Method for determining peroxide value in liquid medicine preparation containing surfactant

Abstract

According to the method for determining the peroxide value in the liquid medicine preparation containing the surfactant, the use of an organic solvent is avoided, the harm to a human body and the environmental pollution are not caused, the method is green and environment-friendly, and meanwhile, the detection cost is low; the method has the advantages of extremely low sample consumption, high sensitivity and good repeatability.

Description

Technical Field

[0001] The invention belongs to the field of drug detection, and in particular relates to a method for determining the peroxide value in a drug liquid preparation containing a surfactant. Background Art

[0002] In order to increase the solubility of drugs, improve the stability of drugs, and improve the suspension effect of suspension liquid preparations, a variety of pharmaceutical excipients such as emulsifiers and solubilizers are often added to pharmaceutical liquid preparations. The characteristics of the excipients have a significant impact on the quality of liquid preparations. Commonly used solubilizers in pharmaceutical liquid preparations include Tweens (polysorbates) and poloxamers. Such excipients often contain ether bonds or double bonds in their molecular structures and are easily oxidized to produce peroxides. Peroxides are unstable and can continue to decompose into aldehydes, ketones, acids and other small molecular compounds that are harmful to human health. Therefore, it is necessary to accurately detect and control the peroxide value of pharmaceutical liquid preparations.

[0003] The peroxide value detection in the General Chapter 0713 of Part IV of the 2020 Edition of the Chinese Pharmacopoeia adopts the chemical titration method, but this method requires the use of a large amount of toxic and harmful organic solvents such as chloroform, which poses a threat to the health of operators, and the subsequent treatment of the waste liquid is difficult, which increases the detection cost; using the manual titration method, it is not easy to control the amount of titrant added, which is easy to cause operational errors; in addition, the detection endpoint of this method needs to be determined by observing the color change by human eyes, which leads to the existence of artificial subjective errors, and there is also color interference problem for colored or dark samples, and the method has poor reproducibility; the method stipulates that the detection dosage is 5g, and the content of solubilizers in general drug preparations is low. In order to achieve the detection dosage and the corresponding detection concentration, a large amount of samples are required for concentration and enrichment. The pretreatment process may cause the peroxide value to increase, resulting in inaccurate results, and also increases the difficulty of detection. If the drug liquid preparation is directly used for detection without pretreatment, its peroxide value is low, difficult to detect, and the result is not accurate.

[0004] The document "Iodometric Potentiometric Titration of the Peroxide Value of Sirolimus Oral Solution" discloses a potentiometric titration method for determining the peroxide value in a pharmaceutical preparation, using methanol instead of traditional chloroform, which reduces the toxicity of the reagent used to a certain extent. However, this method still has certain defects: 1. The literature does not provide data on the accuracy of the method. When we repeated the method, we found that the method had low accuracy; 2. The lowest total peroxide value detected by the literature method is 14.8 μmol, the method has a high detection limit, and the sample usage is large; 3. Methanol is used in the method, which increases the detection cost and pollutes the environment; 4. Acetic acid is used in the method to adjust the pH, and acetic acid has the problem of peroxidation, causing detection errors; 5. The method is vigorously stirred during titration, which easily causes the original iodine and the generated iodine in the system to volatilize, resulting in low test results.

[0005] Therefore, in view of the defects of the prior art, it is necessary to explore a more accurate, rapid and low-cost method for determining the peroxide value of liquid preparations of surfactant-containing drugs. Summary of the invention

[0006] The purpose of the present invention is to provide a method for determining the peroxide value of a surfactant-containing liquid pharmaceutical preparation, aiming to solve the technical problems of poor detection accuracy, high detection limit and non-green environmental protection of the peroxide value in the existing surfactant-containing liquid pharmaceutical preparations.

[0007] To achieve the above-mentioned object of the invention, the present invention provides a method for determining the peroxide value in a pharmaceutical liquid preparation containing a surfactant, comprising the following steps:

[0008] The pharmaceutical liquid preparation containing a surfactant is diluted with water to obtain a sample to be tested, the pH is adjusted to acidity with phosphoric acid, potassium iodide solution is added, and then iodine titration solution is added to the solution, mixed evenly, reacted in a dark place, titrated with sodium thiosulfate titration solution, and the peroxide value of the pharmaceutical liquid preparation is calculated according to the amount of sodium thiosulfate used.

