A fluorine [ 18 F] Methods for detecting ethanol content and residual solvent in tucipyr injection

Abstract

This invention provides a fluorine [ 18 [F] The method for detecting ethanol content and residual solvents in tucipyr injection relates to the field of pharmaceutical analysis and detection technology, including: gas chromatography detection, where residual solvents include acetonitrile and dimethyl sulfoxide. The gas chromatography conditions are as follows: chromatographic column: SH-PolarWax; diluent: N,N -Dimethylformamide; Column temperature: programmed temperature ramp, initial temperature 35-45℃, hold for 4-8 min; then ramp to 160℃ at 35-45℃ / min, hold for 1-5 min; then ramp to 200℃ at 6-14℃ / min, hold for 4-10 min. The chromatographic conditions of this invention can remove fluorine [ 18 [F]Tuxepin injection achieves excellent separation of ethanol and residual solvent, and can be used for fluorine [ 18 F] Fluoride in toxetine injection 18 Determination and control of ethanol and residual solvent in tuxedopyr injection.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical analysis and detection technology, and in particular to a fluorine […]. 18 F] Method for detecting ethanol content and residual solvent in tucipyr injection. Background Technology

[0002] fluorine[ 18 [F] Tuxepin injection is a positron emission tomography (PET) radiopharmaceutical that plays an important role in the diagnosis of cardiovascular diseases, neurodegenerative diseases, and especially malignant tumors.

[0003] fluorine[ 18 The formulation of tuxedopyr injection is a physiological saline solution containing 1.5 mg / ml cysteine ​​and 2.1 mg / ml anhydrous disodium hydrogen phosphate in 10% ethanol. During preparation, ethanol is used as a co-solvent, and its content should be controlled below 10% to maintain the solubility of the compound in solution and ensure formulation stability. Acetonitrile and dimethyl sulfoxide are used as solvents for the fluorination reaction and participate in the synthetic labeling reaction. According to the 2025 edition of the Chinese Pharmacopoeia and ICH Q3D requirements: the content of acetonitrile should be less than 410 ppm, and the content of dimethyl sulfoxide should be less than 5000 ppm. Therefore, fluorine... 18 The content of ethanol and residual solvents (acetonitrile, dimethyl sulfoxide) in tuxedopyr injection is one of the factors affecting drug quality. The content of ethanol and residual solvents should be strictly controlled to ensure that the quality and safety of the drug are controllable.

[0004] Methods for detecting residual solvents in positron-emitting radiopharmaceuticals often rely on gas chromatography using headspace sampling, split or splitless direct injection, and cold column injection. Headspace sampling analysis requires a large sample size, is time-consuming, and involves fluorine […]. 18 [F] The dimethyl sulfoxide in toxetine injection has a high boiling point, making this injection method unsuitable; when directly injecting the sample through a conventional split or splitless heated injection port, due to the high boiling point of dimethyl sulfoxide, this injection method is not recommended. 18 [F] Toxopyr injection is an aqueous solution containing 10% ethanol. Aqueous matrix is ​​an undesirable solvent for gas chromatography. Excessive water content not only results in poor injection precision and column durability, but also causes the injection liner to expand in volume after sample vaporization, leading to liner overload, poor peak area reproducibility, and contamination of the inlet and septum purging lines. Cold column head injection is suitable for gas chromatography samples with large boiling point differences, but this equipment is rarely equipped in routine laboratories, resulting in poor method versatility. In addition, inorganic salts in the formulation can increase column bleed, dissolve the stationary phase, damage the inert coating and moisture resistance, leading to decreased column efficiency and peak tailing.

[0005] Therefore, an analytical method should be developed that can simultaneously detect fluorine [ 18It is essential and urgent to detect the content of ethanol and residual solvents acetonitrile and dimethyl sulfoxide in F]toxipyrene injection. Summary of the Invention

[0006] This invention provides a fluorine [ 18 A method for detecting ethanol content and residual solvent in fosetyl-P-ethyl injection (F) is provided. This method can detect fluoride […]. 18 Rapid determination of ethanol content and residual solvent in F]toxipyrene injection.

