A method for purifying epinephrine tartrate

Abstract

The application discloses a refining method of adrenaline tartrate, and belongs to the technical field of organic synthesis of medicines. The method uses a mixed solvent of acetone and water as a recrystallization system, adrenaline tartrate crude product is dissolved in deoxygenated water, acetone is slowly added to form a mixed solvent, low-temperature crystallization is carried out under nitrogen protection, the obtained wet product is dried under low-temperature vacuum conditions, and nitrogen is intermittently introduced to maintain an oxygen-free environment, and high-purity adrenaline tartrate is obtained. The method is combined with nitrogen protection and low-temperature crystallization throughout the whole process, effectively inhibits the generation of oxidation impurities, significantly improves the solution color and clarity of the product, and further reduces the content of D-adrenaline chiral impurities. The yield of the refined product can reach 85%, the content is greater than or equal to 99.5%, the content of key impurities meets the limit requirement of the European Pharmacopoeia, the solution is colorless and clear, and the method is suitable for large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical organic synthesis technology, specifically relating to a purification method for adrenaline tartrate. Background Technology

[0002] Epinephrine tartrate, also known as L-3,4-dihydroxy-alpha-((methylamino)methyl)benzyl alcohol-L-tartrate hydrogen salt, is a white crystalline powder. It is primarily used for the resuscitation of cardiac arrest and anaphylactic shock, and can also be used to treat other allergic diseases. This product is a salt of epinephrine and L-tartaric acid. The key step in the synthetic process is the salt-forming reaction of chiral resolved epinephrine and L-tartaric acid to obtain epinephrine tartrate. The structural formula of epinephrine tartrate is shown below.

[0003]

[0004] In the production process of epinephrine, DL-adrenaline is typically chirally resolved in methanol using an L-tartaric acid chiral resolving agent, producing tartaric epinephrine salts. These salts are then adjusted with alkali to obtain L-adrenaline. However, the tartaric epinephrine salts produced in the epinephrine production process are prepared in anhydrous organic solvents, and the clarity, color, content, related substances, specific rotation, and crystal flowability of the solution do not meet the quality standards for tartaric epinephrine pharmaceuticals. Therefore, it is necessary to develop a refining process for tartaric epinephrine to improve its product quality.

[0005] Literature review revealed that Li Libiao and Zheng Ai described a chiral resolution process for DL-adrenaline using L-tartaric acid in their journal article "Research on Synthetic Process of Adrenaline," but did not describe the salt-forming purification process of tartaric acid adrenaline. Liang Dawei and Wang Yueqiu's article "Research on the Synthesis of (-)-Norepinephrine Bitartrate" described a salt-forming process for norepinephrine bitartrate; however, this process primarily aims to achieve chiral resolution through crystallization in an aqueous solvent. Its main drawback is extremely low yield, and it does not examine crystal flowability, product purity, chiral impurities, solution clarity, or color, making it unsuitable for developing a tartaric acid adrenaline purification process.

[0006] Patent application CN117658833A discloses a mixed solvent for the purification of L-adrenaline and its salts, and a method for purifying L-adrenaline and its salts. This application describes a method for purifying L-adrenaline and its salts by crystallizing adrenaline salts using a mixed solvent of methanol, ethanol, and water to reduce chiral impurities. This application provides a good reference for developing a purification process for adrenaline tartrate; however, the method described in this application primarily focuses on purifying and reducing chiral impurities, and cannot effectively control indicators such as solution clarity and color, oxidative impurities, and other specific impurities. Therefore, it cannot meet the European Pharmacopoeia standards for this product.

[0007] Because both epinephrine tartrate and its racemic epinephrine intermediate are easily oxidized and discolored, and the European Pharmacopoeia has extremely high requirements for the clarity and color of the solution of this product, requiring the solution to be colorless, and also has strict requirements for content, specific impurities, and chiral impurities, it is essential to develop a purification method for epinephrine tartrate to ensure that the product quality meets all the requirements of the pharmacopoeia quality standards. Summary of the Invention

[0008] The purpose of this invention is to provide a purification method for epinephrine tartrate to obtain epinephrine tartrate with high purity, few impurities, high chiral purity, and good properties that meets the standards of the European Pharmacopoeia.

[0009] Because the tartrate epinephrine molecule contains catecholamine structures, the product is easily oxidized. One of the main objectives in developing a refining process is to control its oxidation during production or effectively remove related oxidizing impurities to achieve clarity and colorlessness in the solution. Surprisingly, it has been found that crystallization using a mixture of acetone and water is superior to crystallization using a mixture of alcohol and water. The former results in a less sensitive crystallization solution to oxygen in the air, producing a product with better color and more stable properties.

