High-purity low-endotoxin pharmaceutical adjuvant sodium dihydrogen phosphate dihydrate and preparation method thereof

Abstract

The invention relates to the technical field of compound refining and purification, in particular to a high-purity low-endotoxin pharmaceutical adjuvant sodium dihydrogen phosphate dihydrate and a preparation method thereof. Comprising the following steps: mixing industrial-grade sodium dihydrogen phosphate dihydrate with pure water to form a first solution; a heavy metal complexing agent is added into the first solution, and a second solution is formed after heating and stirring reaction; prefabricated activated carbon is added into the second solution, and a third solution is formed after heating and stirring reaction; and filtering the third solution while hot, concentrating under reduced pressure until a crystal film appears in the solution, naturally cooling and crystallizing, and performing solid-liquid separation to obtain the high-purity low-endotoxin pharmaceutical adjuvant sodium dihydrogen phosphate dihydrate. After refining and purification, the purity is greater than 99 wt%, the content of heavy metals is not greater than 0.0005 wt%, the content of endotoxin is lower than 2.5 EU / g, and the pharmaceutical adjuvant level is reached.

Description

Technical Field

[0001] This invention relates to the field of compound purification technology, specifically to a high-purity, low-endotoxin pharmaceutical excipient, sodium dihydrogen phosphate dihydrate, and its preparation method. Background Technology

[0002] Sodium dihydrogen phosphate dihydrate is an inorganic compound with the chemical formula NaH₂PO₄·2H₂O. It is the dihydrate form of sodium dihydrogen phosphate and has wide applications in industry, food, and medicine. In food processing, it can be used to adjust pH and maintain food stability. Industrially, it is used in water treatment, electroplating, and metal surface treatment. In molecular biology and biochemistry, it is used to prepare biological buffer solutions. In the pharmaceutical field, it can be used as an excipient and buffer for drugs. As a pharmaceutical excipient, sodium dihydrogen phosphate dihydrate has excellent buffering capacity, helping drugs to be preserved for a long time in stable acidic or alkaline environments, and improving drug efficacy and solubility. It is widely used in injectable, oral, and topical drug formulations.

[0003] Ordinary industrial-grade sodium dihydrogen phosphate dihydrate products contain high levels of metal ions such as iron, calcium, arsenic, aluminum, and copper, as well as heavy metal impurities. Furthermore, they are susceptible to microbial contamination during production, resulting in high endotoxin levels, which fails to meet the requirements for pharmaceutical excipients. Endotoxins are components of the cell walls of Gram-negative bacteria and possess good heat resistance and stability. Humans are extremely sensitive to bacterial endotoxins, which can trigger various physiological reactions. Low doses of endotoxins can cause fever, while higher doses can lead to circulatory problems, endotoxin shock, and even death. Therefore, the development of a high-purity, low-endotoxin pharmaceutical-grade sodium dihydrogen phosphate dihydrate preparation process is urgently needed.

[0004] Currently, patented technologies related to sodium dihydrogen phosphate dihydrate mainly focus on the production process and related equipment application of industrial-grade sodium dihydrogen phosphate. There are no literature reports on the preparation of high-purity, low-endotoxin sodium dihydrogen phosphate dihydrate by refining and purifying industrial-grade raw materials. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a high-purity, low-endotoxin pharmaceutical excipient, sodium dihydrogen phosphate dihydrate, and its preparation method. This invention uses industrial-grade sodium dihydrogen phosphate dihydrate as raw material, which is then refined and purified to a purity greater than 99 wt%, heavy metals not exceeding 0.0005 wt%, and endotoxin levels below 2.5 EU / g, thus meeting pharmaceutical excipient standards.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0007] The first aspect of this invention provides a method for preparing high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate, comprising the following steps:

[0008] S1. Mix industrial-grade sodium dihydrogen phosphate dihydrate with pure water to form the first solution;

[0009] S2. Add a heavy metal complexing agent to the first solution, heat and stir to react and form a second solution;

[0010] S3. Add pre-made activated carbon to the second solution, heat and stir to react and form a third solution;

[0011] S4. After filtering the third solution while it is still hot, the filtrate is concentrated under reduced pressure until a crystal film appears in the solution. It is then cooled naturally to allow for cooling and crystallization. After solid-liquid separation, high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate is obtained.

[0012] Furthermore, the mixing temperature of the industrial-grade sodium dihydrogen phosphate dihydrate and pure water is 60-70℃; the mass percentage of the industrial-grade sodium dihydrogen phosphate dihydrate in the first solution is 50%-80%.