[0007] This invention provides a fluorine [ 18 F] The method for detecting ethanol content and residual solvent in tuxedopyr injection is to use gas chromatography. The residual solvent includes acetonitrile and dimethyl sulfoxide. The conditions for gas chromatography are as follows:

[0008] Column: SH-PolarWax;

[0009] Diluent: N,N -Dimethylformamide;

[0010] Column temperature: Program temperature rise, starting at 35-45℃ and holding for 4-8 min; then increase the temperature to 160℃ at 35-45℃ / min and hold for 1-5 min; then increase the temperature to 200℃ at 6-14℃ / min and hold for 4-10 min.

[0011] Preferably, the column temperature is: initial temperature 40℃, held for 5-6 minutes; then increased to 160℃ at 40-45℃ / min, held for 2-3 minutes; then increased to 200℃ at 8-10℃ / min, held for 5 minutes.

[0012] More preferably, the column temperature is: an initial temperature of 40°C, held for 5 minutes; then increased to 160°C at 40°C / min, held for 2 minutes; and then increased to 200°C at 10°C / min, held for 5 minutes.

[0013] This invention uses an SH-PolarWax column as the chromatographic column, with a stationary phase bonded to cross-linked polyethylene glycol. The low-leakage polyethylene glycol column ensures a long column life. The robust stationary phase can withstand repeated water injections, and the plate number of each sample remains stable over long-term injections. It is suitable for fluoride […]. 18 F] Detection of ethanol and residual solvent in tucipyr injection.

[0014] This invention selects N,N Dimethylformamide, as a diluent, is not only miscible with ethanol, acetonitrile, and dimethyl sulfoxide, but also ensures that its retention times with these substances do not interfere with each other. Using the specific heating procedure described above, fluorine […] can be achieved. 18Effective separation and detection of ethanol, acetonitrile, and dimethyl sulfoxide in toxetine injection. 18 [F]toxipyrene has no response in the FID detector and does not interfere with the efficient separation of ethanol, acetonitrile and dimethyl sulfoxide.

[0015] This invention, through optimization of chromatographic conditions, achieves the detection of fluorine [under the aforementioned chromatographic conditions]. 18 The rapid analysis of ethanol and residual solvents acetonitrile and dimethyl sulfoxide in F] tucipyr injection showed good precision and robustness, meeting the quality control requirements for ethanol content and residual solvents in this formulation, thus ensuring the quality and safety of the drug.

[0016] Furthermore, the conditions for the gas chromatography method also include an injection volume of 0.5-1 μL. Since water has a high expansion coefficient, selecting an appropriate injection volume can optimize peak shape and improve injection precision. When the injection volume is controlled within the above range, the peak shapes of each solvent are good, and the injection precision and signal-to-noise ratio are also good.

[0017] Preferably, the injection volume is 0.5 μL.

[0018] Furthermore, the gas chromatography method uses direct injection with a split ratio of 10-30:1. Since water has a high expansion coefficient, selecting an appropriate split ratio can optimize peak shape and improve injection precision. When the split ratio is controlled within the above range, each solvent peak has good shape, and the injection precision and signal-to-noise ratio are good.

[0019] Preferably, the split ratio is 20:1.

[0020] Furthermore, the conditions for the gas chromatography method also include one or more of the following characteristics:

[0021] Inlet temperature: 180-220℃;

[0022] Detector temperature: 240-280℃;

[0023] Carrier gas: nitrogen or helium;

[0024] Purging flow rate: 20-30 mL / min;

[0025] Hydrogen flow rate: 30-50 mL / min;

[0026] Airflow rate: 180-260 mL / min.

[0027] Preferably, the injection port temperature is 200°C, the detector temperature is 250°C, the carrier gas is nitrogen, the tail gas flow rate is 24.0 mL / min, the hydrogen flow rate is 32.0 mL / min, and the air flow rate is 200 mL / min.

[0028] Furthermore, the flow rate of the carrier gas is 0.8-1.2 mL / min, preferably 1.0 mL / min.

[0029] Furthermore, the detector is an FID detector.

[0030] Furthermore, the SH-PolarWax has dimensions of 30m × 0.32mm × 0.25μm.

[0031] Furthermore, the detection method includes the following steps: preparing a reference solution and a test solution using the diluent; then injecting the reference solution and the test solution into a gas chromatograph, detecting them under the conditions of the gas chromatography method, recording the chromatograms, and calculating the content of ethanol and residual solvent using the external standard method.

