα radiation, tube voltage 40KV, tube current 40mA, 2θ scan range 5°~40°2θ, step size 0.013°.

[0022] Slit conditions: emission slit is 114°, anti-scattering slit is 7.5mm.

[0023] In the embodiments and comparative examples of this application, the purity of tegorazan was determined by HPLC, and the conditions for the HPLC method were as follows: Chromatographic column: Shim-pack Scepter C18-120, 4.6 × 150 mm, 5 μm; Mobile phase: 10 mmol / L ammonium acetate as mobile phase A, acetonitrile as mobile phase B; The detection wavelength was 220 nm; the column temperature was 30 °C; the flow rate was 1.0 ml / min; and the injection volume was 5 μl.

[0024] The elution gradient is shown in Table 1 below: Table 1 HPLC elution gradient

[0025] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0026] Example 1

[0027] The purpose of this embodiment is to provide a method for preparing amorphous tegorazan solids, as follows: Step 1: Add 1.00 kg of tegorazan solid (purity 99.51%) to 2.00 kg of tetrahydrofuran and stir at 30°C until dissolved.

[0028] Step 2: Add 5.00 kg of n-heptane to a 30 L reactor and cool to -10 °C. Rapidly add tegorazan tetrahydrofuran solution to the n-heptane at a rate of 100 mL / min. After the addition is complete, maintain the temperature at -10 °C and stir to allow crystallization to occur for 1 h. Filter the solution, wash the filter cake with 1.00 kg of n-heptane, and dry the filter cake under reduced pressure at 55 °C for 15 h to obtain 992.50 g of a white solid with a yield of 99.2% and a purity of 99.99%. The XRPD spectrum is shown below. Figure 1 As shown, the experimental results indicate that its crystal form is amorphous.

[0029] This embodiment demonstrates a complete process for preparing amorphous tegorazan using optimized conditions (tegorazan:tetrahydrofuran:n-heptane = 1:2:5, crystallization temperature -10°C, dropping rate 100 mL / min, and vacuum drying at 55°C). At a scale-up of 1.00 kg, the yield reached 99.2%, and the product purity increased to 99.99%. XRPD patterns showed typical amorphous diffuse peaks with no crystal diffraction peaks, confirming the stability and reliability of the process. The resulting product has high purity, pure crystal form, and uniform solid dispersion without adhesion to the walls, providing a foundation for subsequent industrial production.

[0030] In addition, the amorphous tegorazan prepared under the aforementioned conditions was placed in a stability chamber, and the effects of different temperatures and humidity levels on its stability were investigated. The test results are shown in Table 2. Table 2 Results of stability study of amorphous tegorazan

[0031] The above experimental results show that the stability of the prepared amorphous tegorazan was investigated under two different humidity and temperature conditions (25℃ / 60%RH and 40℃ / 75%RH) as shown in Table 2. The results indicate that the purity of the samples remained at 99.99% at all time points, and the crystal form remained amorphous with no signs of crystal transformation. This demonstrates that the amorphous tegorazan prepared by this method possesses excellent physical and chemical stability and can meet the requirements for long-term drug storage.

[0032] Comparative Example 1: Investigating the effect of cooling crystallization in a single solvent on crystal form. Step 1: Add 10.00 g of tegorazan solid (purity 99.51%) to an organic solvent, wherein the mass ratio of organic solvent to tegorazan is 5:1, and stir at 30°C until dissolved.

[0033] Step 2: Rapidly cool to 5℃, maintain the temperature and stir to crystallize for 1 h, filter, dry the filter cake at 55℃ under reduced pressure to obtain tegorazan solid, XRPD analysis, organic solvent types and detection results are shown in Table 3: Table 3. Effects of different organic solvents on tegorazan crystallization

[0034] The above experimental results show that tegorazane has good solubility in methanol, isopropanol, n-butanol, dioxane, 2-methyltetrahydrofuran, DMF, NMP, DMAC, DMSO, dichloromethane, and tetrahydrofuran, which prevents solid precipitation after cooling following dissolution. When dissolved in solvents with slightly lower solubility, such as acetonitrile, ethanol, ethyl acetate, isopropyl acetate, and acetone, the resulting tegorazane solids obtained by rapid cooling and crystallization were all in the A crystal form (XRPD patterns are shown below). Figure 2(As shown). Tegolazan has poor solubility in methyl tert-butyl ether, isopropyl ether, water, and n-heptane, and cannot be dissolved to precipitate crystals.

