Method and equipment for measuring content of aluminum in aluminum adjuvant

Abstract

The invention provides a determination method and determination equipment for the content of aluminum in an aluminum adjuvant, and the determination method comprises the following steps: heating and dissolving the aluminum adjuvant in an alkaline solution to form a primary mixed solution; adding an acid solution into the primarily mixed solution, and forming a first mixed solution after the primarily mixed solution reaches a target pH value; adding an ethylene diamine tetraacetic acid titrating solution and an acetate buffer solution into the first mixed solution, heating, taking out, and cooling to room temperature to form a first solution to be titrated; after indicating liquid is added into the first to-be-titrated solution, titration is conducted through a zinc titrating solution till the color is changed, the total aluminum content in the aluminum adjuvant is calculated according to the volume of consumed titrating solution, and the total aluminum content comprises the amorphous aluminum content and the crystalline aluminum content. The method for determining the aluminum content in the aluminum adjuvant is simple and convenient to operate and low in cost, the aluminum content in the aluminum adjuvant can be directly and rapidly detected without drying, and the accuracy and convenience of evaluation of key indexes of the aluminum adjuvant can be effectively improved.

Description

Technical Field

[0001] The invention relates to a method and equipment for determining the aluminum content in an aluminum adjuvant, and belongs to the field of biomedical methods. Background Art

[0002] As an immune adjuvant, aluminum adjuvant has long been widely recognized for its safety and immune enhancement effects in the field of vaccine preparation and biological products in my country, and has become an important auxiliary component in vaccine research and development. The types of aluminum adjuvants mainly include aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, mixed systems of aluminum hydroxide and aluminum phosphate, and adjuvant systems composed of other adjuvant components. Among them, aluminum hydroxide adjuvant and aluminum phosphate adjuvant are the most widely used. On the one hand, it enhances the immunogenicity of the vaccine by enhancing antigen presentation, enhancing Th2 cell-mediated adaptive immune response, activating B cells to induce antibody production, and activating complement; on the other hand, there are also safety hazards, which can induce allergic reactions and produce neurotoxicity. Therefore, strict quality control of aluminum adjuvants is a key factor that directly affects the efficacy and safety of vaccines. Among them, the key indicators for judging aluminum adjuvants include aluminum content and crystal ratio, which are also important criteria for controlling the repeatability of aluminum adjuvant production process.

[0003] At present, the commonly used method for detecting the aluminum content in aluminum adjuvants is mainly titration by disodium ethylenediaminetetraacetic acid (EDTA-2Na) titration according to the method recommended by the Chinese Pharmacopoeia III (2020 edition), and the content of aluminum adjuvant in the test sample is calculated according to the consumption of zinc titration solution. At present, the Chinese Pharmacopoeia uses strong acid to dissociate samples. In actual testing, this method is difficult to destroy a variety of commercially available and homemade samples, and the tested aluminum content is very different from the labeled amount. After combined analysis of XRD data, this method is difficult to accurately analyze aluminum adjuvants with complex crystal components. It is indeed necessary to propose a new method for determining the aluminum content in aluminum adjuvants to achieve the control of aluminum adjuvant content. At the same time, the composition ratio of each crystal form can be analyzed to further control the repeatability of the process.

[0004] The titration endpoint is determined by visual inspection based on the color change of the indicator, which is easily affected by human factors. This patent also proposes an aluminum content test calculation system to reduce the error of this method. Summary of the invention

[0005] The purpose of the present invention is to provide a method for determining the aluminum content in an aluminum adjuvant which is simple to operate and low in cost.

[0006] To achieve the above object, the present invention provides a method for determining the aluminum content in an aluminum adjuvant, and the method for determining the total aluminum content in the aluminum adjuvant comprises:

[0007] The aluminum adjuvant is heated and dissolved in the alkaline solution to form a primary mixed solution;

[0008] adding an acidic solution to the primary mixed solution so that the primary mixed solution reaches a target pH, thereby forming a first mixed solution;

[0009] Adding disodium ethylenediaminetetraacetic acid titration solution and acetate buffer to the first mixed solution, heating and then taking out and cooling to room temperature to form a first solution to be titrated;

[0010] After adding the indicator solution to the first solution to be titrated, the solution is titrated with zinc titrant until it changes color, and the total aluminum content in the aluminum adjuvant is calculated based on the volume of the consumed titrant, wherein the total aluminum content includes the amorphous aluminum content and the crystalline aluminum content.

[0011] As a further improvement of the present invention, the alkaline substance in the alkaline solution includes any one of sodium hydroxide, potassium hydroxide and ammonia water, and the concentration of the alkaline substance in the alkaline solution is 0.5-20%.

[0012] As a further improvement of the present invention, the method for determining the content of amorphous aluminum in the aluminum adjuvant comprises:

[0013] heating and dissolving the aluminum adjuvant in the acidic solution to form a second mixed solution;

[0014] Adding disodium ethylenediaminetetraacetic acid titration solution and buffer solution to the second mixed solution, heating and then taking out and cooling to room temperature to form a second solution to be titrated;

[0015] After adding the indicator solution to the second solution to be titrated, the solution is titrated with zinc titrant until the solution changes color, and the amorphous aluminum content in the aluminum adjuvant is calculated based on the volume of the consumed titrant.

[0016] As a further improvement of the present invention, the crystalline aluminum content in the aluminum adjuvant is equal to the difference between the total aluminum content and the amorphous aluminum content.

[0017] As a further improvement of the present invention, the acidic substance in the acidic solution includes any one of hydrochloric acid, acetic acid, phosphoric acid, nitric acid, sulfuric acid, and lactic acid, and the concentration of the acidic substance in the acidic solution is 50-100%.

[0018] As a further improvement of the present invention, the concentration of the disodium ethylenediaminetetraacetic acid titration solution is 0.05-1 mol / L, the ratio of the amount of the disodium ethylenediaminetetraacetic acid titration solution added to the amount of the aluminum adjuvant added is 10-1, the pH value of the acetate buffer solution is 3.0-6.5, and the ratio of the amount of the buffer solution added to the amount of the disodium ethylenediaminetetraacetic acid titration solution added is 1-5.

[0019] As a further improvement of the present invention, the indicator solution includes any one or a combination of methyl red and xylenol orange, and the ratio of the added amount of the indicator solution to the added amount of the disodium ethylenediaminetetraacetic acid titration solution is 0.05 to 0.5.

[0020] As a further improvement of the present invention, the measurement range of the aluminum adjuvant in the determination method is 0.01 to 15 mg / ml.