[0032] Furthermore, in the reference solution, the volume concentration of ethanol is 0.3-2.0%, the mass concentration of acetonitrile is 12.26-81.70 μg / mL, and the mass concentration of dimethyl sulfoxide is 150.07-1000.46 μg / mL.

[0033] Furthermore, the test solution is prepared using... N,N - Dimethylformamide will react with the fluorine to be detected. 18 F]Tuxedopyr injection diluted 5-10 times.

[0034] Preferably, the fluorine to be detected [ 18 The dilution factor for F] tucipyr injection is 10 times.

[0035] This invention provides a fluorine [ 18 The beneficial effects of the method for detecting ethanol content and residual solvent in tuxedopyr injection: The chromatographic conditions of this invention can detect fluorine […]. 18 [F] A good separation between ethanol and residual solvent in toxetine injection is achieved. This method has good system applicability, precision, specificity, and accuracy, and can be used for fluorine [ 18 F] Fluoride in toxetine injection 18 The determination and control of ethanol and residual solvent in fluoroquinolone injection was achieved, enabling the control of fluorine […]. 18 Rapid analysis and detection of ethanol content and residual solvent in F] toxetine injection products, meeting the requirements of fluorine [ 18 F] Requirements for quality control of ethanol content and residual solvent in tuxedopyr injection. Attached Figure Description

[0036] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0037] Figure 1 This is the gas chromatogram of the test solution in Example 1.

[0038] Figure 2 This is the gas chromatogram of the reference solution in Example 1.

[0039] Figure 3 This is the gas chromatogram of ethanol in Experiment Example 2.

[0040] Figure 4 This is the gas chromatogram of isopropanol in Experiment Example 2.

[0041] Figure 5 This is the gas chromatogram of acetonitrile from Experiment Example 2.

[0042] Figure 6 In Experiment Example 2 N,N Gas chromatogram of dimethylformamide.

[0043] Figure 7 This is the gas chromatogram of dimethyl sulfoxide from Experiment Example 2.

[0044] Figure 8 This is the gas chromatogram of n-methylpyrrolidone from Experiment Example 2. Detailed Implementation

[0045] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0046] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0047] Example 1

[0048] This embodiment provides a fluorine [ 18 The method for detecting ethanol content and residual solvent in tuxedopyr injection is as follows:

[0049] (1) Preparation of reference solution: Accurately weigh 41 mg acetonitrile and 500 mg dimethyl sulfoxide, respectively, and place them in a 10 mL volumetric flask containing an appropriate amount of water. Dilute to the mark with water, mix well, and label as stock solution-1. Accurately measure 1.0 mL of stock solution-1 and 1.0 mL of ethanol, place them in a 10 mL volumetric flask containing an appropriate amount of water, dilute to the mark with water, mix well, and label as reference stock solution. Accurately measure 1.0 mL of reference stock solution, place it in a 10 mL volumetric flask, and dilute with water. N,N Dilute dimethylformamide to the mark, mix well, and label as reference solution.

[0050] (2) Preparation of test solution: Take 0.5 ml of fluorine [ 18 F] Tuxepin injection (from Atomic High-Tech Co., Ltd., production batch number: 20250924), placed in a container containing an appropriate amount of N,N In a 5 mL volumetric flask containing dimethylformamide, use... N,N Dilute dimethylformamide to the mark and mix well.

[0051] (3) Detection method: The reference solution and the test solution were directly injected into the gas chromatograph. The chromatographic conditions were as follows: SH-PolarWax column (30m×0.32mm×0.25μm); injection volume: 0.5μL; injection port temperature: 200℃; FID detector temperature: 250℃; carrier gas: nitrogen, flow rate: 1.0mL / min; make-up gas flow rate: 24.0mL / min; hydrogen flow rate: 32.0mL / min; air flow rate: 200mL / min; split ratio: 20:1. The temperature program is shown in Table 1.