[0009] According to an embodiment of the present invention, the surfactant is selected from non-ionic surfactants, such as at least one of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and poloxamer.

[0010] According to an embodiment of the present invention, the peroxide value of the sample to be tested may be 0.5-100 μmol, more preferably 1-50 μmol.

[0011] According to an embodiment of the present invention, the pH value may be adjusted to about 4-5 by using phosphoric acid to adjust the pH value to acidic.

[0012] According to an embodiment of the present invention, the potassium iodide solution is a saturated potassium iodide aqueous solution.

[0013] According to an embodiment of the present invention, based on the volume of the sample to be tested being 100 v, the amount of potassium iodide solution added may be 1-20 v, more preferably 6-10 v.

[0014] According to an embodiment of the present invention, potassium iodide solution is added, shaken, and then iodine titrant is added to the solution. The shaking time is, for example, 0.5-8 minutes, such as 1-5 minutes.

[0015] According to an embodiment of the present invention, the concentration of the iodine titration solution is 0.0005-0.01 mol / L, preferably 0.001-0.005 mol / L, such as 0.001 mol / L, 0.002 mol / L, 0.003 mol / L.

[0016] According to an embodiment of the present invention, based on the volume of the sample to be tested as 100 v, the volume of the iodine titration solution added may be 0.125-50 v, for example 0.5-20 v, such as 1 v, 2 v, 5 v, 8 v, 10 v;

[0017] According to an embodiment of the present invention, based on the volume of the sample to be tested being 100v, the iodine titrant is 0.5v of 0.005mol / L iodine aqueous solution.

[0018] According to an embodiment of the present invention, the reaction time in the dark is 5-12 min, such as 6-10 min.

[0019] According to an embodiment of the present invention, the concentration of the sodium thiosulfate titration solution is 0.0005-0.01 mol / L, for example, 0.001-0.005 mol / L, such as 0.001 mol / L, 0.002 mol / L, 0.003 mol / L. According to an embodiment of the present invention, the pharmaceutical liquid preparation can be selected from the suspending agent for triptorelin acetate microspheres for injection (polysorbate 80, mannitol, disodium hydrogen phosphate, sodium dihydrogen phosphate), the suspending agent for octreotide acetate microspheres for injection (poloxamer 188, sodium carboxymethyl cellulose, mannitol), the special solvent for aripiprazole microspheres for injection (polysorbate 80, mannitol, sodium carboxymethyl cellulose), paliperidone palmitate injection (polysorbate 20, polyethylene glycol 4000, citric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide).

[0020] According to an embodiment of the present invention, the titration can be performed using a potentiometric titrator, which is preferably equipped with a redox electrode.

[0021] According to an embodiment of the present invention, the titration result can be corrected by a blank test.

[0022] According to an embodiment of the present invention, the preparation method comprises the following steps:

[0023] Dilute the liquid drug preparation with water, take 100 ml, adjust the pH to about 4-5 with phosphoric acid, add 6-10 ml of saturated potassium iodide solution, shake for 0.5-5 minutes, add 1 ml or 0.5 ml of 0.005 mol / L iodine titrant, shake well, react in a dark place for 5-12 minutes, and immediately put it into a potentiometric titrator equipped with a redox electrode after the reaction is completed, and titrate with 0.001 mol / L sodium thiosulfate titrant. The peroxide value is calculated based on the amount of sodium thiosulfate used, and the titration result is corrected with a blank test.

[0024] According to an embodiment of the present invention, the peroxide value is calculated according to the following formula:

[0025] Peroxide value (μmol) = (V-V0) × C × 1000

[0026] V: volume of sodium thiosulfate titrant consumed by the sample to be tested (mL);

[0027]

[0028] C: concentration of sodium thiosulfate titration solution (mol / L).

