A kind of refining and purification method of pharmaceutical grade phenoxyethanol

Abstract

The invention discloses a method for refining and purifying pharmaceutical-grade phenoxyethanol, and relates to the pharmaceutical field. The method for refining and purifying pharmaceutical-grade phenoxyethanol comprises: adding a solvent and a boiling-assisting solid powder to a crude product of industrial-grade phenoxyethanol, heating to reflux, stirring and refining, and then distilling to obtain a crude refined liquid and a solvent distillate; the crude refined liquid is further reduced in pressure and stirred for refining, and then cooled, coarsely filtered, and sterilized and filtered to obtain pharmaceutical-grade phenoxyethanol. The method for refining and purifying pharmaceutical-grade phenoxyethanol provided in the present application can purify impurities such as phenol, ethylene oxide, dioxane, ethylene glycol, etc. in the crude product of phenoxyethanol to almost no detection, effectively improve the purity of the product, meet the requirements for pharmaceutical use, and solve the problem that the related substances of commercially available industrial-grade phenoxyethanol such as phenol do not meet the requirements for pharmaceutical use.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical technology, and more specifically to a method for refining and purifying pharmaceutical-grade phenoxyethanol. Background Art

[0002] In addition to being used as a pharmaceutical excipient, phenoxyethanol is also used as an antibacterial preservative in cosmetics and topical pharmaceutical preparations at a concentration of 0.5%-1.0%. It can also be used as a preservative and antibacterial agent in vaccines. A 2.2% solution and a 2.0% cream can be used as a disinfectant for superficial wounds, burns, and mild infections of the skin and mucous membranes. Phenoxyethanol has a narrow antibacterial spectrum and is most often used in combination with other antibacterial agents, such as parabens, to obtain a broader spectrum of antibacterial activity.

[0003] Currently, most industrialized production processes are to add phenol and ethylene oxide using sodium acetate or sodium hydroxide as a catalyst. Process-grade phenoxyethanol will inevitably have problems with residual phenol, ethylene oxide, dioxane, ethylene glycol and other impurities.

[0004] As a pharmaceutical excipient, phenoxyethanol is mainly included in the American, European and Chinese Pharmacopoeias. The requirements of the Pharmacopoeias are shown in Table 1.

[0005] Table 1 Quality standard of pharmaceutical excipient grade phenoxyethanol

[0006]

[0007]

[0008]

[0009] It can be seen that phenoxyethanol, as a pharmaceutical excipient, has strict requirements on related impurities. Pharmaceutical-grade finished products must control phenol ≤ 0.1%, ethylene oxide must not exceed 0.0001%, and dioxane must not exceed 0.001%. At the same time, other largest impurities such as ethylene glycol must also be controlled at ≤ 0.1%. Both industrial-grade and cosmetic-grade phenoxyethanol on the market are difficult to meet pharmaceutical-grade requirements.

[0010] Therefore, there is an urgent need to develop an effective phenoxyethanol refining and purification process to obtain a pharmaceutical-grade phenoxyethanol product with low impurity content, high product purity and pharmaceutical requirements. Summary of the invention

[0011] The purpose of the present invention is to provide a method for refining and purifying pharmaceutical grade phenoxyethanol to solve the above problems.

[0012] A method for refining and purifying pharmaceutical-grade phenoxyethanol, comprising:

[0013] Adding a solvent and a boiling-assisting solid powder to a crude industrial-grade phenoxyethanol product, heating to reflux, stirring and refining, and then distilling to obtain a crude refined liquid and a solvent distillate;

[0014] The crude refined liquid is further refined under reduced pressure and stirring, and then cooled, coarsely filtered, and sterilized and filtered to obtain pharmaceutical grade phenoxyethanol.

[0015] Preferably, the solvent comprises one or more of toluene, petroleum ether with a boiling point range of 90-110° C., and n-heptane.