[0035] Based on the above results, subsequent attempts were made to use methyl tert-butyl ether, isopropyl ether, water, and n-heptane as poor solvents. The tert-gorazan solid was first dissolved in a good solvent that is miscible with it, and then rapidly added to the poor solvent to prepare the amorphous tert-gorazan solid.

[0036] This comparative study investigated the effects of 21 different solvents on the crystal form of tegorazan using a single-solvent cooling crystallization system. The results showed that in solvents with moderate solubility, such as acetonitrile, ethanol, and ethyl acetate, A-type solids precipitated after cooling; however, in good solvents such as methanol, tetrahydrofuran, and dioxane, no solids precipitated after cooling; and some solvents (such as methyl tert-butyl ether, water, and n-heptane) could not dissolve the solids completely. This experiment confirms that the amorphous form cannot be obtained by cooling with a single solvent, suggesting that the preparation of amorphous tegorazan depends on specific solvent systems or process conditions.

[0037] Comparative Example 2: Investigating the effects of different good solvents and different poor solvents on tegorazone crystallization. Step 1: Add 10.00 g of tegorazan solid (purity 99.51%) to a good solvent, wherein the mass ratio of the good solvent to tegorazan is 3:1, and stir at 30°C until dissolved.

[0038] Step 2: Add the unsuitable solvent, where the mass ratio of the unsuitable solvent to tegorazan is 10:1. Cool to 5°C, and add the mixed solution of tegorazan and the good solvent dropwise to the unsuitable solvent at a rate of 5 ml / min. After the addition is complete, maintain the temperature at 5°C and stir to induce crystallization for 1 h. Filter, and dry the filter cake under reduced pressure at 55°C to obtain solid tegorazan. XRPD analysis is performed, and the results of solvent type and crystal form detection for the good and unsuitable solvents are shown in Table 4. Table 4. Effects of different combinations of good and bad solvents on tegorazan crystallization.

[0039] When water is used as a poor solvent for crystallization, the resulting solid is mostly A-type crystal or a mixture of amorphous and A-type crystals (XRPD patterns are shown in the image). Figure 3 It is impossible to obtain pure amorphous tagorasan solid. Furthermore, water is a poor solvent, and the solid tends to stick to the walls during crystallization, making it impossible to form a uniformly dispersed solid.

[0040] When methyl tert-butyl ether and isopropyl ether are used as poor solvents, some good solvent crystals fail to precipitate solids. The solids that do precipitate are mostly A crystals or a mixture of A crystals and amorphous solids when detected by XRPD, and pure amorphous tagorasan solids cannot be obtained.

[0041] When using n-heptane as a poor solvent, it was found that when tetrahydrofuran was used as a good solvent, the crystallized solid was amorphous and well-dispersed, with virtually no adhesion to the walls or agglomeration. However, when other solvents such as ethanol and isopropanol were used as good solvents, mixed crystals were observed during crystallization.

[0042] The above experiments screened the crystallization effects of different good / poor solvent combinations as antisolvents, testing a total of 29 combinations. The results showed that only when the good solvent was tetrahydrofuran and the poor solvent was n-heptane could pure amorphous tegorazan solid be obtained; other combinations, such as water and methanol, water and acetone, and dioxane and n-heptane, either precipitated A-type crystals or mixed crystals, often accompanied by solid adhesion to the walls. These experiments demonstrate that the tetrahydrofuran / n-heptane system is a unique and effective combination for preparing pure amorphous tegorazan.

[0043] Example 2: Investigating the effect of the amount of the good solvent tetrahydrofuran on the crystallization of tegorazan. Based on Comparative Example 2, the effect of the amount of the good solvent tetrahydrofuran on the crystal form was further investigated. The specific experimental method is as follows: Step 1: Add 10.00 g of tegorazan solid (purity 99.51%) to tetrahydrofuran, where the amount of tetrahydrofuran is shown in Table 5 below, and stir at 30°C until dissolved.