[0052]

[0053] Fluorine was obtained by external standard method. 18 The contents of ethanol and residual solvents acetonitrile and dimethyl sulfoxide in tuximab injection were as follows: fluorine [ 18 The ethanol content of the [F]toxidide injection was 8.2%, acetonitrile content was not detected, and dimethyl sulfoxide content was not detected. The gas chromatogram of the test solution is shown below. Figure 1 As shown, the gas chromatogram of the reference solution is as follows. Figure 2 As shown.

[0054] This invention detects fluorine [ 18 The optimization experiments of gas chromatographic conditions for ethanol and residual solvents acetonitrile and dimethyl sulfoxide in tuxedopyr injection are shown in Experiments 1-4, as detailed below:

[0055] Experiment Example 1: Column Optimization Experiment

[0056] Preparation of reference solution: Accurately weigh 41 mg acetonitrile and 500 mg dimethyl sulfoxide, respectively, and place them in a 10 mL volumetric flask containing an appropriate amount of water. Dilute to the mark with water, mix well, and label as Stock Solution-1. Accurately measure 1.0 mL of Stock Solution-1 and 1.0 mL of ethanol, place them in a 10 mL volumetric flask containing an appropriate amount of water, dilute to the mark with water, mix well, and label as Reference Stock Solution. Accurately measure 1.0 mL of Reference Stock Solution, place it in a 10 mL volumetric flask, dilute to the mark with water, mix well, and label as Reference Solution.

[0057] Detection method: The reference solution was directly injected into the gas chromatograph. Six consecutive injections were performed to observe changes in the ethanol tailing factor and theoretical plate number. The chromatographic conditions were as follows: SH-PolarWax column and DB-624 column (30m × 0.32mm × 0.25μm); injection volume: 0.5μL; injection port temperature: 200℃; FID detector temperature: 250℃; carrier gas: nitrogen, flow rate: 1.0mL / min; make-up gas flow rate: 24.0mL / min; hydrogen flow rate: 32.0mL / min; air flow rate: 200mL / min; split ratio: 20:1. The temperature program is shown in Table 1.

[0058] fluorine[ 18 The solvents involved in F] tucipyr injection, ethanol, acetonitrile, and dimethyl sulfoxide, have boiling points of 78.3℃, 82℃, and 189℃, respectively. All three substances are polar compounds. First, the DB-624 column, which is commonly used for residual solvents, was selected. The DB-624 column is a neutral column bonded and crosslinked with 6% cyanopropylphenyl and 94% dimethyl polysiloxane. It is often used to analyze volatile compounds in pharmaceuticals. However, after continuous injection, ethanol caused severe tailing, and the column plate number dropped significantly, making subsequent analytical experiments impossible. The results are shown in Table 2.

[0059] The SH-PolarWax stationary phase is bonded to cross-linked polyethylene glycol. The low-leakage polyethylene glycol column ensures a long column life. The stationary phase is robust and can withstand repeated water sample injections. The plate number of each sample remains stable over long-term injections. This type of column is used for further method development.

[0060]

[0061] Experiment Example 2: Diluent Optimization Experiment

[0062] Although the SH-PolarWax column is water-resistant, prolonged direct injection of aqueous solutions can affect column life and the FID detector. Fluorine [ 18[F] Tuxepin injection is a physiological saline solution containing 1.5 mg / ml cysteine ​​and 2.1 mg / ml anhydrous disodium hydrogen phosphate in 10% ethanol. The diluent must be miscible with water and solvents involved in the synthesis such as acetonitrile and dimethyl sulfoxide. Isopropanol (boiling point 82.5℃) and n-methylpyrrolidone (boiling point 202℃) are preferred. N,N Method development was carried out using dimethylformamide (boiling point 153℃) as a diluent.

[0063] Detection method: Take isopropanol, n-methylpyrrolidone, N,N Dimethylformamide, ethanol, acetonitrile, and dimethyl sulfoxide were directly injected into the gas chromatograph to investigate the retention times of each solvent. The chromatographic conditions were as follows: SH-PolarWax column (30m × 0.32mm × 0.25μm); injection volume: 0.5μL; injection port temperature: 200℃; FID detector temperature: 250℃; carrier gas: nitrogen, flow rate: 1.0mL / min; make-up gas flow rate: 24.0mL / min; hydrogen flow rate: 32.0mL / min; air flow rate: 200mL / min; split ratio: 20:1. The temperature program is shown in Table 1, and the results are shown in Table 3. Figures 3-8 As shown:

[0064]

[0065] As shown in Table 3, using the temperature program in Table 1, and employing an SH-PolarWax column, each solvent (isopropanol, n-methylpyrrolidone, ...) was introduced. N,N (Dimethylformamide, ethanol, acetonitrile, and dimethyl sulfoxide), isopropanol and ethanol have similar retention times, and dimethyl sulfoxide's boiling point of 189℃ is close to that of n-methylpyrrolidone's 202℃, and their retention times are also similar. Therefore, isopropanol and n-methylpyrrolidone are not suitable for detecting fluorine. 18 F] Diluents for ethanol and residual solvents in toxepide injection, and N, N - Dimethylformamide has a boiling point between that of dimethyl sulfoxide and ethanol acetonitrile, and retention time does not interfere with its boiling point. Therefore, it is selected... N,N - Dimethylformamide is used as a diluent in this invention.

[0066] Experiment Example 3: Optimization Experiment of Injection Volume and Split Ratio

[0067] Preparation of limit of quantitation (LOQ) solutions: Accurately weigh 41 mg acetonitrile and 500 mg dimethyl sulfoxide, respectively, and place them in a 10 mL volumetric flask containing an appropriate amount of water. Dilute to the mark with water, mix well, and label as Stock Solution-1. Accurately measure 1.0 mL of Stock Solution-1 and 1.0 mL of ethanol, place them in a 10 mL volumetric flask containing an appropriate amount of water, dilute to the mark with water, mix well, and label as Reference Stock Solution. Accurately measure 1.0 mL of Reference Stock Solution, place it in a 10 mL volumetric flask, and... N,N Dilute dimethylformamide to the mark, mix well, and label as reference solution. Accurately measure 3.0 mL of the reference solution and place it in a 10 mL volumetric flask. N,N Dilute dimethylformamide to the mark and mix well.

[0068] Detection method: Limit of quantitation (LOQ) solutions were directly injected into the gas chromatograph to investigate the retention times of each solvent. Chromatographic conditions were as follows: SH-PolarWax column (30m × 0.32mm × 0.25μm); injection volume: 0.5μL; injection port temperature: 200℃; FID detector temperature: 250℃; carrier gas: nitrogen, flow rate: 1.0mL / min; make-up gas flow rate: 24.0mL / min; hydrogen flow rate: 32.0mL / min; air flow rate: 200mL / min. Split ratios were adjusted to 20:1 and 30:1. The temperature program is shown in Table 1, and the results are shown in Table 4.

[0069] When the injection volume was adjusted to 0.5 μL and the split ratio to 20:1, the peak shapes of each solvent were good, and the injection precision and signal-to-noise ratio were also good.

[0070]

[0071] Experiment Example 4: Optimization Experiment of Heating Program

[0072] Based on Example 1, the effect of the heating program was examined. The results are shown in Table 5.

[0073] As shown in Table 5, the initial temperature holding time (4, 6, and 8 min) had no effect on the separation degree of ethanol and acetonitrile.

[0074] To accelerate the analysis, the temperature was increased to 160℃ at a rate of 40℃ / min. N,N Dimethylformamide (153℃) boiling point, held for 2 min, then heated to 200℃ at a low heating rate of 6-14℃ / min, held for 5 min. Results showed that when heating from 160℃ to 200℃ at a rate of 10℃ / min, dimethyl sulfoxide reacted with... N,N -Dimethylformamide can be separated well, with a resolution of 5.5 > 1.5;

[0075] To ensure the removal of water vapor and various solvents from the sample chromatographic column and to maintain the measurement rate, it is preferable to maintain the temperature at 200℃ for 5 minutes.

