A method for preparing sodium oleate for injection

Abstract

The present application relates to the field of medicine manufacturing, and relates to a preparation method of sodium oleate for injection, comprising the following steps: taking fresh oil tea seeds or oil olive fruits, crushing the oil tea seeds or oil olive fruits in a pulverizer, mixing the crushed oil tea seeds or oil olive fruits with an adsorbent, adding a mixed solvent 1 to remove a proper amount of saturated fatty acids through low-temperature crystallization, adding sodium hydroxide to the upper liquid, stirring and reacting for a period of time, cooling and filtering, adding a mixed solvent 2 to the obtained filter cake for recrystallization and purification, and drying under reduced pressure to obtain the sodium oleate for injection. The present application solves the problem that it is difficult to obtain high-quality sodium oleate for injection, especially high-oleic-acid-content sodium oleate for injection without trans fatty acids, in the prior art.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical manufacturing, and specifically to a method for preparing sodium oleate for injection. Background Technology

[0002] Sodium oleate, also known as sodium octadecenoate or oleic acid soap, is a fatty acid salt, a white to slightly yellow powder or lumpy solid. In pharmaceuticals, sodium oleate is used as an emulsifier, solubilizer, transdermal penetration enhancer, and matrix for creams and ointments. It is used in the manufacture of creams, suppositories, emulsions, etc., and is often combined with other matrices to adjust their hardness. Adding a small amount of sodium oleate to fat emulsions can adjust the HLB value of egg yolk lecithin, facilitating the formation of smaller droplets, increasing the absolute value of the potential, and thus forming a stable O / W system.

[0003] Current sodium oleate preparation processes use oleic acid as a raw material through saponification. However, oleic acid is typically obtained through high-temperature distillation of fatty acids, a process that is energy-intensive, environmentally challenging, and poorly adaptable to industrialization. Furthermore, oleic acid is prone to heat-sensitive reactions at high temperatures, producing trans fatty acids that negatively impact product quality. Therefore, it is necessary to address the sourcing and processing issues of oleic acid. In particular, studies have shown that trans fatty acids can cause arteriosclerosis and thrombosis, promote oxidation, induce inflammation, damage cell integrity, and disrupt the nervous system, thus harming human health. In addition, current market specifications for sodium oleate include sodium oleate containing oleic acid, sodium oleate (for injection), sodium oleate (45-55% oleic acid), sodium oleate (containing more than 80% oleic acid), and sodium oleate (low-alkali). Different oleic acid contents are used in different formulations. The preparation of sodium oleate with an oleic acid content of 70-85% that simultaneously meets all impurity requirements for injection is a significant challenge. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing sodium oleate for injection, so as to solve the problem that it is difficult to obtain high-quality sodium oleate for injection, especially the problem of obtaining sodium oleate for injection with high oleic acid content and no trans fatty acids, in the prior art.

[0005] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0006] A method for preparing sodium oleate for injection includes the following steps:

[0007] S1. Take fresh camellia seeds or olives, crush them, and mix them with the adsorbent to obtain a mixture;

[0008] S2. Take the mixture, add mixed solvent 1 to dissolve it, and then crystallize it at low temperature to obtain the upper liquid;

[0009] S3. Add sodium hydroxide to the upper liquid, stir and react, cool and filter to obtain filter cake;

[0010] S4. The filter cake is dissolved in mixed solvent 2, recrystallized, and dried to obtain sodium oleate product for injection.

[0011] In step S2, adding mixed solvent 1 and crystallizing at low temperature can remove an appropriate amount of saturated fatty acids.

[0012] Preferably, in step S2, the mixed solvent 1 comprises a ternary mixed solvent consisting of alkanes, alcohols, and water; in step S4, the mixed solvent 2 comprises alcohols and water.

[0013] In step S2, if a ternary mixed solvent is not used, crystals may not precipitate, or crystals may precipitate but the oleic acid content may remain unchanged or even decrease, thus failing to achieve the effect of increasing the proportion of oleic acid.

[0014] In step S4, sodium oleate is difficult to dissolve using only alcohol, and sodium oleate is difficult to precipitate using only water. Only by adding a certain proportion of water to the alcohol can sodium oleate be dissolved and successfully recrystallized for purification.

[0015] Preferably, in step S2, the alkane in the mixed solvent 1 includes one or more of n-hexane and petroleum ether; the alcohol in the mixed solvent 1 includes one or more of methanol and ethanol; and in step S4, the alcohol in the mixed solvent 2 includes one or more of methanol and ethanol.

[0016] Preferably, in step S2, the volume fraction of water in the mixed solvent 1 is 0.5-1.5%; in step S4, the volume fraction of water in the mixed solvent 2 is 3-7%.

[0017] Preferably, in step S2, the volume ratio of alkanes to alcohols in the mixed solvent 1 is 1:1 to 5.