[0016] Preferably, the amount of the solvent used is 0.5-3 times the mass of the crude industrial-grade phenoxyethanol.

[0017] Preferably, the boiling-aiding solid powder includes one or more of molecular sieves, zeolites, silica gel powder, and stannous oxide.

[0018] Preferably, the amount of the boiling-aid solid powder is 0.01%-0.5% of the mass of the crude industrial-grade phenoxyethanol.

[0019] Preferably, the temperature of the reduced pressure stirring refining is 100-140° C., and the time is 0.5-6 h.

[0020] Preferably, the vacuum degree of the reduced pressure stirring purification is less than or equal to 5 kPa.

[0021] Preferably, the pore size of the filter element used for the coarse filtration is not less than 1 μm.

[0022] Preferably, the pore size of the filter element for sterilizing filtration is 0.45 μm or 0.22 μm.

[0023] Preferably, the solvent distillate is used for recovery and recycling.

[0024] According to the technical content disclosed in the present invention, the following beneficial effects are achieved:

[0025] The present application provides a method for refining and purifying pharmaceutical-grade phenoxyethanol, which uses industrial-grade phenoxyethanol as a raw material, removes azeotropic impurities such as ethylene oxide and dioxane through solvent azeotropic refining treatment, and then removes high-boiling impurities such as ethylene glycol and phenol through high-temperature and reduced-pressure refining to obtain pharmaceutical-grade high-purity phenoxyethanol; the method refines the impurity aldehydes, alcohols, and ethers in the crude industrial-grade phenoxyethanol to almost undetectable levels, effectively improves the product purity, meets pharmaceutical requirements, and solves the problem of excessive impurities in commercially available industrial-grade phenoxyethanol. DETAILED DESCRIPTION

[0026] The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses.

[0027] Technologies, methods, and equipment known to ordinary technicians in the relevant art may not be discussed in detail, but where appropriate, the technologies, methods, and equipment should be considered as part of the specification.

[0028] In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not limiting. Therefore, other examples of the exemplary embodiments may have different values.

[0029] The raw material information and sources used in the following specific examples are shown in Table 2:

[0030] Table 2 List of main raw materials

[0031] Serial number raw material Purity / Information source 1 Phenoxyethanol Industrial Grade Jiangsu Haian Petrochemical Plant 2 Molecular sieve Reagent grade Pingxiang Keyang Chemical Co., Ltd. 3 Silicone powder 200 mesh Pingxiang Keyang Chemical Co., Ltd. 4 Zeolite Reagent grade Pingxiang Keyang Chemical Co., Ltd. 5 Stannous Oxide Industrial Grade Pingxiang Keyang Chemical Co., Ltd. 6 Petroleum ether Boiling range 90-110℃ Sinopharm Chemical Reagents 7 n-Heptane Reagent grade Sinopharm Chemical Reagents 8 Toluene Reagent grade Nanjing Chemical Reagents

[0032] Example 1

[0033] This embodiment provides a method for refining and purifying pharmaceutical grade phenoxyethanol, which specifically comprises the following steps:

[0034] 1000g crude phenoxyethanol (purity 99.37%, phenol 0.15%, ethylene oxide 13ppm, dioxane 21ppm) was added to a three-necked flask, 0.5g of 200-mesh silica gel powder was added, a thermometer, water separator, condenser, etc. were placed on the flask, 1000g of toluene was added, the temperature was controlled to 110-113°C, refluxed and stirred for 30min, the water separator valve was opened for liquid separation, the evaporated toluene liquid was collected until no liquid was evaporated, the crude refined liquid was temperature controlled to 105°C, the vacuum pump was turned on, the vacuum degree was controlled to 2-3kpa, and reduced pressure refining was performed for 2h, the reduced pressure concentration refining was stopped, the temperature was cooled to room temperature, coarsely filtered through a 3um filter bag, and then filtered through a 0.22um filter element to obtain 973.4g of refined pharmaceutical grade phenoxyethanol, and the refined product was colorless. The purity of the product submitted for inspection is 99.81%, the maximum single impurity is 0.05%, phenol is 0.06%, ethylene oxide is 0.6ppm, dioxane is 1.9ppm, and ethylene glycol is 0.01%. The product meets the quality requirements of the 2020 edition of the Chinese Pharmacopoeia.