[0076]

[0077] This invention detects fluorine [ 18 The methodological investigation of gas chromatographic conditions for ethanol and residual solvents acetonitrile and dimethyl sulfoxide in tuximab injection is shown in Examples 5-7, as detailed below:

[0078] Experimental Example 5: System Suitability and Sample Injection Precision Investigation

[0079] System suitability requirements: No interfering peaks should be present at the positions of the analyte peaks in the blank solution; if interfering peaks are present, their peak areas should not exceed 50% of the corresponding solvent peak area in the sensitivity solution; the signal-to-noise ratio of acetonitrile and dimethyl sulfoxide peaks in the sensitivity solution should be ≥10; the relative standard deviation of the ethanol peak area in six consecutive reference solutions should be ≤5.0%, and the relative standard deviation of the acetonitrile and dimethyl sulfoxide peak areas should be ≤10%; the relative standard deviation of the ethanol peak area in all reference solutions should be ≤5.0%, and the relative standard deviation of the acetonitrile and dimethyl sulfoxide peak areas should be ≤10%; the relative standard deviation of the retention time of each solvent in all working reference solutions should be ≤1.0%.

[0080] This experimental example demonstrates the use of a blank diluent ( N,N The suitability of the methodology system and the precision of injection were investigated using a methylformamide (MCM) solution, a sensitivity solution, a working control solution, and a verification control solution.

[0081] Solution preparation:

[0082] Blank solution / diluent: N,N -Dimethylformamide;

[0083] Reference stock solution: Weigh 80.46 mg acetonitrile and 1010.16 mg dimethyl sulfoxide, respectively, and place them in a 20 mL volumetric flask containing an appropriate amount of water. Dilute to the mark with water, mix well, and label as Stock Solution-1. Accurately measure 1.0 mL of Stock Solution-1 and 1.0 mL of ethanol, place them in a 10 mL volumetric flask containing an appropriate amount of water, dilute to the mark with water, mix well, and label as Reference Stock Solution.

[0084] Working reference solution: Transfer 1 mL of the reference stock solution into a 10 mL volumetric flask, add an appropriate amount of diluent to dissolve and dilute to the mark, and shake well;

[0085] Verification reference solution: Weigh 81.65 mg acetonitrile and 1001.92 mg dimethyl sulfoxide, respectively, and place them in a 10 mL volumetric flask containing an appropriate amount of water. Dilute to the mark with water, mix well, and label as Stock Solution-1. Accurately measure 1.0 mL of Stock Solution-1 and 1.0 mL of ethanol, place them in a 10 mL volumetric flask containing an appropriate amount of water, dilute to the mark with water, mix well, and label as Verification reference stock solution. Transfer 1 mL of the verification reference stock solution to a 10 mL volumetric flask, add an appropriate amount of diluent to dissolve and dilute to the mark, and shake well.

[0086] Sensitivity solution (30% level): Transfer 3 mL of the working control solution to a 10 mL volumetric flask, add an appropriate amount of diluent to dissolve and dilute to the mark, and shake well.

[0087] Chromatographic detection: After baseline equilibration of the gas chromatograph, injection was performed according to the following chromatographic conditions: SH-PolarWax column (30m × 0.32mm × 0.25μm); injection volume: 0.5μL; split ratio: 20:1; injection port temperature: 200℃; FID detector temperature: 250℃; carrier gas: nitrogen, flow rate: 1.0mL / min; make-up gas flow rate: 24.0mL / min; hydrogen flow rate: 32.0mL / min; air flow rate: 200mL / min; split ratio: 20:1. The temperature program is shown in Table 1. One injection each of blank solution, sensitivity solution, and verification reference solution, and six injections of working reference solution were performed. The chromatograms were then saved.

[0088] The results are shown in Tables 6-8. As can be seen from Tables 6-8, the blank solution had no interfering peaks at the positions of the solvent peaks. The signal-to-noise ratios (S / N) of acetonitrile and dimethyl sulfoxide in the sensitivity solution were 24 and 60, respectively. The relative standard deviations of the peak areas of ethanol in the reference solution for six consecutive tests were 0.3%, and the relative standard deviations of the peak areas of acetonitrile and dimethyl sulfoxide were 0.9% and 0.2%, respectively. The relative standard deviations of the retention times of each specified solvent in the reference solution for six consecutive tests were 0.04%, 0.03%, and 0.00%, respectively. The recovery rate of ethanol in the reference solution was 106.6%, and the recoveries of acetonitrile and dimethyl sulfoxide were 99.5% and 103.8%, respectively. The method system suitability test met the acceptable standard, and the method injection precision was good.