[0044] Step 2: Add 100.00 g of n-heptane, cool to 5℃, and add tegorazan tetrahydrofuran solution dropwise to n-heptane at a rate of 5 ml / min. After the addition is complete, keep the mixture at 5℃ and stir to induce crystallization for 1 h. Filter the solution, and dry the filter cake under reduced pressure at 55℃ to obtain tegorazan solid. XRPD analysis is performed, and the results are shown in Table 5. Table 5 Effect of tetrahydrofuran dosage on tegorazan crystallization

[0045] The experimental results show that, with a fixed heptane dosage of 10 times, the mass ratio of tetrahydrofuran to tegorazane was investigated from 1:1 to 5:1. The solids obtained in all ratios were amorphous with a purity consistently above 99.97%. However, as the tetrahydrofuran dosage increased, the yield gradually decreased from 98.8% to 85.4%, and a small amount of agglomeration occurred when the dosage exceeded 5 times. This is because the amorphous solid has good solubility in tetrahydrofuran; the higher the tetrahydrofuran dosage, the stronger the viscosity of the precipitated solid, thus leading to agglomeration. The results indicate that the amount of tetrahydrofuran has no effect on the crystal form, but it does affect the yield and solid morphology. An optimal mass ratio of tegorazane to tetrahydrofuran of 1:2 can ensure a high yield while obtaining a well-dispersed powder.

[0046] Example 3: Investigating the effect of n-heptane dosage on tegorazane crystallization Based on Example 2, the effect of the amount of the undesirable solvent n-heptane on the crystallization of tegorazone was further investigated. The specific experimental method is as follows: Step 1: Add 10.00 g of tegorazan solid (purity 99.51%) to 20.00 g of tetrahydrofuran and stir at 30°C until dissolved.

[0047] Step 2: Add n-heptane, the amount of which is shown in Table 6 below. Cool to 5℃, and add the tegorazan tetrahydrofuran solution dropwise to the n-heptane at a rate of 5 ml / min. After the addition is complete, keep the mixture at 5℃ and stir to induce crystallization for 1 h. Filter the solution, and dry the filter cake under reduced pressure at 55℃ to obtain tegorazan solid. XRPD analysis is performed, and the results are shown in Table 6. Table 6 Effect of n-Heptane Dosage on Tegorazan Crystallization

[0048] The experimental results above indicate that, with a fixed tetrahydrofuran dosage of 2 times, the mass ratio of n-heptane to tegorazan was investigated from 3:1 to 20:1. All ratios yielded amorphous solids with yields consistently between 96.8% and 98.8%, and purities exceeding 99.98%. The system was more viscous when the n-heptane dosage was 3 times, while the solids were well dispersed at 5 times and above. This suggests that when the n-heptane to tegorazan mass ratio is between 3:1 and 50:1, the amount of n-heptane has no significant effect on crystal form and purity. Considering both cost and operability, a 1:5 mass ratio of tegorazan to n-heptane is optimal for preparing amorphous tegorazan.

[0049] Example 4: Investigating the effect of different crystallization temperatures on tegorazan crystallization Step 1: Add 10.00 g of tegorazan solid (purity 99.51%) to 20.00 g of tetrahydrofuran and stir at 30°C until dissolved.

[0050] Step 2: 50.00 g of n-heptane was cooled to different temperatures, and tegorazan tetrahydrofuran solution was added dropwise to n-heptane at a rate of 5 ml / min. After the addition was complete, the mixture was kept at the same temperature and stirred to induce crystallization for 1 h. The mixture was then filtered, and the filter cake was dried under reduced pressure at 55 °C to obtain tegorazan solid. XRPD analysis was performed, and the results are shown in Table 7. Table 7 Effect of crystallization temperature on Tegolazan crystallization

[0051] The above experiments systematically investigated the effect of crystallization temperature from -30℃ to 35℃ on the crystal form. The results showed that when the temperature was ≤15℃, the obtained solids were all amorphous, with a yield ≥97.5%; when the temperature rose to 20~25℃, the product became mixed crystals and the solid became sticky; at 30~35℃, it completely transformed into the A crystal form and agglomerated. This experiment clarified that low temperature is key to maintaining stable amorphous preparation during the preparation process, and the optimal temperature of -10℃ to -5℃ can ensure a good solid morphology while maintaining amorphity and avoiding the risk of crystal transformation during the preparation process.

[0052] Example 5: Investigating the effect of different crystallization times on tegorazan crystallization Step 1: Add 10.00 g of tegorazan solid (purity 99.51%) to 20.00 g of tetrahydrofuran and stir at 30°C until dissolved.

