WO2021073099A1 - 一种多级连续反应结晶生产布洛芬的方法 - Google Patents

一种多级连续反应结晶生产布洛芬的方法 Download PDF

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WO2021073099A1
WO2021073099A1 PCT/CN2020/092189 CN2020092189W WO2021073099A1 WO 2021073099 A1 WO2021073099 A1 WO 2021073099A1 CN 2020092189 W CN2020092189 W CN 2020092189W WO 2021073099 A1 WO2021073099 A1 WO 2021073099A1
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ibuprofen
crystallizer
crystallization
reaction
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French (fr)
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杜德平
周玲
寇祖星
张美景
孙科
夏丙堃
郭发志
张玲
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山东新华制药股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/132—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing rings
    • C07C53/134—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing rings monocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/10—Process efficiency

Definitions

  • the invention belongs to the field of medicine and chemical industry, and relates to a continuous crystallization method of ibuprofen.
  • Ibuprofen has a chemical name of 2-(4-isobutylphenyl)propionic acid and its molecular formula is C 13 H 18 O 2 ; it is easily soluble in organic solvents such as ethanol, acetone, chloroform or ether, and is almost insoluble in water. Its anti-inflammatory, antipyretic and analgesic effects are definite, and the side effects are small. It has become the three pillars of antipyretic and analgesic drugs alongside aspirin and acetaminophen. Ibuprofen is a safe and effective antipyretic in clinical application.
  • antipyretic effect is more obvious than paracetamol during high fever, and the antipyretic time is longer; the analgesic effect is 16-32 times stronger than aspirin, and the antipyretic effect is similar to aspirin But the effect is longer, the gastrointestinal side effects are lighter, and it is easy to tolerate.
  • the production method of ibuprofen in the prior art mainly adopts batch crystallization.
  • the production of ibuprofen generally adopts the rearranged ester synthesized in the previous step plus sodium hydroxide. It is hydrolyzed to form ibuprofen sodium salt, and then acidified with hydrochloric acid to obtain the product ibuprofen.
  • the ibuprofen component exists in the form of a high-viscosity oily and liquid-liquid separation from the solvent, which is called oil precipitation.
  • CN200310114695.8 A batch crystallization preparation process of ibuprofen microcrystalline products is provided.
  • the crystallization process is to dissolve crude ibuprofen in 60°C high-temperature ethanol-water mixture, petroleum ether, hexane and other organic solvents, and then put this high-temperature solution into the corresponding solution at -5°C and mix, and increase
  • the supersaturation of ibuprofen is lowered and the small crystals of ibuprofen are precipitated. Due to the rapid cooling of the high-temperature solution, a great supersaturation is generated, resulting in explosive nucleation, and the product is finely broken.
  • the median particle size of the product is less than 45 ⁇ m.
  • the patented preparation process is only suitable for the preparation of microcrystalline products, and the bulk drug of ibuprofen used for direct compression or canning of capsules often requires large-diameter crystal products.
  • the ethanol aqueous solution in the acidification step not only introduces new impurity ibuprofen ethyl ester, but also has oil precipitation, which leads to a decrease in product purity.
  • CN201210328660.3 A method for batch crystallization refining of ibuprofen is provided. Add crude ibuprofen to organic solvents such as cyclohexane, n-heptane, chloroform, heat to 50-80°C and stir to dissolve, cool to room temperature naturally, place the solution at -10-0°C to crystallize, filter, and place in an ice bath It is washed with an organic solvent in the state, and the final product is obtained after crystallization is repeated 3 to 5 times, and the purity of the product is increased to more than 99.5%. This process is only suitable for the purification and impurity removal of the ibuprofen product process.
  • organic solvents such as cyclohexane, n-heptane, chloroform
  • CN201210195713.9 A method for intermittent production and purification of ibuprofen is provided. Ibuprofen sodium salt is dissolved in water, activated carbon is added for decolorization, filtered, the temperature is reduced to 30°C, and hydrochloric acid is added dropwise to acidify the pH to 3, and an oxidant is added to remove impurities The double bond in 2-[4-(2-methyl-1-propenyl)phenyl]propionic acid is oxidized to hydroxyl, which increases the solubility of impurities in water, and then removes them in the water washing process. This method is only suitable for the purification and impurity removal of impurity 2-[4-(2-methyl-1-propenyl)phenyl]propionic acid.
  • the present invention provides a multi-stage continuous reaction crystallization method for producing ibuprofen, which is characterized in that it comprises the following steps:
  • the oil-forming tank continuously conveys materials to the first-stage reaction crystallizer, and at the same time, the acidic aqueous solution is continuously added to the first-stage reaction crystallizer, and the pH value of the first-stage reaction crystallizer is controlled at 6.0 ⁇ 6.4, the material liquid temperature is controlled at 35 ⁇ 45°C;
  • the final reaction crystallizer continuously conveys materials to the centrifugal unit. After centrifugation, the wet crystals of crude ibuprofen are obtained; the wet crystals enter the washing tank, where they are stirred and washed with purified water and dried to obtain Bulofen. Fen products.
  • the concentration of the aqueous solution of sodium ibuprofen in step (1) is 0.05 ⁇ 0.09g/ml
  • step (1) the average residence time of the intermediate oil tank based on the feed of the sodium ibuprofen salt solution is 0.5 to 1 hour.
  • the method for producing ibuprofen by multi-stage continuous reaction crystallization is characterized in that: the acidic aqueous solution is selected from
  • hydrochloric acid phosphoric acid
  • acetic acid nitric acid
  • sulfuric acid aqueous solution.
  • the method for producing ibuprofen by multi-stage continuous reaction crystallization is characterized in that: the continuous crystallization operation stage
  • the number is 2 to 4 levels
  • the three-stage continuous crystallization operation is that before step (3), one-stage crystallization operation can be added to form three-stage continuous crystallization; the first-stage reaction crystallizer in step (2) continuously conveys materials to the second-stage reaction crystallizer, and at the same time , The acidic aqueous solution is continuously added to the secondary reaction crystallizer, the pH value of the secondary reaction crystallizer is controlled at 5.1-5.4, and the temperature of the material liquid is controlled at 35-45°C; the secondary reaction crystallizer continues to the final stage of reaction crystallization Conveying materials;
  • the four-stage continuous crystallization operation is that before step (3), two-stage crystallization operations can be added to form four-stage continuous crystallization; the first-stage reaction crystallizer in step (2) continuously conveys materials to the second-stage reaction crystallizer, At the same time, the acidic aqueous solution is continuously added to the secondary reaction crystallizer, the pH value of the secondary reaction crystallizer is controlled at 5.3 ⁇ 5.7, and the temperature of the material liquid is controlled at 35 ⁇ 45°C; the secondary reaction crystallizer continuously reacts to the third stage.
  • the crystallizer conveys materials, and at the same time, the acidic aqueous solution is continuously added to the three-stage reaction crystallizer, and the pH value of the three-stage reaction crystallizer is controlled at 4.7-5.0, and the temperature of the material liquid is controlled at 35-45°C; the three-stage reaction crystallizer Continuously convey materials to the final reaction crystallizer.
