A hormone crude mother liquor crystallization device
By incorporating a stirring shaft, scraper, and anti-adhesion layer within the crystallization tank, and combining this with a composite coating of nano-silicon and graphene oxide, the adhesion problem during the crystallization process of prednisolone mother liquor was solved, thereby improving crystallization efficiency and product yield.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANDONG XINHUA PHARMA CO LTD
- Filing Date
- 2026-04-27
- Publication Date
- 2026-06-02
AI Technical Summary
The existing chemical separation process for prednisolone products suffers from low yield and high cost. In particular, during the mother liquor crystallization process, prolonged high-temperature concentration leads to the precipitation of colloids, which affects product quality and yield.
A crystallization device for crude hormone mother liquor is used, which includes a stirring shaft and a scraper installed inside the crystallization tank, and a polytetrafluoroethylene protective plate and an anti-adhesion layer installed on the outside of the scraper. Combined with an anti-adhesion coating composed of nano-silicon and graphene oxide, the crystallization efficiency is improved and adhesion is avoided.
It improves crystallization efficiency and the removal efficiency of materials after crystallization, avoids adhesion, and improves product quality and yield.
Smart Images
Figure CN122124492A_ABST
Abstract
Description
Technical Field
[0001] This application relates to a device for crystallizing crude hormone mother liquor. Background Technology
[0002] Prednisolone (11β,17α,21-trihydroxypregn-1,4-diene-3,20-one) is a class of glucocorticoid drugs and an important steroid compound. To date, this product has completed official registration in China, the European Union, India, and other countries, and sales demand is increasing daily. From January to October 2023, 5.5 tons of prednisolone were delivered to warehouses. Prednisolone production is projected to reach 25 tons in 2024, making it a mainstay product of Workshop 203 in recent years.
[0003] The chemical separation process for prednisolone products suffers from low yield and high cost: during the biocatalytic process, 80% of hydrocortisone is converted to prednisolone, while the remaining 20% remains unconverted. When using Girard's reagent T for separation, the unconverted hydrocortisone and a small amount of prednisolone react with Girard's reagent T to generate water-soluble substances that enter the mother liquor system, resulting in a low average yield of only 77.53%.
[0004] Before acidification, methanol needs to be removed from the mother liquor of prednisolone products. During small-scale studies, due to the small batch size and short concentration time, the problem of colloid formation from prolonged heating was not exposed. In pilot production, we used a conventional reactor for vacuum concentration. The long concentration time (2-3 hours) and high reactor temperature caused the reaction system to change from pale yellow to dark yellow. During subsequent acid addition and crystallization, a small amount of colloid precipitated, resulting in low yield, uneven intermediate material, and unstable quality in this process. Analysis revealed that the root cause was the presence of Girald reagent T and acetic acid in the mother liquor, which inevitably caused side reactions during prolonged high-temperature concentration. Therefore, it is necessary to improve the existing drying method. Summary of the Invention
[0005] To address the aforementioned problems, this application proposes a crystallization device for crude hormone mother liquor, comprising a crystallization tank, an internal stirring shaft with several spaced scrapers on the stirring shaft, a crystallization plate positioned outside the scrapers within the crystallization tank, a heat exchange tube between the crystallization plate and the crystallization tank, and an anti-adhesion layer on the inner wall of the crystallization plate; a vertically positioned polytetrafluoroethylene (PTFE) protective plate is positioned outside the scrapers, and the PTFE protective plate is movably in contact with the anti-adhesion layer. This application, through the combined arrangement of the PTFE protective plate and the anti-adhesion layer, utilizes the flexibility and non-adhesive properties of the anti-adhesion layer to improve crystallization and post-crystallization removal efficiency, avoid adhesion, and enhance scraping efficiency.
[0006] Preferably, the stirring shaft is powered by a stirring motor.
[0007] Preferably, a conical outlet channel is provided at the bottom of the crystallization plate, a vertical outlet pipe is provided at the bottom of the conical outlet channel, and an outlet valve is provided on the vertical outlet pipe.
[0008] Preferably, the anti-adhesion layer comprises the following raw materials in parts by weight: Silicone resin emulsion: 20-40 parts; polytetrafluoroethylene emulsion: 40-50 parts; polytetrafluoroethylene particles: 1-2 parts; nano-silicon: 0.5-1 part; graphene oxide: 1-2 parts; NaOH: 0.4-0.6 parts.
