Method for measuring content of moisture in matched medicine box for technetium [99mTc] radiopharmaceutical injection through combination of portable gas stove and Karl Fischer moisture meter

Abstract

The invention provides a method for determining the content of moisture in a matched medicine box for injection of technetium [99mTc] radiopharmaceutical by a combined method of a cassette stove and a Karl Fischer moisture meter, which comprises the following steps: heating the medicine box by using the cassette stove, then conveying the moisture into a Karl Fischer test solution of the Karl Fischer moisture meter, stirring and then determining the moisture. According to the method, the moisture in the complex components of the stannous MIBI medicine box for injection can be accurately measured, the specificity is good, methanol and auxiliary material components have no interference in moisture detection, the accuracy is high, the reproducibility is good, the linear range is wide, and the automation degree is high.

Description

Technical Field

[0001] The present invention relates to the field of moisture detection technology, and in particular to a method for determining technetium using a combination of a furnace and a Karl Fischer titrator. 99m Method for determining the water content in a kit for injectable radiopharmaceuticals containing Tc]. Background Art

[0002] technetium [99m The kit for injection of radioactive drugs is a freeze-dried powder injection kit. 99m Mo- 99m Tc generator is used in conjunction with different technetium [ 99m Tc] radiopharmaceutical injection kit can prepare different types of technetium [ 99m Tc] radioactive drugs for injection, is technetium [ 99m Tc] is one of the most important raw materials for the production of radiopharmaceuticals.

[0003] The coulometric titration method currently used in the 2025 edition of the Chinese Pharmacopoeia, "0832 Determination of Water," has the following issues: 1. The sample must be precisely weighed, which can easily lead to operational errors. 2. The sample must be dissolved and transferred in an anhydrous solvent, which can easily lead to operational errors during the transfer process. Furthermore, the anhydrous solvent has limited solubility in Karl Fischer solution. As the number of tests increases, the solvent and sample will precipitate into the Karl Fischer solution, causing problems such as electrode dullness and residual water accumulation in the solution. 3. The transfer and titration steps in this method are inevitably affected by ambient temperature and humidity. 4. The relative error in sample measurement is large, and repeatability is poor.

[0004] technetium[ 99m The residual moisture in the freeze-dried powder in the kit for injection of radioactive drugs plays a very important role in the freeze-drying process. Excessive moisture in the freeze-dried product will destroy the framework structure of the preparation, causing it to deform, thereby causing exogenous heat conduction and accelerating thermal radiation, which greatly affects the stability and effectiveness of the freeze-dried preparation. The moisture in the freeze-dried preparation has a significant impact on the properties, appearance, hygiene and shelf life of the kit. Therefore, moisture is not only a key quality inspection indicator for freeze-dried preparations, but also one of the important items for stability assessment. The influencing factors of the moisture determination process should be controlled as much as possible to ensure the accuracy and reliability of the moisture content determination in the freeze-dried preparation. Summary of the Invention

[0005] The present invention aims to solve one of the technical problems in the prior art to a certain extent. To this end, one object of the present invention is to provide a method for determining technetium [ 99m Method for determining the water content in a kit for injectable radiopharmaceuticals containing Tc].

[0006] The present invention proposes a method for determining technetium by using a combination of a furnace and a Karl Fischer titrator. 99m A method for determining the water content in a kit for injectable radiopharmaceuticals comprising: The medicine box is heated in a cassette furnace, and then the water is transferred to the Karl Fischer test solution of the Karl Fischer titrator and stirred before the water content is measured.

