Studies On Preparation And Quality Control Of Compoud Tilidine Hydrochloride Sustained-release Tablets

Compoud tilidine hydrochloride sustained-release tablets, consist of tilidine hydrochloride and naloxone hydrochloride, are narcotis analgesics.Tilidine hydrochloride is a synthetic opioid narcotic analgesics acting on the central nervous system, can be used for severe acute and chronic pain. Naloxone hydrochloride is an opium-ceptor antagonist,and it plays specific antagonism for intoxication produced by narcotic analgesic drugs in therapeutic doses,without affecting analgesia of tilidine. When an addict is excessive orally or intravenously, naloxone produces pharmacological activity leading to withdrawal syndrome.In the present reasearch,we studied preparation process and the quality control methods of compoud tilidine hydrochloride sustained-release tablets, including appearance, identification, assay, dissolution, content uniformity, related substances etc.PartⅠ: Studies on the preparation method of compoud tilidine hydrochloride sustained- release tabletsObjective: To study the preparation method of compound tilidine hydrochloride sustained-release tablets. It can reduce the frequency of administration, and opioid receptor antagonism of naloxone helps to reduce the risk of tilidine being abused.Methods: The reference product was hydrophilic gel skeleton tablet. On the basis of raw materials compatibility test results, we determined the basic formulation. According to the results of pre-experiment, the drying conditions and coating conditions were determined. In the single factor test, we changed the amounts of pharmaceutical adjuvants to optimize factor range. The experiment scheme of optimum fomula was designed by using Design Expert. By adopting the HPMC(X1) and MCC(X2) as the independentvariables, and adopting the cumulative release rates in the p H1.2 medium of self-made product and of reference product at different time(15min、1h、4h、8h) as the dependent variables(Y1、Y2、Y3、Y4), multiple regression equations model was established. When the variance analysis of it had been significant, the model was used to establish the optimum formula that validated by comparing the release profiles of self-made product and reference product in the four different dissolution media.Results: Raw materials compatibility test confirmed that the pharmaceutical adjuvants had no negative effect on the main ingredient. Release characteristic of the new sample according to the optimum formula was similar to that of the reference sample, f2: 87、85、84. The concentration of coating solution was determined to be 18%. The appearance of samples was good after 2 hours coating. The process had good stability. The release curves of scale-up productions were similar to those of the reference products, too.Conclusion: The products: moderate hardness, smooth surface, good stability. The process with relatively wide pressure range was easy to control. The impurities of the samples were no more than those of the active pharmaceutical ingredients(APIs). Pharmaceutical adjuvants had no influence on determination of samples. The tablet friability was small. The release characteristics of the self-made products were similar to those of the reference products. The result of scale-up experiment indicated that the process was repeatable and feasible.Part Ⅱ: Studies on the quality control methods and stability of compound tilidine hydrochloride sustained-release tabletsObjective: To establish the quality control methods of compound tilidine hydrochloride sustained-release tablets by studying assay, examination(including related substances, release, content uniformity) of it. And then to study its stability.Methods: The determination and the related substances of compound tilidine hydrochloride sustained-release tablets were performed with reversed phase high performance liquid chromatography by using a C18 Xchargecolumn(250mm×4.6mm,5μm). The mobile phase consisted of 0.01mol/L ammonium carbonate solution(adjusted to p H 8 with 50% phosphoric acid)-acetonitrile at a ratio of 45:55(v/v). The flow rate was 1.0ml/min. And the injection volume was 10μl. The detection wavelength was 230 nm. The chromatographic separations were performed at 30℃.And the same chromatographic conditions were used to determine content uniformity. The HPLC retention time for determinating content was used to identify the sample. In vitro release test was performed in a dissolution apparatus using the first method according to Ch P. The stirring rates was 75 rpm. The volume of p H1.2 hydrochloric acid solution used as release medium was 900 ml. The temperature was maintained at 37±0.5℃, sampling at 15 min, 1h, 2h, 4h, 8h. The samples were analyzed with HPLC.The chemical and physical stability of compound tilidine sustained-release tablets was investigated under the high temperature, high humidity, strong illumination conditions and accelerated conditioin. The samples were observed for change in appearance, related substances, drug content and release characteristics at the end of study.Results: Assay: The linear range of tilidine hydrochloride content was 5.18μg/ml~310.91μg/ml with the regression equation being y=6.09x-0.033,r=1.000; and the linear range of naloxone hydrochloride content was 0.41~24.66μg/ml with the regression equation being y=12.975x+0.1596,r=1.000. The average recovery rate of tilidine hydrochloride was 100.4% with RSD of 0.48%, and that of naloxone hydrochloride was 101.3% with RSD of 0.69%.Related substances: The degradation products were well separated from the two main peaks after high temperature, high humidity, light, acid, base, and oxidative damage. And the supplementary materials had no influence in determination of related substances. The detection limit of tilidine hydrochloride was 1.04 ng, and that of naloxone hydrochloride was 0.04 ng. In addition, impurity A 2.40 ng, impurity B 1.26 ng, impurity C 1.38 ng, impurity I 0.41 ng. And according to the above order, the average recoveries of theimpurities were 100.1%, 100.2%, 100.3%, 100.2%; the corresponding RSD: 0.28%, 0.38%, 0.36%, 0.37%; the linear ranges: 0.481~14.415μg/ml, 0.504~15.105μg/ml, 0.550~16.485μg/ml, 0.041~1.223μg/ml. Peak areas were significantly linear function of impurity concentrations.Determination of release rate: the supplementary materials had no interference for the determination. It was feasible to treat the samples with membrane filtration.Stability experiment: The samples in the relative humidity 92.5%RH conditions for 10 days were hygroscopic swelling in appearance, but the samples in the relative humidity 75%RH conditions had no obvious change in appearance. The result of accelerated experiment showed the data were not significantly different from before, except that the impurities content increased slightly.Conclusion: The methods of assay, related substances and dissolution for compound tilidine hydrochloride sustained-release tablets are specific, sensitive, accurate, and reproducible. And the methods are able to provide a scientific basis for quality control.