[0029] Beneficial Effects

[0030] The present invention provides a method for determining the peroxide value of a surfactant-containing liquid pharmaceutical preparation, which has the following main advantages:

[0031] (1) Low detection limit and high accuracy, capable of measuring peroxide values ​​as low as 0.5 μmol, with a recovery rate of 88.46% to 114.10% and good repeatability;

[0032] (2) The sample amount is very small, and there is no need to enrich the sample, which also avoids the long pre-treatment time of concentration and enrichment, and the risk of increasing the peroxide value and making the measured peroxide value too large. In addition, the dilution ratio of the sample to water can be adjusted according to the actual detection requirements to meet the measurement range of different peroxide values;

[0033] (3) It avoids the use of organic solvents, does not cause harm to the human body and environmental pollution, is green and environmentally friendly, and has low detection costs. DETAILED DESCRIPTION

[0034] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0035] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0036] In Examples 1-6 of the present invention, the peroxide value in the preparation is tested by taking the suspending agent for injection of triptorelin acetate microspheres as an example, and the easily oxidizable auxiliary material in the suspending agent is polysorbate 80.

[0037] Example 1: Investigation of reaction conditions

[0038] The specific steps are as follows:

[0039] Take 100ml water (pH adjusted to about 4.50 with phosphoric acid), add 3ml 0.5μmol / ml hydrogen peroxide solution (pH adjusted to about 4.50 with phosphoric acid), shake well, add different volumes of saturated potassium iodide, shake for a certain time, add 1ml iodine titration solution (0.005mol / L), shake well, react in the dark for a certain time, and make the sample solution. Take the same volume of water (pH adjusted to about 4.50 with phosphoric acid), do not add saturated potassium iodide solution, and perform the rest of the operation as the sample solution as the blank solution. The peroxide value of hydrogen peroxide was determined by potentiometric titration. The test parameters and results are shown in Table 1.

[0040] Table 1 Reaction conditions investigation results

[0041]

[0042] Result analysis: The theoretical peroxide value of the added hydrogen peroxide in the test is about 3.0. As shown in Table 1, when the amount of saturated potassium iodide added is 6-10 ml, the shaking time after adding saturated potassium iodide is 0.5-5 min, and the dark reaction time after adding iodine titration solution is 5-12 min, the actual measured value is equivalent to the theoretical value. The test conditions can realize the accurate determination of the peroxide value of the sample.

[0043] Example 2: Investigation of different solvents and pH adjusting agents

[0044] The specific steps are as follows:

[0045] Take 100ml of solvent (adjusted to pH 4.50 with phosphoric acid), add 3ml of 0.5μmol / ml hydrogen peroxide solution (adjusted to pH 4.50 with phosphoric acid), shake well, add 6ml of saturated potassium iodide, shake for 3min, add 1ml of iodine titration solution (0.005mol / L), shake well, and place in the dark for 8min as sample solution. Take the same volume of solvent (adjusted to pH 4.50 with phosphoric acid), do not add saturated potassium iodide solution, and perform the rest of the operation as the sample solution as blank solution. The peroxide value of hydrogen peroxide was measured by potentiometric titration. The results are shown in Table 2.

[0046] Take 100ml of water (adjust pH to about 4.50 with phosphoric acid, acetic acid or formic acid), add 3ml of 0.5μmol / ml hydrogen peroxide solution (adjust pH to about 4.50 with phosphoric acid, acetic acid or formic acid), shake well, add 6ml of saturated potassium iodide, shake for 3min, add 1ml of iodine titration solution (0.005mol / L), shake well, and place in the dark for 8min as sample solution, take the same volume of water (adjust pH to about 4.50 with phosphoric acid, acetic acid or formic acid), do not add saturated potassium iodide solution, and perform the rest of the operation as the sample solution as blank solution. The peroxide value of hydrogen peroxide was measured by potentiometric titration, and the results are shown in Table 2.

[0047] Table 2 Results of investigation of different solvents and pH adjusting agents

[0048]

[0049] Result analysis: The theoretical peroxide value of the hydrogen peroxide added in the experiment is about 3.0. As shown in Table 2, the use of acetic acid or formic acid to adjust the pH makes the measured peroxide value deviate from the theoretical value, while the use of methanol or ethanol as the reaction solvent makes the measured result lower. When chloroform is used as the reaction solvent, no potential jump can be measured.

[0050] Example 3: pH range investigation

[0051] The pH of the sample solution was adjusted to 4.0-5.0 with phosphoric acid, and the pH durability range was examined.

[0052] Equipment: FiveEasy Plus FE28 pH meter

[0053] Experimental method: Accurately measure 100 ml of the suspension agent for triptorelin acetate microspheres for injection (batch number: W01Z-220608), add 3.5, 3.7, and 3.9 ml of 1% phosphoric acid solution respectively, shake well, and measure the pH value of the sample. The results are shown in Table 3.