[0007] The present invention provides a combined method for determining technetium using a furnace and a Karl Fischer titrator. 99m The kit for injection of radioactive drugs for Tc] uses a dry carrier gas to transfer the precipitated water in the test sample to a Karl Fischer titrator after heating the test sample kit at a constant temperature in a cassette furnace. The water is then reacted with the Karl Fischer test solution in the titrator for electrode determination. The entire moisture detection method is automatic and efficient, and is not affected by operator error, the anhydrous organic solvent used to dissolve the test sample, or the ambient temperature and humidity. This method achieves accurate determination of water in the complex components of the stannous tin injection MIBI kit, has good specificity, and does not interfere with the moisture detection caused by methanol and excipient components. It has high accuracy, good reproducibility, a wide linear range, and a high degree of automation, achieving the goal of [ 99m Rapid, efficient, interference-free, and automated determination of water content in kits for injectable Tc radiopharmaceuticals.

[0008] In some embodiments of the present invention, a temperature scan is performed on the medicine box to determine the heating temperature of the medicine box.

[0009] In some embodiments of the present invention, the temperature scanning range is 40°C to 280°C.

[0010] In some embodiments of the present invention, the temperature scan has a carrier gas flow rate of 80 mL / min, a stirring time of 10 s, and a scan rate of 3° C. / min.

[0011] In some embodiments of the present invention, the kit comprises a DTPA kit, an EHIDA kit, a MIBI kit, an MDP kit, a GH kit, a PYP kit, a PHY kit, an EC kit, or a MAA kit.

[0012] As an example, see Figures 1-9 .

[0013] In some embodiments of the present invention, the heating temperature of the DTPA medicine box is 230°C; the heating temperature of the DTPA medicine box is 230°C; the heating temperature of the EHIDA medicine box is 150°C; the heating temperature of the MIBI medicine box is 130°C; the heating temperature of the MDP medicine box is 180°C; the heating temperature of the GH medicine box is 187°C; the heating temperature of the PYP medicine box is 160°C; the heating temperature of the PHY medicine box is 166°C; the heating temperature of the EC medicine box is 178°C; and the heating temperature of the MAA medicine box is 170°C.

[0014] In some embodiments of the present invention, when the Karl Fischer titrator measures a blank drift value, the instrument drift stability value is less than 20 μg / min.

[0015] In some embodiments of the present invention, the Karl Fischer test solution of the Karl Fischer titrator has a stirring time of 60 seconds and a Karl Fischer reaction time of 5 minutes.

[0016] In some embodiments of the present invention, the carrier gas flow rate of the Karl Fischer titrator is 80 mL / min.

[0017] In some embodiments of the present invention, the carrier gas is selected from dry air.

[0018] In some embodiments of the present invention, the moisture content of the medicine box is greater than or equal to 50 μg, preferably 50 μg to 1000 μg.

[0019] The present invention has at least the following beneficial effects: Compared with the coulometric titration method, the method provided by the present invention has the advantages of accuracy, high precision, good repeatability, no interference from the anhydrous organic solvent used to dissolve the test sample, high degree of automation, short measurement time, no influence of human factors and environmental temperature and humidity and instrument equipment on the measurement results, etc., which makes the measurement results more accurate. At the same time, it has the advantage that the measurement process and electronic data can be tracked and traced later, and better solves the problem of the existing methods such as the moisture measurement method in the current Chinese Pharmacopoeia on the 99m There is an error in the measurement of water content in the kit for injectable Tc radiopharmaceuticals.

[0020] (2) The present invention provides a combined method of a cassette furnace and a Karl Fischer titrator for the determination of technetium [ 99m The research on the moisture content of the kit for injection of radioactive drugs has opened up a new path and provided a reference method for the determination of moisture content in other freeze-dried drug kits, which is conducive to providing patients with high-quality, long-term stable technetium [ 99m The Tc] labeling kit has good social benefits and can accurately reflect the true situation of the water content in the sample in a timely manner. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the technical solutions in the present invention or the prior art, a brief introduction is given below to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0022] Figure 1 1 is a temperature scanning curve of a DTPA kit according to an embodiment of the present invention; Figure 2 is a temperature scanning curve of a DTPA medicine box according to another embodiment of the present invention; Figure 3 is the temperature scanning curve of the EHIDA kit of the present invention; Figure 4 is the temperature scanning curve of the MIBI kit of the present invention; Figure 5 is the temperature scanning curve of the MDP medicine box of the present invention; Figure 6 is the temperature scanning curve of the PYP kit of the present invention; Figure 7 is the temperature scanning curve of the PHY medicine box of the present invention; Figure 8 is the temperature scanning curve of the EC kit of the present invention; Figure 9 is the temperature scanning curve of the MAA kit of the present invention; Figure 10 This is the linear range evaluation result of the determination method in Example 1 of the present invention. DETAILED DESCRIPTION