[0018] Preferably, in step S1, the mass of the adsorbent is 1% to 5% of the mass of the fresh camellia seeds or olives; in step S2, the volume-to-mass ratio of the mixed solvent 1 to the mixture is 2 to 4 ml: 1 g; in step S4, the volume-to-mass ratio of the mixed solvent 2 to the filter cake is 8 to 12 ml: 1 g.

[0019] Preferably, in step S1, the pulverization includes pulverization using a pulverizer; in step S2, the low-temperature crystallization temperature is -5 to -20°C; in step S3, the reaction temperature is 50 to 65°C; in step S4, the recrystallization is performed 1 to 3 times, and the drying includes vacuum drying.

[0020] Preferably, in step S1, the mixing includes one or more of stirring and kneading; in step S3, the temperature of the cooling and filtering is -10 to 10°C; and in step S4, the temperature of the drying is 30 to 50°C.

[0021] Preferably, in step S1, the adsorbent includes one or more of activated clay, silica gel, and alumina; in step S3, the mass of sodium hydroxide is 10% to 20% of the mass of the upper liquid; and in step S4, the drying temperature is 35 to 45°C.

[0022] A sodium oleate product for injection obtained by the method described above.

[0023] Compared with the prior art, implementing the present invention has the following beneficial effects:

[0024] This invention proposes a method for preparing sodium oleate for injection. The raw materials are widely available and easily obtained. The hydrolysis of oils into fatty acids and the saponification of fatty acids occur simultaneously, simplifying the process steps, reducing energy consumption, and thus lowering costs. This method is suitable for industrial production. The resulting sodium oleate for injection meets the standards of the Chinese Pharmacopoeia. The process does not produce trans fatty acids, and some oxidation indicators, such as peroxide value, are far below the limits. Furthermore, the low-temperature crystallization process after adding mixed solvent 1 can reduce the content of saturated fatty acids, increasing the oleic acid content in sodium oleate by approximately 3-5%, thus enriching the range of sodium oleate products with different oleic acid contents. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be described in further detail below so that those skilled in the art can better understand and implement it. However, the embodiments given are not intended to limit the invention. Modifications or substitutions made to the methods, steps, or conditions of this invention without departing from the spirit and substance of the invention are all within the scope of this invention. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art.

[0026] Example 1

[0027] Take 200g of fresh camellia seeds, crush them, and mix them thoroughly with 5g of alumina. Add a mixed solvent 1 consisting of 150ml of hexane, 300ml of methanol, and 5ml of water. Stir and crystallize at -10℃ for 9 hours. Take the supernatant and concentrate it until no hexane remains. Add 6g of sodium hydroxide and react at 55℃ for 3 hours. Cool to 5℃. Add the resulting filter cake to a mixed solvent 2 consisting of 500ml of methanol and 20ml of water for recrystallization and purification. Dry under reduced pressure at 40℃ for 24 hours to obtain the final product, sodium oleate for injection. The key indicators are as follows:

[0028]

[0029]

[0030] Example 2

[0031] Take 1 kg of fresh olive fruit, crush it, and knead it thoroughly with 12 g of activated clay. Add a mixed solvent 1 consisting of 400 ml of petroleum ether, 2 L of ethanol, and 20 ml of water. Stir and crystallize at -13℃ for 12 h. Take the supernatant, concentrate it until petroleum ether is removed, add 40 g of sodium hydroxide, react at 60℃ for 2 h, and cool to 2℃. Add the resulting filter cake to a mixed solvent 2 consisting of 3 L of ethanol and 100 ml of water for recrystallization and purification. Dry under reduced pressure at 50℃ for 18 h to obtain the final product, sodium oleate for injection. The key indicators are as follows:

[0032]

[0033]

[0034] Example 3

[0035] Take 5 kg of fresh camellia seeds, crush them, and mix them thoroughly with 250 g of silica gel. Add a mixed solvent 1 consisting of 8 L of hexane, 8 L of methanol, and 200 ml of water. Stir and crystallize at -18 °C for 9 h. Take the supernatant and concentrate it until no hexane remains. Add 250 g of sodium hydroxide and react at 50 °C for 4.5 h. Cool to 8 °C. Add the resulting filter cake to a mixed solvent 2 consisting of 15 L of methanol and 1 L of water for recrystallization and purification. Dry under reduced pressure at 45 °C for 20 h to obtain the final product, sodium oleate for injection. The key indicators are as follows:

[0036]

[0037]