[0009] Preferably, 0.5-1 parts of nano-silicon, 1-2 parts of graphene oxide, and 0.4-0.6 parts of NaOH are placed in 2-3 times their mass of water for a first mixing reaction to obtain a first mixture. This application achieves dispersion of silicon and carbon in the system by allowing nano-silicon to undergo a limited reaction with sodium hydroxide, followed by composite with graphene oxide. Based on this dispersion, silicon and carbon are then incorporated into silicone resin emulsions and polytetrafluoroethylene emulsions, ensuring uniform coating and coating quality during spraying.
[0010] Preferably, the first mixture is prepared according to the following method: First, add NaOH and nano-silicon to water simultaneously, stir thoroughly, and heat to 60-80℃ and maintain for 2-3 hours; Then slowly add graphene oxide to the first mixture and stir for at least 30 minutes until the graphene oxide is evenly dispersed in it, and finally obtain the first mixture.
[0011] Preferably, the anti-adhesion layer is prepared according to the following method: Silicone resin emulsion, polytetrafluoroethylene emulsion, polytetrafluoroethylene particles, and the first mixture are mixed and thoroughly mixed to obtain an anti-adhesion coating. The anti-adhesion coating is repeatedly sprayed onto the inner wall of the crystallization plate to obtain an anti-adhesion layer.
[0012] Preferably, the number of repeated sprayings is no less than 3. The coating obtained in this application can be applied by spraying, which is simple to operate. Under operating conditions, the thickness of each spraying is relatively constant, about 0.2 mm, which is highly controllable and can ensure construction efficiency and quality.
[0013] Preferably, the thickness of the anti-adhesion layer is 0.5-1 mm.
[0014] Preferably, the silicone resin emulsion is an aqueous solution with a mass concentration of 40-50 wt%; the polytetrafluoroethylene emulsion is an aqueous solution with a mass concentration of 55-60 wt%.
[0015] This application can bring the following beneficial effects: 1. This application uses a combination of a polytetrafluoroethylene protective plate and an anti-adhesion layer. By utilizing the flexibility and non-adhesive properties of the anti-adhesion layer, the efficiency of crystallization and removal after crystallization is improved, adhesion is avoided, and scraping efficiency is increased.
[0016] 2. This application achieves the dispersion of silicon and carbon in the system by carrying out a limited reaction between nano-silicon and sodium hydroxide, and then combining it with graphene oxide. Based on this dispersion, silicon and carbon are dispersed into silicone resin emulsion and polytetrafluoroethylene emulsion, thereby ensuring the uniformity and quality of spraying during spraying.
[0017] 3. The coating obtained in this application can be applied by spraying, which is simple to operate. Under operating conditions, the thickness of a single spray is relatively constant, about 0.2 mm, which is highly controllable and can ensure construction efficiency and quality. Attached Figure Description
[0018] The accompanying drawings, which are included to provide a further understanding of this application and form part of this application, illustrate exemplary embodiments and are used to explain this application, but do not constitute an undue limitation of this application. In the drawings: Figure 1 This is a schematic diagram of the structure of this application. Detailed Implementation
[0019] To clearly illustrate the technical features of this solution, the following detailed description, in conjunction with the accompanying drawings, will be provided.
[0020] For mechanical mechanisms, such as Figure 1 As shown, a crystallization device for crude hormone mother liquor includes a crystallization tank 1, a stirring shaft 2 inside the crystallization tank 1, a plurality of scrapers 3 spaced apart on the stirring shaft 2, a crystallization plate 4 outside the crystallization tank 1 outside the scrapers 3, a heat exchange tube 5 between the crystallization plate 4 and the crystallization tank 1, and an anti-adhesion layer 6 on the inner wall of the crystallization plate 4; a vertically arranged polytetrafluoroethylene protective plate 7 outside the scrapers 3, the polytetrafluoroethylene protective plate 7 being movably abutting against the anti-adhesion layer 6.
[0021] The stirring shaft 2 is powered by a stirring motor 11. A conical outlet channel 8 is provided at the bottom of the crystallization plate 4, a vertical outlet pipe 9 is provided at the bottom of the conical outlet channel 8, and an outlet valve 10 is provided on the vertical outlet pipe 9.
[0022] The anti-adhesive layer comprises the following parts by weight of raw materials: Silicone resin emulsion: 20-40 parts; polytetrafluoroethylene emulsion: 40-50 parts; polytetrafluoroethylene particles: 1-2 parts; nano-silicon: 0.5-1 part; graphene oxide: 1-2 parts; NaOH: 0.4-0.6 parts.