[0010] Since this product is more easily oxidized in solution than in solid, in order to control the generation of oxidative impurities and reduce the formation of ketone bodies and other related impurities, the crystallization process of this invention adopts a crystallization method under nitrogen gas protection to fully replace the air in the crystallization solution and completely protect the crystallization system.

[0011] If the wet crystals of this product come into contact with air or the temperature rises during the drying process, oxidation impurities will increase. Therefore, the drying process of this invention strictly controls the drying temperature and drying time, and adopts a vacuum drying method with intermittent nitrogen flow to ensure that the flowing nitrogen fully carries away the residual solvent vapor and avoids discoloration or increase of impurities in the product during the drying process.

[0012] The objective of this invention can be achieved through the following technical solutions: A method for purifying epinephrine tartrate includes the following steps: S1. Dissolve crude epinephrine tartrate in deoxygenated water to form a solution; S2. Cool the solution described in S1 to 13-17°C, and slowly add an organic solvent to form a mixed solvent, wherein the organic solvent is acetone. S3. Under the protection of an inert gas, recrystallize at a crystallization temperature of -5℃ to -8℃. S4. After crystallization is complete, wet crystals are obtained by separation; S5. The wet crystals are vacuum dried at 35-40°C, with nitrogen gas intermittently introduced during the drying process to maintain an oxygen-free environment, to obtain refined adrenaline tartrate.

[0013] Furthermore, in S1, the deoxygenated water is obtained by passing purified water through nitrogen gas with a purity ≥99.99% at room temperature for 30-60 minutes with a stirring rate of 100-200 rpm to remove dissolved oxygen from the water.

[0014] Furthermore, in S1, the solution is prepared by adding crude adrenaline tartrate to a sealed dissolving vessel containing deoxygenated water, stirring at 20-25°C and a stirring speed of 200-300 rpm for 20-40 minutes until the crude product is completely dissolved.

[0015] Furthermore, in S1, the weight ratio of crude adrenaline tartrate to deoxygenated water is 1.0:(1.5~3.0).

[0016] Furthermore, in S2, the method for preparing the mixed solvent is as follows: the temperature of the system is reduced to 13-17℃ by cooling the solution obtained in S1 at a cooling rate of 0.5-1℃ / min, and then acetone is added at a rate of 5-10g / min while stirring. The stirring rate is maintained at 200-300rpm until the solution becomes slightly turbid, thus obtaining the mixed solvent.

[0017] Furthermore, in S2, the weight ratio of acetone to deoxygenated water is (4.0~5.0):1.0; preferably 4.0:1.0.

[0018] Furthermore, in step S3, the inert gas is nitrogen.

[0019] Furthermore, in step S3, the crystallization time is 4 to 6 hours, preferably 5 hours.

[0020] Furthermore, in step S4, the specific separation step involves using a nitrogen-protected pressure filtration device to filter the crystallization system of step S4 with a 0.22μm polytetrafluoroethylene filter membrane. During the filtration process, the system temperature is maintained below -5℃, and the filter cake is collected to obtain wet crystals.

[0021] Furthermore, in step S5, the vacuum drying temperature is 35–40°C, the vacuum degree is -0.08–-0.1 MPa, and the drying time is 6–10 hours, preferably 8 hours.

[0022] Furthermore, in step S5, the nitrogen gas is introduced every 2 hours with a purity of ≥99.99% for 10-15 minutes each time, and the nitrogen flow rate is 0.5-1L / min.

[0023] The beneficial effects of this invention are: (1) In the crude product dissolution stage, the present invention uses deoxygenated water as a solvent to cut off the path of contact between tartaric epinephrine and oxygen, effectively reducing the generation of oxidative impurities; at the same time, a mild dissolution temperature and reasonable stirring conditions are used to ensure that the crude product is fully dissolved and there is no local over-concentration, thus avoiding the undissolved crude product from encapsulating impurities.

[0024] (2) Compared with the traditional alcohol-water crystallization system, the present invention uses an acetone-water mixed solvent, which can significantly reduce the sensitivity of tartrate adrenaline to oxygen in solution and further reduce the generation of oxidative impurities. By using a suitable temperature environment (13-17℃) and slowly adding acetone, combined with a reasonable stirring rate, the precipitation of fine crystals caused by a sudden increase in local solvent concentration is avoided, promoting the formation of a regular and dense crystal structure and improving product flowability. At the same time, this solvent system can use the difference in solubility to inhibit the precipitation of chiral impurities (D-adrenaline), improve chiral purity, and the crystallization yield is significantly better than that of the traditional alcohol-water system.

