Method for determining palladium element impurity in iodixanol by using iridium element as internal standard element

Abstract

The invention discloses a method for determining a palladium element impurity in iodixanol by using an iridium element as an internal standard element. The method is good in specificity and high in sensitivity, trace residues of palladium (Pd) element impurities in iodixanol can be effectively detected, interference of sample treatment on impurity detection is effectively reduced, it is ensured that the palladium (Pd) element impurities can be accurately quantified, and the requirements of laws and regulations for residue detection of the palladium (Pd) element impurities are met.

Description

Technical Field

[0001] This invention relates to the field of chemical drug analysis and detection technology, specifically to a method for determining palladium impurities in iodixanol using iridium as an internal standard. Background Technology

[0002] Iodixanol is often used clinically as a contrast agent. It organically binds with iodine and absorbs radiation in blood vessels or tissues in the body, and is commonly used for contrast and imaging.

[0003] Palladium (Pd) is a route-dependent toxin that can be introduced into the human body through manufacturing processes and routes of administration. It is relatively likely to be found in pharmaceuticals, and its source and route of administration should be subject to risk assessment. Iodixanol uses palladium-containing catalysts in its manufacturing process; therefore, palladium (Pd) is an element intentionally added during iodixanol production. ICH Q3D(R2) requires a risk assessment of samples containing intentionally added palladium (Pd).

[0004] However, there is currently no literature on the control of palladium (Pd) impurities in iodixanol. The maximum daily dosage of iodixanol contrast agent reaches tens of grams, resulting in a very small limit for palladium (Pd) impurities. For iodixanol, which is readily soluble in water, pretreatment by changing the digestion method is not feasible. Existing techniques commonly employ pharmacopoeia-provided methods such as heavy metal testing, atomic absorption spectrometry, and standard addition methods to detect palladium, often using indium (In) as an internal standard. However, the standard addition method requires adding the sample to a linear solution, adding many weighing steps, making the operation cumbersome. Furthermore, excessively high sample concentrations can easily clog the injection cone, causing instrument malfunction. When using Indium as an internal standard, the matrix effect is too strong, affecting the In response and failing to meet accuracy requirements.

[0005] This invention employs inductively coupled plasma mass spectrometry (ICP-MS) with iridium (Ir) as an internal standard to determine the impurity content of palladium (Pd) in iodixanol. The operation is simple and easy to perform, does not damage the instrument, meets the sensitivity requirements, and fills the gap in the research method of palladium impurity in iodixanol. Summary of the Invention

[0006] The purpose of this invention is to provide a method for determining palladium (Pd) impurities in iodixanol using iridium (Ir) as an internal standard element, which is simple and easy to operate.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] A method for determining palladium impurities in iodixanol using iridium as an internal standard includes the following steps:

[0009] 1) Preparation of the test solution

[0010] Accurately weigh an appropriate amount of iodixanol, dilute it with diluent, and shake well to obtain the test solution;

[0011] 2) Preparation of a series of linear solutions

[0012] A series of linear solutions were prepared by diluting a 1000 μg / mL national standard solution of palladium with a diluent.

[0013] 3) Prepare internal standard solution

[0014] Iridium was selected as the internal standard element, and the national standard solution of iridium (1000 μg / mL) was diluted with diluent to prepare the internal standard solution.

[0015] 4) Prepare blank solution

[0016] Blank solution: diluent;

[0017] 5) Measurement

[0018] The test solution, blank solution, and a series of linear solutions were measured and injected into the inductively coupled plasma mass spectrometer. An internal standard solution was added online during the measurement. The concentration of palladium in the iodixanol solution was calculated by linear equation to obtain the residual amount of palladium impurity in iodixanol.

[0019] Specifically, the test solution is prepared as follows: accurately weigh approximately 50 mg of iodixanol and place it in a 10 mL plastic volumetric flask, dilute with diluent, bring to volume, and shake well.

[0020] Specifically, the concentrations of the series of linear solutions are: 0.03 ng / mL, 0.09 ng / mL, 0.15 ng / mL, 0.3 ng / mL, 0.45 ng / mL, and 0.6 ng / mL.

[0021] Specifically, the concentration of the internal standard solution is 20 ng / mL.

[0022] Specifically, the diluent is a 2% dilute nitric acid solution.

[0023] Specifically, the operating parameters of the inductively coupled plasma mass spectrometer (ICP-MS) are as follows:

[0024]

[0025] Specifically, this detection method can quantitatively detect palladium down to a minimum of 0.0011 ppm.