[0021] Another object of the present invention is to provide a device for determining the aluminum content in an aluminum adjuvant, which can automatically control the titration process and the titration endpoint and has accurate measurement.

[0022] To achieve the above object, the present invention provides an aluminum content determination device, comprising:

[0023] A titration component configured to titrate the solution to be titrated using the above-mentioned method for determining the aluminum content in the aluminum adjuvant;

[0024] A picture comparison component, which obtains a picture of the solution to be titrated, and compares and analyzes the picture with a preset picture;

[0025] A control component; based on the comparison and analysis results of the image comparison component, the dripping amount, dripping speed, dripping time and interval time of the measuring device are automatically controlled, and the aluminum content in the aluminum adjuvant is automatically calculated according to the consumption volume of the titration solution.

[0026] As a further improvement of the present invention, the titration component includes a driving part, a dropping part, a liquid storage part and a reaction part; the solution to be titrated is arranged in the reaction part, and the titration liquid is arranged in the liquid storage part; the driving part connects the liquid storage part and the dropping part, and is configured to drive the titration liquid to the dropping part and titrate it to the reaction part; the measuring device also includes a calibration component, and the calibration component is configured to calibrate the dropping accuracy of the driving part.

[0027] The beneficial effects of the present invention are:

[0028] The present invention provides a method for determining the aluminum content in an aluminum adjuvant by heating and dissolving the aluminum adjuvant in an alkaline solution to form a primary mixed solution, and adding an acidic solution to the primary mixed solution to adjust the target pH of the primary mixed solution, thereby destroying the crystalline structure in the aluminum adjuvant and dissolving more free Al. 3+ , avoid Al 3+ The problem of inaccurate determination of aluminum content caused by incomplete destruction can be solved, thereby accurately measuring the aluminum content of aluminum adjuvants in complex crystal forms.

[0029] The method for determining the aluminum content in an aluminum adjuvant of the present invention can quickly and accurately identify the total aluminum content, amorphous aluminum content and crystalline aluminum content in an aluminum adjuvant with a complex crystal form, thereby being able to analyze the composition ratio of various aluminum contents in each aluminum adjuvant with a complex crystal form, and further control the repeatability of the process.

[0030] The device for measuring the aluminum content in an aluminum adjuvant of the present invention can automatically measure and calculate the total aluminum content, the amorphous aluminum content and the crystalline aluminum content in the aluminum adjuvant, thereby avoiding the human error of visually observing the titration end point. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is a flow chart of a method for determining the total aluminum content in an aluminum adjuvant of the present invention;

[0032] Figure 2 It is a flow chart of a method for determining the content of amorphous aluminum in an aluminum adjuvant of the present invention;

[0033] Figure 3 The X-ray diffraction patterns of the three aluminum adjuvants tested in the examples of the present invention;

[0034] Figure 4 The X-ray diffraction patterns of two commercially available aluminum adjuvants in the examples of the present invention;

[0035] Figure 5 This is a picture of the initial mixed solution of the test sample B in Example 1 of the present invention;

[0036] Figure 6 This is a picture of the second mixed solution of the test sample B in Example 1 of the present invention;

[0037] Figure 7 The X-ray diffraction pattern of the sample B and the second mixed solution of the sample B after washing and drying in Example 1 of the present invention;

[0038] Figure 8 This is a transmission electron microscope image of the sample B and the second mixed solution of the sample B after cleaning in Example 1 of the present invention;

[0039] Fig. 9 This is the dissolution picture of the test sample B in Comparative Example 1 of the present invention;

[0040] Fig.10 The figure is a schematic diagram of the structure of a device for measuring the aluminum content in an aluminum adjuvant according to the present invention. DETAILED DESCRIPTION

[0041] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0042] See also Figures 1 to 9As shown, the present invention provides a method for determining the aluminum content in an aluminum adjuvant. The method can quickly and accurately determine the total aluminum content in the aluminum adjuvant, and can analyze the composition ratio of various aluminum contents in aluminum adjuvants of various complex crystal forms.

[0043] Aluminum adjuvants, especially aluminum adjuvants with complex crystal forms, include amorphous aluminum adjuvants and aluminum adjuvants with high crystallinity. Different crystal forms of aluminum adjuvants have different effects on vaccine efficacy and safety. Therefore, it is necessary to accurately detect the aluminum content and crystal form ratio in aluminum adjuvants to improve vaccine efficacy and safety, and control the repeatability of aluminum adjuvant production process.

[0044] See also Figure 1 As shown, the present invention provides a method for determining the aluminum content in an aluminum adjuvant, and the method for determining the total aluminum content in the aluminum adjuvant comprises:

[0045] S11: heating and dissolving the aluminum adjuvant in the alkaline solution to form a primary mixed solution;

[0046] S12: adding an acidic solution to the primary mixed solution so that the primary mixed solution reaches a target pH, thereby forming a first mixed solution;

[0047] S13: adding disodium ethylenediaminetetraacetic acid titration solution and acetate buffer to the first mixed solution, heating and then taking out and cooling to room temperature to form a first solution to be titrated;

[0048] S14: After adding an indicator solution to the first solution to be titrated, titrate with a zinc titrant until it changes color, and calculate the total aluminum content in the aluminum adjuvant based on the volume of the consumed titrant, wherein the total aluminum content includes an amorphous aluminum content and a highly crystalline aluminum content.

[0049] Furthermore, the alkaline substance in the alkaline solution includes any one of sodium hydroxide, potassium hydroxide and ammonia water.

[0050] The concentration of the alkaline substance in the alkaline solution is 0.5-20%. The amount of the alkaline solution added is 1-20 mL.

[0051] The heating temperature of the aluminum adjuvant in the alkaline solution is 50-100° C., and the heating time is 0.2-20 minutes.

[0052] Furthermore, the acidic substance in the acidic solution includes any one of hydrochloric acid, acetic acid, phosphoric acid, nitric acid, sulfuric acid, and lactic acid.

[0053] The concentration of the acidic substance in the acidic solution is 50-100%. The amount of the acidic solution added is 0.02-5 mL.

[0054] Furthermore, the measurement range of the total aluminum content of the aluminum adjuvant in the determination method is 0.01 to 15 mg / ml.

[0055] See also Figure 2 As shown, the method for determining the content of amorphous aluminum in the aluminum adjuvant comprises:

[0056] S21: heating and dissolving the aluminum adjuvant in the acidic solution to form a second mixed solution;

[0057] S22: adding disodium ethylenediaminetetraacetic acid titration solution and buffer solution to the second mixed solution, heating and then taking out and cooling to room temperature to form a second solution to be titrated;

[0058] S23: adding an indicator solution to the second solution to be titrated, titrating with a zinc titration solution until the solution changes color, and calculating the amorphous aluminum content in the aluminum adjuvant based on the volume of the consumed titration solution.