[0054] Table 3 pH results of different 1% phosphoric acid addition amounts

[0055]

[0056] Equipment: Wantong 905 potentiometric titrator, redox electrode

[0057] Experimental method: 100ml of suspending agent for injection of triptorelin acetate microspheres (batch number: W01Z-220608) was measured, and 3.5, 3.7, and 3.9ml of 1% phosphoric acid solution were added respectively, and 6ml of saturated potassium iodide was added and shaken for 3min, and 0.5ml of iodine titration solution (0.005mol / L) was added, and shaken well, and placed in a dark place for 8min as a sample solution. Another equal volume of suspending agent for injection of triptorelin acetate microspheres was taken, and no saturated potassium iodide solution was added. The rest of the operations were the same as the sample solution, and the blank solution was used. The above experimental method was repeated twice, and the peroxide value of the suspending agent for injection of triptorelin acetate microspheres was determined by potentiometric titration. The results are shown in Table 4.

[0058] Table 4 pH durability range inspection results

[0059]

[0060]

[0061] Result analysis: Referring to the provisions of the 9101 Validation Guidelines for Analytical Methods in the General Chapters of the Fourth Part of the 2020 Edition of the Chinese Pharmacopoeia, the repeatability RSD limit of the measured component at the level of 1 μg / g is 8%. The peroxide value level in this sample is <1 μg / g. From the results in the above table, it can be seen that in the pH range of about 4-5, the measured peroxide value RSD is 3.33%, which is less than 8%, indicating that this method can be applied in the pH range of 4-5.

[0062] Example 4: Precision Study

[0063] The peroxide value of the suspension of triptorelin acetate microspheres for injection in the same batch was measured on two separate days.

[0064] Sample: Suspension agent for triptorelin acetate microspheres for injection

[0065] Equipment: Wantong 905 potentiometric titrator, redox electrode

[0066] Experimental method: accurately measure 100ml of suspending agent for injection of triptorelin acetate microspheres (batch number: W01Z-220608), add 3.7ml of 1% phosphoric acid solution, shake well, add 6ml of saturated potassium iodide and shake for 3min, add 0.5ml of iodine titration solution (0.005mol / L), shake well, place in the dark for 8min, as sample solution, take the same volume of suspending agent for injection of triptorelin acetate microspheres, do not add saturated potassium iodide solution, and perform the same operation as the sample solution as blank solution. Repeat the above experimental method twice, and determine the peroxide value of suspending agent for injection of triptorelin acetate microspheres by potentiometric titration. The results are shown in Table 5.

[0067] Table 5 Precision inspection results

[0068]

[0069] Result analysis: From the results in the above table, we can see that the RSD of the sample peroxide value measured within two days is 6.87%, which is less than the limit of 8% specified in the pharmacopoeia, and the method precision is good.

[0070] Example 5: Accuracy test

[0071] The peroxide value of triptorelin acetate microspheres suspension for injection was determined by hydrogen peroxide recovery test.

[0072] Equipment: Wantong 905 potentiometric titrator, redox electrode

[0073] Experimental method: accurately measure 100ml of suspending agent for injection of triptorelin acetate microspheres (batch number: W01Z-220621-1), add 3.7ml 1% phosphoric acid solution, shake well, add 1, 2, and 8ml 0.4μmol / mL hydrogen peroxide solution respectively, shake well, add 6ml saturated potassium iodide solution, shake for 3min, add 0.5ml iodine titration solution (0.005mol / L), shake well, react in the dark for 8min, and make the sample solution. Take the same volume of suspending agent for injection of triptorelin acetate microspheres, do not add saturated potassium iodide solution, and do the same sample solution for the rest of the operation as the blank solution. Repeat the above experimental method three times, and measure the peroxide value of the suspending agent for injection of triptorelin acetate microspheres by potentiometric titration. The results are shown in Table 6.

[0074] Table 6 Accuracy test results

[0075]

[0076] Result analysis: According to the Chinese Pharmacopoeia 2020 edition, the content of the tested component is 1μg / g and the recovery limit is 75-120% at the level of 1μg / g. The peroxide value level in this sample is <1μg / g. From the results in the above table, it can be seen that the measured recovery rate is between 88.46% and 114.10%, which meets the pharmacopoeia standards. This method has good accuracy.