  • the method for producing ibuprofen by multi-stage continuous reaction crystallization is characterized in that the number of continuous crystallization operation stages is 2 stages.
  • the method for producing ibuprofen by multi-stage continuous reaction crystallization is characterized in that the average residence time of each stage of continuous reaction crystallization based on the feed of each stage of ibuprofen sodium salt aqueous solution is 0.6-1.5 hours.
  • the method for producing ibuprofen by multi-stage continuous reaction crystallization is characterized in that the average residence time of the washing tank based on the ibuprofen solid-liquid mixed phase in step (4) is 0.15-0.5 hours.
  • the method for producing ibuprofen by multi-stage continuous reaction crystallization is characterized in that: when the continuous crystallization starts, the ibuprofen can be added to the first-stage reaction crystallizer in the raw material liquid that flows into the first-stage crystallizer within 1 hour. Seed crystals with a sodium salt content of 0.05-0.1% (g/ml).
  • the method for producing ibuprofen by multi-stage continuous reaction crystallization is characterized in that the acidic aqueous solution is selected from 37% (g/ml) hydrochloric acid.
  • the ibuprofen component exists in the form of a high-viscosity oil and liquid-liquid separation from the solvent, which is called oil-out phenomenon, because the oil formation and reaction crystallization are at the same time during the intermittent production process. It is carried out in one device, so that the supersaturation of ibuprofen in the oil phase continues to accumulate with the inflow of the acidic solution, which eventually causes explosive nucleation, leading to problems such as small particle size, low purity, and low bulk density. In order to weaken and reduce the impact of oil precipitation on the product, a large amount of seed crystals are usually added before the solution bursts into nucleation, but this method will reduce the batch yield of the product.
  • Patent CN201210195713.9 uses water as a solvent to react and crystallize, which produces severe oil precipitation, resulting in a large number of crystals that burst out instantly, resulting in thick crystal slurry, poor stirring, and fine needle-like product particle size, with a bulk density of 0.3-0.5. g/ml, purity is about 99%, particle size is about 100 ⁇ m.
  • the final product is obtained after repeating crystallization for 3 to 5 times in the patent CN201210328660.3, the purity of the product is finally increased to 99.5%, and the yield is very low, only 45.88%.
  • step (1) produces an oily phase rich in solute ibuprofen.
  • step (2) The crystal can serve as a seed crystal to continue to consume the supersaturation of the subsequent continuous input solution in step (2), so that the ibuprofen crystals continue to grow.
  • seed crystals with 0.05-0.1% sodium ibuprofen content in the raw material liquid flowing into the first-stage reaction crystallizer within 1 hour can be added to the first-stage crystallizer in step (2), which can more effectively reduce the instability of the process , The continuous crystallization process reaches a steady state as soon as possible.
  • this application effectively solves the effect of the oil precipitation phenomenon of intermittent reaction crystallization on the purity and particle size of the product.
  • the effect of the treatment method is obvious, and the product yield and quality are improved. Production costs are reduced.
  • the average crystal size of the ibuprofen product of this application has an average particle size of 350-450 ⁇ m. As shown in Figure 2, the particle size is uniform, the main content of the product is high, the purity is more than 99.9%, and the bulk density is more than 0.60g/ml. Impurities may cause side effects, and the yield is over 96%, which improves production efficiency.
  • the continuous reaction crystallization process of ibuprofen of the present invention has stable crystallization conditions, uniform product quality, and production capacity several times or even ten times higher than intermittent operation, and is suitable for industrialized production.
  • the multi-stage continuous reaction crystallization process of ibuprofen provided by the present invention not only effectively solves the problems of small particle size and low purity of the product due to oil precipitation phenomenon in the intermittent production process, but also has the production capacity in continuous production compared with the intermittent process High, stable process parameters, small equipment footprint, low energy consumption, low environmental pollution, high product quality and good consistency.
  • Figure 1 An electron microscope photo of ibuprofen crystal obtained by the applicant according to the conditions of patent CN201210195713.9 through repeated experiments;
  • FIG. 1 Electron micrograph of ibuprofen crystal obtained by the method provided in this application.
  • the sodium ibuprofen aqueous solution is used as a raw material to conduct multi-stage reaction crystallization with hydrochloric acid, and the formed ibuprofen crystal slurry is continuously discharged and enters the separation, washing, drying and other processes to prepare the finished ibuprofen.
  • the specific steps of its continuous crystallization production method are:
  • Reaction to oil Continuously add an aqueous solution of ibuprofen sodium salt with a concentration of 0.06g/ml to the oil tank, and at the same time, add the aqueous hydrochloric acid solution to the oil tank, and control the pH value of the oil tank at 6.9.
  • the temperature is controlled at 40°C, and the average residence time of the oil tank based on the feed of the sodium ibuprofen salt solution is 0.5 hours;
  • the oil-forming tank continuously conveys materials to the first-stage reaction crystallizer, and at the same time, the hydrochloric acid aqueous solution is added to the first-stage reaction crystallizer, and the pH value of the first-stage reaction crystallizer is controlled to 6.0 , The liquid temperature is controlled at 40°C, and the average residence time of the first-stage reaction crystallization based on the feed of the sodium ibuprofen salt solution is 1 hour;
  • the first-stage reaction crystallizer continuously conveys materials to the second-stage reaction crystallizer, and at the same time, the hydrochloric acid aqueous solution is added to the second-stage reaction crystallizer, and the pH value of the second-stage reaction crystallizer is changed. Controlled at 3.2, liquid temperature controlled at 40°C, the average residence time of the second-stage reaction crystallization based on the feed is 1 hour;
  • the second-stage reaction crystallizer continuously conveys materials to the filtering equipment, and after filtration, the wet crystals of crude ibuprofen are obtained; the wet crystals enter the washing tank, and the washing uses purified water, which is stirred and washed in the washing tank and dried. Ibuprofen products.
  • the average residence time of the washing tank based on the solid-liquid mixed phase of ibuprofen is 0.5 hours.
  • the average particle size of the ibuprofen product is 375 ⁇ m, the bulk density is 0.61 g/ml, and the purity is 99.92%.
  • the yield based on the sodium salt of ibuprofen in the raw material solution is 97%.
  • the sodium ibuprofen aqueous solution is used as a raw material to conduct multi-stage reaction crystallization with phosphoric acid, and the formed ibuprofen crystal slurry is continuously discharged and enters the separation, washing, drying and other processes to prepare the finished ibuprofen.
  • the specific steps of its continuous crystallization production method are:
  • Reaction to oil Continuously add an aqueous solution of sodium ibuprofen with a concentration of 0.09g/ml to the oil tank, and at the same time, add the phosphoric acid aqueous solution to the oil tank, set the pH of the oil tank at 6.7, and the temperature of the material liquid Controlled at 35°C, the average residence time of the oil tank based on the feed of the sodium ibuprofen salt solution is 0.5 hours;
  • One-stage reaction crystallization Add seed crystals with 0.05-0.1% sodium ibuprofen content in the raw material liquid flowing into the first-stage crystallizer within 1 hour into the first-stage reaction crystallizer, and the oil-forming tank continuously reacts to the first stage.