[0025] (3) The present invention introduces an inert gas (nitrogen) for protection during the crystallization stage, which can fully replace the air in the crystallization system, avoid contact between tartrate epinephrine and oxygen in solution, and reduce the secondary generation of oxidative impurities; by using a low temperature environment (-5℃ to -8℃) and utilizing the difference in solubility between tartrate epinephrine and chiral impurities (D-epinephrine) in the mixed solvent, the precipitation of chiral impurities is further suppressed, while promoting the full growth of the target product crystal, reducing impurity encapsulation, and improving the chiral purity and crystal integrity of the product.

[0026] (4) In the wet crystal drying stage, the present invention adopts low temperature vacuum drying (35-40°C), which avoids the surge of oxidation impurities caused by high temperature and can quickly remove the residual solvent in the wet crystal, reducing the long-term contact between the solvent and the product; at the same time, by intermittently introducing high-purity nitrogen, the trace amount of air in the drying environment is replaced in time, and an oxygen-free atmosphere is always maintained to avoid oxidation and discoloration of the wet crystal during the drying process. Detailed Implementation

[0027] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below.

[0028] The main problems to be solved in the purification of adrenaline tartrate are: First, its molecule contains a catecholamine structure (ortho-dihydroxyl group), which is chemically active and easily reacts with oxygen to generate oxidative impurities such as quinones and adrenaline (impurity C), resulting in discoloration of the solution and failure to meet the clarity standards; Second, its chiral center (α-carbon) easily forms D-adrenaline chiral impurities, which are difficult to completely separate using conventional processes; Third, the oxidation rate of this substance in solution is much higher than in solid state, and secondary oxidation is easily caused by high temperature / air contact during the drying of wet crystals.

[0029] In some embodiments, a method for purifying epinephrine tartrate includes the following steps: S1. Dissolve crude epinephrine tartrate in deoxygenated water to form a solution; If ordinary purified water is used to dissolve the crude product directly, the oxygen in the water will react with the catecholamine structure to generate oxidative impurities (such as impurities A and C), which will be difficult to remove in subsequent purification.

[0030] S2. Cool the solution described in S1 to 13-17°C, and slowly add an organic solvent to form a mixed solvent, wherein the organic solvent is acetone. Traditional refining processes use alcohol-water mixed solvents, but alcohol solvents are highly polar, which enhances the reactivity of tartaric acid adrenaline molecules with oxygen, leading to an increase in oxidized impurities; moreover, the alcohol-water system has little difference in the solubility of D-adrenaline, resulting in poor removal of chiral impurities.

[0031] The present invention uses an acetone-water mixed solvent, which has the following advantages: (1) Acetone has lower polarity than alcohols, which can reduce the oxidation sensitivity of tartrate adrenaline in solution; (2) The synergistic effect of acetone and water can amplify the difference in solubility between tartrate adrenaline and impurities, and inhibit the co-crystallization of impurities.

[0032] Cooling to 13-17℃ is to create a suitable supersaturation environment: if the temperature is too high, the solubility of tartaric acid adrenaline is high, and it will be difficult to precipitate even after adding acetone; if the temperature is too low, fine crystals may precipitate even without adding acetone, and these fine crystals easily adsorb impurities, leading to a decrease in purity.

[0033] S3. Under the protection of an inert gas, recrystallize at a crystallization temperature of -5℃ to -8℃. The oxidation rate of adrenaline tartrate in solution is 5-10 times that in solid state. During the crystallization stage, the system is still in solution and needs to be continuously isolated from oxygen, so an inert gas is introduced for protection.

[0034] The crystallization temperature is set to -5℃ to -8℃ to enhance the removal of chiral impurities. The low-temperature environment significantly amplifies the solubility difference between L-tartrate epinephrine and D-epinephrine—the solubility of the L-form drops sharply at this temperature, causing it to precipitate preferentially; the D-form still has relatively high solubility and mostly remains in the mother liquor, thus achieving efficient separation of chiral impurities. If the temperature is above -5℃, the solubility difference narrows, and D-epinephrine easily precipitates with the L-form; if the temperature is below -8℃, the mixed solvent (acetone-water) easily freezes, causing the crystallization system to solidify and making separation impossible.

[0035] S4. After crystallization is complete, wet crystals are obtained by separation; After crystallization, the surface of the wet crystals is covered with mother liquor containing impurities (including D-adrenaline and oxidized impurities), which needs to be removed by separation. However, the wet crystals have a high water content and strong surface activity, and are easily oxidized when exposed to air. Therefore, the separation process needs to be treated to prevent oxidation and avoid secondary pollution.

[0036] S5. The wet crystals are vacuum dried at 35-40°C, with nitrogen gas intermittently introduced during the drying process to maintain an oxygen-free environment, to obtain refined adrenaline tartrate.