[0059] Among them, in two titration experiments, the concentration of the disodium ethylenediaminetetraacetic acid titration solution is 0.05-1 mol / L, the ratio of the amount of the disodium ethylenediaminetetraacetic acid titration solution added to the amount of the aluminum adjuvant added is 10-1, the pH value of the acetate buffer is 3.0-6.5, and the ratio of the amount of the buffer added to the amount of the disodium ethylenediaminetetraacetic acid titration solution added is 1-5. Such a setting makes the titration color reaction more obvious, and the color development is not obvious beyond the limit, and the test result is inaccurate.

[0060] Furthermore, the indicator solution includes any one or a combination of methyl red and xylenol orange.

[0061] The ratio of the amount of the indicator solution added to the amount of the disodium ethylenediaminetetraacetic acid titration solution added is 0.05 to 0.5. This arrangement makes the titration color reaction more obvious, and the color development is not obvious beyond the limit, and the test result is inaccurate.

[0062] Furthermore, the crystalline aluminum content in the aluminum adjuvant is equal to the difference between the total aluminum content and the amorphous aluminum content.

[0063] In order to clearly illustrate the method for determining the aluminum content in an aluminum adjuvant of the present invention, the present invention selects three aluminum adjuvants prepared by different processes and two commercially available aluminum adjuvants as test samples for determination. Among them, the three aluminum adjuvants prepared by different processes are test sample A (labeled concentration is 10.0 mg / ml), test sample B (labeled concentration is 10.0 mg / ml), test sample C (labeled concentration is 10.0 mg / ml), and commercially available InvivoGen adjuvant 2% (labeled concentration 10.0 mg / ml), Danish aluminum adjuvant (The labeled concentration is 10.0 mg / ml). Among them, the X-ray diffraction patterns of test sample A, test sample B, and test sample C are as follows: Figure 3 As shown, the X-ray diffraction patterns of two commercially available aluminum adjuvants are shown in Figure 4 shown.

[0064] The following description is described with specific embodiments, but those skilled in the art will appreciate that the present invention is not limited thereto.

[0065] Embodiment 1:

[0066] (1) Determination of total aluminum content in aluminum adjuvants:

[0067] Three aluminum adjuvants prepared by different processes were used, namely, sample A (labeled concentration of 10.0 mg / ml), sample B (labeled concentration of 10.0 mg / ml), sample C (labeled concentration of 10.0 mg / ml), and commercially available InvivoGen adjuvant 2% (labeled concentration 10.0 mg / ml), Danish aluminum adjuvant (labeled concentration is 10.0 mg / ml), there are 5 kinds of aluminum adjuvants in total, 1 ml of each aluminum adjuvant is dissolved in 5 bottles of 10 ml 10% sodium hydroxide solution, heated at 70°C for 1 min, and all 5 aluminum adjuvants are completely dissolved to form a primary mixed solution.

[0068] 85% phosphoric acid was added to the primary mixed solution, and the pH of the primary mixed solution was adjusted to 5.0 to form a first mixed solution.

[0069] Add 5 ml of 0.5 mol / L disodium ethylenediaminetetraacetic acid titration solution and 10 ml of acetic acid-ammonium acetate (pH=4.6) buffer solution to the first mixed solution, heat at 70° C. for 5 min, take out and cool to room temperature to form a first solution to be titrated.

[0070] Add 1 ml of xylenol orange indicator solution to the first solution to be titrated, and titrate with 0.05 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration endpoint, and the titration result is corrected with a blank test.

[0071] Calculate according to the following formula (hereinafter referred to as titration formula):

[0072]

[0073] Where:

[0074] V0 is the volume of zinc titration solution consumed in the blank test, ml;

[0075] V1 is the volume of zinc titration solution consumed by the test sample, ml;

[0076] C is the concentration of zinc titration solution, mol / L;

[0077] V2 is the volume of the test sample, ml;

[0078] 26.98 is the molecular weight or relative atomic mass of aluminum.

[0079] Repeat the above steps and conduct three or more parallel experiments to calculate the total aluminum content in each aluminum adjuvant.

[0080] (2) Determination of amorphous aluminum content in aluminum adjuvants:

[0081] 1 ml of each aluminum adjuvant was dissolved in 2 ml of 85% phosphoric acid solution, and heated at 70° C. for 1 min to dissolve the aluminum adjuvant to form a second mixed solution.

[0082] Add 5 ml of 0.5 mol / L disodium ethylenediaminetetraacetate titration solution and 10 ml of acetic acid-ammonium acetate (pH=4.6) buffer solution to the second mixed solution, heat at 70° C. for 5 min, take out and cool to room temperature to form a second solution to be titrated.

[0083] Add 1 ml of xylenol orange indicator solution to the second solution to be titrated, and titrate with 0.05 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration endpoint, and the titration result is corrected with a blank test. Repeat the above steps and perform three or more parallel experiments. Use the titration formula to calculate the content of amorphous aluminum in the aluminum adjuvant.

[0084] (3) Determination of crystalline aluminum content in aluminum adjuvants:

[0085] The calculated total aluminum content minus the amorphous aluminum content, the difference is the crystalline aluminum content in the aluminum adjuvant. It should be noted that the crystalline aluminum content mentioned in the context of the present invention refers to the aluminum content with high crystallinity.

[0086] In Example 1, the test concentrations of the test products are shown in Table 1 below:

[0087] Table 1 Total aluminum content, amorphous aluminum content and crystalline aluminum content in five test samples

[0088]

[0089] From Table 1, it can be seen that different types of test samples contain different amounts of amorphous aluminum and crystalline aluminum. Since the crystal complexity of aluminum adjuvants is positively correlated with the proportion of crystalline aluminum they contain, among the five test samples, the crystal complexity of aluminum adjuvants is: Test Sample A > Test Sample B > InvivoGen adjuvant 2%>Danish aluminum adjuvant>test substance C.

[0090] By measuring the amorphous aluminum content and crystalline aluminum content in each type of aluminum adjuvant, the crystal ratio in the aluminum adjuvant can be analyzed more clearly, thereby strictly controlling the quality of the aluminum adjuvant, and also helping to control the repeatability of the aluminum adjuvant production process.

[0091] Figure 5 and Figure 6 The test sample B is used as an example for the determination experiment. As shown in Table 1, the total aluminum content in the sample B is 10.00 mg / ml, of which the amorphous aluminum content is 2.32 mg / ml, the crystalline aluminum content is 7.68 mg / ml, and the proportion of crystalline aluminum is 76.80%. That is, the crystallinity of the sample B is higher and the crystal form is more complex.