[0026] Compared with the prior art, the present invention has the following beneficial technical effects:

[0027] (1) Compared with the heavy metal testing methods provided in the pharmacopoeia, the method of the present invention has better specificity and greatly improved sensitivity, and can effectively detect trace residues of palladium (Pd) element impurities in a certain amino acid, meeting the regulatory requirements for the residual detection of palladium (Pd) element impurities.

[0028] (2) Compared with pharmacopoeia methods and other methods such as atomic absorption detection, the method of the present invention uses internal standard calibration, which can effectively reduce the interference of sample processing on impurity detection and ensure that palladium (Pd) element impurities can be accurately quantified.

[0029] (3) Compared with the standard addition method of inductively coupled plasma mass spectrometry of the same type, the standard addition method requires adding the sample to the linear solution, which increases many weighing steps, is cumbersome, and the sample concentration is too high, which can easily cause the injection cone to block and cause instrument failure. The method of the present invention uses the uncommon iridium (Ir) element as the internal standard element for calibration, which does not require adding the sample to the linear solution. The method is simple and easy to implement and does not damage the instrument.

[0030] (4) The method of the present invention can fill the gap in the research method of palladium element impurity in iodixanol and provide a reference for the research of other element impurities in iodixanol. Attached Figure Description

[0031] Figure 1 This is the standard curve of impurity palladium. Detailed Implementation

[0032] To enhance understanding of the present invention, the present invention will be further described in detail below with reference to embodiments and accompanying drawings. These embodiments are only used to explain the present invention and do not constitute a limitation on the scope of protection of the present invention.

[0033] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0034] The detection method described in this invention is mainly for the detection of palladium elemental impurities, and is calculated using the standard curve method.

[0035] The information on the instruments and reagents used in the implementation of the detection method of the present invention is shown in the table below:

[0036]

[0037] Example 1

[0038] This embodiment provides a method for detecting palladium impurities in iodixanol using iridium as an internal standard.

[0039] 1. Testing conditions

[0040] The operating parameters of the inductively coupled plasma mass spectrometer (ICP-MS) are shown in Table 1 below:

[0041] Table 1: Instrument Parameters

[0042]

[0043] 2. Detection Method

[0044] (1) Diluent: 2% dilute nitric acid solution

[0045] (2) Preparation of test solution

[0046] Test solution: Accurately weigh about 50 mg of iodixanol and place it in a 10 mL plastic volumetric flask. Dilute with diluent, bring to volume, and shake well.

[0047] (3) Preparation of reference solution

[0048] Stock solution 1 (Pd: 2000ng / mL): Accurately measure 0.1mL of the national standard solution of palladium into a 50mL plastic volumetric flask, dilute with diluent, bring to volume, and mix well;

[0049] Stock Solution 2 (Pd: 6ng / mL): Accurately measure 0.15mL of Stock Solution 1 to 50mL into a plastic volumetric flask, dilute with diluent, bring to volume, and mix well;

[0050] Reference solution (system suitability solution) (Pd: 0.3 ng / mL): Accurately measure 2 to 10 mL of 0.5 mL stock solution into a plastic volumetric flask, dilute with diluent, bring to volume, and mix well;

[0051] (4) Prepare an internal standard solution using iridium as the internal standard element.

[0052] Internal standard stock solution (Ir: 4000 ng / mL): Accurately measure 0.2 mL of the national standard solution of iridium into a 50 mL plastic volumetric flask, dilute with diluent, bring to the mark, and mix well.

[0053] Internal standard solution (Ir: 20 ng / mL): Accurately measure 0.25 mL of the internal standard stock solution into a 50 mL plastic volumetric flask, dilute with diluent, bring to volume, and mix well;

[0054] (5) Preparation of a series of linear solutions

[0055] Linear blank solution BLK: diluent.

[0056] Linear solution L-1 (Pd: 0.03 ng / mL): Accurately measure 0.05 mL of the stock solution into a plastic volumetric flask, dilute with diluent, bring to the mark, and mix well;

[0057] Linear solution L-2 (Pd: 0.09 ng / mL): Accurately measure 0.15 mL of the stock solution into a plastic volumetric flask, dilute with diluent, bring to the mark, and mix well;

[0058] Linear solution L-3 (Pd: 0.15 ng / mL): Accurately measure 0.25 mL of the stock solution into a plastic volumetric flask, dilute with diluent, bring to the mark, and mix well;

[0059] Linear solution L-4 (Pd: 0.3 ng / mL): Accurately measure 0.5 mL of the stock solution into a plastic volumetric flask, dilute with diluent, bring to volume, and mix well;

[0060] Linear solution L-5 (Pd: 0.45 ng / mL): Accurately measure 2 to 10 mL of the stock solution into a plastic volumetric flask, dilute with diluent, bring to volume, and mix well;

[0061] Linear solution L-6 (Pd: 0.6 ng / mL): Accurately measure 1 mL of the stock solution into a plastic volumetric flask and dilute with diluent to the mark. Mix well.