[0023] The first mixture is prepared by mixing 0.5-1 parts of nano-silicon, 1-2 parts of graphene oxide, and 0.4-0.6 parts of NaOH in 2-3 times the mass of water to obtain the first mixture.
[0024] S1. Preparation of the first mixture: First, add 0.4-0.6 parts NaOH and 0.5-1 parts nano-silicon to water simultaneously, stir thoroughly, and heat to 60-80℃ and maintain for 2-3 hours; Then slowly add 1-2 parts of graphene oxide to the first mixture, stirring for at least 30 minutes until the graphene oxide is evenly dispersed, thus obtaining the first mixture.
[0025] S2. Preparation of anti-adhesion coating: Mix 20-40 parts of silicone resin emulsion, 40-50 parts of polytetrafluoroethylene emulsion, 1-2 parts of polytetrafluoroethylene particles, and the first mixture thoroughly to obtain an anti-adhesion coating.
[0026] The silicone resin emulsion is an aqueous solution with a mass concentration of 40-50 wt%; the polytetrafluoroethylene emulsion is an aqueous solution with a mass concentration of 55-60 wt%.
[0027] S3. Preparation of the anti-adhesion layer: An anti-adhesion layer is obtained by repeatedly spraying the anti-adhesion coating onto the inner wall of the crystallization plate.
[0028] The coating is applied repeatedly at least three times, and the thickness of the anti-adhesion layer is 0.5-1 mm.
[0029] Specifically, it is prepared according to the following method: Example 1: S101. Preparation of the first mixture: First, add 0.4 parts NaOH and 0.5 parts nano-silicon to water simultaneously, stir thoroughly, and heat to 60°C for 3 hours. Then slowly add 1 part of graphene oxide to the first mixture, stirring for no less than 30 minutes until the graphene oxide is evenly dispersed, and finally obtain the first mixture.
[0030] S102. Preparation of anti-adhesion coating: Mix 20 parts of silicone resin emulsion, 40 parts of polytetrafluoroethylene emulsion, 1 part of polytetrafluoroethylene particles, and the first mixture thoroughly to obtain an anti-adhesion coating.
[0031] The silicone resin emulsion is an aqueous solution with a mass concentration of 40 wt%; the polytetrafluoroethylene emulsion is an aqueous solution with a mass concentration of 55 wt%.
[0032] S103. Preparation of the anti-adhesion layer: An anti-adhesion layer is obtained by repeatedly spraying the anti-adhesion coating onto the inner wall of the crystallization plate.
[0033] The coating is applied repeatedly three times, and the thickness of the anti-adhesion layer is 0.5 mm.
[0034] The mother liquor obtained by the above method was used in the crystallization process of our company's prednisolone product. It was sprayed onto the surface of a clean plate. After the operating conditions were reached, the amount of crystals recovered in 24 hours was recorded as 231 kg. After the operation was stopped, there were no obvious scratches on the surface of the anti-adhesion layer, and there was basically no crystal adhesion.
[0035] Example 2: S201. Preparation of the first mixture: First, add 0.6 parts NaOH and 1 part nano-silicon to water simultaneously, stir thoroughly, and heat to 80°C and maintain for 2 hours; Then slowly add 2 parts of graphene oxide to the first mixture, stirring for no less than 30 minutes until the graphene oxide is evenly dispersed, and finally obtain the first mixture.
[0036] S202. Preparation of anti-adhesion coating: Mix 40 parts of silicone resin emulsion, 50 parts of polytetrafluoroethylene emulsion, 2 parts of polytetrafluoroethylene particles, and the first mixture thoroughly to obtain an anti-adhesion coating.
[0037] The silicone resin emulsion is a 50 wt% aqueous solution; the polytetrafluoroethylene emulsion is a 60 wt% aqueous solution.
[0038] S203. Preparation of the anti-adhesion layer: An anti-adhesion layer is obtained by repeatedly spraying the anti-adhesion coating onto the inner wall of the crystallization plate.
[0039] The coating is applied repeatedly 5 times, and the thickness of the anti-adhesion layer is 1 mm.
[0040] The mother liquor obtained by the above method was used in the crystallization process of our company's prednisolone product. It was sprayed onto the surface of a clean plate. After the operating conditions were reached, the amount of crystals recovered in 24 hours was recorded as 276 kg. After the operation was stopped, there were no obvious scratches on the surface of the anti-adhesion layer, and there was basically no crystal adhesion.
[0041] Comparative Example 1: Based on Example 1, the same characterization experiments were performed without an anti-adhesion layer.