[0013] Furthermore, the heavy metal complexing agent is selected from phytic acid or phytate; the heating and stirring reaction temperature after adding the heavy metal complexing agent is 60-70℃, and the reaction time is 1-2h; the amount of heavy metal complexing agent added is 0.1%-0.5% of the mass of the industrial grade sodium dihydrogen phosphate dihydrate.

[0014] Furthermore, the heating and stirring reaction temperature after adding the pre-prepared activated carbon is 60-70℃, and the reaction time is 1-2h; the amount of pre-prepared activated carbon added is 0.5%-2% of the mass of the industrial-grade sodium dihydrogen phosphate dihydrate.

[0015] Furthermore, the pre-made activated carbon is pre-made coconut shell activated carbon. Pre-making refers to: immersing the coconut shell activated carbon in nitric acid solution and stirring at 70-90℃ for 1-5 hours, and then washing it with water until neutral.

[0016] Furthermore, the mass percentage of the nitric acid solution is 10%-30%; the mass-to-volume ratio of the coconut shell activated carbon to the nitric acid solution is 1g:10-50mL. Nitric acid treatment can increase the content of oxygen-containing functional groups on the surface of activated carbon, enhancing its adsorption capacity for polar substances; in addition, endotoxins form negatively charged micelles in solution, and the oxygen-containing functional groups on the surface of activated carbon can enhance its adsorption capacity for endotoxins.

[0017] Furthermore, the hot filtration process involves first filtering through an activated carbon filter and then through a 0.22-micron filter membrane. The filtrate is then concentrated under reduced pressure at 40-45°C.

[0018] The second aspect of this invention provides a high-purity, low-endotoxin pharmaceutical excipient, sodium dihydrogen phosphate dihydrate, prepared by the above-described preparation method, which simultaneously meets the following criteria: purity greater than 99 wt%, heavy metals not exceeding 0.0005 wt%, and endotoxins less than 2.5 EU / g.

[0019] Furthermore, it must meet the following criteria: purity greater than 99.0 wt%, water-insoluble matter ≤ 0.005 wt%, Fe ≤ 0.0001 wt%, Ca ≤ 0.005 wt%, arsenic ≤ 0.0001 wt%, heavy metals ≤ 0.0005 wt%, and endotoxin 0.1-2.5 EU / g.

[0020] Beneficial technical effects: This invention uses inexpensive industrial-grade sodium dihydrogen phosphate dihydrate as raw material and employs a combination of complexation, adsorption purification, and recrystallization to prepare a high-purity, low-endotoxin pharmaceutical-grade sodium dihydrogen phosphate dihydrate product. Through the purification method of this invention, industrial-grade sodium dihydrogen phosphate dihydrate can be refined into a pharmaceutical-grade sodium dihydrogen phosphate dihydrate product with a purity greater than 99%, heavy metal content ≤0.0005%, and endotoxin content below 2.5 EU / g.

[0021] This invention introduces phytic acid or sodium phytate to complex Fe, Ga and other metallic impurities and trace heavy metal ions to form precipitates, avoiding the use of toxic heavy metal removal reagents such as Na2S and PS5 and further improving the effect of removing metal ion impurities; by using activated coconut shell carbon to adsorb endotoxins, the endotoxin content of the product is further reduced, thereby improving the purity of the obtained sodium dihydrogen phosphate dihydrate. Detailed Implementation

[0022] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] Unless otherwise specifically stated, the numerical values ​​set forth in these embodiments do not limit the scope of the invention. Techniques and methods known to those skilled in the art may not be discussed in detail, but where appropriate, such techniques and methods should be considered part of the specification. In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values. It should be noted that values ​​expressed, for example, as "within the range of ab" or "between the range of ab," do not include the endpoint values ​​a and b; values ​​expressed as "for ab," "is ab," or "ab" include the endpoint values ​​a and b.

[0024] Furthermore, it should be noted that the use of terms such as "first" and "second" to define the solution is merely for the purpose of distinguishing the solutions in each step. Unless otherwise stated, the above terms have no special meaning and therefore should not be construed as limiting the scope of protection of this invention.

[0025] Experimental methods not specified in the following examples are generally performed according to national standards; if there is no corresponding national standard, they are performed according to general standard requirements or general methods.

[0026] Sodium dihydrogen phosphate dihydrate, also known as sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dihydrate, etc., has the molecular formula NaH2PO4·2H2O.