  • the crystallizer conveys materials, and at the same time, the phosphoric acid solution is added to the first-stage reaction crystallizer, the pH of the first-stage reaction crystallizer is controlled at 6.3, and the temperature of the material liquid is controlled at 35°C.
  • the first-stage reaction crystallization is based on ibuprofen
  • the average residence time of the sodium salt aqueous solution feed is 1 hour;
  • the first-stage reaction crystallizer continuously conveys materials to the second-stage reaction crystallizer, and at the same time, the phosphoric acid aqueous solution is added to the second-stage reaction crystallizer, and the pH value of the second-stage reaction crystallizer is 5.4 ,
  • the temperature of the feed liquid is controlled at 35°C, and the average residence time of the second-stage reaction crystallization based on the feed is 1 hour;
  • the second-stage reaction crystallizer continuously conveys materials to the third-stage reaction crystallizer, and at the same time, the phosphoric acid aqueous solution is added to the third-stage reaction crystallizer, and the pH value of the third-stage reaction crystallizer is changed. 4.0, the temperature of the feed liquid is controlled at 35°C, and the average residence time of the third-stage reaction crystallization based on the feed is 1 hour;
  • the third-stage reaction crystallizer continuously conveys materials to the filtering equipment, and after filtration, the wet crystals of crude ibuprofen are obtained; the wet crystals enter the washing tank, and the washing uses purified water, which is stirred and washed in the washing tank and dried. , Deibuprofen products.
  • the average residence time of the washing tank based on the solid-liquid mixed phase of ibuprofen is 0.5 hours.
  • the average particle size of the ibuprofen product is 402 ⁇ m, the bulk density is 0.64 g/ml, and the purity is 99.94%.
  • the yield based on the ibuprofen sodium salt in the raw material solution is 98%.
  • the sodium ibuprofen aqueous solution is used as a raw material to conduct multi-stage reaction crystallization with acetic acid, and the formed ibuprofen crystal slurry is continuously discharged, and enters the next step of separation, washing, drying and other processes to prepare the finished ibuprofen.
  • reaction to oil Continuously add an aqueous solution of sodium ibuprofen with a concentration of 0.07g/ml to the oil forming tank, and the material is distributed from the top of the oil tank to the coil
  • the acetic acid aqueous solution is added to the oil tank, and the acetic acid aqueous solution is also added to the oil tank in the form of a distribution coil from the top of the oil tank.
  • the pH value of the oil tank is at 6.7, the liquid temperature is 35°C, and the average residence time of the oil tank based on the feed is 0.5 hours;
  • the oil-forming tank continuously conveys materials to the first-stage reaction crystallizer, and this material enters the reaction crystallizer from the middle and upper part of the first-stage reaction crystallizer, and at the same time, the acetic acid aqueous solution is added to the first-stage reaction crystallizer.
  • the aqueous solution of acetic acid is fed from the top of the first-stage reaction crystallizer to the first-stage reaction crystallizer in the form of a distribution coil, and the pH of the first-stage reaction crystallizer is controlled at 6.3.
  • the feed liquid temperature of the first-stage reaction crystallizer is controlled at 35°C, and the average residence time of the first-stage reaction crystallizer based on the feed is 1 hour;
  • the first-stage reaction crystallizer continuously conveys materials to the second-stage reaction crystallizer.
  • the material enters the reaction crystallizer from the middle and upper part of the second-stage reaction crystallizer.
  • the acetic acid aqueous solution is added to the reaction crystallizer.
  • the aqueous solution of acetic acid is fed into the crystallizer in the form of a distribution coil from the top of the second-stage reaction crystallizer, and the pH of the second-stage reaction crystallizer is controlled at 5.1.
  • the feed liquid temperature of the secondary reaction crystallizer is controlled at 35°C, and the average residence time of the second stage reaction crystallization based on the feed is 1 hour;
  • the second-stage reaction crystallizer continuously conveys materials to the third-stage reaction crystallizer.
  • the material enters the reaction crystallizer from the middle and upper part of the third-stage reaction crystallizer.
  • the acetic acid aqueous solution is added to the reaction crystallizer.
  • the acetic acid aqueous solution is fed into the third-stage reaction crystallizer in the form of a distribution coil from the top of the third-stage reaction crystallizer, and the pH of the third-stage reaction crystallizer is controlled at 3.5.
  • the jacket water controls the liquid temperature of the third-stage reaction crystallizer at 35°C, and the average residence time of the third-stage reaction crystallizer based on the feed is 1 hour;
  • the third-stage reaction crystallizer continuously pumps materials to the centrifugal unit, and obtains wet crystals of crude ibuprofen after centrifugation.
  • the wet crystals are transported into the washing tank in the form of a hopper. Purified water at room temperature is used for washing, which is stirred and washed in the washing tank.
  • the average residence time of the washing tank based on the liquid phase is 0.5 hours. Dry, get ibuprofen product.
  • the average particle size of the ibuprofen product is 421 ⁇ m, the bulk density is 0.64 g/ml, the purity is 99.91%, and the yield based on the sodium salt of ibuprofen is 96%.
  • the nitric acid solution is also added to the oil tank in the form of a distribution coil from the top of the oil tank to control the pH of the oil tank. 6.5.
  • the temperature of the material liquid is controlled at 45°C, and the average residence time of the oil tank based on the feed is 0.5 hours;
  • One-stage reaction crystallization Add seed crystals with 0.05-0.1% sodium ibuprofen content in the raw material liquid flowing into the first-stage crystallizer within 1 hour into the first-stage reaction crystallizer, and the oil-forming tank continuously reacts to the first stage.
  • the crystallizer conveys the material, which enters the reaction crystallizer from the middle and upper part of the first-stage reaction crystallizer.
  • the nitric acid aqueous solution is added to the first-stage reaction crystallizer, and the nitric acid aqueous solution is distributed from the top of the first-stage reaction crystallizer.
  • the coil form flow is added to the first-stage reaction crystallizer, the pH of the first-stage reaction crystallizer is controlled at 6.0, and the temperature of the feed liquid of the first-stage reaction crystallizer is controlled at 45°C through the jacket water.
  • the average residence time of one-stage reaction crystallization based on the feed is 0.6 hours;
  • the first-stage reaction crystallizer continuously conveys materials to the second-stage reaction crystallizer.
  • the materials enter the reaction crystallizer from the middle and upper part of the second-stage reaction crystallizer.
  • the nitric acid aqueous solution is added to the reaction crystallizer.
  • the aqueous solution of nitric acid is fed into the second-stage reaction crystallizer in the form of a distribution coil from the top of the second-stage reaction crystallizer, and the pH of the second-stage reaction crystallizer is controlled at 5.7.
  • the jacket water controls the material liquid temperature of the second-stage reaction crystallizer at 45°C, and the average residence time of the second-stage reaction crystallizer based on the feed is 0.6 hours;
  • the second-stage reaction crystallizer continuously conveys materials to the third-stage reaction crystallizer.
  • the material enters the reaction crystallizer from the middle and upper part of the third-stage reaction crystallizer.
  • the nitric acid aqueous solution is added to the reaction crystallizer.