[0038] Example 4

[0039] Take 50 kg of fresh olives, crush them, and knead them thoroughly with 2 kg of activated clay. Add a mixed solvent 1 consisting of 50 L of n-hexane, 100 L of ethanol, and 1.5 L of water. Stir and crystallize at -20 °C for 15 h. Take the supernatant and concentrate it until no n-hexane remains. Add 2 kg of sodium hydroxide and react at 63 °C for 1.5 h. Cool to 10 °C. Add the resulting filter cake to a mixed solvent 2 consisting of 160 L of ethanol and 8 L of water for recrystallization and purification. Dry under reduced pressure at 35 °C for 40 h to obtain the final product, sodium oleate for injection. The key indicators are as follows:

[0040]

[0041]

[0042] Comparative Example 1

[0043] 200g of dried camellia seeds were pressed into oil. Using 800ml of ethanol as a solvent, 25g of sodium hydroxide was added. The saponification temperature was 80℃, and the time was 3 hours. After cooling, filtering, and drying the saponification solution, sodium oleate was obtained. The key indicators were tested as follows:

[0044]

[0045]

[0046] Comparative Example 1 represents the existing process. A comparison between the examples and Comparative Example 1 shows that using fresh camellia seeds as raw material, compared to using camellia seeds dried at high temperatures to extract tea oil, results in a significantly lower peroxide value for the final sodium oleate and the absence of trans fatty acids. Furthermore, the sodium oleate preparation method with a low-temperature crystallization process proposed in this invention can enrich the oleic acid content of sodium oleate to approximately 85%, thus diversifying the range of sodium oleate products with different oleic acid contents.

[0047] Comparative Example 2

[0048] The sodium oleate purchased from manufacturer A and the sodium oleate obtained in this invention were compared by testing the oleic acid content, trans fatty acids, and peroxide value. The results are shown in the table below:

[0049] Oleic acid content (%) Trans fatty acids (%) Peroxide value Sodium oleate prepared in Example 1 84.6 0 0.26 Sodium oleate from manufacturer A 98.3 0.78 3.66

[0050] As can be seen from Comparative Example 2, the sodium oleate prepared by hydrolyzing fatty acids and then distilling at high temperature to obtain pure oleic acid has an oleic acid content of 98.3%, but 0.78% trans fatty acids were generated during the preparation process, and the peroxide value reached 3.66. Its quality level is significantly lower than that of the sodium oleate prepared in this invention.

[0051] The above-disclosed embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. Therefore, any equivalent variations made in accordance with the claims of the present invention are still within the scope of the present invention.

Claims

1. A method for preparing sodium oleate for injection, characterized by, The method comprises the following steps: S1, taking fresh oil tea seeds or olea europaea fruits, crushing and mixing with adsorbent to obtain a mixture; S2, taking the mixture, adding mixed solvent 1 to dissolve and low-temperature crystallization to obtain an upper liquid; S3, adding the upper liquid to sodium hydroxide for stirring reaction, cooling and filtering to obtain a filter cake; S4, adding the filter cake to mixed solvent 2 for dissolution and recrystallization, and drying to obtain an injection sodium oleate product; In step S2, the mixed solvent 1 comprises a ternary mixed solvent composed of alkanes, alcohols and water; the alkanes in the mixed solvent 1 comprise one or more of n-hexane and petroleum ether; the alcohols in the mixed solvent 1 comprise one or more of methanol and ethanol; the volume fraction of water in the mixed solvent 1 is 0.5-1.5%; the volume ratio of alkanes to alcohols in the mixed solvent 1 is 1:1-5; In step S4, the mixed solvent 2 comprises alcohols and water; the alcohols in the mixed solvent 2 comprise one or more of methanol and ethanol; the volume fraction of water in the mixed solvent 2 is 3-7%.

2. The method for preparing sodium oleate for injection according to claim 1, characterized by, In step S1, the mass of the adsorbent is 1%-5% of the mass of the fresh oil tea seeds or olea europaea fruits; in step S2, the volume-mass ratio of the mixed solvent 1 to the mixture is 2-4 ml:1 g; in step S4, the volume-mass ratio of the mixed solvent 2 to the filter cake is 8-12 mL:1 g.

3. The method for preparing sodium oleate for injection as described in claim 1, characterized in that, In step S1, the crushing comprises crusher crushing; in step S2, the low-temperature crystallization temperature is-5--20℃; in step S3, the reaction temperature is 50-65℃; in step S4, the recrystallization times are 1-3 times, and the drying comprises reduced-pressure drying.

4. The method for preparing sodium oleate for injection as described in claim 1, characterized in that, In step S1, the mixing comprises one or more of stirring mixing and kneading; in step S3, the cooling and filtering temperature is-10-10℃; in step S4, the drying temperature is 30-50℃.

5. The method for preparing sodium oleate for injection as described in claim 1, characterized in that, In step S1, the adsorbent comprises one or more of activated clay, silica gel and alumina; in step S3, the mass of sodium hydroxide is 10%-20% of the mass of the upper liquid; in step S4, the drying temperature is 35-45℃.

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