A method for purifying and refining pharmaceutical grade potassium sorbate

Abstract

A purification and refining method for pharmaceutical-grade potassium sorbate, comprising the following steps: S1 dissolution: putting food-grade potassium sorbate into a mixed solvent, stirring and mixing, soaking and dissolving, wherein the mixed solvent is a mixed solvent composed of anhydrous ethanol and glycerol; the food-grade potassium sorbate is prepared by sorbic acid and potassium hydroxide; S2 solid-liquid separation: the suspension dissolved in S1 is subjected to solid-liquid separation; S3 drying: the solid separated in S2 is dried, that is, pharmaceutical-grade potassium sorbate is obtained. The purification and refining method for pharmaceutical-grade potassium sorbate quickly removes the remaining impurities that affect the pH value of potassium sorbate, namely sorbic acid or potassium hydroxide, and further removes other impurities soluble in organic solvents, thereby further improving the purity of potassium sorbate; the purification and refining method is simple to operate, has a high yield, and the purified pharmaceutical-grade potassium sorbate has stable performance and good product quality.

Description

Technical Field

[0001] The invention relates to the technical field of potassium sorbate preparation, in particular to a method for purifying and refining pharmaceutical-grade potassium sorbate. Background Art

[0002] Pharmaceutical grade potassium sorbate is white or off-white flaky or granular crystals, or crystalline powder, odorless or slightly odorous. It is easy to absorb moisture and oxidatively decompose and change color when stored in the air for a long time. The specific operation of its pH detection is: weigh 1.0g sample, accurate to 0.01g, dissolve in about 20mL of carbon dioxide-free water, add 2 drops of phenolphthalein indicator solution, if the solution appears light red, add 0.25mL of 0.1mol / L hydrochloric acid standard titration solution, shake well, and the light red should disappear; if it is colorless, add 0.25ml of 0.1mol / L sodium hydroxide titration solution, it should first turn light red. Compared with food-grade potassium sorbate (GB 1886.39-2015A.10 free alkali test stipulates that the analysis steps of pH are: weigh 1.0g sample, accurate to 0.01g, dissolve in about 20mL of carbon dioxide-free water, add 2 drops of phenolphthalein indicator solution to show red, then add 0.40mL of 0.1mol / L sulfuric acid standard titration solution, shake well, and the red color should disappear;), the pH control range of pharmaceutical-grade potassium sorbate is narrower. Generally, the pH value of 1% pharmaceutical-grade potassium sorbate aqueous solution is 7-8.

[0003] At present, the synthesis of food-grade potassium sorbate usually uses sorbic acid as a raw material, and potassium hydroxide is added for neutralization reaction to obtain potassium sorbate. In the production process, it is impossible to accurately control sorbic acid and potassium hydroxide to achieve complete neutralization, that is, there may be too much sorbic acid in food-grade potassium sorbate, causing potassium sorbate to be acidic, or too much potassium hydroxide, resulting in potassium sorbate being alkaline. However, the prior art does not disclose efficient removal of trace impurities such as sorbic acid or potassium hydroxide remaining in potassium sorbate, and there is no related research and technical report on the refining process / method for preparing medicinal-grade potassium sorbate using food-grade potassium sorbate as a raw material. Summary of the invention

[0004] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a method for purifying and refining medicinal-grade potassium sorbate which uses food-grade potassium sorbate as a raw material and is simple to operate.

[0005] The technical solution adopted by the present invention to solve its technical problem is:

[0006] A method for purifying and refining pharmaceutical grade potassium sorbate, the method comprising the following steps:

[0007] S1 dissolving: putting food-grade potassium sorbate into a mixed solvent, stirring, mixing, soaking and dissolving, wherein the mixed solvent is a mixed solvent composed of anhydrous ethanol and glycerol; the food-grade potassium sorbate is prepared from sorbic acid and potassium hydroxide;

[0008] S2 solid-liquid separation: the suspension dissolved in S1 is separated into solid and liquid;

[0009] S3 drying: drying the solid separated in S2, that is, obtaining pharmaceutical grade potassium sorbate.