[0089]

[0090]

[0091]

[0092] Experiment Example 6: Specificity Investigation

[0093] This experimental example demonstrates the use of a blank diluent ( N,N Method specificity was investigated using dimethylformamide, ethanol single-standard solution, acetonitrile single-standard solution, dimethyl sulfoxide single-standard solution, and 100% level spiked test solution.

[0094] Solution preparation:

[0095] Blank solution / diluent: N,N -Dimethylformamide;

[0096] Working control solution: Same as the working control solution in Experiment Example 5;

[0097] Ethanol single standard solution: Transfer 1 mL of ethanol solution to a 10 mL volumetric flask, add an appropriate amount of diluent to dissolve and dilute to the mark, then take 1 mL of the above solution, transfer it to a 10 mL volumetric flask, add an appropriate amount of diluent to dissolve and dilute to the mark, and shake well;

[0098] Acetonitrile single standard solution: Transfer 22.82 mg of acetonitrile to a 50 mL volumetric flask, add an appropriate amount of diluent to dissolve and dilute to the mark, then take 1 mL of the above solution, transfer it to a 10 mL volumetric flask, add an appropriate amount of diluent to dissolve and dilute to the mark, and shake well;

[0099] Dimethyl sulfoxide single standard solution: Transfer 249.19 mg of dimethyl sulfoxide to a 50 mL volumetric flask, add an appropriate amount of diluent to dissolve and dilute to the mark, then take 1 mL of the above solution, transfer it to a 10 mL volumetric flask, add an appropriate amount of diluent to dissolve and dilute to the mark, and shake well;

[0100] Blank excipient solution: According to the formulation, weigh an appropriate amount of cysteine ​​and anhydrous disodium hydrogen phosphate, and prepare a 0.9% sodium chloride solution of 1.5 mg / ml cysteine ​​and 2.1 mg / ml anhydrous disodium hydrogen phosphate.

[0101] 100% Horizontal Spiked Test Solution: Weigh 205.08 mg acetonitrile and 2504.62 mg dimethyl sulfoxide into a 50 mL volumetric flask containing an appropriate amount of water. Dilute to the mark with blank excipient solution, mix well, and label as Stock Solution-1. Accurately measure 1.0 mL of Stock Solution-1 and 1.0 mL of ethanol into a 10 mL volumetric flask containing an appropriate amount of diluent. Dilute to the mark, mix well, and label as 100% Horizontal Stock Solution. Transfer 1 mL of the 100% Horizontal Stock Solution into a 10 mL volumetric flask, add... N,N Dissolve an appropriate amount of dimethylformamide and dilute to the mark, then shake well;

[0102] Chromatographic detection: After baseline equilibration of the gas chromatograph, inject one sample each of the blank solution, ethanol single-standard solution, acetonitrile single-standard solution, dimethyl sulfoxide single-standard solution, working reference solution, and 100% level spiked test solution according to the chromatographic conditions in Example 5. Save the chromatogram. The results are shown in Table 9.

[0103]

[0104] As shown in Table 9, the ratio of the retention time of each solvent in the individually labeled solution to the average retention time of each solvent in the six consecutive working reference solutions ranged from 0.98 to 1.02. The resolution between acetonitrile and ethanol in the 100% level spiked test solution was 12.5, and the resolution between dimethyl sulfoxide and acetonitrile was 37.9.

[0105] Experiment Example 7 Accuracy Examination

[0106] Solution preparation:

[0107] Blank excipient solution: According to the formulation, weigh an appropriate amount of cysteine ​​and anhydrous disodium hydrogen phosphate, and prepare a 0.9% sodium chloride solution of 1.5 mg / ml cysteine ​​and 2.1 mg / ml anhydrous disodium hydrogen phosphate.

[0108] Reference solution: See the working reference solution in Experimental Example 5;

[0109] Verification of the reference standard: See the same as the verification of the reference standard solution in Experimental Example 5;

[0110] Accuracy Stock Solution: Accurately weigh 204.26 mg acetonitrile and 2501.16 mg dimethyl sulfoxide, respectively, and place them in a 20 mL volumetric flask containing an appropriate amount of blank excipient solution. Dilute to the mark with the blank excipient solution, mix well, and label as Accuracy Stock Solution-1. Accurately measure 1 mL of Accuracy Stock Solution-1 and 2.5 mL of ethanol, place them in a 50 mL volumetric flask containing an appropriate amount of blank excipient solution, dilute to the mark with the blank excipient solution, mix well, and the solution is ready.

