| Oxandrolone, which is an improver of lipid and protein catabolism, can promote the assimilation of body protein. It is used as an assistant drug for HIV-infection, severe burn injury, osteoporosis and children Turner syndrome.This paper presents a systematical research on the selection of synthesis route of the drug substance and its structural establishment and the quality control methodology in order to control it in the course of the actual yields.After synthesizing all kinds of the synthesis routes of oxandrolone in the home and abroads, the paper establishes and optimizes the synthesis route that the starting material, mestanolone, is suffered with bromination, debromination, oxidation and reducition to obtain oxandrolone according to the principle of brief operation, low-cost and low-contamination. In the first step, the bromine is added directly to avoid losing and it is safety and innoxious to use ozone in the third step. Each reaction is judged to be complete by TLC analysis on silica gel 60 plates with detection by spraying with 10% sulphuric acid in ethanol solution and heating at 110℃. The craft route is brief and feasible and the total yield is 35.2%. The structural establishment is made for the compound with the methods of elements analysis, UV, IR, NMR and its structure is conformed.In the quality research of oxandrolone this paper focuses on studies of systematical measuring methodology of relevant substances, residual organic solvents, contents and the stability. In the examination of relevant substance, apply the sample solutions to silica gel 60 plates, and the eluant is a mixture of toluene and isopropyl alcohol(90:10). After the solvent evaporation, spray with 10% sulphuric acid in ethanol solution and heating at 110℃. It is selective to separate the intermediates and degradation productions.The sensitivity, tolerance and accuracy are good to control the relevant substances. Some organic solvents such as methanol, ethanol, tetrahydrofuran, N,N-dimethylforamide and ethyl acetate are used in the courae of synthesis and refining. The residual organic solvents are determined by GC. The preferential method to determine the content of the drug substance is volumetry. First the lactone is open with a alcoholysis reaction, then applyes a counter titration with hydrochloric acid in the present of phenolphthalein. It is indicated that oxandrolone is rather stable besides the relevant substances are increasing slightly on the conditions of high temperature, high humidity and illumination. So it. is necessary to preserve it in well-closed, light-resistant containers at room temperature. The relevant substances, disintegration, uniformity and contents are investigated especially in the tablets quality research. The TLC is also used to detect the relevant substances. The contents of the tablets are determined by GC with a SE-30(30m×0.32mm, 1μm) column and the carrier is nitrogen. A simple chemiluminescence method for the determination of oxandrolone with flow injection technique is proposed, which is based on oxandrolone enhancing the chemiluminescence from cerium(IV)-sulphite system.The linear range for oxandrolone is 0.1～10mg/L and the limit of detection is 4.8×10-3mg/L. The relative standard deviation (n = 11, C=1.0mg/L) is 3.3%.The brief synthesis route is low-contamination and feasible. A comparatively rounded study whose methods are classical is carried out for the quality of drug substance and its preparation. This quality critetion can be used to control and evaluate oxandrolone and its preparation's quality. The study helps to the new drug's declaring.
|
PDF Full Text Request