[0077] Example 6: Comparison with existing methods

[0078] Equipment: Wantong 905 potentiometric titrator, redox electrode

[0079] Experimental methods:

[0080] (1) Comparative Example: Accurately measure 2 ml of hydrogen peroxide solution (0.4 μmol / ml) and place it in a titration container. Add 20 ml of methanol and shake gently to dissolve. Add 20 ml of water, add 5 ml of acetic acid-sodium acetate buffer (pH 4.5), shake well, add 2.0 ml of saturated potassium iodide solution, accurately add 5 ml of iodine titration solution (0.01 mol / L), seal tightly, shake well, place in a dark place at 15-25°C for 5 min, and titrate to the endpoint with sodium thiosulfate titration solution (0.01 mol / L) using potentiometric titration method while vigorously stirring while dripping. Separately accurately measure 2 ml of 0.4 μmol / ml hydrogen peroxide solution, except for the saturated potassium iodide solution, add the above-mentioned reaction reagents in sequence in the same way, and titrate to the endpoint with sodium thiosulfate titration solution (0.01 mol / L) as a blank test.

[0081] (2) The method of the present invention: accurately measure 2 ml of hydrogen peroxide solution (0.4 μmol / ml), put it in a beaker, add 100 ml of water, adjust the pH to 4.5 with phosphoric acid, add 6 ml of saturated potassium iodide solution, shake for 3 minutes, add 0.5 ml of iodine titrant (0.005 mol / L), shake well, react in the dark for 8 minutes, and titrate to the end point with sodium thiosulfate titrant (0.001 mol / L) by potentiometric titration while vigorously stirring while dripping; take another equal volume (0.4 μmol / ml) of hydrogen peroxide solution, except for the saturated potassium iodide solution, add the above-mentioned reaction reagents in sequence in the same way, and titrate to the end point with sodium thiosulfate titrant (0.001 mol / L) as a blank test.

[0082] Table 7 Method comparison results

[0083] method sample Measured peroxide value (μmol) Added peroxide value (μmol) Recovery rate (%) Comparative Example Hydrogen Peroxide 0.83 1.57 53.0 Method of the present invention Hydrogen Peroxide 1.61 1.57 102.8

[0084] Result analysis: From Table 7, it can be seen that the comparative example has poor accuracy when measuring the peroxide value at the 1.6 μmol level and cannot truly reflect the peroxide value of the measured sample. Compared with the comparative example, the method of the present invention has high detection sensitivity and high accuracy.

[0085] Example 7: Application of the method - Determination of peroxide value of a pharmaceutical liquid preparation

[0086] Equipment: Wantong 905 potentiometric titrator, redox electrode

[0087] Experimental samples: Suspension agent for triptorelin acetate microspheres for injection, sample numbers: 1-17 (where 1 is a normal sample, 2-4 are samples placed at 39°C for 1 day, 5 is a sample placed at 39°C for 2 days, 6 and 8 are samples placed at 39°C for 4 days, 7 is a sample placed at 39°C for 6 days, 9-11 are samples placed at 39°C for 7 days, 12-14 are samples placed at 45°C for 2 days, 17 is a sample placed at 45°C for 3.5 days, and 15 and 16 are samples placed at 45°C for 4 days); Suspension agent for octreotide acetate microspheres for injection, sample number: 18; Special solvent for aripiprazole microspheres for injection, sample number: 19; Paliperidone palmitate injection, sample number: 20; Tween 20, sample number: 21.

[0088] Experimental method: Measure (weigh) several batches of triptorelin acetate microsphere suspension for injection, octreotide acetate microsphere suspension for injection, aripiprazole microsphere special solvent for injection, paliperidone palmitate injection, Tween 20, dilute with appropriate amount of water, adjust pH to 4.5 with phosphoric acid, add 6ml saturated potassium iodide and shake for 3min, add 0.5ml iodine titration solution (0.005mol / L), shake well, place in the dark for 8min, and make sample solution. Take the same volume (mass) of liquid drug preparation, do not add saturated potassium iodide solution, and do the same sample solution for the rest of the operation as blank solution. The peroxide value of the liquid drug preparation was determined by potentiometric titration, and the results are shown in Table 8.