[0023] Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without creative work shall fall within the scope of protection of the present invention. The present invention will be described below with reference to specific embodiments. It should be noted that these embodiments are merely illustrative and do not limit the present invention in any way.

[0024] The embodiments of the present invention use Mettler-Toledo's InMotion KF Oven Autosampler, C30S moisture meter, and XPR / 205 1 / 100,000 electronic analytical balance. Karl Fischer titration standard solid: Merck KGaA (Germany); Methoxyisocyanate: ABX Company; MIBI kit and MDP kit: Atom Hi-Tech Co., Ltd.; DTPA kit: Beijing Shihong Pharmaceutical Co., Ltd., Atom High-Tech Co., Ltd.; EHIDA kit, PHY kit, MAA kit: Wuxi Jiangyuan Industrial Technology and Trade Co., Ltd. Jiangyuan Pharmaceutical Factory; ECD kit, GH kit: Jiangyuan Pharmaceutical Factory, Jiangsu Institute of Atomic Medicine; PYP medicine box, EC medicine box: Beijing Xinkesida Pharmaceutical Technology Co., Ltd.; Stannous chloride dihydrate: Aladdin Biochemical Technology Co., Ltd.

[0025] Example 1 (1) Pretreatment of medicine boxes and consumables The 10ml vials and stoppers used for measurement must be dried at 105°C for 4 hours in advance. The outer label of the medicine box should be soaked in ethanol and then removed. Then, the aluminum-plastic combination cover should be removed before testing.

[0026] (2) Operating parameters of the cassette furnace and Karl Fischer titrator When measuring the blank drift value, the instrument drift stability value was less than 20 μg / min, the stirring time was 60 s, the Karl Fischer reaction time was 5 min, and the carrier gas flow rate was 80 mL / min.

[0027] (3) Analytical method durability test instrument parameters The DTPA, EHIDA, MIBI, MDP, GHPYP, PHY, EC, and MAA cartridges were investigated for suitable constant temperature heating using a cassette furnace. Instrument parameters were set as follows: temperature scan range 40°C–280°C, carrier gas flow rate 80 mL / min, stirring time 10 s, and scan rate 3°C / min. During the temperature scan, the water release temperature should be slightly higher than the free water release temperature of the substance in the cartridge and lower than the bound water release temperature of the substance in the cartridge. The temperature scan curve for the cartridge is shown in Figure 1. Figure 1-9 .

[0028] The heating temperature of the cassette furnace is shown in Table 1.

[0029] Table 1 (4) According to the requirements of the Chinese Pharmacopoeia "9101 Validation Guidelines for Analytical Methods", the established furnace-Karl Fischer titrator method for the determination of technetium [ 99m Methodological validation of the water content in the kit for injection of [Tc] radiopharmaceuticals (accuracy and precision were determined using the MIBI kit).

[0030] (4-1) Linearity and range test: Accurately weigh Karl Fischer titration standard solid samples with water weights of 50, 100, 400, 600, and 1000 μg and perform the measurement according to step (2). The linear correlation coefficient r should be ≥ 0.990.

[0031] The linear range evaluation results are shown in Figure 10 , it can be seen that the moisture content has a good linear relationship in the range of 51.9~1001.7μg / bottle, the linear equation is y=0.96x+77.32, and the correlation coefficient r=0.9996.

