Research on the production technology of citicoline 10mg/ml-100ml injection liquid

Abstract

Background: Mongolia has one of the highest rates of stroke with annual incidence of 290 per 100,000 population and higher prevalence stroke caused death occurring 49.0 per 100,000 population. In the developed countries, cerebral infarction accounted for 87% of all stroke cases. In Mongolia, the incidence of brain infarction and intracerebral hemorrhage ratio is 1:1 thereby showing inadequate control of hypertension and insufÏcient preventive measures against stroke. In our country, the majority of injectable drugs used in neurological disorders treatment are imported. Therefore, there is a urgent need to introduce high quality domestic drug production in our country. Aim: Aim of this study is to develop technology for extracting injectable solution of Citicoline 10mg/ml-100ml and evaluate the quality of injection. Materials and Methods: We determined sodium content of citicoline with spectrophotometric method, sodium and potassium ion content with flame photometric method, calcium ion content with complexonometric method, total chloride amount with argentometric MOR method, lactate amount with reverse titration method. Results: We measured 10mg/ml of citicoline from raw materials and added appropriate amount of excipients in appropriate order, prepared 15000ml of solution, packed in non-PVC packaging, steamed 10 minutes at 1210C. Within the 6 samples model S3 was proven to be more suitable than other models in terms of quality, so a consistent qualitative study was conducted on this sample. Stored at 25±20C, 30±20C temperature, 30±5%, 65±5% relative humidity, it maintained its stable quality at 9 and 6 months of real-time and intermediate conditions testing. When sodium ion content was determined by flame photometric method, relative standard deviation of less than 2.0% thus meeting standard criteria. Citicoline quantity was determined by spectrophotometric method relative standard deviation was less than 2.0% which also met requirement criteria. Relative standard deviations of 0.35% and 1.43% were obtained in determining the accuracy of the mean value, which was within appropriate range. The correlation coefÏcient of the standard curve was R2=0.999, confirming the linear association. Sterile and febrile quality was measured with microbiology assessment. Bacterial endotoxin of Citicoline 100 mg/ml-1000 ml injection solution was lower than allowed limit. There was no sediment, murkiness or sign of bacterial growth detected during 14 days in culture medium under normal light thus conclude that our injectable solution as sterile. Conclusions: 1. 3 series of S3 model Citicoline 10mg/ml-100ml injectable liquid with Polyolepin non-PVC packaging has maintained its stable quality for 9 months when evaluated by chemical and microbiological indicators in real-time and intermediate conditions tests. 2. When evaluated in terms of precision, repeatability, precision of the mean value, and linearity with validation of the flame photometric and spectrophotometric analysis methods product did not exceed acceptable limits. 3. Citicoline 10mg/ml-100ml injection liquid does not exceed the limit of bacterial endotoxin and was sterile thus meeting the requirements of microbiological parameters.