Method for detecting impurities in chloral hydrate sample

Abstract

The invention belongs to the field of pharmaceutical analysis, and particularly relates to a method for detecting impurities in a chloral hydrate sample, which comprises the following steps of: performing optimization pretreatment on the chloral hydrate sample, and performing accurate quantitative analysis on trichloromethane impurities in the sample by adopting a gas chromatography direct injection combined temperature programming technology. The method has the characteristics of high specificity, high accuracy and strong durability.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical analysis, and particularly relates to a method for detecting impurities in chloral hydrate samples. Background Art

[0002] Chloral hydrate is a drug that can be used to treat insomnia and anti-convulsions, and its chemical name is 2,2,2-trichloro-1,1-ethanediol. Chloral hydrate is unstable under high temperature, alkaline, oxidative or light conditions and is prone to degradation. Its degradation products will affect the safety of the drug and pose a hazard to the health of patients. Although the quality standards of chloral hydrate are included in the pharmacopoeias of many countries, the existing standards have not established effective control methods for its degradation products, lack reference quality standards for degradation impurities, and there are deficiencies in the product quality control system.

[0003] The main degradation products of chloral hydrate include chloroform, dichloroacetaldehyde and trichloroacetic acid. Among them, dichloroacetaldehyde and trichloroacetic acid have ultraviolet absorption characteristics and can be quantitatively controlled by ordinary high performance liquid chromatography-ultraviolet detection method (HPLC-UV), while chloroform has no ultraviolet absorption and no retention in liquid chromatography, so it cannot be detected by HPLC-UV method. On the other hand, although chloroform can be detected by gas chromatography, since it is the main degradation product of chloral hydrate under high temperature conditions, the high temperature of the injection port during direct injection of gas chromatography or the high temperature heating step during headspace injection will induce secondary degradation of chloral hydrate to produce chloroform, resulting in a falsely high detection result of chloroform in the sample, seriously interfering with the evaluation of the true impurity level, thus increasing the difficulty of product quality control.

[0004] As a class II solvent specified in ICH Q3D, chloroform has clear genotoxicity and carcinogenic risks, and the existing detection methods cannot well meet the requirements of quality control of chloral hydrate samples. Therefore, it is necessary to develop a detection method for chloroform impurities in chloral hydrate that can avoid sample degradation interference and has high accuracy. Summary of the Invention

[0005] Aiming at the defects existing in the prior art, the present invention provides a method for separating and detecting impurities in chloral hydrate samples. After optimizing the pretreatment of chloral hydrate samples, the method adopts gas chromatography direct injection combined with programmed temperature rising technology to achieve accurate quantitative analysis of chloroform impurities in the samples, and has the characteristics of high specificity, high accuracy and strong durability.

[0006] A method for detecting impurities in chloral hydrate samples, characterized in that the detection method is gas chromatography, and comprises the following steps:

[0007] (1) Prepare a reference solution: Weigh chloroform and dissolve it in a diluent to obtain.

[0008] (2) Prepare the test solution: Weigh the chloral hydrate sample, directly add the diluent to dissolve and extract it, and retain the diluent layer solution to obtain it;

[0009] (3) Use gas chromatography for direct injection and programmed temperature rise method for detection, and record the chromatogram;

[0010] Among them, the impurity is chloroform, and the diluent is an organic solvent;

[0011] The gas chromatography conditions are as follows: Use a capillary column with polyethylene glycol as the stationary liquid as the chromatographic column, adopt a flame ionization detector, the inlet temperature is 150 - 250 °C, and the detector temperature is 200 - 300 °C;

[0012] The temperature programming is as follows: The initial temperature is 35 - 45 °C, maintain for 5 - 30 min, then increase the temperature to 200 - 250 °C at a rate of 70 - 90 °C / min, and maintain for 5 - 30 min.

[0013] Further preferably, the diluent is n - heptane.

[0014] Further preferably, the chromatographic column is Agilent DB - WAX, 30 m × 0.53 mm × 1.0 μm or a chromatographic column with equivalent polarity.

[0015] Further preferably, the inlet temperature is 200 °C.

[0016] Further preferably, the detector temperature is 250 °C.

[0017] Further preferably, the temperature programming is as follows: The initial temperature is 40 °C, maintain for 15 min, then increase the temperature to 220 °C at a rate of 80 °C / min, and maintain for 10 min.

[0018] Further preferably, the chloral hydrate sample includes chloral hydrate raw material and / or preparation. More preferably, the preparation includes any dosage form of oral solution, syrup, enema.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0020] The method of the present invention has good specificity, accuracy and durability, can accurately and efficiently quantitatively detect chloroform in chloral hydrate raw materials and preparations, effectively solves the problem of deviation in impurity detection results caused by sample thermal instability in the prior art, and provides a reliable analysis means for the quality control of chloral hydrate. At the same time, the detection steps of the method of the present invention are simple and the applicability is strong. Description of the Drawings

[0021] Figure 1 It is the chromatogram of the blank solvent obtained by using the detection method of Example 1.

