Study On Preparation Process, Quality Control And Special Safety Of Acetaminophen Injection

Acetaminophen is commonly known as paracetamol, it is an acetanilide antipyretic analgesic, oral preparation has decades of history in clinical application. This product is cyclooxygenase inhibitor by selectively inhibiting the hypothalamic temperature regulating central prostaglandin synthesis and it leads to peripheral vasodilation and sweating to antipyretic role, the antifebrile effects and strength similar to that of aspirin; by inhibiting prostaglandin synthesis and release and increasing the threshold of pain to achieve the analgesic effect, but analgesic effect is weaker than aspirin, it is effective for light and moderate pain. Commonly used dosage forms are tablets, capsules and small capacity injections.Acetaminophen is the most commonly used non-steroidal anti-inflammatory analgesics and antipyretics, due to its instability in aqueous solution, so oral preparation in clinical application although has several decades of history, it has no the advent of intravenous formulations until November 2010, the FDA approved the Cadence Pharmaceutical Limited Company to develop the large volume injection “Ofirmev” for bringing down the temperature, treating the light to moderate pain and the moderate to severe pain therapy by assisting the opioids. Ofirmev is acetaminophen preparation infused by intravenous. It has the characteristics of bringing down the temperature, stopping the pain, reducing the consumption and increasing the satisfaction of patients. It is a safety and effective intravenous infusing drug that widely applied to bring down the temperature and stop the pain in the clinical.In aqueous solution, it is easy to be hydrolyzed and not easy to be made into injection, but the injection has the advantages of rapid onset and is suitable for patients who cannot be taken orally. It plays an important role inclinical application.Objective: To study the formulation process of acetaminophen injection,to ensure the quality and the stability of the product.Method:1 Preparation process research1.1 Nitrogen filling methodThe nitrogen is injected into products through 5 different ways, by detecting the final products to determine the best way to protect the products.1.2 Effects of medicinal charcoal on active drug and auxiliary agentStudy the effect on target material through 2 ways that befort adding the medicinal active carbon in the target material and after it.1.3 The selection of sterilization conditionsThe changes of the samples were studied by the method of 121℃,12 minutes and 115℃,30 minutes to sterilize.1.4 The selection of pH range of diluted liquidStudy the effect of different pH values(4, 4.5, 5, 6, 5.5, 6.5, 7) on the quality of finished products.1.5 Study on the total amount of adding medicinal activated carbonStudy the activated carbon respectively according to dilute with total volume of 0.01%(g/ml), 0.02%(g/ml), 0.03%(g/ml) join quantity influences on the targets of the samples.2 The quality research of acetaminophen injectionTaking the three batches of pilot products as the research object, the original products as the reference preparation, according to the physical and chemical properties of acetaminophen and the characteristics of the large infusion preparations for the study of methodology of each component content and related substances and other inspection items of acetaminophen injection;through influencing factor test and a six-month stability test, we preliminarily understand the product stability, and it provides the basis for the production,packaging, storage, transportation conditions and the period of validity.3 Special safety testAcetaminophen injection hemolysis, the body active allergy and blood vessels irritation are studied by a certain test method.Result:1 Preparation process research resultsThrough the single factor test, the key technology is studied, and the preparation process of the high quality and stability of the acetaminophen injection can be determined:Adding moderate fresh injection water and putting amount of manniot in the concentrated tank, after stirring and dissolving, adding amount of activated carbon(according to dilute with the total volume of 0.01%g/ml), stirring evenly, after boiling 10 minutes, filtering to the diluted tank.Add the amount of water injection, followed by the addition of two sodium phosphate, hydrochloric acid cysteine and acetaminophen, stirring to make it fully dissolved, adding amount of activated carbon(according to dilute with the total volume of 0.01%g/ml), stirring evenly, filtering to the diluted tank.Mixing the concentrated liquid above under the nitrogen protection,adding the fresh injection water to the total amount, stirring evenly, detecting the content and pH value, we get the diluted liquid.Filtering, checking the clarity of the liquid, filling under the nitrogen protection, sealing, sterilizing under the temperature of 121 ℃, 12 minutes,inspection, packing.2 Quality research results2.1 The content of acetaminophen was detected by HPLC, the methodology validation results showed that linear relationship and repeatability of the method are good, and intermediate precision is high.2.2 Two kinds of liquid phase conditions were used to investigate the related substances. The methodology validation results showed that the specificity was good, and the security was high, and it could be used to detect the impurities in the preparation effectively and be able to quantify accurately.2.3 The test results of three batches of samples were consistent with the3 Special safety test quality standard. The content of acetaminophen in the 0 days and in the period of stability were stable in the range of 98.0%~102.0%. Although the content of cysteine hydrochloride decreased slightly, it kept above 50% and can effectively guarantee the quality of the products; the content of the related substances was far less than 0.1%, this was consistent with “Ofirmev”.This product in vitro hemolysis was negative, the allergic reaction was weaker than that of “Ofirmev”, and the vascular stimulation was consistent with “Ofirmev”.Conclusion: The research of the preparation process and quality standard is reasonable, the method is feasible, the product safety is reliable, and the stability is good.