[0027] The raw materials used below are industrial-grade sodium dihydrogen phosphate dihydrate, with the following specifications: purity 98.0 wt%, water-insoluble matter 0.05 wt%, Fe content 0.05 wt%, Ca content 0.08 wt%, arsenic content 0.01 wt%, heavy metal content 0.002 wt%, and endotoxin 16 EU / g. The heavy metal content was detected by atomic absorption spectrometry, and the endotoxin content was detected by the Limulus Amebocyte Lysate (LAL) reagent method. The testing methods for other indicators are in accordance with HG / T 2767-2009.

[0028] Example 1

[0029] The preparation method of high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate includes the following steps:

[0030] S1. Mix 500.0g of industrial grade sodium dihydrogen phosphate dihydrate with 250.0mL of ultrapure water, heat to 70℃, and stir to dissolve to form the first solution;

[0031] S2. Add 0.5g of phytic acid to the first solution, heat and stir at 70°C for 2 hours to form the second solution;

[0032] S3. Add 10g of pre-made coconut shell activated carbon to the second solution, and continue to heat and stir at 70°C for 2 hours to form the third solution.

[0033] The pre-prepared coconut shell activated carbon is prepared by mixing coconut shell activated carbon with 30wt% nitric acid solution at a mass-volume ratio of 1g:20mL, stirring and reacting at 70℃ for 2h, separating the solid and liquid, and washing the solid part with water until neutral to obtain the pre-prepared coconut shell activated carbon.

[0034] S4. The third solution is filtered while hot, first through an activated carbon filter and then through a 0.22μm microfiltration membrane. The filtrate is concentrated under reduced pressure at 40-45℃ until a crystal film appears in the solution. The vacuum is then turned off and the pressure is restored to normal. The solution is allowed to cool naturally for crystallization. The solid and liquid components are separated by centrifugation. The solid portion is dried at 32℃ for 1 hour to obtain high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate.

[0035] Example 2

[0036] The preparation method of high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate includes the following steps:

[0037] S1. Mix 500.0g of industrial grade sodium dihydrogen phosphate dihydrate with 250.0mL of ultrapure water, heat to 65℃, and stir to dissolve to form the first solution;

[0038] S2. Add 1.5g of phytic acid to the first solution, heat and stir at 65°C for 2 hours to form the second solution;

[0039] S3. Add 5g of pre-made coconut shell activated carbon to the second solution, and continue to heat and stir at 65°C for 2 hours to form the third solution.

[0040] The pre-prepared coconut shell activated carbon is prepared by mixing coconut shell activated carbon with 20wt% nitric acid solution at a mass-volume ratio of 1g:30mL, stirring and reacting at 80℃ for 4h, separating the solid and liquid, and washing the solid part with water until neutral to obtain the pre-prepared coconut shell activated carbon.

[0041] S4. The third solution is filtered while hot, first through an activated carbon filter and then through a 0.22μm microfiltration membrane. The filtrate is concentrated under reduced pressure at 40-45℃ until a crystal film appears in the solution. The vacuum is then turned off and the pressure is restored to normal. The solution is allowed to cool naturally for crystallization. The solid and liquid components are separated by centrifugation. The solid portion is dried at 35℃ for 1 hour to obtain high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate.

[0042] Example 3

[0043] The preparation method of high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate includes the following steps:

[0044] S1. Mix 500.0g of industrial grade sodium dihydrogen phosphate dihydrate with 250.0mL of ultrapure water, heat to 60℃, and stir to dissolve to form the first solution;

[0045] S2. Add 2.5g of sodium phytate to the first solution, heat and stir at 60°C for 2 hours to form the second solution;

[0046] S3. Add 4g of pre-made coconut shell activated carbon to the second solution, and continue to heat and stir at 60°C for 2 hours to form the third solution;

[0047] The pre-prepared coconut shell activated carbon is prepared by mixing coconut shell activated carbon with 10wt% nitric acid solution at a mass-volume ratio of 1g:40mL, stirring and reacting at 90℃ for 5h, separating the solid and liquid, and washing the solid part with water until neutral to obtain the pre-prepared coconut shell activated carbon.

[0048] S4. The third solution is filtered while hot, first through an activated carbon filter and then through a 0.22μm microfiltration membrane. The filtrate is concentrated under reduced pressure at 40-45℃ until a crystal film appears in the solution. The vacuum is then turned off and the pressure is restored to normal. The solution is allowed to cool naturally for crystallization. The solid and liquid components are separated by centrifugation. The solid portion is dried at 30℃ for 1 hour to obtain high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate.

[0049] Comparative Example 1

[0050] The purification method for industrial-grade sodium dihydrogen phosphate dihydrate in this case is the same as in Example 1, except that S2 is not performed.