[0037] Wet crystals need to be dried to remove residual solvent, but high temperature will accelerate oxidation, so low temperature vacuum drying is used; the vacuum environment can lower the boiling point of the solvent, and 35-40℃ can remove the solvent quickly and avoid high temperature oxidation; at the same time, a small amount of air may seep in during the vacuum drying process, so nitrogen needs to be purged intermittently to replace the air and maintain an oxygen-free environment.

[0038] In some embodiments, in step S1, deoxygenated water is obtained by passing purified water through nitrogen gas with a purity ≥99.99% at room temperature for 30-60 minutes with a stirring rate of 100-200 rpm to remove dissolved oxygen from the water.

[0039] Nitrogen, as an inert gas, can displace dissolved oxygen in water. High purity avoids the introduction of other impurities and ensures thorough deoxygenation. If the purity is insufficient, residual oxygen can still cause oxidation. If the bubbling time is too short, dissolved oxygen in the water cannot completely escape, and there is still a risk of oxidation; if the time is too long (>60 minutes), production efficiency will be reduced. Setting an appropriate stirring rate can accelerate the contact between nitrogen and water and promote oxygen escape.

[0040] In some embodiments, in step S1, the solution is prepared by adding crude adrenaline tartrate into a sealed dissolving vessel containing deoxygenated water, stirring at 20-25°C and a stirring speed of 200-300 rpm for 20-40 minutes until the crude product is completely dissolved.

[0041] A closed dissolving vessel is used because if the dissolving process is open, air will re-enter the system, negating the oxygen-controlling effect of the deoxygenated water. The closed design isolates air and maintains an oxygen-free dissolving environment. Temperatures that are too low (<20℃) will reduce the solubility of the crude product, leading to incomplete dissolution (undissolved particles encapsulating impurities); temperatures that are too high (>25℃) will accelerate the oxidation reaction between the crude product and residual oxygen. Conversely, if the dissolution rate is too low or the time too short, the crude product is prone to leaving impurities due to insufficient dissolution; if the rate is too high, it may cause localized overheating, accelerating oxidation.

[0042] In some embodiments, in step S1, the weight ratio of crude adrenaline tartrate to deoxygenated water is 1.0:(1.5~3.0).

[0043] Insufficient water content leads to incomplete dissolution of the crude product, resulting in excessive impurities after purification. Excessive water content reduces the supersaturation of the subsequent crystallization system, making it difficult to fully extract tartaric acid adrenaline and significantly decreasing the yield.

[0044] In some embodiments, in step S2, the mixed solvent is prepared by: cooling the solution obtained in step S1 to 13-17°C at a cooling rate of 0.5-1°C / min, then adding acetone at a rate of 5-10 g / min while stirring at a stirring rate of 200-300 rpm until the solution becomes slightly turbid, thus obtaining the mixed solvent.

[0045] The cooling rate should be 0.5-1℃ / min. Cooling too quickly will cause large temperature fluctuations in the system and a sudden increase in local supersaturation; cooling too slowly will result in low production efficiency.

[0046] The acetone loading rate should be 5-10 g / min. If the loading is too fast, the local acetone concentration will rise sharply, which will cause tartaric acid adrenaline to precipitate rapidly and form small crystals. If the loading is too slow, the process time will be extended and the efficiency will be reduced. 5-10 g / min can ensure that the acetone is evenly dispersed, promote the formation of regular and dense crystals, and reduce the adsorption of impurities.

[0047] The stirring speed should be set to 200-300 rpm. If the speed is too low, the mixing will be insufficient and local crystallization will still occur; if the speed is too high, it may break the crystals that have already formed.

[0048] In some embodiments, in step S2, the weight ratio of acetone to deoxygenated water is (4.0~5.0):1.0; preferably 4.0:1.0.

[0049] If the ratio is too low, the acetone content will be insufficient, the polarity of the mixed solvent will be too high, the solubility of tartaric acid epinephrine will not decrease significantly, the crystallization yield will be low, and the solubility difference of D-epinephrine will be small, resulting in incomplete removal of chiral impurities. If the ratio is too high, the acetone content will be too high, the solvent polarity will be too low, and non-polar impurities will easily co-crystallize with tartaric acid epinephrine, increasing the total impurity content.

[0050] In some embodiments, the inert gas in step S3 is nitrogen.

[0051] The chemical inertness of nitrogen can completely replace the air in the crystallization system, preventing adrenaline tartrate from reacting with oxygen to form adrenaline (impurity C) during the crystallization process. In addition, nitrogen does not react with acetone, water or adrenaline tartrate, eliminating the risk of introducing impurities, and its low cost makes it suitable for industrial production.