[0042] The mother liquor obtained by the above method was used in the crystallization process of our company's prednisolone product. After reaching the operating conditions, the amount of crystals recovered in 24 hours was recorded as 181 kg. After the operation was stopped, there were crystals adhering to the crystallization plate.
[0043] Comparative Example 2: Based on Example 1, instead of preparing a first mixture, all raw materials were mixed together in one step, and the same characterization experiments were performed.
[0044] The mother liquor obtained by the above method was used in the crystallization process of our company's prednisolone product. After reaching the operating conditions, the amount of crystals recovered in 24 hours was recorded as 208 kg. After the operation was stopped, there were crystals adhering to the crystallization plate.
[0045] Comparative Example 3: Based on Example 1, the NaOH in S101 was replaced with 1 part, and the same characterization experiment was performed.
[0046] The mother liquor obtained by the above method was used in the crystallization process of our company's prednisolone product. After reaching the operating conditions, the amount of crystals recovered in 24 hours was recorded as 197 kg. After the operation was stopped, there were crystals adhering to the crystallization plate.
[0047] The various embodiments in this specification are described in a progressive manner. Similar or identical parts between embodiments can be referred to interchangeably. Each embodiment focuses on describing the differences from other embodiments. In particular, the system embodiments are basically similar to the method embodiments, so the description is relatively simple; relevant parts can be referred to the descriptions in the method embodiments.
[0048] The above are merely embodiments of this application and are not intended to limit the scope of this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of the claims of this application.
Claims
1. A device for crystallizing crude hormone mother liquor, characterized in that: The device includes a crystallization tank, an internal stirring shaft, a number of spaced scrapers on the stirring shaft, a crystallization plate on the outside of the scrapers, a heat exchange tube between the crystallization plate and the crystallization tank, an anti-adhesion layer on the inner wall of the crystallization plate, and a vertically arranged polytetrafluoroethylene (PTFE) protective plate on the outside of the scrapers, wherein the PTFE protective plate and the anti-adhesion layer are movably abutted against each other.
2. The hormone crude mother liquor crystallization device according to claim 1, characterized in that: The stirring shaft is powered by a stirring motor.
3. The hormone crude mother liquor crystallization device according to claim 1, characterized in that: A conical outlet channel is set at the bottom of the crystallization plate, a vertical outlet pipe is set at the bottom of the conical outlet channel, and an outlet valve is set on the vertical outlet pipe.
4. The hormone crude mother liquor crystallization device according to claim 1, characterized in that: The anti-adhesion layer comprises the following raw materials in parts by weight: Silicone resin emulsion: 2-4 parts; polytetrafluoroethylene emulsion: 4-5 parts; polytetrafluoroethylene particles: 1-2 parts; nano-silicon: 0.5-1 part; graphene oxide: 1-2 parts; NaOH: 0.4-0.6 parts.
5. The hormone crude mother liquor crystallization device according to claim 4, characterized in that: Nano-silicon: 0.5-1 part; Graphene oxide: 1-2 parts; 0.4-0.6 parts of NaOH are placed in 2-3 times the mass of water to carry out the first mixing reaction to obtain the first mixture.
6. The hormone crude mother liquor crystallization device according to claim 5, characterized in that: The first mixture was prepared according to the following method: First, add NaOH and nano-silicon to water simultaneously, stir thoroughly, and heat to 60-80℃ and maintain for 2-3 hours; Then slowly add graphene oxide to the first mixture, stirring for at least 3 minutes. The mixture is kept in the solution for min until the graphene oxide is evenly dispersed, thus obtaining the first mixture.
7. The hormone crude mother liquor crystallization device according to claim 5, characterized in that: The anti-adhesion layer is prepared according to the following method: Silicone resin emulsion, polytetrafluoroethylene emulsion, polytetrafluoroethylene particles, and the first mixture are mixed and thoroughly mixed to obtain an anti-adhesion coating. The anti-adhesion coating is repeatedly sprayed onto the inner wall of the crystallization plate to obtain an anti-adhesion layer.
8. A hormone crude mother liquor crystallization apparatus according to claim 7, characterized in that: The number of spraying applications should be no less than 3.
9. A hormone crude mother liquor crystallization device according to claim 4, characterized in that: The thickness of the anti-adhesion layer is 0.5-1mm.
10. A hormone crude mother liquor crystallization device according to claim 4, characterized in that: The silicone resin emulsion is an aqueous solution with a mass concentration of 40-50 wt%; the polytetrafluoroethylene emulsion is an aqueous solution with a mass concentration of 55-60 wt%.