[0032] (4-2) Specificity test: According to the 99m The formula composition of the kit for the injection of radioactive drugs is as follows: a certain amount of excipients is weighed and the moisture content is determined according to step (2). The specificity effect experiment of each kit excipient is repeated twice in parallel. The moisture effect of each excipient should be less than 20 μg / bottle. The moisture test results are shown in Table 2.

[0033] Table 2 As shown in Table 2, the water precipitated from the two excipients in each bottle of medicine box was less than 20 μg.

[0034] (4-3) Precision evaluation a. Repeatability: Operator 1 measured the moisture content of six MIBI kits. The results are shown in Table 3. Table 3 shows that the relative standard deviation (RSD) of the moisture repeatability test results was less than 4%.

[0035] Table 3 b. Intermediate Precision: Another operator repeated the above steps and calculated the moisture content of each of the 12 test samples (MIBI kits). The results are shown in Table 4. Table 4 shows that the relative standard deviation (RSD) of the intermediate precision test results for the moisture content of the 12 MIBI kits was <4%.

[0036] Table 4 (4-4) Accuracy: A sample with a water content of 670 μg corresponding to the Karl Fischer titration standard solid was accurately weighed and the water content was determined. The recovery was calculated using a linear equation. The results are shown in Table 5. As shown in Table 5, the water recovery was between 80% and 120%.

[0037] Table 5 (4-5) Comparison of blank subtraction method: Accurately weigh a sample with a water content of 500 μg corresponding to the Karl Fischer titration standard solid. The recovery rate is calculated by a linear equation. At the same time, three bottles of blank sample bottles are measured and the average value is taken. The measurement results are shown in Table 6. It can be seen that the water recovery rate after subtracting the blank is significantly deviated from the true value.

[0038] Table 6 Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A combined method for the determination of technetium using a furnace and Karl Fischer titrator 99m The method for determining the water content in a kit for injection of radioactive drugs is characterized in that: include: The medicine box is heated in a cassette furnace, and then the water is transferred to the Karl Fischer test solution of the Karl Fischer titrator and stirred before the water content is measured.

2. The method according to claim 1, characterized in that The medicine box is subjected to a temperature scan to determine the heating temperature of the medicine box.

3. The method according to claim 2, characterized in that The temperature scanning range is 40°C to 280°C.

4. The method according to claim 2, characterized in that The temperature scan had a carrier gas flow rate of 80 mL / min, a stirring time of 10 s, and a scan rate of 3° C. / min.

5. The method according to any one of claims 1 to 4, characterized in that The medicine kit includes a DTPA medicine kit, an EHIDA medicine kit, a MIBI medicine kit, an MDP medicine kit, a GH medicine kit, a PYP medicine kit, a PHY medicine kit, an EC medicine kit or a MAA medicine kit.

6. The method according to claim 5, characterized in that The heating temperature of the DTPA medicine box is 230°C; the heating temperature of the DTPA medicine box is 230°C; the heating temperature of the EHIDA medicine box is 150°C; the heating temperature of the MIBI medicine box is 130°C; the heating temperature of the MDP medicine box is 180°C; the heating temperature of the GH medicine box is 187°C; the heating temperature of the PYP medicine box is 160°C; the heating temperature of the PHY medicine box is 166°C; the heating temperature of the EC medicine box is 178°C; and the heating temperature of the MAA medicine box is 170°C.

7. The method according to any one of claims 1 to 4, characterized in that When the Karl Fischer titrator measures a blank drift value, the instrument drift stability value is less than 20 μg / min.

8. The method according to any one of claims 1 to 4, characterized in that The Karl Fischer test solution of the Karl Fischer titrator has a stirring time of 60 seconds and a Karl Fischer reaction time of 5 minutes.

9. The method according to any one of claims 1 to 4, characterized in that The carrier gas flow rate of the Karl Fischer titrator is 80 mL / min; And / or, the carrier gas is selected from dried air.

10. The method according to any one of claims 1 to 4, characterized in that The moisture content of the medicine box is greater than or equal to 50 μg, preferably 50 μg to 1000 μg.

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