[0111] Methodological accuracy was investigated by preparing test samples with different accuracy levels, as detailed in Table 10. The recovery rate at each level was calculated using the following formula:

[0112]

[0113] In the formula: A s To ensure accuracy, the peak areas of each solvent in the solution are calculated.

[0114] A std The average peak area of ​​each solvent in the reference solution for six consecutive samples;

[0115] C std This refers to the weight or volume of each solvent in the reference solution;

[0116] C s To ensure accuracy, weigh or measure the volume of each solvent in the solution.

[0117]

[0118] Note: 100% level accuracy solution is also 100% level spiked test sample solution; the results of the first 3 100% sample solutions are used to evaluate accuracy, and the results of all 6 100% sample solutions are used to evaluate repeatability.

[0119] The results are shown in Tables 11-13.

[0120]

[0121]

[0122]

[0123] As shown in Tables 11-13, ethanol, acetonitrile, and dimethyl sulfoxide have good accuracy within the range of 30%-200%.

[0124] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A fluorine [ 18 The method for detecting ethanol content and residual solvent in toxetine injection (F) is characterized by... The residual solvents, including acetonitrile and dimethyl sulfoxide, were detected using gas chromatography. The gas chromatography conditions were as follows: Column: SH-PolarWax; Diluent: N,N -Dimethylformamide; Column temperature: Program temperature rise, starting at 35-45℃ and holding for 4-8 min; then increase the temperature to 160℃ at 35-45℃ / min and hold for 1-5 min; then increase the temperature to 200℃ at 6-14℃ / min and hold for 4-10 min.

2. The fluorine [according to claim 1] 18 The method for detecting ethanol content and residual solvent in toxetine injection (F) is characterized by... The conditions for the gas chromatography method also include: an injection volume of 0.5-1 μL.

3. The fluorine [according to claim 1] 18 The method for detecting ethanol content and residual solvent in toxetine injection (F) is characterized by... The gas chromatography method uses direct injection with a split ratio of 10-30:

1.

4. The fluorine [according to claim 1] 18 The method for detecting ethanol content and residual solvent in toxetine injection (F) is characterized by... The conditions for the gas chromatography method also include one or more of the following characteristics: Inlet temperature: 180-220℃; Detector temperature: 240-280℃; Carrier gas: nitrogen or helium; Purging flow rate: 20-30 mL / min; Hydrogen flow rate: 30-50 mL / min; Airflow rate: 180-260 mL / min.

5. The fluorine [according to claim 4] 18 The method for detecting ethanol content and residual solvent in toxetine injection (F) is characterized by... The flow rate of the carrier gas is 0.8-1.2 mL / min.

6. The fluorine [according to claim 4] 18 The method for detecting ethanol content and residual solvent in toxetine injection (F) is characterized by... The detector is an FID detector.

7. The fluorine [according to any one of claims 1-6] 18 The method for detecting ethanol content and residual solvent in toxetine injection (F) is characterized by... The SH-PolarWax has dimensions of 30m × 0.32mm × 0.25μm.

8. The fluorine [according to any one of claims 1-6] 18 The method for detecting ethanol content and residual solvent in toxetine injection (F) is characterized by... Includes the following steps: The reference solution and the test solution were prepared using the diluent; then the reference solution and the test solution were injected into a gas chromatograph and detected under the conditions of the gas chromatography method. The chromatograms were recorded, and the contents of ethanol and residual solvent were calculated using the external standard method.

9. The fluorine [according to claim 8] 18 The method for detecting ethanol content and residual solvent in toxetine injection (F) is characterized by... The reference solution contained ethanol at a volume concentration of 0.3-2.0%, acetonitrile at a mass concentration of 12.26-81.70 μg / mL, and dimethyl sulfoxide at a mass concentration of 150.07-1000.46 μg / mL.

10. The fluorine [according to claim 8] 18 The method for detecting ethanol content and residual solvent in toxetine injection (F) is characterized by... The test solution was prepared using... N,N - Dimethylformamide will react with the fluorine to be detected. 18 F]Tuxedopyr injection diluted 5-10 times.

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