[0053] Step 2: Cool 50.00 g of n-heptane to -10℃, and add tegorazan tetrahydrofuran solution dropwise to n-heptane at a rate of 5 ml / min. After the addition is complete, maintain the temperature at -10℃ and stir to induce crystallization. Filter the solution, and dry the filter cake under reduced pressure at 55℃ to obtain tegorazan solid. XRPD analysis was performed, and the crystallization time and results are shown in Table 8. Table 8 Effect of crystallization time on tegorazan crystallization

[0054] The above experimental results show that the effect of crystallization time from 0.5 h to 72 h on the crystal form was investigated at a low temperature of -10℃. The solids obtained at all time points were amorphous, and the yield and purity showed no significant changes. This indicates that under the optimal low temperature condition of -10℃, the amorphous state is very stable, and prolonged stirring will not induce crystal transformation. The process window is wide, suitable for flexible operation in industrial production. We also investigated the effect of different crystallization times at other crystallization temperatures, and the results are shown in Comparative Example 3.

[0055] Comparative Example 3 investigates the effects of different crystallization temperatures and times on the crystallization of tegorazan. Step 1: Add 10.00 g of tegorazan solid (purity 99.51%) to 20.00 g of tetrahydrofuran and stir at 30°C until dissolved.

[0056] Step 2: 50.00 g of n-heptane was cooled to different temperatures. A tegorazan tetrahydrofuran solution was added dropwise to the n-heptane at a rate of 5 ml / min. After the addition was complete, the mixture was kept at the same temperature and stirred to induce crystallization. The mixture was filtered, and the filter cake was dried under reduced pressure at 55°C to obtain tegorazan solid. XRPD analysis was performed. The specific crystallization temperature, crystallization time, and detection results are shown in Table 9. Table 9. Effects of different crystallization temperatures and times on Tegrazan crystallization.

[0057] The above experimental results indicate that the effect of crystallization time on crystal form was investigated in five temperature ranges: -5~0℃, 0~5℃, 10~15℃, 20~25℃, and 30~35℃. The results show that the higher the temperature, the faster the crystal transformation rate: mixed crystals began to appear after 48 hours at 0~5℃; mixed crystals appeared after 24 hours at 10~15℃; complete transformation to crystal form A was achieved in only 2 hours at 20~25℃; and crystal form A was obtained in 0.5 hours at 30~35℃. This comparative experiment quantitatively reveals the relationship between temperature and crystal transformation kinetics, and further corroborates the necessity of low temperature in maintaining stable amorphous preparation during the preparation process.

[0058] Example 6: Investigating the effect of different dropping rates on tegorazan crystallization Step 1: Add 200.00 g of tegorazan solid (purity 99.51%) to 400.00 g of tetrahydrofuran and stir at 30°C until dissolved.

[0059] Step 2: Cool 1.00 kg of n-heptane to -10℃, and add tegorazan tetrahydrofuran solution dropwise to n-heptane at different rates. After the addition is complete, maintain the temperature at -10℃ and stir to induce crystallization for 15 h. Filter, and dry the filter cake under reduced pressure at 55℃ to obtain tegorazan solid. XRPD analysis is performed. The specific dropping rates and detection results are shown in Table 10. Table 10 Effect of dropping rate on tegorazan crystallization

[0060] The above experimental results show that, under optimized low-temperature conditions, the effect of dropping rate from 2 mL / min to 120 mL / min on the crystallization results was investigated. The solids obtained at all dropping rates were amorphous, with yields ranging from 98.0% to 99.3%, and the solids were uniformly dispersed. No adhesion to the walls or agglomeration due to excessively fast dropping rates was observed. This indicates that the tetrahydrofuran / n-heptane system is insensitive to dropping rate, has good process adaptability, and is easy to scale up for production.

[0061] Example 7: Investigating the effect of different tegorazan feed amounts on tegorazan crystallization.

[0062] Step 1: Add different amounts of tegorazan solid (purity 99.51%) to tetrahydrofuran at a mass ratio of 2 times the amount of tegorazan, and stir at 30°C until dissolved.