[0010] The sorbic acid or potassium hydroxide remaining in the food-grade potassium sorbate in S1 can be quickly dissolved in anhydrous ethanol and glycerol. However, the solubility of potassium sorbate in anhydrous ethanol is extremely low (0.3 g / 100 ml, 20° C.), and it is insoluble in glycerol. Therefore, by soaking the potassium sorbate crystalline solid in a mixed solvent of ethanol and glycerol, the sorbic acid or potassium hydroxide remaining in the potassium sorbate crystalline solid, or other impurities soluble in ethanol / glycerol but insoluble in water can be removed; the applicant compared the pH of the food-grade potassium sorbate used in S1 dissolved in water with the pH of the pharmaceutical-grade potassium sorbate aqueous solution obtained after purification and refining, and found that by using the mixed solvent of anhydrous ethanol and glycerol of the present invention, the sorbic acid or potassium hydroxide remaining in the raw material can be effectively removed, and the pH of the pharmaceutical-grade potassium sorbate can be stabilized at 6.8 to 7.3.

[0011] Moreover, ethanol and glycerol can be quickly separated from potassium sorbate, and the residual amount is low; in addition, ethanol and glycerol have good safety performance, and even low-dose residues will not affect the performance and safety of pharmaceutical-grade potassium sorbate.

[0012] In a certain exemplary embodiment, the volume ratio of anhydrous ethanol to glycerol is 30-97:3-70 (V / V), and glycerol is used to isolate air from entering the mixed solvent, thereby effectively preventing potassium sorbate from contacting with air, reducing the possibility of potassium sorbate absorbing moisture or being oxidized, and ensuring the product quality and purity of potassium sorbate.

[0013] Preferably, when the aqueous solution of food-grade potassium sorbate is acidic, the volume ratio of anhydrous ethanol to glycerol in the mixed solvent is 90-97:3-10 (V / V); when the aqueous solution of food-grade potassium sorbate is alkaline, the volume ratio of anhydrous ethanol to glycerol in the mixed solvent is 30-45:55-70 (V / V). Since potassium hydroxide reacts in anhydrous ethanol to form potassium ethanolate and water (equilibrium process), water evaporates after heating (forming a constant boiling with ethanol), and may completely turn into potassium ethanolate when boiling, reducing the recovery rate of ethanol. Considering the subsequent recovery and reuse process of ethanol, the applicant determines that the aqueous solution of raw food-grade potassium sorbate is alkaline, and increases the proportion of glycerol in the mixed solvent to ensure that potassium hydroxide and ethanol form potassium ethanolate while reducing the loss of anhydrous ethanol, thereby improving the solvent recovery rate and reducing the cost of purification and refining.

[0014] Preferably, in S1, the feeding ratio of potassium sorbate to the mixed solvent is 1:1.2-1.5 (W / V), ensuring that potassium sorbate is always immersed in the mixed solvent during the dissolution process, and is immersed at room temperature for 10-30 minutes, ensuring that the sorbic acid or potassium hydroxide remaining in the potassium sorbate is fully dissolved in the mixed solvent, and can also effectively avoid the phenomenon that the solubility of potassium sorbate in the mixed solvent increases due to the increase in temperature during high-temperature immersion, resulting in a decrease in the yield of potassium sorbate.

[0015] The purification and refining method further comprises: S4 distillation to recover the solvent: subjecting the liquid separated in S2 to atmospheric distillation or reduced pressure distillation to recover the ethanol, and returning it to S1 for recycling.

[0016] The pharmaceutical grade potassium sorbate has a content of ≥99.8%, a transmittance of ≥98.5%, and a pH value of 7.0±0.2 in a 1% aqueous solution.

[0017] The beneficial effects of the purification and refining method of a pharmaceutical grade potassium sorbate of the present invention are as follows:

[0018] Food-grade potassium sorbate has good solubility in a mixed solvent of ethanol and glycerol, while potassium sorbate is insoluble or slightly soluble in the above mixed solvent, and thus the remaining impurities that affect the pH of potassium sorbate, such as sorbic acid or potassium hydroxide, can be quickly removed, ensuring that the pH of pharmaceutical-grade potassium sorbate meets the requirements of pharmaceutical excipients and that the pH of its aqueous solution fluctuates only within a small range; and further removing other impurities (such as pigments) soluble in organic solvents, further improving the purity of potassium sorbate.