[0052] In some embodiments, the crystallization time in step S3 is 4 to 6 hours, preferably 5 hours.

[0053] Too short a time will result in insufficient crystal growth, leading to excessive total impurities; too long a time will mean that crystal growth has reached its limit, and extending the time will only increase energy consumption and production costs.

[0054] In some embodiments, the specific separation step in S4 is to use a nitrogen-protected pressure filtration device to filter the crystallization system of step S4 with a 0.22 μm polytetrafluoroethylene filter membrane. During the filtration process, the system temperature is maintained below -5°C, and the filter cake is collected to obtain wet crystals.

[0055] Nitrogen-protected pressure filtration can quickly separate the mother liquor from the wet crystals. Nitrogen protection can isolate the wet crystals from air and prevent them from oxidizing and changing color. If separation without protection is used, the color of the wet crystals will change from white to light yellow, and the content of oxidized impurities will increase.

[0056] The 0.22μm pore size filter membrane can trap fine impurity particles in the mother liquor, further reducing the total impurities; the polytetrafluoroethylene material is resistant to corrosion by solvents such as acetone and water, and will not react with adrenaline tartrate, thus avoiding the introduction of impurities by the filter membrane leachate.

[0057] Maintaining a low temperature during the separation process prevents the dissolution of tartaric epinephrine in the wet crystals and avoids the re-adsorption of D-epinephrine in the mother liquor onto the surface of the wet crystals due to temperature increases, thus ensuring stable chiral purity.

[0058] In some embodiments, in step S5, the drying temperature of vacuum drying is 35-40°C, the vacuum degree is -0.08--0.1 MPa, and the drying time is 6-10 hours, preferably 8 hours.

[0059] Insufficient vacuum results in slow solvent evaporation, requiring drying time to be extended to more than 12 hours, and wet crystals are prone to oxidation; excessive vacuum may cause crystal structure collapse, affecting product flowability.

[0060] If the drying time is too short, the product will have too high a moisture content, making it prone to moisture absorption and oxidation during storage; if the time is too long, it may lead to over-drying and increased crystal brittleness.

[0061] In some embodiments, in step S5, nitrogen gas is introduced every 2 hours, with a purity of ≥99.99%, for 10-15 minutes each time, and the nitrogen flow rate is 0.5-1 L / min.

[0062] Nitrogen should be introduced every 2 hours to promptly replace the solvent that evaporates in the drying oven. Each 10-15 minute interval ensures thorough air replacement; too short a time will result in insufficient replacement, while too long a time will disrupt the vacuum environment and prolong the drying time. Too low a flow rate leads to low replacement efficiency, while too high a flow rate will cause temperature fluctuations inside the drying oven, affecting the uniformity of drying.

[0063] The synergistic effect of all steps and parameters resulted in the final preparation of epinephrine tartrate that met the standards of the European Pharmacopoeia. (1) Control of oxidative impurities: S1 deoxygenated water (source oxygen control) → S2 acetone system (reduce oxidation sensitivity) → S3 / S4 / S5 nitrogen protection (process oxidation prevention), so that impurity A ≤ 0.16%, impurity C ≤ 0.1%, and the solution is clear and colorless; (2) Removal of chiral impurities: S2 acetone-water system (difference in solubility) → S3 low-temperature crystallization (scale-up difference), so that D-adrenaline ≤0.8%; (3) Content and total impurities: S4 filter membrane retention (removal of fine impurities) → S5 drying to remove solvent, so that the content is ≥99.5% and the total impurities are ≤0.3%; (4) Stability assurance: Low moisture content (≤0.5%) and oxygen-free drying ensure that there is no significant change in impurities after 3 months of product storage.

[0064] The specific embodiments of the present invention will be described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments.

[0065] Example 1

[0066] This embodiment provides a method for purifying epinephrine tartrate, which is prepared through the following steps: S1. Add 40g of deoxygenated water to a 500mL three-necked reaction flask (deoxygenation method: at room temperature, bubble the purified water with nitrogen gas of ≥99.99% purity at a stirring speed of 150rpm for 40min). Then, add 20g of crude epinephrine tartrate to the reaction flask. Stir in a closed environment at 24℃ and 250rpm for 30 minutes until the crude product is completely dissolved to form a solution. S2. Cool the solution obtained in S1 to 15°C at a cooling rate of 0.8°C / min. Then, slowly add 160g of acetone at a rate of 8g / min, while maintaining a stirring rate of 250rpm, until the solution becomes slightly turbid. S3. Further cool the S2 system to -5℃, and stir and crystallize within this temperature range for 5 hours under nitrogen protection; S4. After crystallization, a nitrogen-protected pressure filtration device is used to filter the system using a 0.22μm polytetrafluoroethylene filter membrane while maintaining the system temperature below -5℃. The filter cake is collected to obtain wet crystals. S5. Transfer the obtained wet crystals to a vacuum drying oven and dry them at 37℃ and a vacuum of -0.09MPa. During the drying process, nitrogen gas with a purity ≥99.99% is introduced every 2 hours at a flow rate of 0.8L / min for 12 minutes each time to maintain an oxygen-free environment and remove solvent vapors. The total drying time is 6 hours. After drying, collect the material to obtain purified adrenaline tartrate.