  • the aqueous solution of nitric acid is fed into the third-stage reaction crystallizer in the form of a distribution coil from the top of the third-stage reaction crystallizer, and the pH of the third-stage reaction crystallizer is controlled at 5.0.
  • the jacket water controls the liquid temperature of the third-stage reaction crystallizer at 45°C, and the average residence time of the third-stage reaction crystallizer based on the feed is 0.6 hours;
  • the third-stage reaction crystallizer continuously conveys materials to the fourth-stage reaction crystallizer.
  • the material enters the reaction crystallizer from the middle and upper part of the fourth-stage reaction crystallizer, and at the same time, the nitric acid aqueous solution is added to the reaction crystallizer.
  • the aqueous solution of nitric acid is fed into the fourth-stage reaction crystallizer in the form of a distribution coil from the top of the fourth-stage reaction crystallizer, and the pH of the fourth-stage reaction crystallizer is controlled at 3.3.
  • the jacket water controls the temperature of the feed liquid of the fourth-stage reaction crystallizer at 45°C, and the average residence time of the fourth-stage reaction crystal based on the feed is 0.6 hours;
  • the fourth-stage reaction crystallizer continuously pumps materials to the centrifugal unit, and obtains wet crystals of crude ibuprofen after centrifugation.
  • the wet crystals are transported into the washing tank in the form of a hopper. Purified water at room temperature is used for washing, which is stirred and washed in the washing tank.
  • the average residence time of the washing tank based on the liquid phase is 0.15 hours. Dry, get ibuprofen product.
  • the average particle size of the ibuprofen product is 386 ⁇ m, the bulk density is 0.61 g/ml, the purity is 99.92%, and the yield based on the sodium salt of ibuprofen is 97%.
  • the sodium ibuprofen aqueous solution is used as a raw material to conduct multi-stage reaction crystallization with sulfuric acid, and the formed ibuprofen crystal slurry is continuously discharged, and enters the next step of separation, washing, drying and other processes to prepare the finished ibuprofen.
  • the specific steps of the continuous crystallization production method are as follows: (1) Reaction to oil: Continuously add an aqueous solution of sodium ibuprofen with a concentration of 0.08g/ml to the oil forming tank, and the material is distributed from the top of the oil tank to the distribution coil.
  • the sulfuric acid aqueous solution is added to the oil tank, and the sulfuric acid aqueous solution is also added to the oil tank in the form of a distribution coil from the top of the oil tank, and the pH of the oil tank is controlled at 6.8.
  • the temperature of the material liquid is controlled at 35°C, and the average residence time of the oil tank based on the feed is 1 hour;
  • One-stage reaction crystallization Add seed crystals with 0.05-0.1% sodium ibuprofen content in the raw material liquid flowing into the first-stage crystallizer within 1 hour into the first-stage reaction crystallizer, and the oil-forming tank continuously reacts to the first stage.
  • the crystallizer conveys the material, which enters the reaction crystallizer from the middle and upper part of the first-stage reaction crystallizer.
  • the sulfuric acid aqueous solution is added to the first-stage reaction crystallizer, and the sulfuric acid aqueous solution is distributed from the top of the first-stage reaction crystallizer.
  • the coil form flow is added to the first-stage reaction crystallizer, the pH of the first-stage reaction crystallizer is controlled at 6.4, and the temperature of the feed liquid of the first-stage reaction crystallizer is controlled at 35°C through the jacket water.
  • the average residence time based on the feed is 1.5 hours;
  • the first-stage reaction crystallizer continuously conveys materials to the second-stage reaction crystallizer.
  • the material enters the reaction crystallizer from the middle and upper part of the second-stage reaction crystallizer.
  • the sulfuric acid aqueous solution is added to the reaction crystallizer.
  • the aqueous solution of sulfuric acid is fed into the second-stage reaction crystallizer in the form of a distribution coil from the top of the second-stage reaction crystallizer, and the pH of the second-stage reaction crystallizer is controlled at 5.3.
  • the jacket water controls the liquid temperature of the second-stage reaction crystallizer at 35°C, and the average residence time of the second-stage reaction crystallizer based on the feed is 1.2 hours;
  • the second-stage reaction crystallizer continuously conveys materials to the third-stage reaction crystallizer, and the material enters the reaction crystallizer from the middle and upper part of the third-stage reaction crystallizer.
  • the sulfuric acid aqueous solution is added to the reaction crystallizer.
  • the aqueous solution of sulfuric acid is fed into the third-stage reaction crystallizer in the form of a distribution coil from the top of the third-stage reaction crystallizer, and the pH of the third-stage reaction crystallizer is controlled at 4.7.
  • the jacket water controls the temperature of the feed liquid of the third-stage reaction crystallizer at 35°C, and the average residence time of the third-stage reaction crystallizer based on the feed is 1.2 hours.
  • the third-stage reaction crystallizer continuously conveys materials to the fourth-stage reaction crystallizer, and the material enters the reaction crystallizer from the middle and upper part of the fourth-stage reaction crystallizer.
  • the sulfuric acid aqueous solution is added to the reaction crystallizer.
  • the sulfuric acid aqueous solution is fed into the fourth-stage reaction crystallizer in the form of a distribution coil from the top of the fourth-stage reaction crystallizer, and the pH of the fourth-stage reaction crystallizer is controlled at 3.0.
  • the jacket water controls the temperature of the feed liquid of the fourth-stage reaction crystallizer at 35°C, and the average residence time of the fourth-stage reaction crystal based on the feed is 1.2 hours;
  • the fourth-stage reaction crystallizer continuously pumps materials to the centrifugal unit, and obtains wet crystals of crude ibuprofen after centrifugation.
  • the wet crystals are transported into the washing tank in the form of a hopper. Purified water at room temperature is used for washing, which is stirred and washed in the washing tank.
  • the average residence time of the washing tank based on the liquid phase is 0.5 hours. Dry, get ibuprofen product.
  • the average particle size of the ibuprofen product is 433 ⁇ m, the bulk density is 0.61 g/ml, the purity is 99.95%, and the yield based on the sodium salt of ibuprofen is 98%.