[0019] Since potassium sorbate is insoluble in the mixed solvent used in the present invention, pharmaceutical-grade potassium sorbate can be obtained by solid-liquid separation and then drying. Compared with the conventional method of using activated carbon to adsorb and remove impurities from a potassium sorbate aqueous solution in the prior art (such as a potassium sorbate granulation method disclosed in CN105198731), the purification and refining method of the present invention can efficiently remove residual raw material sorbic acid or potassium hydroxide, is simple to operate, and has a yield of up to 88.5%. The purified pharmaceutical-grade potassium sorbate has stable performance and good product quality.

[0020] Since the density of ethanol (0.7893 g / cm 3 ) and the density of glycerol (1.261 g / cm 3 ) are both less than the density of potassium sorbate (1.36 g / cm 3 ), therefore, potassium sorbate is always located below the mixed solvent in ethanol and glycerol, and glycerol can effectively prevent air from entering the mixed solvent, thereby avoiding the phenomenon that potassium sorbate is oxidized and decomposed during the dissolution, soaking and impurity removal process to reduce product quality, and at the same time facilitates the subsequent rapid and effective separation of solid and liquid. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 — is a process flow chart of a purification and refining method for pharmaceutical grade potassium sorbate of the present invention (applicable to edible grade potassium sorbate (acidic) raw materials);

[0022] Figure 2 — is a process flow chart of a purification and refining method for pharmaceutical grade potassium sorbate of the present invention (applicable to edible grade potassium sorbate (alkaline) raw materials). DETAILED DESCRIPTION

[0023] The present invention is further described below in conjunction with the accompanying drawings and embodiments.

[0024] Comparative Example 1 and Examples 1 and 2 use edible grade potassium sorbate from the same batch. After testing and analysis, the pH of the edible grade potassium sorbate 1% aqueous solution is 6.5, and it is preliminarily determined that sorbic acid remains in the potassium sorbate.

[0025] Comparative Example 1

[0026] A method for purifying and refining pharmaceutical grade potassium sorbate comprises the following steps:

[0027] S1. Dissolution and decolorization: Dissolve 400 kg of food-grade potassium sorbate (acidic) in 520 L of water, add 1.56 kg of activated carbon, heat to 50 ° C, stir for 30 min, and filter while hot;

[0028] S2. Concentration and crystallization: The filtered liquid in step S1 was concentrated at a temperature of 65 ° C and a vacuum degree of -0.07 MPa, and the filtrate was concentrated to a specific gravity of 1.40 g / mL, cooled to 25 ° C, crystallized at 30.mim, and the crystalline solid was separated;

[0029] S3 soaking and filtering: the crystalline solid obtained in step S2 was added to 500L ethanol and soaked for 60min, and filtered;

[0030] S4. Drying: Dry the crystals obtained by filtration in step S3 at 105° C. to obtain pharmaceutical grade potassium sorbate.

[0031] The recovery rate of the purified potassium sorbate in this example is 82.4%; the purity of potassium sorbate is 99.1%, and the pH of its 1% aqueous solution is 6.7.

[0032] Example 1

[0033] Reference Figure 1 A method for purifying and refining pharmaceutical grade potassium sorbate comprises the following steps:

[0034] S1 dissolution: 400 kg of food-grade potassium sorbate (acidic) is added to 500 L of a mixed solvent, and stirred and mixed, and soaked and dissolved at room temperature for 30 min, that is, the feed ratio of potassium sorbate to the mixed solvent is 1:1.25 (W / V), that is, the amount of the mixed solvent is 500 L; the mixed solvent is a mixed solvent composed of anhydrous ethanol and glycerol in a volume ratio of 90:10; the food-grade potassium sorbate is prepared from sorbic acid and potassium hydroxide;

[0035] S2 solid-liquid separation: the suspension dissolved in S1 is separated into solid and liquid;

[0036] S3 drying: The solid separated in S2 is dried at 105°C to obtain pharmaceutical grade potassium sorbate.

[0037] The recovery rate of the purified potassium sorbate in this example is 88.5%; the purity of potassium sorbate is 99.6%, and the pH of its 1% aqueous solution is 6.9.