[0092] Depend on Figure 5 It can be seen that after adding alkaline solution (sodium hydroxide) to sample B and heating it, the aluminum adjuvant is completely dissolved, and the initial mixed solution is colorless and transparent. This indicates that the amorphous aluminum hydroxide, high-crystallinity aluminum hydroxide, AlOOH, etc. in sample B are completely destroyed, forming free AlO 2- Subsequently, phosphoric acid solution was added to the initial mixed solution of sample B to react and all of it was converted into Al 3+ , forming a first mixed solution of test sample B.

[0093] Depend on Figure 6 It can be seen that after the sample B was heated and dissolved in the acidic solution, the second mixed solution of the sample B was white and turbid. This is because the sample B has a high degree of crystallinity and a complex crystal form, and only part of the amorphous aluminum structure can be dissolved in the acidic solution. That is, only the amorphous aluminum hydroxide is dissolved and destroyed to form Al 3+ , while aluminum hydroxide and AlOOH with higher crystallinity were not dissolved.

[0094] The sample B, the first mixed solution of the sample B and the second mixed solution of the sample B were centrifuged and washed with deionized water at 20000 rpm, and the supernatant was tested to obtain an X-ray diffraction pattern (such as Figure 7 ). Figure 7 It can be seen that the sample could not be centrifuged out of the first mixed solution of test sample B, which indicates that the aluminum adjuvant colloid in the sample was destroyed and completely converted into Al 3+ However, a sample can be separated from the second mixed solution of sample B. After the sample is cleaned and dried, it is tested and found that an obvious crystal spectrum can still appear in the sample. The peak of the crystal spectrum appears at the same place as the peak of sample B.

[0095] See also Figure 8As shown, the left picture is a projection electron microscope image of sample B, showing that the sample is a rod-shaped crystalline sample with amorphous flocs around it. The right picture is a projection electron microscope image of sample B after washing with the second mixed solution. It can be seen from the right picture that the rod-shaped crystals of the second mixed solution are more obvious, and there is basically no amorphous material around it.

[0096] By adopting the method of the present invention, the contents of crystalline aluminum and amorphous aluminum in each of the five test samples can be accurately measured.

[0097] Example 2

[0098] In Example 2, the same five aluminum adjuvant test samples as those in Example 1 were used, except that in this example, the alkaline solution was a 5% ammonia solution, and the acidic solution was a 50% nitric acid solution.

[0099] (1) Determination of total aluminum adjuvant content:

[0100] 0.5 ml of each aluminum adjuvant was dissolved in 20 ml of 5% ammonia solution and heated at 70° C. for 2 min. All five aluminum adjuvants were completely dissolved to form a primary mixed solution.

[0101] 50% nitric acid solution was added to the initial mixed solution to adjust the pH to 3.0 to obtain the first mixed solution.

[0102] Add 10 ml of 0.1 mol / L disodium ethylenediaminetetraacetic acid titration solution and 30 ml of acetic acid-ammonium acetate (pH=3.0) buffer solution to the first mixed solution, heat at 100° C. for 10 min, take out and cool to room temperature to form a first solution to be titrated.

[0103] Add 1 ml of methyl orange indicator solution to the first solution to be titrated, and titrate with 0.05 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration end point, and the titration result is corrected with a blank test.

[0104] Calculate the aluminum content according to the formula, repeat the above steps, and perform three or more parallel experiments to calculate the total aluminum content in each aluminum adjuvant.

[0105] (2) Determination of the content of amorphous aluminum adjuvant:

[0106] 0.5 ml of each aluminum adjuvant was taken and dissolved in 3 ml of 50% nitric acid solution, and heated at 100° C. for 0.5 min to dissolve the aluminum adjuvant to form a second mixed solution.

[0107] Add 10 ml of 0.1 mol / L disodium ethylenediaminetetraacetic acid titration solution and 30 ml of acetic acid-ammonium acetate (pH=3.0) buffer solution to the second mixed solution, heat at 100° C. for 10 min, take out and cool to room temperature to form a second solution to be titrated.

[0108] Add 1 ml of xylenol orange indicator solution to the second solution to be titrated, and titrate with 0.05 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration endpoint, and the titration result is corrected with a blank test. Repeat the above steps and perform three or more parallel experiments. Use the titration formula to calculate the content of amorphous aluminum in the aluminum adjuvant.

[0109] (3) Determination of crystalline aluminum content in aluminum adjuvants:

[0110] The calculated total aluminum content minus the amorphous aluminum content is used to obtain the crystalline aluminum content in the aluminum adjuvant.

[0111] In Example 2, the test concentrations of the test products are shown in Table 2 below:

[0112] Table 2 Total aluminum content, amorphous aluminum content and crystalline aluminum content in five test samples

[0113]

[0114] It can be seen from Table 2 that different types of test samples contain different amounts of amorphous aluminum and crystalline aluminum. The crystal complexity of aluminum adjuvants in the five test samples is: Test sample A > Test sample B > InvivoGen adjuvant 2%>Danish aluminum adjuvant>test sample C. That is, the results obtained in Example 2 are consistent with those in Example 1. This shows that the determination method of the present invention has high consistency and good parallelism, and can quickly detect the total aluminum content, amorphous aluminum content and crystalline aluminum content in aluminum adjuvant.

[0115] Example 3

[0116] In Example 3, the same five aluminum adjuvant test samples as in Example 1 were used, except that in this example, the alkaline solution was a 6% potassium hydroxide solution and the acidic solution was a 50% hydrochloric acid solution.

[0117] (1) Determination of total aluminum adjuvant content:

[0118] 0.8 ml of each aluminum adjuvant was dissolved in 20 ml of 6% potassium hydroxide solution and heated at 85°C for 2 min to form a primary mixed solution.

[0119] Add 50% hydrochloric acid solution to the initial mixed solution to adjust the pH to 4.5 to obtain a first mixed solution;

[0120] Add 2 ml of 1 mol / L disodium ethylenediaminetetraacetic acid titration solution and 25 ml of acetic acid-ammonium acetate (pH=4.5) buffer solution to the first mixed solution, heat at 85° C. for 5 min, take out and cool to room temperature to form a first solution to be titrated;

[0121] Add 1 ml of methyl orange indicator solution to the first solution to be titrated, and titrate with 0.1 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration end point, and the titration result is corrected with a blank test.