[0051] Comparative Example 2

[0052] The purification method for industrial-grade sodium dihydrogen phosphate dihydrate in this case is the same as in Example 1, except that S3 is not performed.

[0053] Comparative Example 3

[0054] The purification method for industrial-grade sodium dihydrogen phosphate dihydrate in this case is the same as that in Example 1, except that coconut shell activated carbon (untreated with nitric acid) is used in S3.

[0055] Comparative Example 4

[0056] The purification method for industrial-grade sodium dihydrogen phosphate dihydrate in this case is the same as that in Example 1. The difference is that coconut shell activated carbon treated with alkali solution is used in S3. The coconut shell activated carbon is treated with a 2% NaOH solution at 40°C with stirring for 2 hours. The mass-volume ratio of coconut shell activated carbon to sodium hydroxide aqueous solution is 1g:20mL. Then it is washed with pure water until neutral.

[0057] Comparative Example 5

[0058] The purification method for industrial-grade sodium dihydrogen phosphate dihydrate in this case is the same as that in Example 1. The difference is that in S3, coconut shell activated carbon treated with hydrochloric acid is used. The coconut shell activated carbon is treated with a 1% HCl solution at 40°C with stirring for 2 hours. The mass-volume ratio of coconut shell activated carbon to hydrochloric acid aqueous solution is 1g:20mL. Then it is washed with pure water until neutral.

[0059] Test case

[0060] The physical properties of the products prepared in each case were analyzed, and the results are shown in Table 1.

[0061] Table 1. Indicators of sodium dihydrogen phosphate dihydrate after purification in the examples and comparative examples.

[0062]

[0063] As shown in Table 1, the sodium dihydrogen phosphate dihydrate prepared by the method of the present invention has a purity of over 99%, extremely low heavy metal content, and endotoxin content of less than 2 EU / g, reaching the level of pharmaceutical excipients.

[0064] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate, characterized in that, Includes the following steps: S1. Mix industrial-grade sodium dihydrogen phosphate dihydrate with pure water to form the first solution; S2. Add a heavy metal complexing agent to the first solution, heat and stir to react and form a second solution; S3. Add pre-made activated carbon to the second solution, heat and stir to react and form a third solution; S4. After filtering the third solution while it is still hot, the filtrate is concentrated under reduced pressure until a crystal film appears in the solution. It is then cooled naturally to allow for cooling and crystallization. After solid-liquid separation, high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate is obtained.

2. The method for preparing high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate according to claim 1, characterized in that, The mixing temperature of the industrial-grade sodium dihydrogen phosphate dihydrate and pure water is 60-70℃; the mass percentage of the industrial-grade sodium dihydrogen phosphate dihydrate in the first solution is 50%-80%.

3. The method for preparing high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate according to claim 1, characterized in that, The heavy metal complexing agent is selected from phytic acid or phytate; the heating and stirring reaction temperature after adding the heavy metal complexing agent is 60-70℃ and the reaction time is 1-2h; the amount of heavy metal complexing agent added is 0.1%-0.5% of the mass of the industrial grade sodium dihydrogen phosphate dihydrate.

4. The method for preparing high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate according to claim 1, characterized in that, The heating and stirring reaction temperature after adding the pre-prepared activated carbon is 60-70℃, and the reaction time is 1-2h; the amount of pre-prepared activated carbon added is 0.5%-2% of the mass of the industrial grade sodium dihydrogen phosphate dihydrate.

5. The method for preparing high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate according to claim 4, characterized in that, The pre-made activated carbon is pre-made coconut shell activated carbon. Pre-making refers to: immersing the coconut shell activated carbon in nitric acid solution and stirring at 70-90℃ for 1-5 hours, and then washing it with water until neutral.

6. The method for preparing high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate according to claim 5, characterized in that, The mass percentage of the nitric acid solution is 10%-30%; the mass-to-volume ratio of the coconut shell activated carbon to the nitric acid solution is 1g:10-50mL.

7. The method for preparing high-purity, low-endotoxin pharmaceutical excipient sodium dihydrogen phosphate dihydrate according to claim 1, characterized in that, The hot filtration process involves first filtering through an activated carbon filter and then through a 0.22-micron filter membrane. The filtrate is then concentrated under reduced pressure at 40-45°C.

8. A high-purity, low-endotoxin pharmaceutical excipient, sodium dihydrogen phosphate dihydrate, characterized in that... The sodium dihydrogen phosphate dihydrate product is prepared by the preparation method described in any one of claims 1-7 and simultaneously meets the following indicators: purity greater than 99wt%, heavy metals not exceeding 0.0005wt%, and endotoxin 0.1-2.5EU / g.

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