[0067] Example 2

[0068] Compared with Example 1, this embodiment differs in that the amount of deoxygenated water and acetone used is increased. The specific implementation steps of S1-S2 are as follows: S1. Add 60g of deoxygenated water to a 500mL three-necked reaction flask (deoxygenation method: at room temperature, bubble the purified water with nitrogen gas of ≥99.99% purity at a stirring speed of 150rpm for 40min). Then, add 20g of crude epinephrine tartrate to the reaction flask. Stir in a closed environment at 24℃ and 250rpm for 30min until the crude product is completely dissolved to form a solution. S2. Cool the solution obtained in S1 to 15°C at a cooling rate of 0.8°C / min. Then, slowly add 240g of acetone at a rate of 8g / min, while maintaining a stirring rate of 250rpm, until the solution becomes slightly turbid. The remaining raw materials and preparation process are the same as in Example 1.

[0069] Example 3

[0070] Compared with Example 1, the difference in this embodiment is that only the amount of acetone is increased. The specific implementation steps of S2 are as follows: S2. Cool the solution obtained in S1 to 15°C at a cooling rate of 0.8°C / min. Then, slowly add 200g of acetone at a rate of 8g / min, while maintaining a stirring rate of 250rpm, until the solution becomes slightly turbid. The remaining raw materials and preparation process are the same as in Example 1.

[0071] Example 4

[0072] Compared with Example 1, the difference in this embodiment is that the amount of deoxygenated water and acetone is reduced. The specific implementation steps of S1-S2 are as follows: S1. Add 30g of deoxygenated water to a 500mL three-necked reaction flask (deoxygenation method: at room temperature, bubble with nitrogen gas of ≥99.99% purity at 150rpm for 40min). Then, add 20g of crude epinephrine tartrate to the reaction flask. Stir in a closed environment at 24℃ and 250rpm for 30min until the crude product is completely dissolved to form a solution. S2. Cool the solution obtained in S1 to 15°C at a cooling rate of 0.8°C / min. Then, slowly add 120g of acetone at a rate of 8g / min, while maintaining a stirring rate of 250rpm, until the solution becomes slightly turbid. The remaining raw materials and preparation process are the same as in Example 1.

[0073] Example 5

[0074] Compared with Example 1, the difference in this embodiment is that the amount of deoxygenated water and acetone is reduced. The specific implementation steps of S1-S2 are as follows: S1. Add 30g of deoxygenated water to a 500mL three-necked reaction flask (deoxygenation method: at room temperature, bubble with nitrogen gas of ≥99.99% purity at 150rpm for 40min). Then, add 20g of crude epinephrine tartrate to the reaction flask. Stir in a closed environment at 24℃ and 250rpm for 30min until the crude product is completely dissolved to form a solution. S2. Cool the solution obtained in S1 to 15°C at a cooling rate of 0.8°C / min. Then, slowly add 150g of acetone at a rate of 8g / min, while maintaining a stirring rate of 250rpm, until the solution becomes slightly turbid. The remaining raw materials and preparation process are the same as in Example 1.

[0075] Comparative Example 1

[0076] The difference between this comparative example and Example 1 is that the deoxygenated water is replaced with purified water. The specific implementation steps of S1 are as follows: S1. Add 40g of purified water to a 500mL three-necked reaction flask; then add 20g of crude epinephrine tartrate to the reaction flask. Stir at 24℃ and 250rpm in a closed environment for 30 minutes until the crude product is completely dissolved to form a solution; The remaining raw materials and preparation process are the same as in Example 1.

[0077] Comparative Example 2

[0078] The difference between this comparative example and Example 1 is that the mixed solvent is not cooled and is kept at room temperature. The specific implementation steps of S2 are as follows: S2. At room temperature, slowly add 160g of acetone to the solution obtained in S1 at a rate of 8g / min, while maintaining a stirring rate of 250rpm, until the solution becomes slightly turbid. The remaining raw materials and preparation process are the same as in Example 1.