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Abstract

本发明公开了一种布洛芬连续结晶工艺，采用多级连续结晶的方式得到了布洛芬产品；多级连续反应结晶包括反应成油、二～四级反应结晶、脱水洗涤步骤，调控各步的pH和温度。该方法有效解决了布洛芬反应结晶过程中的油析引起的爆发成核现象，结晶工艺条件稳定，操作控制简单，并且以水为溶剂降低了对环境的污染，所得的布洛芬晶体粒度大且均匀，产品纯度和收率高，提高了结晶工艺运行的稳定性和产品质量，降低了生产成本，实现了布洛芬的稳定化工业生产。

Description

一种多级连续反应结晶生产布洛芬的方法 技术领域
本发明属于医药化工领域，涉及一种布洛芬连续结晶方法。
背景技术
布洛芬，化学名称为2-(4-异丁基苯基)丙酸，其分子式为C 13H 18O 2；易溶于乙醇、丙酮、氯仿或乙醚等有机溶剂，在水中几乎不溶。其抗炎、解热和镇痛效果确切，不良反应小，与阿司匹林、对乙酰氨基酚并列成为解热镇痛的三大支柱药物。布洛芬在临床应用中是安全有效的退热药，高烧时其退热效果比扑热息痛更明显，且退热时间较长；镇痛作用比阿司匹林强16-32倍，退热作用与阿司匹林相似但作用更持久，胃肠道不良反应较轻，易耐受。
目前，现有技术中布洛芬的生产方法主要采用间歇结晶法，考虑到实际生产成本、收率和技术可实施性，布洛芬生产一般是采用上步合成的重排酯加氢氧化钠水解形成布洛芬钠盐，再加入盐酸酸化得到产品布洛芬。在酸化步骤中，布洛芬组分以高粘度的油态形式存在并且和溶剂发生液液分离，称为油析现象，由于在间歇生产过程中成油和反应结晶在同一个设备中进行，使得油相中布洛芬过饱和度随着酸性溶液的流入持续累积，最终引起爆发成核，导致产品粒度细小，晶体易碎、易团聚，由此造成产品过滤困难、溶剂残留多、洗涤难度大、干燥时间长、纯度低等问题，影响产品质量。因此还需在乙醇、水等溶剂中，用冷却结晶的方式进行进一步纯化精制。此工艺方法生产效率低，且纯化精制过程使用大量有机溶剂，对环境污染程度大。并且，在间歇生产过程中为了降低油析现象对产品质量的影响，通常在溶液爆发成核前添加大量的晶种，造成产品的批次产量降低。
CN200310114695.8：提供了一种布洛芬微晶产品的间歇结晶制备工艺。其结晶工艺是将布洛芬粗品溶解于60℃高温乙醇水混合液、石油醚、己烷等有机溶剂中，然后再将此高温溶液投入到-5℃低温相应的溶液中混合，通过增大布洛芬的过饱和度再降温析出布洛芬的小结晶，由于高温溶液的迅速降温，产生极大的过饱和度，导致爆发成核，产品细碎，产品中位粒度45μm以下。该专利制备工艺仅适用于微晶产品的制备，而用于直接压片或胶囊罐装的布洛芬原料药往往需要大粒径晶型的产品。并且酸化步骤的乙醇水溶液中不仅会引入新的杂质布洛芬乙酯还存在着油析现象，导致产品纯度降低。
CN201210328660.3：提供了一种布洛芬的间歇结晶精制方法。将布洛芬粗品加入环己烷、正庚烷、氯仿等有机溶剂中，加热至50-80℃搅拌溶解，自然冷却至室温后将溶液置于-10-0℃结晶，过滤，在冰浴状态下用有机溶剂洗涤，重复结晶3～5次后得最终产品，产品纯度提高到99.5％以上。该工艺仅适用于对布洛芬产品工艺的精制除杂，多次重复过滤、洗涤不适用于晶粒的生长形成，并且消耗较多的有机溶剂，对环境造成污染。能耗较高，由于重复结晶 3～5次，其收率较低仅有45.88％，结晶周期长，不适合大批量生产。
CN201210195713.9：提供了一种布洛芬间歇生产精制的方法，将布洛芬钠盐加水溶解，加入活性炭脱色，过滤，降温至30℃滴加盐酸酸化至pH为3，加入氧化剂，将杂质2-[4-(2-甲基-1-丙烯基)苯基]丙酸中的双键氧化为羟基，增加杂质在水中的溶解度，进而在水洗过程将其去除。该方法仅适用于对杂质2-[4-(2-甲基-1-丙烯基)苯基]丙酸进行精制除杂，未对产品纯度进行充分说明，并且布洛芬钠盐在酸化过程中会出现因油析引起的爆发成核现象，导致晶体粒度细小，申请人按照该专利中条件重复实验得到的布洛芬晶体电镜照片如附图1所示，产品粒径100μm左右。
发明内容
本发明提供了一种多级连续反应结晶生产布洛芬的方法，其特征在于包括如下步骤：
(1)反应成油：连续向成油罐加入布洛芬钠盐水溶液，同时，将酸性水溶液加入成油罐中，将成油罐的pH值控制在6.5～6.9，料液温度控制在35～45℃；
(2)一级反应结晶：成油罐连续向第一级反应结晶器输送物料，同时，将酸性水溶液连续加入到第一级反应结晶器中，将第一级反应结晶器的pH值控制在6.0～6.4，料液温控制在35～45℃；
(3)末级反应结晶：前一级反应结晶器连续向末级反应结晶器输送物料，同时，将酸性水溶液连续加入到末级反应结晶器中，将末级反应结晶器的pH值控制在3.0～4.0，料液温控制在354～5℃；
(4)脱水洗涤：末级反应结晶器连续向离心机组输送物料，离心后得到布洛芬粗品的湿晶体；湿晶体进入洗涤罐，在洗涤罐中用纯化水搅拌洗涤，干燥，得布洛芬产品。
所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：
步骤(1)中布洛芬钠盐水溶液的浓度0.05～0.09g/ml；
步骤(1)中成油罐基于布洛芬钠盐水溶液进料的平均停留时间为0.5～1小时。
所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：所述的酸性水溶液选自
盐酸、磷酸、乙酸、硝酸或硫酸水溶液中的一种。
所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：所述的连续结晶操作级
数为2～4级；
所述的连续结晶操作3级为在步骤(3)之前，可以增加一个级结晶操作，形成三级连续结晶；步骤(2)的一级反应结晶器连续向二级反应结晶器输送物料，同时，将酸性水溶液连续加入到二级反应结晶器中，将二级反应结晶器的pH值控制在5.1～5.4，料液温控制在35～45℃；二级反应结晶器连续向末级反应结晶器输送物料；
所述的连续结晶操作4级为在步骤(3)之前，可以增加两个级结晶操作，形成四级连续结晶；步骤(2)的一级反应结晶器连续向二级反应结晶器输送物料，同时，将酸性水溶液连续加入到二级反应结晶器中，将二级反应结晶器的pH值控制在5.3～5.7，料液温控制在35～45℃；二级反应结晶器连续向三级反应结晶器输送物料，同时，将酸性水溶液连续加入到三级反应结晶器中，将三级反应结晶器的pH值控制在4.7～5.0，料液温控制在35～45℃；三级反应结晶器连续向末级反应结晶器输送物料。
所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：所述的连续结晶操作级数为2级。
所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：各级连续反应结晶基于各级布洛芬钠盐水溶液进料的平均停留时间为0.6～1.5小时。