[0062] (6) Accurately measure the test solution, blank solution and series of linear solutions respectively, and inject them into the inductively coupled plasma mass spectrometer. Add the internal standard solution online during the measurement. With the corrected response value y of palladium as the ordinate and the concentration x as the abscissa, calculate the concentration of palladium in the iodixanol solution through the linear equation to obtain the residual amount of palladium impurity in iodixanol.

[0063] 3. Formula for calculating the residual amount of palladium impurity

[0064]

[0065] In the formula: C X —Concentration of palladium impurities in the test solution —Concentration of palladium in the blank solution;

[0066] V X —The dilution volume of the test sample;

[0067] W X —The sample weight.

[0068] Example 2: Comparison of Ir and Sc elements as internal standards

[0069] 100% limit spiking solution: Accurately weigh approximately 50 mg of iodixanol and place it in a 10 mL plastic volumetric flask. Add 0.5 mL of stock solution II, dilute with diluent, and bring to the mark. Shake well.

[0070] Internal standard stock solution 2 (Sc: 4000 ng / mL): Accurately measure 0.2 mL of the national standard solution of scandium into a 50 mL plastic volumetric flask, dilute with diluent, bring to volume, and mix well.

[0071] Internal standard solution 2 (Sc: 20ng / mL): Accurately measure 0.25mL of internal standard stock solution 2 into a 50mL plastic volumetric flask, dilute with diluent, bring to volume, and mix well;

[0072] Take 100% limit spiked solution and test solution under Example 1, inject them into inductively coupled plasma mass spectrometer according to the detection conditions of Example 1, add internal standard solution II and internal standard solution under Example 1 online respectively, and determine the recovery rate of palladium impurities. The results are shown in Tables 2 and 3 below.

[0073] Table 2: Recovery results of palladium (Pd) with scandium as internal standard

[0074] Pd Weigh (mg) Measured amount (ppm) Dosage (ppm) Recovery rate (%) Sample 51.84 0.000 NA NA Recovery 100% 52.47 0.038 0.057 65.65

[0075] Table 3: Recovery results of palladium (Pd) with iridium as internal standard

[0076] Pd Weigh (mg) Measured amount (ppm) Dosage (ppm) Recovery rate (%) Sample 51.84 0.001 NA NA Recovery 100% 52.47 0.064 0.057 110.30

[0077] Experimental results show that the recovery rate of palladium (Pd) with scandium as internal standard is not in the range of 70% to 150%, while the recovery rate of palladium (Pd) with iridium as internal standard is not in the range of 70% to 150%. Therefore, iridium was chosen as the internal standard element for the determination of palladium.

[0078] Example 3: Repeatability Detection

[0079] Following the preparation method of the test solution in Example 1, three different batches of test solutions were prepared, with two parallel preparations of each batch. The solutions were injected into the inductively coupled plasma mass spectrometer according to the detection conditions in Example 1. The results are shown in Table 4 below.

[0080] Table 4: Repeatability Test Results

[0081] Sample number Palladium (Pd) (ppm) Sample 1-1 0.002 Sample 1-2 0.002 Average value (sample 1) 0.002 Sample 2-1 0.001 Sample 2-2 0.001 Average value (sample 2) 0.001 Sample 3-1 0.001 Sample 3-2 0.001 Average value (sample 3) 0.001 limit 0.06

[0082] As shown in the table above, the palladium impurities in all three batches of iodixanol met the limit requirements.

[0083] Example 4: Linear Examination

[0084] The test solution, blank solution, internal standard solution, and linear solutions from Example 1 were taken. The internal standard solution was added online during the determination, and the solutions were injected into the inductively coupled plasma mass spectrometer according to the detection conditions of Example 1. The working curve of palladium was obtained by plotting the corrected response value y of palladium on the ordinate and the concentration x on the abscissa. The results are shown in Table 5 and... Figure 1 .

[0085] Table 5: Linearity Results for Palladium (Pd)

[0086] element Linear equations Correlation coefficient r Palladium (Pd) y = 9380.8935 * x + 5.5313 0.999

[0087] The results in the table above show that the linear correlation coefficient r of palladium (Pd) impurities is not less than 0.990, indicating a good linear relationship.