[0038] Example 2

[0039] Reference Figure 1 A method for purifying and refining pharmaceutical grade potassium sorbate comprises the following steps:

[0040] S1 dissolution: 400 kg of food-grade potassium sorbate (acidic) is added to 500 L of a mixed solvent, stirred and mixed, and soaked at room temperature for 30 min to dissolve. The feed ratio of potassium sorbate to the mixed solvent is 1:1.5 (W / V), that is, the amount of the mixed solvent is 600 L; the mixed solvent is a mixed solvent composed of anhydrous ethanol and glycerol in a volume ratio of 90:10; the food-grade potassium sorbate is prepared from sorbic acid and potassium hydroxide;

[0041] S2 solid-liquid separation: the suspension dissolved in S1 is separated into solid and liquid;

[0042] S3 drying: drying the solid separated in S2 at 105°C, i.e. obtaining pharmaceutical grade potassium sorbate;

[0043] S4 distillation and solvent recovery: the liquid separated by S2 is subjected to atmospheric distillation or reduced pressure distillation to recover ethanol, and is returned to S1 for recycling.

[0044] The recovery rate of the purified potassium sorbate in this example is 85.6%; the purity of potassium sorbate is 99.75%, and the pH of its 1% aqueous solution is 7.0.

[0045] The refined pharmaceutical grade potassium sorbate obtained in Comparative Example 1, Examples 1 and 2 and the raw food grade potassium sorbate were tested and compared, and the detection method was based on the Chinese Pharmacopoeia and GB 1886.39-2015 Food Safety National Standard Food Additive Potassium Sorbate, and the results are shown in Table 1.

[0046] Table 1 Potassium sorbate test results

[0047]

[0048]

[0049] As can be seen from the results in Table 1, the potassium sorbate obtained by the purification and refining method of pharmaceutical grade potassium sorbate according to the present invention meets the standards of the 2015 edition of the Chinese Pharmacopoeia, and has great improvements in content, pH of aqueous solution, etc. compared with the raw material, indicating that the refining method can effectively remove the residual sorbic acid in potassium sorbate; and the purity of the obtained potassium sorbate product is ≥99.5%, and the finished product yield is as high as 88.5%, indicating that the proposed production process is stable and feasible, the process is controllable, the quality is stable, and the reproducibility is good.

[0050] Comparative Example 2 and Example 3 use edible grade potassium sorbate from the same batch. After testing and analysis, the pH of the edible grade potassium sorbate 1% aqueous solution is 9.0.

[0051] Comparative Example 2

[0052] A method for purifying and refining pharmaceutical grade potassium sorbate comprises the following steps:

[0053] S1. Dissolution and decolorization: Dissolve 400 kg of food-grade potassium sorbate (alkaline) in 520 L of water, add 1.56 kg of activated carbon, heat to 50 ° C, stir for 30 min, and filter while hot;

[0054] S2. Concentration and crystallization: The filtered liquid in step S1 was concentrated at a temperature of 65 ° C and a vacuum degree of -0.07 MPa, and the filtrate was concentrated to a specific gravity of 1.40 g / mL, cooled to 25 ° C, crystallized at 30.mim, and the crystalline solid was separated;

[0055] S3 soaking and filtering: the crystalline solid obtained in step S2 was added to 600L ethanol and soaked for 60min, and filtered;

[0056] S4. Drying: Dry the crystals obtained by filtration in step S3 at 105° C. to obtain pharmaceutical grade potassium sorbate.

[0057] The recovery rate of the purified potassium sorbate in this example is 83.2%; the purity of potassium sorbate is 99.3%, and the pH of its 1% aqueous solution is 7.5.