所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：步骤(4)中洗涤罐基于布洛芬固液混合相的平均停留时间为0.15～0.5小时。
所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：连续结晶开车时，可在一级反应结晶器中加入1小时内流入一级结晶器的原料液中布洛芬钠盐含量0.05-0.1％(g/ml)的晶种。
所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：所述的酸性水溶液选自37％(g/ml)的盐酸。
在布洛芬制备的酸化步骤中，布洛芬组分以高粘度的油态形式存在并且和溶剂发生液液分离，称为油析现象，由于在间歇生产过程中成油和反应结晶在同一个设备中进行，使得油相中布洛芬过饱和度随着酸性溶液的流入持续累积，最终引起爆发成核，导致产品粒度小、纯度低、堆密度低等问题。为了减弱和降低油析现象对产品的影响，通常在溶液爆发成核前添加大量的晶种，但此法会降低产品的批次收率。专利CN201210195713.9采用水为溶剂的反应结晶，产生严重的油析现象，导致大量晶体瞬间爆发形成造成的晶浆粘稠，搅拌状态差，且产品粒度细小的针状，松密度为0.3～0.5g/ml，纯度99％左右，粒度100μm左右。专利CN201210328660.3中重复结晶3～5次后得最终产品，产品纯度最终提高到99.5％，其收率很低，仅为45.88％。
本申请通过设立单独的成油处理和多级反应结晶步骤，有效消除了布洛芬结晶过程中的爆发成核现象。步骤(1)的成油操作产生富含溶质布洛芬的油相，结晶开车时在步骤(2)的第一级反应结晶器中通过增大过饱和度的方式消除油相，所产生的晶体可以充当晶种继续消耗步骤(2)中后续连续输入的溶液的过饱和度，使布洛芬晶体不断长大。或者也可以在步骤(2)一级结晶器中加入1小时内流入一级反应结晶器的原料液中布洛芬钠盐含量0.05-0.1％ 的晶种，更有效的缩短流程的不稳定性，连续结晶过程尽快达到稳态。
本申请通过在连续结晶开车时添加少量晶种的方式，有效解决了间歇反应结晶的油析现象对产品纯度和粒度造成的影响，处理方法效果明显，并且产品收率和质量均有所提高、生产成本降低。
本发明具有的优点和有益效果是：
(1)本申请布洛芬产品的平均晶体粒度平均粒径350-450μm，如附图2所示，粒度均一，产品主含量高，纯度99.9％以上，松密度0.60g/ml以上，解决了杂质可能带来的副作用问题，并且收率达96％以上，提高了生产效率。
(2)本申请简化了布洛芬制备工艺步骤，通过设立单独的成油处理和多级反应结晶步骤，有效避免了因油析现象导致的晶体聚结和杂质包藏现象，产品纯度明显提高，不需要多次重结晶，一次结晶产品纯度达到99.9％，产品纯度和总收率高，三废排放少。
(3)本发明的布洛芬连续反应结晶工艺的结晶条件稳定，产品质量均一，产能较间歇操作高出几倍甚至十几倍，适合于工业化生产。
本发明提供的一种布洛芬多级连续反应结晶工艺，不仅有效解决了间歇生产过程中由于油析现象导致的产品粒度小、纯度低等问题，而且相对于间歇过程，连续生产具有生产能力高、工艺参数稳定、设备占地面积小、能耗低、对环境污染程度较小、产品质量高一致性好等优势。
附图说明
图1按照专利CN201210195713.9条件申请人重复实验得到的布洛芬晶体电镜照片；
图2本申请提供的方法得到的布洛芬晶体电镜照片。
具体实施方式
下面结合实施例对本发明做进一步说明。
实施例1
以布洛芬钠水溶液为原料，与盐酸进行多级反应结晶，形成的布洛芬晶体浆料连续排出，进入分离、洗涤、干燥等工序，制取布洛芬成品。其连续结晶的生产方法的具体步骤为：
(1)反应成油：连续向成油罐加入浓度为0.06g/ml的布洛芬钠盐水溶液，同时，将盐酸水溶液加入成油罐中，将成油罐的pH值控制在6.9，料液温控制在40℃，成油罐基于布洛芬钠盐水溶液进料的平均停留时间为0.5小时；
(2)一级反应结晶：成油罐连续向第一级反应结晶器输送物料，同时，将盐酸水溶液加入到第一级反应结晶器中，将第一级反应结晶器的pH值控制在6.0，液温控制在40℃，第一级反应结晶基于布洛芬钠盐水溶液进料的平均停留时间为1小时；
(3)二级反应结晶：第一级反应结晶器连续向第二级反应结晶器输送物料，同时，将盐酸水溶液加入到第二级反应结晶器中，将第二级反应结晶器的pH值控制在3.2，液温控制在40℃，第二级反应结晶基于进料的平均停留时间为1小时；
(4)脱水洗涤：第二级反应结晶器连续向过滤设备输送物料，过滤后得到布洛芬粗品的湿晶体；湿晶体进入洗涤罐，洗涤使用纯化水，在洗涤罐中搅拌洗涤，干燥，得布洛芬产品。洗涤罐基于布洛芬固液混合相的平均停留时间为0.5小时。
布洛芬产品平均粒径为375μm，松密度0.61g/ml，纯度99.92％，基于原料液中布洛芬钠盐的收率为97％。
实施例2
以布洛芬钠水溶液为原料，与磷酸进行多级反应结晶，形成的布洛芬晶体浆料连续排出，进入分离、洗涤、干燥等工序，制取布洛芬成品。其连续结晶的生产方法的具体步骤为：
(1)反应成油：连续向成油罐加入浓度为0.09g/ml的布洛芬钠盐水溶液，同时，将磷酸水溶液加入成油罐中，将成油罐的pH值在6.7，料液温度控制在35℃，成油罐基于布洛芬钠盐水溶液进料的平均停留时间为0.5小时；
(2)一级反应结晶：一级反应结晶器中加入1小时内流入一级结晶器的原料液中布洛芬钠盐含量0.05-0.1％的晶种，成油罐连续向第一级反应结晶器输送物料，同时，将磷酸水溶液加入到第一级反应结晶器中，将第一级反应结晶器的pH控制在6.3，料液温度控制在35℃，第一级反应结晶基于布洛芬钠盐水溶液进料的平均停留时间为1小时；
(3)二级反应结晶：第一级反应结晶器连续向第二级反应结晶器输送物料，同时，将磷酸水溶液加入到第二级反应结晶器中，第二级反应结晶器的pH值5.4，料液温度控制在35℃，第二级反应结晶基于进料的平均停留时间为1小时；
(4)三级反应结晶：第二级反应结晶器连续向第三级反应结晶器输送物料，同时，将磷酸水溶液加入到第三级反应结晶器中，将第三级反应结晶器的pH值4.0，料液温度控制在35℃，第三级反应结晶基于进料的平均停留时间为1小时；
(5)脱水洗涤：第三级反应结晶器连续向过滤设备输送物料，离过滤后得到布洛芬粗品的湿晶体；湿晶体进入洗涤罐，洗涤使用纯化水，在洗涤罐中搅拌洗涤，干燥，得布洛芬产品。洗涤罐基于布洛芬固液混合相的平均停留时间为0.5小时。
布洛芬产品平均粒径为402μm，松密度0.64g/ml，纯度99.94％，基于原料液中布洛芬钠盐的收率为98％。
实施例3
以布洛芬钠水溶液为原料，与乙酸进行多级反应结晶，形成的布洛芬晶体浆料连续排出， 进入下步分离、洗涤、干燥等工序，制取布洛芬成品。其连续结晶的生产方法的具体步骤为：(1)反应成油：连续向成油罐加入浓度为0.07g/ml的布洛芬钠盐水溶液，该股物料从成油罐顶部以分配盘管的形式流加到成油罐中，同时，将乙酸水溶液加入成油罐中，乙酸水溶液也从成油罐顶部以分配盘管的形式流加到成油罐中，成油罐的pH值在6.7，液温35℃，成油罐基于进料的平均停留时间为0.5小时；
