CN-121978239-A - Method for detecting related substances of chloral hydrate

Abstract

The invention relates to the field of drug detection and analysis, in particular to a method for detecting degradation impurities such as carboxylic acids, aldehydes and the like of chloral hydrate. The detection method adopts high performance liquid chromatography, adopts octadecylsilane chemically bonded silica as a filler, and adopts an ultraviolet detector to detect the wavelength of 195nm plus or minus 2nm. The detection method can realize effective separation of auxiliary material peaks and related substances, has good peak types, meets pharmacopoeia requirements in separation degree between impurity peaks and main peaks and between impurity peaks, and has good specificity. Is suitable for medicine registration quality research of chloral hydrate and preparations thereof.

Inventors

• TANG DANXIA
• CHEN WEI
• YANG WEIJING
• ZHANG XIAOWEI
• DU ZUYIN
• HUANG HAOXI

Assignees

• 成都倍特药业股份有限公司

Dates

Publication Date

20260505

Application Date

20260209

Claims (10)

1. 1. A method for detecting chloral hydrate or related substances of a preparation thereof by adopting liquid chromatography, which is characterized by comprising the following steps: precisely weighing proper amount of chloral hydrate or its preparation, and diluting with solvent to obtain sample solution; injecting the sample solution into a high performance liquid chromatograph, and detecting according to chromatographic conditions; the chromatographic conditions include octadecylsilane chemically bonded silica as stuffing, ultraviolet detector of 195nm + -2 nm wavelength, acid containing water solution as mobile phase A and acetonitrile as mobile phase B, and gradient elution.
2. 2. The method of claim 1, wherein the mobile phase a comprises an aqueous phosphoric acid solution.
3. 3. The method according to claim 1, wherein the concentration of the mobile phase A is selected from 0.05% -0.5%, and further from 0.10% -0.30%.
4. 4. The method of claim 1, wherein the gradient elution comprises the following procedure:
5. 5. The method according to claim 1, wherein the related substance comprises formic acid, acetic acid, dichloroacetaldehyde hydrate, dichloroacetic acid, trichloroacetic acid, 5-hydroxymethylfurfural.
6. 6. The method of claim 1, wherein the filler is selected from Waters XBridge Shield RP or JADE-PAK KP-C18.
7. 7. The method according to claim 1, wherein the column Wen Xuanzi is at 25-70 ℃, further at 25 ℃ or 40-50 ℃, further at 25 ℃ to 27 ℃ or 42 ℃ to 45 ℃.
8. 8. The method according to claim 1, wherein the content of formic acid in the chromatogram of the sample solution is not more than 0.5%, or/and the content of acetic acid is not more than 0.5%, or/and dichloroacetic acid is not more than 0.012%, or/and trichloroacetic acid is not more than 0.05%, or/and dichloroacetaldehyde hydrate is not more than 0.10%, or/and 5-hydroxymethylfurfural is not more than 0.02%, or/and other single impurities are not more than 0.15%, or/and the total content of impurities is not more than 1.0%.
9. 9. The method according to claim 1, wherein the chromatographic column has a size of 3.0-5.0 mm in inner diameter, a length of 100-250 mm, a filler particle diameter of 2-5 μm, and further wherein the chromatographic column has a size of 4.6mm in inner diameter, a length of 250mm, and a filler particle diameter of 5 μm.
10. 10. The method according to claim 1, wherein the preparation of chloral hydrate comprises a syrup, an oral solution, a enema, a suppository or a solution to be irrigated, preferably a syrup.

Description

Method for detecting related substances of chloral hydrate Technical Field The invention relates to the technical field of medicine analysis, in particular to a detection method of related substances of chloral hydrate or a preparation thereof. Background The chloral hydrate syrup is a hypnotic sedative drug commonly used in clinic during pediatric examination, has quick administration effect, high safety, approximately physiological sleep, no inhibition of respiration and no obvious side effect, has the chemical name of 2, 2-trichloro-1, 1-glycol and CAS number of 92478-27-8, and has the chemical structural formula as follows: The auxiliary materials used for producing the chloral hydrate syrup mainly comprise sucrose, anhydrous citric acid, essence and the like, the chloral hydrate is easy to degrade under the conditions of heat, oxidation, illumination and the like, and the properties are unstable, especially the stability in aqueous solution is poor. The chloral hydrate can be slowly decomposed in the aqueous solution, and can be quickly decomposed by heating, oxidizing and illumination to generate degradation products such as chloroform, dichloroacetaldehyde, trichloroacetic acid, acetic acid and the like, and the sucrose can be slowly decomposed into 5-hydroxymethylfurfural in the solution. At present, most of the clinical chloral hydrate at home and abroad is syrup or oral solution, and the chloral hydrate is mainly used for pediatrics, so that the quality research of the product needs to be carefully treated. The raw material medicine of chloral hydrate and the oral solution of chloral hydrate are not loaded with related substance inspection items in the national and international pharmacopoeia standards, and the syrup of chloral hydrate is not loaded in the national and international pharmacopoeia standards. The prior art CN115453025A discloses a method for detecting related substances of chloral hydrate, but only partial impurities can be detected. Therefore, the development of a detection method which is more scientific and accurate and has wide applicability is significant. Disclosure of Invention The invention aims to provide a method for simultaneously and effectively separating and measuring chloral hydrate and impurities thereof, which has the advantages of simple and accurate sample preparation mode operation, strong specificity and high sensitivity, and realizes effective quality control of a chloral hydrate preparation. It has been found through extensive research that chloroacetaldehyde hydrate or its syrups are prone to produce various impurities during production or storage, including dichloroacetaldehyde hydrate, 5-hydroxymethylfurfural, formic acid, acetic acid, trichloroacetic acid, dichloroacetic acid. According to the international association guidelines (ICH guidelines) for registration of human drugs, the aforementioned impurities are all required to be detected and controlled, and there are also genotoxic impurities that require strict control. The chemical structure and control of the impurities are summarized in Table 1: TABLE 1 summary of related impurities, structural formula and control basis for chloral hydrate preparations However, the applicant has found that some of the aforementioned impurities have not been reported and studied in the existing chloral hydrate or its syrup, and that the existing method for detecting chloral hydrate or its syrup cannot detect and analyze all of the aforementioned impurities simultaneously. Certain adjuvants of syrups often also interfere with detection. Therefore, the applicant provides an analysis method capable of simultaneously detecting and analyzing the impurities through a large amount of researches, and the method has the advantages of high detection sensitivity, strong specificity, no interference from auxiliary materials and simplicity and accuracy. The invention provides a detection method of a chloral hydrate related substance, which adopts a liquid chromatography method and comprises the following steps: Accurately weighing proper amount of chloral hydrate or its preparation, and diluting with solvent to obtain sample solution. Injecting the sample solution into a high performance liquid chromatograph, and detecting according to chromatographic conditions; The chromatographic conditions include octadecylsilane chemically bonded silica as stuffing, ultraviolet detector of detection wavelength 195nm + -2 nm, acid-containing water solution as mobile phase A and acetonitrile as mobile phase B, and gradient elution. Further, the concentration of the sample solution is 16-24 mg/ml, and further 20 mg/ml. Further, the preparation of the sample solution comprises the steps of taking a proper amount of chloral hydrate syrup, diluting the chloral hydrate syrup to a required concentration by using a solvent, and shaking the mixture uniformly to obtain the sample solution with the chloral hydrate concentration of 16-24 mg/ml. Further, t