[0122] Calculate the aluminum content according to the formula, repeat the above steps, and perform three or more parallel experiments to calculate the total aluminum content in each aluminum adjuvant.

[0123] (2) Determination of the content of amorphous aluminum adjuvant:

[0124] 0.8 ml of each aluminum adjuvant was taken and dissolved in 5 ml of 50% hydrochloric acid solution, and heated at 85° C. for 1 min to dissolve the aluminum adjuvant to form a second mixed solution.

[0125] Add 2 ml of 1 mol / L disodium ethylenediaminetetraacetic acid titration solution and 25 ml of acetic acid-ammonium acetate (pH=4.5) buffer solution to the second mixed solution, heat at 85° C. for 5 min, take out and cool to room temperature to form a second solution to be titrated.

[0126] Add 1 ml of methyl orange indicator to the second solution to be titrated, and titrate with 0.1 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration endpoint, and the titration result is corrected with a blank test. Repeat the above steps and perform three or more parallel experiments. Use the titration formula to calculate the content of amorphous aluminum in the aluminum adjuvant.

[0127] (3) Determination of crystalline aluminum content in aluminum adjuvants:

[0128] The calculated total aluminum content minus the amorphous aluminum content is used to obtain the crystalline aluminum content in the aluminum adjuvant.

[0129] In Example 3, the test concentrations of the test products are shown in Table 3 below:

[0130] Table 3 Total aluminum content, amorphous aluminum content and crystalline aluminum content in five test samples

[0131]

[0132] It can be seen from Table 3 that different types of test samples contain different amounts of amorphous aluminum and crystalline aluminum. The crystal complexity of aluminum adjuvants in the five test samples is: Test sample A > Test sample B > InvivoGen adjuvant 2%>Danish aluminum adjuvant>test sample C. That is, the results obtained in Example 3 are consistent with those in Example 1. This shows that the determination method of the present invention has high consistency and good parallelism, and can quickly detect the total aluminum content, amorphous aluminum content and crystalline aluminum content in aluminum adjuvant.

[0133] Example 4

[0134] In Example 4, the same five aluminum adjuvant test samples as in Example 1 were used, except that in this example, the alkaline solution was a 6% potassium hydroxide solution and the acidic solution was a 70% lactic acid solution.

[0135] (1) Determination of total aluminum adjuvant content:

[0136] 1 ml of each aluminum adjuvant was dissolved in 20 ml of 6% potassium hydroxide solution and heated at 85° C. for 2 min to dissolve the aluminum adjuvant. All five aluminum adjuvants were completely dissolved to form a primary mixed solution.

[0137] 5 ml of 70% lactic acid solution was added to the initial mixed solution to adjust the pH to 4.5 to obtain the first mixed solution.

[0138] 2 ml of 1 mol / L disodium ethylenediaminetetraacetic acid titration solution and 25 ml of acetic acid-ammonium acetate (pH=4.5) buffer solution were added to the first mixed solution, heated at 85° C. for 5 min, and then taken out and cooled to room temperature to form a first solution to be titrated.

[0139] Add 1 ml of methyl orange indicator solution to the first solution to be titrated, and titrate with 0.1 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration end point, and the titration result is corrected with a blank test.

[0140] Calculate the aluminum content according to the formula, repeat the above steps, and perform three or more parallel experiments to calculate the total aluminum content in each aluminum adjuvant.

[0141] (2) Determination of the content of amorphous aluminum adjuvant:

[0142] 1 ml of each aluminum adjuvant was dissolved in 5 ml of 70% lactic acid solution, and heated at 120° C. for 1 min to dissolve the aluminum adjuvant to form a second mixed solution.

[0143] Add 2 ml of 1 mol / L disodium ethylenediaminetetraacetic acid titration solution and 25 ml of acetic acid-ammonium acetate (pH=4.5) buffer solution to the second mixed solution, heat at 120° C. for 5 min, take out and cool to room temperature to form a second solution to be titrated.

[0144] Add 1 ml of methyl orange indicator to the second solution to be titrated, and titrate with 0.1 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration endpoint, and the titration result is corrected with a blank test. Repeat the above steps and perform three or more parallel experiments. Use the titration formula to calculate the content of amorphous aluminum in the aluminum adjuvant.

[0145] (3) Determination of crystalline aluminum content in aluminum adjuvants:

[0146] The calculated total aluminum content minus the amorphous aluminum content is used to obtain the crystalline aluminum content in the aluminum adjuvant.

[0147] In Example 4, the test concentrations of the test products are shown in Table 4 below:

[0148] Table 4 Total aluminum content, amorphous aluminum content and crystalline aluminum content in five test samples

[0149]

[0150] It can be seen from Table 4 that different types of test samples contain different amounts of amorphous aluminum and crystalline aluminum. The crystal complexity of aluminum adjuvants in the five test samples is: Test sample A > Test sample B > InvivoGen adjuvant 2%>Danish aluminum adjuvant>test sample C. That is, the results obtained in Example 4 are consistent with those in Example 1. This shows that the determination method of the present invention has high consistency and good parallelism, and can quickly detect the total aluminum content, amorphous aluminum content and crystalline aluminum content in aluminum adjuvant.

[0151] Example 5

[0152] In Example 5, the same five aluminum adjuvant test samples as in Example 1 were used, except that in this example, the alkaline solution was a 6% potassium hydroxide solution and the acidic solution was a 50% sulfuric acid solution.

[0153] (1) Determination of total aluminum adjuvant content:

[0154] 1 ml of each aluminum adjuvant was dissolved in 20 ml of 6% potassium hydroxide solution and heated at 85° C. for 2 min to dissolve the aluminum adjuvant. All five aluminum adjuvants were completely dissolved to form a primary mixed solution.

[0155] 5 ml of 50% sulfuric acid solution was added to the initial mixed solution to adjust the pH to 4.5 to obtain the first mixed solution.

[0156] Add 2 ml of 1 mol / L disodium ethylenediaminetetraacetic acid titration solution and 25 ml of acetic acid-ammonium acetate (pH=4.5) buffer solution to the first mixed solution, heat at 85° C. for 5 min, take out and cool to room temperature to form a first solution to be titrated;

[0157] Add 1 ml of methyl orange indicator solution to the first solution B to be titrated, and titrate with 0.1 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration end point, and the titration result is corrected with a blank test.

[0158] Calculate the aluminum content according to the formula, repeat the above steps, and do three or more parallel experiments. Calculate the total aluminum content in each aluminum adjuvant

[0159] (2) Determination of the content of amorphous aluminum adjuvant:

[0160] 1 ml of each aluminum adjuvant was taken and dissolved in 5 ml of 50% sulfuric acid solution, and heated at 70° C. for 1 min to dissolve the aluminum adjuvant to form a second mixed solution.