[0035] Example 2

[0036] This embodiment provides a method for refining and purifying pharmaceutical grade phenoxyethanol, which specifically comprises the following steps:

[0037] 1000g crude phenoxyethanol (purity 99.37%, phenol 0.15%, ethylene oxide 13ppm, dioxane 21ppm) was added to a three-necked flask, and 0.5g of stannous oxide was added. A thermometer, water separator, condenser, etc. were placed on the flask. 1000g of n-heptane was added, and the temperature was controlled to 98-100°C. The mixture was refluxed and stirred for 30min. The water separator valve was opened for separation. The evaporated n-heptane liquid was collected until no liquid was evaporated. The crude refined liquid was temperature controlled to 125°C, and the vacuum pump was turned on to control the vacuum degree to 1-2kpa. The reduced pressure refining was carried out for 3h. The reduced pressure concentration refining was stopped, and the temperature was lowered to room temperature. The mixture was coarsely filtered through a 2um filter bag and then filtered through a 0.45um filter element to obtain 981.9g of refined pharmaceutical grade phenoxyethanol. The refined product was colorless. The purity of the product submitted for inspection is 99.81%, the maximum single impurity is 0.04%, phenol is 0.05%, ethylene oxide is 0.7ppm, dioxane is 2.2ppm, and ethylene glycol is not detected. The product meets the quality requirements of the 2020 edition of the Chinese Pharmacopoeia.

[0038] Example 3

[0039] This embodiment provides a method for refining and purifying pharmaceutical grade phenoxyethanol, which specifically comprises the following steps:

[0040] 1000g crude phenoxyethanol (purity 99.37%, phenol 0.15%, ethylene oxide 13ppm, dioxane 21ppm) was added to a three-necked flask, 0.3g zeolite was added, a thermometer, water separator, condenser, etc. were placed, 1000g petroleum ether with a boiling range of 90-110°C was added, the temperature was raised to reflux, refluxed and stirred for 30min, the water separator valve was opened for separation, the evaporated petroleum ether liquid was collected until no liquid was evaporated, the crude refined liquid was temperature controlled to 130°C, the vacuum pump was turned on, the vacuum degree was controlled to 1-2kpa, and reduced pressure refining was carried out for 3h, the reduced pressure concentration refining was stopped, the temperature was lowered to room temperature, coarsely filtered through a 5um filter bag, and then filtered through a 0.45um filter element to obtain 976.4g of refined pharmaceutical grade phenoxyethanol, and the refined product was colorless. The purity of the product submitted for inspection is 99.79%, the maximum single impurity is 0.06%, phenol is 0.08%, ethylene oxide is 0.6ppm, dioxane is 3.4ppm, and ethylene glycol is not detected. The product meets the quality requirements of the 2020 edition of the Chinese Pharmacopoeia.

[0041] In summary, the purity of the refined products obtained in Examples 1-3 is significantly improved, the maximum single impurity is reduced, the product color becomes lighter, and the obtained products are high-purity pharmaceutical-grade phenoxyethanol that meets pharmaceutical requirements.

[0042] Furthermore, in order to determine the optimal time for the second step of vacuum refining, the present invention keeps the other components and process conditions unchanged except for the change of the distillation vacuum refining temperature. The experimental scheme is designed as follows (Examples 4-8):

[0043] Feed ratio: industrial grade phenoxyethanol 1000g; stannous oxide 0.5g.

[0044] Vacuum refining temperature: 130°C.