[0079] Comparative Example 3

[0080] The difference between this comparative example and Example 1 is that the crystallization temperature in S3 is set to 13-17°C, and the specific implementation steps of S3 are as follows: S3. Maintain the system temperature at 15℃ and stir and crystallize for 5 hours within this temperature range under nitrogen protection. The remaining raw materials and preparation process are the same as in Example 1.

[0081] Comparative Example 4

[0082] The difference between this comparative example and Example 1 is that nitrogen gas is continuously introduced during vacuum drying. The specific implementation steps of S5 are as follows: S5. Transfer the obtained wet crystals to a vacuum drying oven and dry them at 37°C and a vacuum of -0.09 MPa for a total drying time of 6 hours. After drying, collect the material to obtain refined adrenaline tartrate.

[0083] The remaining raw materials and preparation process are the same as in Example 1.

[0084] Comparative Example 5

[0085] The comparative method of this comparative reference is implemented through the following steps: Add 20 g of crude epinephrine tartrate and 120 mL of mixed solvent (20 mL water, 40 mL methanol, and 60 mL ethanol) to a 500 mL three-necked reaction flask, and mix thoroughly at 30 °C. Cool to 20 °C to allow crystals to crystallize for 8 hours, filter, and dry under forced air to obtain epinephrine tartrate.

[0086] Performance testing

[0087] In this invention, all crude epinephrine tartrate samples used were from the same batch to facilitate comparison of the purification effects of each embodiment. The test results for crude epinephrine tartrate were as follows: Impurity A 0.4%; Impurity B (L-norepinephrine) 0.2%; Impurity C (adrenaline) 0.3%; Total impurities 0.8%; D-adrenaline 2.5%; Content 98.8%; Solution clarity and color were yellow (standard color No. 3).

[0088] The main quality standards of the European Pharmacopoeia are: content 98.5%~101.0%; impurity A≤0.3%, impurity B≤0.15%, impurity C≤0.2%, total impurities≤0.6%; the solution should be clear and colorless.

[0089] Yield (%) = (Quality of refined product × Content of refined product) / (Material weight of crude product × Initial content of crude product) × 100%

[0090] Performance tests were conducted on Examples 1-5 and Comparative Examples 1-5, and the results are shown in Table 1: Table 1

[0091] As shown in Table 1, the ratio of deoxygenated water to acetone in the crystallization system affects the yield, and there is a yield / impurity balance. Reducing the amount of deoxygenated water can increase the yield. For example, in Examples 4-5 (30g of deoxygenated water, 1.5 times the weight of the crude product), the yield reached 91%-92%, while in Example 1 (40g of deoxygenated water), the yield decreased to 85%, and in Example 2 (60g of deoxygenated water), the yield further decreased to 78%. With the same amount of deoxygenated water, a slightly higher amount of acetone (e.g., 200g of acetone in Example 3 vs. 160g in Example 1) can also increase the yield from 85% to 87%. This is because the less deoxygenated water there is, the higher the concentration of the crude product. After the addition of acetone, the solubility of adrenaline tartrate in the mixed solvent drops sharply, the supersaturation increases, and the target product is more easily precipitated. Increasing the amount of acetone further reduces the solubility and slightly optimizes the supersaturation. However, a decrease in the amount of deoxygenated water used is accompanied by a slight increase in impurities. For example, the total impurities in the 30g group are 0.40% and impurity A is 0.18%, while the total impurities in the 60g group are 0.33% and impurity A is 0.14%. This is because the system concentration is too high under low water volume, and slight local incomplete dissolution leads to a small amount of impurities being encapsulated by crystals. However, all impurities still meet the European Pharmacopoeia standards, which can achieve balance in industrial production.

[0092] Crystallization temperature significantly affects both yield and impurities. Lower temperatures are more conducive to increasing yield but also result in a slight increase in impurities. Example 1 (crystallization temperature -5°C) achieved a yield of 85%, while Comparative Example 3 (crystallization temperature 15°C) only achieved a yield of 64%. The core principle is that temperature directly affects solubility—at -5°C, epinephrine tartrate has extremely low solubility and extremely high supersaturation in the acetone-water system, leading to the precipitation of a large amount of the target product; at 15°C, solubility increases, but the supersaturation drops sharply, resulting in a sharp drop in yield. Simultaneously, the impurities in the low-temperature group were slightly higher than those in the high-temperature group. For example, Example 1 had 0.35% total impurities and 0.65% D-adrenaline, higher than Comparative Example 3's 0.32% total impurities and 0.36% D-adrenaline. This is because crystals grow faster at low temperatures, easily encapsulating trace impurities in the mother liquor, while crystals grow slowly at high temperatures, making it easier for impurities to remain in the mother liquor. However, the impurities in the low-temperature group were still far below the European Pharmacopoeia limits and did not affect product compliance.