[0058] Example 3

[0059] Reference Figure 2 A method for purifying and refining pharmaceutical grade potassium sorbate comprises the following steps:

[0060] S1 dissolution: 400 kg of food-grade potassium sorbate (alkaline) is added to 600 L of a mixed solvent, stirred and mixed, and soaked and dissolved at room temperature for 20 min. The feed ratio of potassium sorbate to the mixed solvent is 1:1.5 (W / V), that is, the amount of the mixed solvent is 600 L; the mixed solvent is a mixed solvent composed of anhydrous ethanol and glycerol in a volume ratio of 30:70; the food-grade potassium sorbate is prepared from sorbic acid and potassium hydroxide;

[0061] S2 solid-liquid separation: the suspension dissolved in S1 is separated into solid and liquid;

[0062] S3 drying: drying the solid separated in S2 at 105°C, i.e. obtaining pharmaceutical grade potassium sorbate;

[0063] S4 distillation and solvent recovery: the liquid separated by S2 is subjected to atmospheric distillation or reduced pressure distillation to recover ethanol, and is returned to S1 for recycling.

[0064] The pH of the food-grade potassium sorbate 1% aqueous solution used in this embodiment is 7.2.

[0065] Compared with Comparative Example 2, the purification and refining method of this embodiment can more efficiently remove the residual potassium hydroxide in potassium sorbate, thereby solving the problem that the pH value of the product does not meet the requirements and the product is alkaline when food-grade potassium sorbate is used to prepare medicinal-grade potassium sorbate.

[0066] The pharmaceutical grade potassium sorbate obtained by the purification and refining method of this embodiment is tested and analyzed according to the requirements of the pharmacopoeia, and the content of the potassium sorbate is ≥99.5%, and the pH of its 1% aqueous solution is 7.2. Compared with the raw material, there is a great improvement in the content, pH of the aqueous solution, etc., indicating that the refining method can effectively remove the residual potassium hydroxide in the potassium sorbate; and the purity of the obtained potassium sorbate product is ≥99.5%, and the finished product yield is 85.8%, indicating that the proposed production process is stable and feasible, the process is controllable, the quality is stable, and the reproducibility is good.

[0067] The invention discloses a purification and refining method for pharmaceutical-grade potassium sorbate. According to actual production needs, the feed ratio of potassium sorbate to a mixed solvent can be adjusted to 1:1.20 (W / V) or 1:1.35 (W / V) or 1:1.40 (W / V), the soaking time can be adjusted to 22 min, 25 min or 28 min, etc., and the volume ratio of anhydrous ethanol to glycerol in the mixed solvent can also be 92:8 or 96:4 or 45:55 or 40:60, etc. The changes of the above technical features can be understood and implemented by those skilled in the art through text description, so no additional drawings are provided for illustration.

Claims

1. A method for purifying and refining pharmaceutical grade potassium sorbate, characterized in that: The purification and refining method comprises the following steps: S1 dissolution: putting food-grade potassium sorbate into a mixed solvent, stirring and mixing, soaking and dissolving, wherein the mixed solvent is a mixed solvent composed of anhydrous ethanol and glycerol; the food-grade potassium sorbate is prepared by sorbic acid and potassium hydroxide; the volume ratio of anhydrous ethanol to glycerol is 30-97:3-70; when the aqueous solution of food-grade potassium sorbate is acidic, the volume ratio of anhydrous ethanol to glycerol in the mixed solvent is 90-97:3-10; when the aqueous solution of food-grade potassium sorbate is alkaline, the volume ratio of anhydrous ethanol to glycerol in the mixed solvent is 30-45:55-70; S2 solid-liquid separation: the suspension dissolved in S1 is separated into solid and liquid; S3 drying: drying the solid separated in S2, that is, obtaining pharmaceutical grade potassium sorbate.

2. The method for purifying and refining pharmaceutical grade potassium sorbate according to claim 1, wherein: In S1, the feeding ratio of potassium sorbate to the mixed solvent is 1:1.2-1.5, and the mixture is soaked at room temperature for 10-30 minutes.

3. The method for purifying and refining pharmaceutical grade potassium sorbate according to claim 1 or 2, characterized in that: The purification and refining method further comprises: S4 distillation to recover the solvent: subjecting the liquid separated in S2 to atmospheric distillation or reduced pressure distillation to recover the ethanol, and returning it to S1 for recycling.

4. The method for purifying and refining pharmaceutical grade potassium sorbate according to claim 1 or 2, characterized in that: The pharmaceutical grade potassium sorbate has a content of ≥99.0%, a transmittance of ≥98.5%, and a pH value of 1% aqueous solution of 6.8-7.3.

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