[0161] Add 2 ml of 1 mol / L disodium ethylenediaminetetraacetic acid titration solution and 25 ml of acetic acid-ammonium acetate (pH=4.5) buffer solution to the second mixed solution, heat at 120° C. for 5 min, take out and cool to room temperature to form a second solution to be titrated.

[0162] Add 1 ml of methyl orange indicator to the second solution to be titrated, and titrate with 0.1 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration endpoint, and the titration result is corrected with a blank test. Repeat the above steps and perform three or more parallel experiments. Use the titration formula to calculate the content of amorphous aluminum in the aluminum adjuvant.

[0163] (3) Determination of crystalline aluminum content in aluminum adjuvants:

[0164] The calculated total aluminum content minus the amorphous aluminum content is used to obtain the crystalline aluminum content in the aluminum adjuvant.

[0165] In Example 5, the test concentrations of the test products are shown in Table 5 below:

[0166] Table 5 Total aluminum content, amorphous aluminum content and crystalline aluminum content in five test samples

[0167]

[0168] It can be seen from Table 5 that different types of test samples contain different amounts of amorphous aluminum and crystalline aluminum. The crystal complexity of aluminum adjuvants in the five test samples is: Test sample A > Test sample B > InvivoGen adjuvant 2%>Danish aluminum adjuvant>test sample C. That is, the results obtained in Example 5 are consistent with those in Example 1. This shows that the determination method of the present invention has high consistency and good parallelism, and can quickly detect the total aluminum content, amorphous aluminum content and crystalline aluminum content in aluminum adjuvant.

[0169] Comparative Example 1

[0170] Comparative Example 1 uses the same five aluminum adjuvant test samples as Example 1, except that the test method uses the aluminum adjuvant detection method in the Chinese Pharmacopoeia for detection, and only phosphoric acid is used for destruction.

[0171] Accurately measure the appropriate amount of 5 test samples (equivalent to 1-10 mg aluminum), place in a 250 ml conical flask, add 1.5 ml of 20% phosphoric acid solution to completely dissolve. Accurately add 10 ml of disodium ethylenediaminetetraacetic acid titration solution (0.05 mol / L) and 10 ml of acetic acid-ammonium acetate buffer (pH 4.5), heat in a boiling water bath for 10 minutes, take out and cool to room temperature, add 1 ml of xylenol orange indicator solution, and titrate with zinc titration solution (0.025 mol / L). When the solution changes from bright yellow to orange, it is the end point, and the titration result is corrected with a blank test.

[0172] Among them, the dissolved solution of the test sample B after adding 20% ​​phosphoric acid solution is as follows Fig. 9 As shown. Fig. 9 It can be seen that the dissolved solution is obviously turbid, indicating that the sample B is not completely dissolved and there is still a large amount of crystalline aluminum that has not been destroyed.

[0173] In Comparative Example 1, the test concentrations of the test products are shown in Table 6 below

[0174] Table 6 Aluminum content in five test samples

[0175]

[0176] From Table 6 and Fig. 9 It can be seen that the simple use of acid digestion in Comparative Example 1 is difficult to process aluminum adjuvants with complex crystal forms, and the aluminum content test results are seriously offset. In addition, the content and proportion of crystalline aluminum in each aluminum adjuvant cannot be obtained.

[0177] Comparative Example 2

[0178] Comparative Example 2 uses the same five aluminum adjuvant test samples as in Example 1, and the total aluminum content is determined by the method of the present invention. The difference is that the amorphous aluminum content is determined by the pharmacopoeia method.

[0179] (1) Determination of total aluminum adjuvant content:

[0180] 1 ml of each aluminum adjuvant was dissolved in 10 ml of 10% sodium hydroxide solution, and heated at 100°C for 1 min to dissolve the aluminum adjuvant. All five aluminum adjuvants were completely dissolved to form a primary mixed solution;

[0181] 20% phosphoric acid solution was added to the initial mixed solution to adjust the pH to 4.5 to obtain the first mixed solution.

[0182] Add 10 ml of 0.05 mol / L disodium ethylenediaminetetraacetic acid titration solution and 10 ml of acetic acid-ammonium acetate (pH=4.5) buffer solution to the first mixed solution, heat at 100° C. for 5 min, take out and cool to room temperature to form a first solution B to be titrated;

[0183] Add 1 ml of xylenol orange indicator solution to the first solution to be titrated, and titrate with 0.025 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration endpoint, and the titration result is corrected with a blank test. Repeat the above steps and perform three or more parallel experiments. Use the titration formula to calculate the total aluminum content in the aluminum adjuvant.

[0184] (2) Determination of the content of amorphous aluminum adjuvant:

[0185] 1 ml of each aluminum adjuvant was dissolved in 1.5 ml of 20% phosphoric acid solution, and heated at 100° C. for 20 min to dissolve the aluminum adjuvant to form a second mixed solution.

[0186] Add 10 ml of 0.05 mol / L disodium ethylenediaminetetraacetic acid titration solution and 10 ml of acetic acid-ammonium acetate (pH=4.5) buffer solution to the second mixed solution, heat at 100° C. for 5 min, take out and cool to room temperature to form a second solution to be titrated.

[0187] Add 1 ml of xylenol orange indicator solution to the first solution to be titrated, and titrate with 0.025 mol / L zinc titrant. When the solution changes from bright yellow to orange, it is the titration endpoint, and the titration result is corrected with a blank test.

[0188] Repeat the above steps and conduct three or more parallel experiments. Use the titration formula to calculate the content of amorphous aluminum in the aluminum adjuvant.

[0189] (3) Determination of crystalline aluminum content in aluminum adjuvants:

[0190] The calculated total aluminum content minus the amorphous aluminum content is used to obtain the crystalline aluminum content in the aluminum adjuvant.

[0191] In Comparative Example 2, the test concentrations of the test products are shown in Table 7 below:

[0192] Table 7 Total aluminum content, amorphous aluminum content and crystalline aluminum content in five test samples

[0193]

[0194]

[0195] As shown in Table 7, in Comparative Example 2, the amorphous aluminum content tested by the pharmacopoeia method is relatively low. The reason may be the influence caused by the low concentration of the acid solution added in the pharmacopoeia method. It shows that a high concentration of acid solution needs to be introduced to facilitate the full destruction of amorphous aluminum hydroxide.