[0063] Step 2: Cool n-heptane (5 times the mass of tegorazan) to -10℃. Add tegorazan tetrahydrofuran solution dropwise to n-heptane at a rate of 5 ml / min (100 ml / min if the tegorazan feed rate is in the kg range). After the addition is complete, maintain the temperature at -10℃ and stir to induce crystallization for 1 h. Filter, and dry the filter cake under reduced pressure at 55℃ for 15 h to obtain solid tegorazan. XRPD analysis is performed. The specific feed rates and test results are shown in Table 11. Table 11 Effect of different tegorazan feed amounts on tegorazan crystallization

[0064] The experimental results above show that, under optimized process conditions, considering the reproducibility and scale-up effect of the process, by gradually increasing the tegorazan feed amount from 10 g to 5.5 kg, the solids obtained in each batch were all amorphous, with yields consistently ranging from 98.0% to 99.2%, and purity reaching 99.99%, exhibiting uniform solid dispersion. This indicates that the process has good linear scale-up capability, no risk of crystal transformation, and is suitable for large-scale industrial production.

[0065] Example 8: Investigating the effects of solvent system and crystallization temperature on the preparation of tegorazan amorphous form. This embodiment aims to systematically investigate the effects of solvent system (tetrahydrofuran / n-heptane vs. 1,4-dioxane / n-heptane) and crystallization temperature (low temperature, medium temperature, high temperature) on the amorphous preparation of tegorazane through multi-factor comparative experiments.

[0066] This experiment consisted of two groups: an experimental group and a control group. The experimental group included group AC, while the control group, prepared according to the method described in Chinese invention patent CN121342808A, included group DF. The effects of different crystallization temperatures in this solvent system on crystal form, yield, and product morphology were investigated. The experimental methods are as follows: Step 1: Add 10.00 g of tegorazan solid (purity 99.51%) to a good solvent. Dissolve group AC by stirring at 30℃ and group DF by stirring at 40℃.

[0067] Step 2: Heptane was cooled to different temperatures. A mixture of tegorazane and a good solvent was added dropwise to the heptane at a rate of 5 ml / min. After the addition was complete, the mixture was kept at the same temperature and stirred to allow crystallization to occur for 1 h / 24 h / 72 h. The crystals were then filtered, and the filter cake was dried under reduced pressure at 55 °C for 15 h to obtain solid tegorazane. XRPD analysis was performed. The specific experimental designs for each group are shown in Table 12, and the experimental results are shown in Table 13. Table 12 Experimental Design of the Effects of Different Solvent Systems and Crystallization Temperatures on Tegorazan Crystallization

[0068] Table 13 Experimental results on the effects of different solvent systems and crystallization temperatures on tegorazan crystallization.

[0069] The above experimental results show that the tetrahydrofuran / n-heptane system has unique advantages over the 1,4-dioxane / n-heptane system, as detailed below: (1) Significantly reduced solvent consumption -- a green economic advantage In the 1,4-dioxane / n-heptane system used in Chinese patent CN121342808A, the amount of n-heptane used is 30 times the mass (volume ratio) of tegorazone, which is approximately 4 times the amount of n-heptane used in this invention. In the tetrahydrofuran / n-heptane system of this invention, the amount of n-heptane used is only 5 times the mass of tegorazone, significantly reducing the total solvent consumption. This saves material costs and reduces energy consumption for solvent recovery and treatment, aligning with the development direction of green pharmaceuticals.

[0070] (2) Temperature tolerance is significantly improved -- the process window is wider. The tetrahydrofuran / n-heptane system stably yields pure amorphous products under both low-temperature (-10~-5℃) and medium-temperature (0~5℃) conditions. Groups B and C remain amorphous even after 72 h of crystallization, demonstrating excellent temperature tolerance. In contrast, the dioxane / n-heptane system only briefly yields amorphous products at low temperatures, but rapidly transforms into crystal form A after extending the crystallization time to 24 h, exhibiting an extremely narrow process window. This difference indicates that the tetrahydrofuran / n-heptane system has higher robustness to temperature fluctuations and is more suitable for addressing potential temperature control deviations in industrial production.

[0071] (3) Excellent tolerance to crystallization time - no risk of crystal transformation during long-term stirring. The tetrahydrofuran / n-heptane system, under low and medium temperature conditions, maintained its amorphous form even after a crystallization time of up to 72 hours, providing ample assurance for flexible scheduling in industrial production. In contrast, the dioxane / n-heptane system, while yielding an amorphous form within 1 hour at low temperatures (Group F) and medium temperatures (Group E), completely transformed into the A-type crystalline form after 24 hours, indicating that its amorphous product is metastable and carries a risk of crystal transformation within a normal production cycle.