[0088] Example 5: Recovery Rate Study

[0089] 100% limit spiking solution: Accurately weigh approximately 50 mg of iodixanol and place it in a 10 mL plastic volumetric flask. Add 0.5 mL of stock solution II, dilute with diluent, and bring to the mark. Shake well.

[0090] Take 100% limit spiked solution, as well as system suitability solution, linear solution, blank solution and test solution under Example 1, and inject them into inductively coupled plasma mass spectrometry according to the detection conditions of Example 1 to determine the recovery rate of palladium impurities. The results are shown in Tables 6 to 8 below.

[0091] Table 6: System Applicability Results

[0092] No. Pd element response value (cps) STD-1 3064 STD-2 3096 STD-3 3089 STD-4 3021 STD-5 2896 STD-6 2944 STD response value RSD (%) 2.72

[0093] Table 7: Linearity Results for Palladium

[0094] element Linear equations Correlation coefficient r Palladium (Pd) y = 9380.8935 * x + 5.5313 0.999

[0095] Table 8: Palladium (Pd) Recovery Results

[0096] Pd Weigh (mg) Measured amount (ppm) Dosage (ppm) Recovery rate (%) Sample 50.70 0.001 NA NA Recovery 100% 50.47 0.062 0.059 101.35

[0097] Experimental results show that the recovery rate of palladium (Pd) is in the range of 70% to 150%, which meets the requirements.

[0098] Example 6: Sensitivity Test

[0099] Take the blank solution of the test sample under Example 1 and inject it into the instrument according to the detection conditions of Example 1. The limit of detection for the analyte is defined as three times the standard deviation (3SD) of 11 consecutive measurements of the blank solution concentration, and the limit of quantitation is defined as ten times the standard deviation (10SD) of 11 consecutive measurements of the blank solution concentration. The results are shown in Table 9 below.

[0100] Table 9: Calculation Results of Limit of Detection and Limit of Quantitation

[0101]

[0102] Note: Detection limit (ppm) = Detection limit (ng / mL) ÷ Sample concentration (mg / mL)

[0103] Limit of quantitation (ppm) = Limit of quantitation (ng / mL) ÷ Sample concentration (mg / mL)

[0104] Experimental results show that the detection limit for palladium is below 10% and the quantitation limit is below 30%, which meets the requirements.

[0105] This invention uses iridium (Ir) as an internal standard element and employs ICP-MS detection. This method exhibits high specificity, effectively reduces interference from sample processing, and significantly improves sensitivity. It can effectively detect trace amounts of palladium (Pd) impurities in a specific amino acid, ensuring accurate quantification of Pd impurities. This method is simple and easy to implement, does not damage instruments, and fills a gap in the research methods for palladium impurities in iodixanol, providing a reference for the study of other elemental impurities in iodixanol.

[0106] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the invention.

Claims

1. A method for determining palladium impurities in iodixanol using iridium as an internal standard, characterized in that, Includes the following steps: 1) Preparation of the test solution Accurately weigh an appropriate amount of iodixanol, dilute it with diluent, and shake well to obtain the test solution; 2) Preparation of a series of linear solutions A series of linear solutions were prepared by diluting a 1000 μg / mL national standard solution of palladium with a diluent. 3) Prepare internal standard solution Iridium was selected as the internal standard element, and the national standard solution of iridium (1000 μg / mL) was diluted with diluent to prepare the internal standard solution. 4) Prepare blank solution Blank solution: diluent; 5) Measurement The test solution, blank solution, and a series of linear solutions were measured and injected into the inductively coupled plasma mass spectrometer. An internal standard solution was added online during the measurement. The concentration of palladium in the iodixanol solution was calculated by linear equation to obtain the residual amount of palladium impurity in iodixanol.

2. The method according to claim 1, characterized in that, The method for preparing the test solution is as follows: accurately weigh about 50 mg of iodixanol and place it in a 10 mL plastic volumetric flask, dilute with diluent, bring to volume, and shake well.

3. The method according to claim 1, characterized in that, The concentrations of the linear solutions are: 0.03 ng / mL, 0.09 ng / mL, 0.15 ng / mL, 0.3 ng / mL, 0.45 ng / mL, and 0.6 ng / mL.

4. The method according to claim 1, characterized in that, The concentration of the internal standard solution was 20 ng / mL.

5. The method according to claim 1, characterized in that, The diluent is a 2% dilute nitric acid solution.

6. The method according to claim 1, characterized in that, The operating parameters of the inductively coupled plasma mass spectrometer are as follows:

7. The method according to claim 1, characterized in that, This detection method can quantitatively detect palladium as low as 0.0011 ppm.

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