[0196] Comparative Example 3

[0197] Comparative Example 3 uses the same five aluminum adjuvant test samples as Example 3, and the determination method also uses the determination method of the present invention. The difference is that compared with Example 3, the amount of alkaline solution is reduced. In Example 3, the alkaline solution is a 6% potassium hydroxide solution, and the amount is 20ml. In Comparative Document 3, the alkaline solution is also a 6% potassium hydroxide solution, and the amount is 0.5ml.

[0198] In Comparative Example 3, the test concentrations of the test products are shown in Table 8 below:

[0199] Table 8 Total aluminum content, amorphous aluminum content and crystalline aluminum content in five test samples

[0200]

[0201] By comparing Table 3 and Table 8, it can be seen that after reducing the amount of alkaline solution used, the content of crystalline aluminum is low, and the calculated proportion of crystalline aluminum in the aluminum adjuvant is reduced. This is because the amount of alkaline solution used is small, resulting in incomplete destruction of the high crystallinity component in the aluminum adjuvant.

[0202] Comparative Example 4

[0203] Comparative Example 4 uses the same five aluminum adjuvant test samples as Example 3, and the determination method also uses the determination method of the present invention. The difference is that compared with Example 3, the concentration of the alkaline substance in the alkaline solution of Comparative Example 4 is increased. In Example 3, the alkaline solution is a 6% potassium hydroxide solution, and the amount is 20ml. In Comparative Document 3, the alkaline solution is a 30% potassium hydroxide solution, and the amount is 20ml.

[0204] In Comparative Example 4, the test concentrations of the test products are shown in Table 9 below:

[0205] Table 9 Total aluminum content, amorphous aluminum content and crystalline aluminum content in five test samples

[0206]

[0207] By comparing Table 3 and Table 9, it can be seen that after increasing the concentration of the alkaline substance in the alkaline solution, the high crystallinity component in the aluminum adjuvant is completely destroyed, and the result is not significantly different from Example 3. However, due to the high concentration of the added alkaline substance, the amount of the added acidic solution for pH adjustment is increased, the indicator concentration in the system is reduced, and the color is difficult to observe.

[0208] See also Fig.10As shown, the present invention provides a device 100 for determining the aluminum content in an aluminum adjuvant. The device 100 can automatically control the titration process and the titration end point, and the measurement is accurate. It can automatically drip a pH regulator, an indicator solution, and the like in the above-mentioned method for determining the aluminum content in an aluminum adjuvant, and use a high-precision automatic dripping system, with an accuracy of 0.5% within each dripping amount range.

[0209] A device 100 for determining aluminum content includes a base 10 and a titration component 20, an image comparison component 30, a control component 40 and a calibration component (not shown) arranged on the base 10.

[0210] The base 10 is provided with a power supply installation portion 11 for connecting an external power supply. The upper surface of the base 10 is a detection plane. The titration component 20 is arranged on the upper surface.

[0211] The titration assembly 20 is configured to titrate the solution to be titrated using the above-mentioned method for determining the aluminum content in the aluminum adjuvant. The titration assembly 20 includes a driving unit (not shown), a dropping unit 21 , a liquid storage unit 22 and a reaction unit 23 .

[0212] The aluminum adjuvant of the test sample is arranged in the reaction part 23. In addition, a heating element is arranged below the reaction part 23 to heat the liquid in the reaction part 23 for reaction.

[0213] An opening is provided above the reaction part 23 to facilitate the dropping part 21 to drop liquid into the reaction part through the opening.

[0214] Furthermore, a stirring device, such as a magnetic stirrer, may be provided in the reaction part 23 to facilitate uniform mixing of the solution in the reaction part.

[0215] The liquid storage part 22 is provided with an alkaline solution, an acidic solution, a disodium ethylenediaminetetraacetic acid titration solution, an acetate buffer solution and an indicator solution. Different liquids are placed separately to avoid mutual influence.

[0216] A mechanical part is arranged above the liquid storage part 22, and a dropping part 21 is arranged on the mechanical part. The dropping part 21 and various liquids in the liquid storage part 22 are connected through pipelines respectively, and the liquid storage part 22 and the dropping part 21 are connected by a driving part to drive the titration liquid to the dropping part 21 and titrate it to the reaction part 23.

[0217] Optionally, the driving unit is a peristaltic pump.

[0218] Optionally, the mechanical part is movably arranged above the liquid storage part 22. The mechanical part includes a lifting system 24 and a horizontal mechanical arm 25, and the dripping part 21 is arranged on the horizontal mechanical arm 25. The lifting system 24 can drive the horizontal mechanical arm 25 and the dripping part 21 to move up and down.

[0219] Optionally, the dripping part 21 is a dripping tube. The dripping tube extends vertically and is at least partially close to the reaction part 23 or extends into the reaction part 23 through an opening.

[0220] Optionally, in order to improve accuracy, different solutions in the liquid storage portion 22 can be dripped through different dripping tubes. Of course, the same dripping tube can also be used for dripping. When using the same dripping tube, the dripping tube is cleaned and dried before use.

[0221] The image comparison component 30 is connected to the control component 40 by signal, and is used to control the automatic customized dripping of the dripping end point. The image comparison component 30 includes a visual recognition system and a comparison analysis system. Among them, the visual recognition system can obtain a picture of the solution to be titrated, and the comparison analysis component can compare and analyze the picture with a preset picture to accurately control the titration end point, avoid manual errors, and improve the accuracy of the measurement.

[0222] The control component 40 is disposed on the base 10 and is provided with a screen, which is an input screen, so as to facilitate the selection of different dosages and dripping speeds and other parameters according to different reagents. The control component 40 can automatically control the dripping amount, dripping speed, dripping time and interval time of the measuring device 100 based on the comparison and analysis results of the image comparison component 30, and automatically calculate the aluminum content in the aluminum adjuvant according to the consumed volume of the titration solution.

[0223] The calibration component can calibrate the dripping accuracy of the drive unit by volume analysis. Due to the different diameters of different pipelines, the calibration component can accurately set the discharge volume corresponding to each revolution of the peristaltic pump, which can ensure the dripping accuracy of the peristaltic pump and achieve a dripping volume of less than 0.5% in milliliters or microliters of liquid processing.

[0224] The specific steps are as follows:

[0225] The aluminum adjuvant of the test sample is arranged in the reaction part 23, and the reaction part 23 can be automatically heated and stirred. The heating temperature and heating time are controlled by the control component 40.

[0226] The alkaline solution is dropped into the reaction part 23 through the dropping part 21, and is heated and dissolved to form a primary mixed solution.

[0227] The acidic solution is dripped into the reaction part 23 through the dripping part 21 to adjust the pH of the initial mixed solution to form a first mixed solution.