[0045] Vacuum refining time: 0.5h, 1.0h, 2.0h, 4.0h,

[0046] Detailed steps:

[0047] Add 1000g crude phenoxyethanol (purity 99.26%, phenol 0.14%, ethylene oxide 13ppm, maximum single impurity 0.25%) to a three-necked flask, add 0.5g stannous oxide, set up a thermometer, water separator, condenser, etc., add 1000g n-heptane, control the temperature to 98-100°C, reflux and stir for 30min, open the water separator valve to separate the liquid, collect the evaporated n-heptane liquid until no liquid evaporates, control the temperature of the crude refined liquid to 130°C, turn on the vacuum pump, control the vacuum degree to 1-2kpa, and perform vacuum refining for a certain period of time, stop vacuum concentration and refining, cool to room temperature, filter through a 2um filter bag, and then filter through a 0.45um filter element to obtain refined pharmaceutical grade phenoxyethanol. Calculate the yield and conduct preliminary quality inspection in accordance with the fourth part of the 2020 edition of the Chinese Pharmacopoeia. The inspection results are shown in Table 3

[0048] Table 3 Vacuum refining time

[0049]

[0050]

[0051] In summary, it can be seen from Table 3 that the second step vacuum refining time has little effect on the refining of ethylene oxide. The reduction of ethylene oxide mainly relies on the azeotropic removal of the solvent in the first step. The phenol removal effect reaches a peak when the second step vacuum refining time is 2h. Increasing the refining time has little effect. The optimal refining time is 2h.

[0052] In summary, the present invention uses industrial-grade or cosmetic-grade phenoxyethanol as a starting raw material, undergoes solvent azeotropic refining, and then undergoes vacuum refining. The product is sterilized and filtered to effectively remove impurities from the raw material, and a high-purity pharmaceutical-grade phenoxyethanol product with less impurities, high purity, light product color, and meeting pharmaceutical requirements is successfully prepared; and the refining method has a simple process, rationally utilizes resources, reduces environmental damage during the production process, and has strong market competitiveness.

[0053] Although some specific embodiments of the present invention have been described in detail by way of example, it will be appreciated by those skilled in the art that the above examples are for illustration only and are not intended to limit the scope of the present invention. It will be appreciated by those skilled in the art that the above embodiments may be modified without departing from the scope and spirit of the present invention. The scope of the present invention is defined by the appended claims.

Claims

1. A method for refining and purifying pharmaceutical grade phenoxyethanol, characterized in that: include: Adding a solvent and a boiling-assisting solid powder to a crude industrial-grade phenoxyethanol product, heating to reflux, stirring and refining, and then distilling to obtain a crude refined liquid and a solvent distillate; The crude refined liquid is further purified by stirring under reduced pressure, and then cooled, coarsely filtered, and sterilized by filtration to obtain pharmaceutical grade phenoxyethanol; The solvent is selected from one or more of toluene, petroleum ether with a boiling range of 90-110° C., and n-heptane; the boiling-assisting solid powder is selected from one or more of molecular sieves, zeolites, silica gel powder, and stannous oxide; the amount of the solvent is 0.5-3 times the mass of the crude industrial-grade phenoxyethanol product, and the amount of the boiling-assisting solid powder is 0.01%-0.5% of the mass of the crude industrial-grade phenoxyethanol product; The temperature of the reduced pressure stirring refining is 100-140° C., and the time is 0.5-6 h; the vacuum degree of the reduced pressure stirring refining is less than or equal to 5 kPa.

2. The method for refining and purifying pharmaceutical grade phenoxyethanol according to claim 1, characterized in that: The pore size of the filter element used for the coarse filtration is not less than 1 μm.

3. The method for refining and purifying pharmaceutical grade phenoxyethanol according to claim 1, characterized in that: The pore size of the filter element for sterilization filtration is 0.45 μm or 0.22 μm.

4. The method for refining and purifying pharmaceutical grade phenoxyethanol according to any one of claims 1 to 3, characterized in that: The solvent distillate is used for recycling.

Images