[0022] Figure 2 It is the chromatogram of the reference substance solution obtained by using the detection method of Example 1.

[0023] Figure 3 It is the chromatogram of the test sample solution obtained by using the detection method of Example 1.

[0024] Figure 4 and Figure 5 They are the chromatograms of the test sample solutions obtained by using the same brand and model but different batch numbers of chromatographic columns in Example 2. Detailed implementation manners

[0025] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. All other examples obtained by those of ordinary skill in the art based on the examples of this application without creative efforts fall within the protection scope of this application.

[0026] Unless otherwise specified, the material information of the following examples and comparative examples is obtained commercially.

[0027] Example 1 Quantitative determination of chloroform content in chloral hydrate by gas-phase direct injection method

[0028] (1) Chromatographic conditions:

[0029] Chromatographic column: A capillary column with polyethylene glycol (Agi lent DB-WAX, 30m×0.53mm×1.0μm) as the stationary liquid;

[0030] Injection port: Split / non-split;

[0031] Split ratio: 5:1;

[0032] Temperature: 200°C;

[0033] Injection volume: 5 μl;

[0034] Flow rate: 2.5 ml / min;

[0035] Detector: Flame ionization detector (FID);

[0036] Temperature: 250°C;

[0037] Temperature programming: The initial temperature is 40°C, maintained for 15 min, heated to 220°C at a rate of 80°C / min, and maintained for 10 min;

[0038] (2) Preparation of the sample to be measured:

[0039] Diluent (blank solvent): n-heptane.

[0040] Reference solution: Weigh accurately about 75 mg of chloroform reference substance, place it in a 50-ml volumetric flask, dissolve and dilute to the mark with the diluent, and shake well; accurately measure 1 ml, place it in a 100-ml volumetric flask, dilute to the mark with the diluent, and shake well to obtain.

[0041] Test solution: Take about 5 g of chloral hydrate enema, weigh accurately, add 50 ml of water, shake ultrasonically to dissolve, transfer to a separating funnel, rinse the beaker with an appropriate amount of n-heptane and transfer to the separating funnel, shake and let stand. After the solution is layered, drain the lower layer of liquid, transfer the upper layer of liquid to a 50-ml volumetric flask, pour the lower layer of solution back into the separating funnel, add an appropriate amount of n-heptane again, repeat the above operation for extraction three times, finally rinse the separating funnel with n-heptane and transfer to the same volumetric flask, and make up the volume to the mark to obtain.

[0042] (3) Determination:

[0043] Accurately measure the blank solvent, reference solution, and test solution, and inject them into the liquid chromatograph respectively, record the chromatograms, as shown respectively in Figures 1-3 Calculate the content of chloroform in the test solution according to the external standard method.

[0044] As can be seen from Figures 1-3 the detection method adopted in the present invention has the characteristics of fast peak emergence, good peak shape, and high accuracy.

[0045] Example 2 Methodological verification

[0046]

[0047]

Claims

1. A method for detecting impurities in a chloral hydrate sample, characterized in that, The detection method is gas chromatography, comprising the following steps: (1) Prepare the reference solution: weigh chloroform and add diluent to dissolve it; (2) Prepare the test solution: weigh the chloral hydrate sample, directly add the diluent to dissolve and extract, and retain the diluent layer solution; (3) Detection is performed using a gas chromatography direct injection and programmed temperature method, and the chromatogram is recorded; Wherein, the impurity is chloroform, and the diluent is an organic solvent; The gas chromatography conditions are: using a capillary column with polyethylene glycol as a stationary liquid as a chromatographic column, using a flame ionization detector, an injection port temperature of 150-250° C., and a detector temperature of 200-300° C.; The heating program is as follows: the initial temperature is 35-45°C, maintained for 5-30 min, then heated to 200-250°C at a rate of 70-90°C / min, and maintained for 5-30 min.

2. The detection method according to claim 1, characterized in that: The diluent is n-heptane.

3. The detection method according to any one of claims 1 to 2, characterized in that: The chromatographic column is Agilent DB-WAX, 30m×0.53mm×1.0μm or a chromatographic column with equivalent polarity.

4. The detection method according to any one of claims 1 to 2, characterized in that: The injection port temperature is 200°C.

5. The detection method according to any one of claims 1 to 2, characterized in that: The detector temperature was 250°C.

6. The detection method according to any one of claims 1-2, characterized in that: The temperature rising program is as follows: the starting temperature is 40°C, maintained for 15 minutes, then raised to 220°C at a rate of 80°C / min, and maintained for 10 minutes.

7. The detection method according to any one of claims 1 to 6, characterized in that: The chloral hydrate sample includes a chloral hydrate raw material and / or a preparation.

8. The detection method according to claim 7, characterized in that: The preparation includes any dosage form of oral solution, syrup and enema.

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