(2)一级反应结晶：成油罐连续向第一级反应结晶器输送物料，该股物料从第一级反应结晶器的中上部进入反应结晶器，同时，将乙酸水溶液加入到第一级反应结晶器中，乙酸水溶液从第一级反应结晶器顶部以分配盘管的形式流加到一级反应结晶器中，将第一级反应结晶器的pH控制在6.3，通过夹套水将第一级反应结晶器的料液温度控制在35℃，第一级反应结晶基于进料的平均停留时间为1小时；
(3)二级反应结晶：第一级反应结晶器连续向第二级反应结晶器输送物料，该股物料从第二级反应结晶器的中上部进入反应结晶器，同时，将乙酸水溶液加入到第二级反应结晶器中，乙酸水溶液从第二级反应结晶器顶部以分配盘管的形式流加到结晶器中，将第二级反应结晶器的pH控制在5.1，通过夹套水将第二级反应结晶器的料液温度控制在35℃，第二级反应结晶基于进料的平均停留时间为1小时；
(4)三级反应结晶：第二级反应结晶器连续向第三级反应结晶器输送物料，该股物料从第三级反应结晶器的中上部进入反应结晶器，同时，将乙酸水溶液加入到第三级反应结晶器中，乙酸水溶液从第三级反应结晶器顶部以分配盘管的形式流加到第三级反应结晶器中，将第三级反应结晶器的pH控制在3.5，通过夹套水将第三级反应结晶器的料液温度控制在35℃，第三级反应结晶基于进料的平均停留时间为1小时；
(5)脱水洗涤：第三级反应结晶器连续向离心机组泵送物料，离心后得到布洛芬粗品的湿晶体。湿晶体以料斗输送的形式进入洗涤罐，洗涤使用常温纯化水，在洗涤罐中搅拌洗涤。洗涤罐基于液相的平均停留时间为0.5小时。干燥，得布洛芬产品。
布洛芬产品平均粒径为421μm，松密度0.64g/ml，纯度99.91％，基于布洛芬钠盐的收率为96％。
实施例4
以布洛芬钠水溶液为原料，与硝酸进行多级反应结晶，形成的布洛芬晶体浆料连续排出，进入下步分离、洗涤、干燥等工序，制取布洛芬成品。其连续结晶的生产方法的具体步骤为：(1)反应成油：连续向成油罐加入浓度为0.05g/ml的布洛芬钠盐水溶液，该股物料从成油罐顶部以分配盘管的形式流加到成油罐中，同时，将硝酸水溶液加入成油罐中，硝酸水溶液也从成油罐顶部以分配盘管的形式流加到成油罐中，将成油罐的pH控制在6.5，料液温度控制 在45℃，成油罐基于进料的平均停留时间为0.5小时；
(2)一级反应结晶：一级反应结晶器中加入1小时内流入一级结晶器的原料液中布洛芬钠盐含量0.05-0.1％的晶种，成油罐连续向第一级反应结晶器输送物料，该股物料从第一级反应结晶器的中上部进入反应结晶器，同时，将硝酸水溶液加入到第一级反应结晶器中，硝酸水溶液从第一级反应结晶器顶部以分配盘管的形式流加到第一级反应结晶器中，将第一级反应结晶器的pH控制在6.0，通过夹套水将第一级反应结晶器的料液温度控制在45℃，第一级反应结晶基于进料的平均停留时间为0.6小时；
(3)二级反应结晶：第一级反应结晶器连续向第二级反应结晶器输送物料，该股物料从第二级反应结晶器的中上部进入反应结晶器，同时，将硝酸水溶液加入到第二级反应结晶器中，硝酸水溶液从第二级反应结晶器顶部以分配盘管的形式流加到第二级反应结晶器中，将第二级反应结晶器的pH控制在5.7，通过夹套水将第二级反应结晶器的料液温度控制在45℃，第二级反应结晶基于进料的平均停留时间为0.6小时；
(4)三级反应结晶：第二级反应结晶器连续向第三级反应结晶器输送物料，该股物料从第三级反应结晶器的中上部进入反应结晶器，同时，将硝酸水溶液加入到第三级反应结晶器中，硝酸水溶液从第三级反应结晶器顶部以分配盘管的形式流加到第三级反应结晶器中，将第三级反应结晶器的pH控制在5.0，通过夹套水将第三级反应结晶器的料液温度控制在45℃，第三级反应结晶基于进料的平均停留时间为0.6小时；
(5)四级反应结晶：第三级反应结晶器连续向第四级反应结晶器输送物料，该股物料从第四级反应结晶器的中上部进入反应结晶器，同时，将硝酸水溶液加入到第四级反应结晶器中，硝酸水溶液从第四级反应结晶器顶部以分配盘管的形式流加到第四级反应结晶器中，将第四级反应结晶器的pH控制在3.3，通过夹套水将第四级反应结晶器的料液温度控制在45℃，第四级反应结晶基于进料的平均停留时间为0.6小时；
(6)脱水洗涤：第四级反应结晶器连续向离心机组泵送物料，离心后得到布洛芬粗品的湿晶体。湿晶体以料斗输送的形式进入洗涤罐，洗涤使用常温纯化水，在洗涤罐中搅拌洗涤。洗涤罐基于液相的平均停留时间为0.15小时。干燥，得布洛芬产品。
布洛芬产品平均粒径为386μm，松密度0.61g/ml，纯度99.92％，基于布洛芬钠盐的收率为97％。
实施例5
以布洛芬钠水溶液为原料，与硫酸进行多级反应结晶，形成的布洛芬晶体浆料连续排出，进入下步分离、洗涤、干燥等工序，制取布洛芬成品。其连续结晶的生产方法的具体步骤为：(1)反应成油：连续向成油罐加入浓度为0.08g/ml的布洛芬钠盐水溶液，该股物料从成油罐 顶部以分配盘管的形式流加到成油罐中，同时，将硫酸水溶液加入成油罐中，硫酸水溶液也从成油罐顶部以分配盘管的形式流加到成油罐中，将成油罐的pH控制在6.8，料液温度控制在35℃，成油罐基于进料的平均停留时间为1小时；
(2)一级反应结晶：一级反应结晶器中加入1小时内流入一级结晶器的原料液中布洛芬钠盐含量0.05-0.1％的晶种，成油罐连续向第一级反应结晶器输送物料，该股物料从第一级反应结晶器的中上部进入反应结晶器，同时，将硫酸水溶液加入到第一级反应结晶器中，硫酸水溶液从第一级反应结晶器顶部以分配盘管的形式流加到第一级反应结晶器中，将第一级反应结晶器的pH控制在6.4，通过夹套水将第一级反应结晶器的料液温度控制在35℃，第一级反应结晶基于进料的平均停留时间为1.5小时；
(3)二级反应结晶：第一级反应结晶器连续向第二级反应结晶器输送物料，该股物料从第二级反应结晶器的中上部进入反应结晶器，同时，将硫酸水溶液加入到第二级反应结晶器中，硫酸水溶液从第二级反应结晶器顶部以分配盘管的形式流加到第二级反应结晶器中，将第二级反应结晶器的pH控制在5.3，通过夹套水将第二级反应结晶器的料液温度控制在35℃，第二级反应结晶基于进料的平均停留时间为1.2小时；
(4)三级反应结晶：第二级反应结晶器连续向第三级反应结晶器输送物料，该股物料从第三级反应结晶器的中上部进入反应结晶器，同时，将硫酸水溶液加入到第三级反应结晶器中，硫酸水溶液从第三级反应结晶器顶部以分配盘管的形式流加到第三级反应结晶器中，将第三级反应结晶器的pH控制在4.7，通过夹套水将第三级反应结晶器的料液温度控制在35℃，第三级反应结晶基于进料的平均停留时间为1.2小时。
(5)四级反应结晶：第三级反应结晶器连续向第四级反应结晶器输送物料，该股物料从第四级反应结晶器的中上部进入反应结晶器，同时，将硫酸水溶液加入到第四级反应结晶器中，硫酸水溶液从第四级反应结晶器顶部以分配盘管的形式流加到第四级反应结晶器中，将第四级反应结晶器的pH控制在3.0，通过夹套水将第四级反应结晶器的料液温度控制在35℃，第四级反应结晶基于进料的平均停留时间为1.2小时；