[0089] Table 8 Determination of peroxide value of liquid preparation containing drugs

[0090]

[0091]

[0092] Result analysis: Compared with the pharmacopoeia method, the pharmacopoeia method uses a large amount of chloroform and glacial acetic acid. These organic reagents are highly volatile, with high purchase costs and waste liquid treatment costs, and are harmful to human health. The present invention does not use organic reagents, is green and environmentally friendly, and has little harm to the health of operators. In addition, the pharmacopoeia method requires chemical titration, and the endpoint judgment is based on color change, which requires the inspector to have certain operating experience. The present invention adopts potentiometric titration, has no special requirements for operator skills, and is simple and easy. The peroxide value determination method of the present invention can meet the determination of pharmaceutical liquid preparations with different peroxide values ​​by adjusting the dilution multiple of the sample, and is a new method for determining the peroxide value of pharmaceutical liquid preparations.

[0093] The above is an exemplary description of the implementation of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of this application.

Claims

1. A method for determining the peroxide value in a pharmaceutical liquid preparation containing a surfactant, comprising the following steps: The pharmaceutical liquid preparation containing a surfactant is diluted with water to obtain a sample to be tested, the pH is adjusted to acidity with phosphoric acid, potassium iodide solution is added, and then iodine titration solution is added to the solution, mixed evenly, reacted in a dark place, titrated with sodium thiosulfate titration solution, and the peroxide value of the pharmaceutical liquid preparation is calculated according to the amount of sodium thiosulfate used.

2. The method according to claim 1, characterized in that The peroxide value of the sample to be tested is 0.5-100 μmol, for example, 1-50 μmol; Preferably, the surfactant is selected from non-ionic surfactants, such as at least one of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and poloxamer.

3. The method according to claim 1 or 2, characterized in that: The step of adjusting the pH to be acidic with phosphoric acid is to adjust the pH to about 4-5.

4. The method according to any one of claims 1 to 3, characterized in that: The potassium iodide solution is a saturated potassium iodide aqueous solution; Preferably, based on the volume of the sample to be tested being 100 v, the amount of potassium iodide solution added is 1-20 v, such as 6-10 v.

5. The method according to any one of claims 1 to 4, characterized in that: The concentration of the iodine titration solution is 0.0005-0.01 mol / L, for example 0.001-0.005 mol / L; Preferably, based on the volume of the sample to be tested being 100 v, the volume of the iodine titrant added is 0.125-50 v, such as 0.5-20 v.

6. The method according to any one of claims 1 to 5, characterized in that: Based on the volume of the sample to be tested being 100 v, the iodine titrant is a 0.5 v 0.005 mol / L iodine aqueous solution.

7. The method according to any one of claims 1 to 6, characterized in that: Add potassium iodide solution, shake, and then add iodine titrant to the solution; the shaking time is, for example, 0.5-5 minutes, such as 1-3 minutes; Preferably, the reaction time in the dark is 5-12 min, such as 6-10 min.

8. The method according to any one of claims 1 to 7, characterized in that: The concentration of the sodium thiosulfate titration solution is 0.0005-0.01 mol / L, for example 0.001-0.005 mol / L.

9. The method according to any one of claims 1 to 8, characterized in that: The liquid drug preparation is selected from the group consisting of a suspending agent for triptorelin acetate microspheres for injection (polysorbate 80, mannitol, disodium hydrogen phosphate, sodium dihydrogen phosphate), a suspending agent for octreotide acetate microspheres for injection (poloxamer 188, sodium carboxymethyl cellulose, mannitol), a special solvent for aripiprazole microspheres for injection (polysorbate 80, mannitol, sodium carboxymethyl cellulose), and paliperidone palmitate injection (polysorbate 20, polyethylene glycol 4000, citric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide).

10. The method according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: Dilute the liquid drug preparation with water, take 100 ml, adjust the pH to about 4-5 with phosphoric acid, add 6-10 ml of saturated potassium iodide solution, shake for 0.5-5 minutes, add 1 ml or 0.5 ml of 0.005 mol / L iodine titrant, shake well, react in a dark place for 5-12 minutes, and immediately put it into a potentiometric titrator equipped with a redox electrode after the reaction is completed, and titrate with 0.001 mol / L sodium thiosulfate titrant. The peroxide value is calculated based on the amount of sodium thiosulfate used, and the titration result is corrected with a blank test.

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