[0093] Controlling the oxygen-free atmosphere during the crystallization system and drying process is crucial for ensuring product impurities and solution color meet standards. Failure to implement oxygen-free control will result in a significant increase in impurities and substandard color. Comparing Example 1 (completely oxygen-free: deoxygenated water + nitrogen protection) with Comparative Example 1 (no deoxygenated water), Comparative Example 4 (drying without nitrogen), and Comparative Example 5 (traditional process without oxygen-free control), it is evident that in Comparative Example 1, impurity A increased from 0.15% to 0.22%, and impurity C increased from 0.10% to 0.15%, resulting in a yellow color (No. 1). In Comparative Example 4, impurity C increased to 0.22% (exceeding the European Pharmacopoeia limit of 0.2%), total impurities increased to 0.82% (exceeding the 0.6% limit), and D-adrenaline reached 1.21% (exceeding the 1.0% limit). In Comparative Example 5, all impurities exceeded limits, resulting in a yellow color (No. 2). This is because the catecholamine structure of adrenaline tartrate readily reacts with oxygen to generate yellow oxidized impurities such as quinones and adrenaline. Failure of anaerobic control leads to uncontrolled oxidation reactions, resulting not only in a surge of impurities but also in the inability of the solution to meet the requirement of being "clear and colorless" due to the color of the oxidation products.

[0094] In summary, the ratio of deoxygenated water to acetone in the crystallization system determines the yield. Reducing the proportion of deoxygenated water improves the yield but slightly increases impurity levels. Lower crystallization temperature also improves the yield but slightly increases impurities. Controlling the oxygen-free atmosphere in the crystallization system and drying process is crucial. Poor control of the oxygen-free environment leads to a significant increase in both known and unknown impurities, and further causes the solution to fail to meet the requirements for clarity and colorlessness.

[0095] The above-disclosed embodiments are merely a few specific examples of the present invention. However, the embodiments of the present invention are not limited thereto, and any variations that can be conceived by those skilled in the art should fall within the protection scope of the present invention.

Claims

1. A method for purifying adrenaline tartrate, characterized in that, Includes the following steps: S1. Dissolve crude epinephrine tartrate in deoxygenated water to form a solution; S2. Cool the solution described in S1 to 13-17°C, and slowly add an organic solvent to form a mixed solvent, wherein the organic solvent is acetone, and the weight ratio of acetone to deoxygenated water is (4.0~5.0):1.

0. S3. Under nitrogen protection, recrystallize at a temperature of -5℃ to -8℃ for 4 to 6 hours. S4. After crystallization, a nitrogen-protected pressure filtration device is used to filter the crystallization system with a 0.22μm polytetrafluoroethylene filter membrane. The system temperature is maintained below -5℃ during the filtration process. The filter cake is collected to obtain wet crystals. S5. The wet crystals are vacuum dried at 35-40°C. Nitrogen gas is intermittently introduced during the drying process to maintain an oxygen-free environment. Nitrogen gas with a purity of ≥99.99% is introduced once every 2 hours for 10-15 minutes each time, with a nitrogen flow rate of 0.5-1 L / min, to obtain purified adrenaline tartrate.

2. The purification method of adrenaline tartrate according to claim 1, characterized in that, In step S1, the deoxygenated water is obtained by passing purified water through nitrogen gas with a purity ≥99.99% at room temperature for 30-60 minutes with a stirring rate of 100-200 rpm to remove dissolved oxygen from the water.

3. The purification method of adrenaline tartrate according to claim 1, characterized in that, In step S1, the solution is prepared by adding crude adrenaline tartrate into a sealed dissolving vessel containing deoxygenated water, stirring at 20-25°C and a stirring speed of 200-300 rpm for 20-40 minutes until the crude product is completely dissolved.

4. The method for purifying epinephrine tartrate according to claim 1, characterized in that, In S1, the weight ratio of crude adrenaline tartrate to deoxygenated water is 1.0:(1.5~3.0).

5. The method for purifying epinephrine tartrate according to claim 1, characterized in that, In S2, the mixed solvent is prepared by cooling the solution obtained in S1 to 13-17℃ at a cooling rate of 0.5-1℃ / min, then adding acetone at a rate of 5-10g / min while stirring at a stirring rate of 200-300rpm until the solution becomes slightly turbid, thus obtaining the mixed solvent.

6. The method for purifying epinephrine tartrate according to claim 1, characterized in that, In step S5, the vacuum degree of vacuum drying is -0.08 to -0.1 MPa, and the drying time is 6 to 10 hours.

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