[0072] (4) Controllable solid form - prevents adhesion to walls and resists agglomeration Under optimized conditions (Group B and Group C), the tetrahydrofuran / n-heptane system produced uniformly dispersed powders without adhesion to walls or agglomeration. In contrast, the dioxane / n-heptane system exhibited varying degrees of adhesion to walls, stickiness, or agglomeration at different temperatures, making it difficult to control the solid morphology and hindering subsequent formulation processes.

[0073] (5) Insensitive to operating parameters - wide adaptability of dropping rate The experimental results of Example 6 show that the tetrahydrofuran / n-heptane system can obtain uniformly dispersed amorphous powder within a dropping rate range of 2~120 mL / min, demonstrating excellent process robustness. However, by repeating Example 3 described in Chinese Invention Patent CN121342808A, the experimental results show that the dioxane / n-heptane system is prone to wall adhesion problems when the dropping rate is too fast or the amount of n-heptane is insufficient, further highlighting the advantages of the tetrahydrofuran / n-heptane system.

[0074] (6) Better long-term crystal form stability Groups B and C showed no change in crystal form after 72 hours. Combined with the long-term stability data from Example 1 (no crystal transformation after 12 months), this demonstrates that the amorphous material prepared using the tetrahydrofuran / n-heptane system exhibits excellent physical stability, meeting the shelf-life requirements of pharmaceutical products. In contrast, the amorphous material obtained using the dioxane / n-heptane system, even at low temperature (Group F) for 1 hour, underwent crystal transformation within 24 hours, posing a serious risk to its long-term storage stability.

[0075] In summary, this embodiment, through multi-factor comparative experiments, systematically verifies the significant advantages of the tetrahydrofuran / n-heptane system in preparing amorphous tegorazone: this system can stably obtain pure amorphous products over a wide temperature range from low to medium temperatures, and exhibits excellent tolerance to process parameters such as crystallization time and dropping rate. The resulting solid has good dispersibility, no wall adhesion, and excellent long-term crystal stability. In contrast, although the 1,4-dioxane / n-heptane system can obtain amorphous products within 1 hour, its amorphous state is metastable. Extending the crystallization time or slight temperature fluctuations quickly transforms it into the A-type crystal form, resulting in an extremely narrow process window, difficulty in controlling the solid morphology, and a solvent consumption approximately four times that of this invention, which is unfavorable for industrial production. The above comparison further demonstrates the uniqueness and superiority of the solvent system and process conditions selected in this invention.

[0076] The above-described embodiments are merely preferred embodiments provided to fully illustrate the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. A method for preparing amorphous tegorazan, characterized in that, Includes the following steps: Step 1: Dissolve tegorazan in tetrahydrofuran to obtain a tetrahydrofuran solution of tegorazan; Step 2: Add the tetrahydrofuran solution of tagorazan obtained in Step 1 dropwise into cooled n-heptane to crystallize, and then filter and dry to obtain amorphous tagorazan.

2. The preparation method according to claim 1, characterized in that, The mass ratio of tegorazan, tetrahydrofuran, and n-heptane is 1:1~5:3~50.

3. The preparation method according to claim 1, characterized in that, The mass ratio of tegorazan, tetrahydrofuran, and n-heptane is 1:2~3:5~20; preferably, the mass ratio of tegorazan, tetrahydrofuran, and n-heptane is 1:2:

5.

4. The preparation method according to claim 1, characterized in that, In step 2, the cooling temperature of the n-heptane is -20°C to 10°C.

5. The preparation method according to claim 1, characterized in that, In step 2, the cooling temperature of the n-heptane is -10°C to -5°C.

6. The preparation method according to claim 1, characterized in that, In step 2, the dropping rate is from 2 mL / min to 100 mL / min.

7. The preparation method according to claim 1, characterized in that, In step 2, the drying is performed under reduced pressure.

8. The preparation method according to claim 7, characterized in that, The temperature for vacuum drying is 50°C to 60°C; preferably, it is 55°C.

9. An amorphous tegolazan product prepared by the method according to any one of claims 1-8.

Images