(6)脱水洗涤：第四级反应结晶器连续向离心机组泵送物料，离心后得到布洛芬粗品的湿晶体。湿晶体以料斗输送的形式进入洗涤罐，洗涤使用常温纯化水，在洗涤罐中搅拌洗涤。洗涤罐基于液相的平均停留时间为0.5小时。干燥，得布洛芬产品。
布洛芬产品平均粒径为433μm，松密度0.61g/ml，纯度99.95％，基于布洛芬钠盐的收率为98％。

Claims (9)

  1. 一种多级连续反应结晶生产布洛芬的方法，其特征在于包括如下步骤：
    (1)反应成油：连续向成油罐加入布洛芬钠盐水溶液，同时，将酸性水溶液加入成油罐中，将成油罐的pH值控制在6.5～6.9，料液温度控制在35～45℃；
    (2)一级反应结晶：成油罐连续向第一级反应结晶器输送物料，同时，将酸性水溶液连续加入到第一级反应结晶器中，将第一级反应结晶器的pH值控制在6.0～6.4，料液温控制在35～45℃；
    (3)末级反应结晶：前一级反应结晶器连续向末级反应结晶器输送物料，同时，将酸性水溶液连续加入到末级反应结晶器中，将末级反应结晶器的pH值控制在3.0～4.0，料液温控制在354～5℃；
    (4)脱水洗涤：末级反应结晶器连续向离心机组输送物料，离心后得到布洛芬粗品的湿晶体；湿晶体进入洗涤罐，在洗涤罐中用纯化水搅拌洗涤，干燥，得布洛芬产品。
  2. 根据权利要求1所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：
    步骤(1)中布洛芬钠盐水溶液的浓度0.05～0.09g/ml；
    步骤(1)中成油罐基于布洛芬钠盐水溶液进料的平均停留时间为0.5～1小时。
  3. 根据权利要求1所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：所述的酸性水溶液选自盐酸、磷酸、乙酸、硝酸或硫酸水溶液中的一种。
  4. 根据权利要求1所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：所述的连续结晶操作级数为2～4级；
    所述的连续结晶操作3级为在步骤(3)之前，可以增加一个级结晶操作，形成三级连续结晶；步骤(2)的一级反应结晶器连续向二级反应结晶器输送物料，同时，将酸性水溶液连续加入到二级反应结晶器中，将二级反应结晶器的pH值控制在5.1～5.4，料液温控制在35～45℃；二级反应结晶器连续向末级反应结晶器输送物料；
    所述的连续结晶操作4级为在步骤(3)之前，可以增加两个级结晶操作，形成四级连续结晶；步骤(2)的一级反应结晶器连续向二级反应结晶器输送物料，同时，将酸性水溶液连续加入到二级反应结晶器中，将二级反应结晶器的pH值控制在5.3～5.7，料液温控制在35～45℃；二级反应结晶器连续向三级反应结晶器输送物料，同时，将酸性水溶液连续加入到三级反应结晶器中，将三级反应结晶器的pH值控制在4.7～5.0，料液温控制在35～45℃；三级反应结晶器连续向末级反应结晶器输送物料。
  5. 根据权利要求1或4所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：所述的连续结晶操作级数为2级。
  6. 根据权利要求1所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：各级 连续反应结晶基于各级布洛芬钠盐水溶液进料的平均停留时间为0.6～1.5小时。
  7. 根据权利要求1所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：步骤(4)中洗涤罐基于布洛芬固液混合相的平均停留时间为0.15～0.5小时。
  8. 根据权利要求1所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：连续结晶开车时，可在一级反应结晶器中加入1小时内流入一级结晶器的原料液中布洛芬钠盐含量0.05-0.1％(g/ml)的晶种。
  9. 根据权利要求1或3所述的一种多级连续反应结晶生产布洛芬的方法，其特征在于：所述的酸性水溶液选自37％(g/ml)的盐酸。
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1314336A (zh) * 2000-03-16 2001-09-26 武汉大学 用双组份手性试剂拆分布洛芬的方法
JP2001335531A (ja) * 2000-05-24 2001-12-04 Sumitomo Chem Co Ltd α−アルキルフェニル酢酸類粒子の製造方法
CN1585630A (zh) * 2001-11-06 2005-02-23 巴斯福股份公司 洛芬晶体的形成方法
CN102311335A (zh) * 2010-06-29 2012-01-11 山东新华制药股份有限公司 高松密度布洛芬的制备工艺
CN102320954A (zh) * 2011-08-11 2012-01-18 天茂实业集团股份有限公司 一种制备布洛芬大晶型的方法
CN104193614A (zh) * 2014-09-28 2014-12-10 山东新华制药股份有限公司 布洛芬结晶的制备方法
CN110627629A (zh) * 2019-10-15 2019-12-31 山东新华制药股份有限公司 一种多级连续反应结晶生产布洛芬的方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1314336A (zh) * 2000-03-16 2001-09-26 武汉大学 用双组份手性试剂拆分布洛芬的方法
JP2001335531A (ja) * 2000-05-24 2001-12-04 Sumitomo Chem Co Ltd α−アルキルフェニル酢酸類粒子の製造方法
CN1585630A (zh) * 2001-11-06 2005-02-23 巴斯福股份公司 洛芬晶体的形成方法
CN102311335A (zh) * 2010-06-29 2012-01-11 山东新华制药股份有限公司 高松密度布洛芬的制备工艺
CN102320954A (zh) * 2011-08-11 2012-01-18 天茂实业集团股份有限公司 一种制备布洛芬大晶型的方法
CN104193614A (zh) * 2014-09-28 2014-12-10 山东新华制药股份有限公司 布洛芬结晶的制备方法
CN110627629A (zh) * 2019-10-15 2019-12-31 山东新华制药股份有限公司 一种多级连续反应结晶生产布洛芬的方法

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