[0228] The disodium ethylenediaminetetraacetic acid titration solution and the acetate buffer solution are dripped into the reaction part 23 through the dripping part 21 to form a first solution to be titrated.

[0229] The indicator is dripped into the reaction part 23 through the dripping part 21, and the zinc titration solution is dripped into the reaction part 23 through the dripping part 21. The dripping amount, dripping speed, dripping time and interval time are controlled by the control component 40.

[0230] The visual recognition system in the image comparison and analysis component 30 can obtain a picture of the solution to be titrated in real time, and the comparison and analysis component can compare and analyze the picture with a preset picture to accurately control the titration endpoint, avoid manual errors, and improve measurement accuracy.

[0231] The control component 40 automatically calculates the total aluminum content in the aluminum adjuvant based on the comparison analysis result of the image comparison component and the consumed volume of the titration solution.

[0232] Similarly, when determining the amorphous aluminum content, the above steps can be referred to for operation, which will not be described in detail here.

[0233] It is important to know that in specific operations, the dripping range can be set arbitrarily from microliters to liters, and multiple modes are available: continuous dripping or intermittent dripping, the dripping speed and the number of dripping times, as well as the time interval between each dripping can be set as needed (including the time required for dripping). For example, if the user selects a dripping speed of 12ml / min, the amount of each drip is 4.5ml, divided into 5 times in a row, and the interval time is 30 seconds, including the time required for dripping. The control mode can be automatic, manual or foot-operated.

[0234] In summary, the method for determining the aluminum content in an aluminum adjuvant of the present invention can accurately and quickly detect the total aluminum content, amorphous aluminum content adjuvant and crystalline aluminum content in a complex crystalline aluminum adjuvant, thereby making up for the defect that the aluminum content in a complex crystalline aluminum adjuvant cannot be accurately measured in the prior art, and is of great significance for the analysis in the development process of aluminum adjuvants and the quality control of finished products. In addition, the determination method of the present invention is simple to operate, the experimental temperature is low, the detection cost is low, and the detection results are accurate and reliable. The device for determining the aluminum content in an aluminum adjuvant of the present invention can accurately identify the titration endpoint, fully automate the titration control, and reduce the error of manual titration.

[0235] The above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for determining the aluminum content in an aluminum adjuvant, characterized in that: The method for determining the total aluminum content in the aluminum adjuvant comprises: The aluminum adjuvant is heated and dissolved in the alkaline solution to form a primary mixed solution; adding an acidic solution to the primary mixed solution so that the primary mixed solution reaches a target pH, thereby forming a first mixed solution; Adding disodium ethylenediaminetetraacetic acid titration solution and acetate buffer to the first mixed solution, heating and then taking out and cooling to room temperature to form a first solution to be titrated; After adding the indicator solution to the first solution to be titrated, the solution is titrated with zinc titrant until it changes color, and the total aluminum content in the aluminum adjuvant is calculated based on the volume of the consumed titrant, wherein the total aluminum content includes the amorphous aluminum content and the crystalline aluminum content.

2. The method for determining the aluminum content in an aluminum adjuvant according to claim 1, characterized in that: The alkaline substance in the alkaline solution includes any one of sodium hydroxide, potassium hydroxide and ammonia water, and the concentration of the alkaline substance in the alkaline solution is 0.5-20%.

3. The method for determining the aluminum content in an aluminum adjuvant according to claim 1, characterized in that: The method for determining the content of amorphous aluminum in the aluminum adjuvant comprises: heating and dissolving the aluminum adjuvant in the acidic solution to form a second mixed solution; Adding disodium ethylenediaminetetraacetic acid titration solution and buffer solution to the second mixed solution, heating and then taking out and cooling to room temperature to form a second solution to be titrated; After adding the indicator solution to the second solution to be titrated, the solution is titrated with zinc titrant until the solution changes color, and the amorphous aluminum content in the aluminum adjuvant is calculated based on the volume of the consumed titrant.

4. The method for determining the aluminum content in an aluminum adjuvant according to claim 3, characterized in that: The crystalline aluminum content in the aluminum adjuvant is equal to the difference between the total aluminum content and the amorphous aluminum content.

5. The method for determining the aluminum content in the aluminum adjuvant according to claim 1 or 3, characterized in that: The acidic substance in the acidic solution includes any one of hydrochloric acid, acetic acid, phosphoric acid, nitric acid, sulfuric acid and lactic acid, and the concentration of the acidic substance in the acidic solution is 50-100%.

6. The method for determining the aluminum content in an aluminum adjuvant according to claim 1 or 3, characterized in that: The concentration of the disodium ethylenediaminetetraacetic acid titration solution is 0.05-1 mol / L, the ratio of the amount of the disodium ethylenediaminetetraacetic acid titration solution added to the amount of the aluminum adjuvant added is 10-1, the pH value of the acetate buffer solution is 3.0-6.5, and the ratio of the amount of the buffer solution added to the amount of the disodium ethylenediaminetetraacetic acid titration solution added is 1-5.

7. The method for determining the aluminum content in an aluminum adjuvant according to claim 1 or 3, characterized in that: The indicator solution comprises any one or a combination of methyl red and xylenol orange, and the ratio of the added amount of the indicator solution to the added amount of the disodium ethylenediaminetetraacetic acid titration solution is 0.05-0.

5.

8. The method for determining the aluminum content in an aluminum adjuvant according to claim 1, characterized in that: The measuring range of aluminum adjuvant in the determination method is 0.01-15 mg / ml.

9. A device for measuring the aluminum content in an aluminum adjuvant, characterized in that: include: A titration component configured to titrate a solution to be titrated using the method for determining the aluminum content in an aluminum adjuvant according to any one of claims 1 to 8; A picture comparison component, which obtains a picture of the solution to be titrated, and compares and analyzes the picture with a preset picture; Control components; Based on the comparison and analysis results of the image comparison component, the dripping amount, dripping speed, dripping time and interval time of the measuring device are automatically controlled, and the aluminum content in the aluminum adjuvant is automatically calculated according to the consumed volume of the titration solution.

10. The device for measuring the aluminum content in an aluminum adjuvant according to claim 9, characterized in that: The titration component includes a driving part, a dropping part, a liquid storage part and a reaction part; the solution to be titrated is arranged in the reaction part, and the titration liquid is arranged in the liquid storage part; the driving part connects the liquid storage part and the dropping part, and is configured to drive the titration liquid to the dropping part and titrate it to the reaction part; the measuring device also includes a calibration component, and the calibration component is configured to calibrate the dropping accuracy of the driving part.

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