Study On Preparation Processand Stability Of Multiple Electrolytes Injection(?)

The multiple electrolytes injection(?)is a compound preparation of various electrolytes.Clinically,it is mainly used for isotonic dehydration to prevent and treat acidosis by supplement the loss of extracellular fluid.The original research company of this product is B.Braun Melsungen AG and was approved for listing in 2005 with trade name of“Sterofundin ISO".In some countries and regions,the name is "Ringerfundin".In December 2012,this product is approved by China with the specification 500mL/bag,1000mL/bag respectively.The formulation of the product we intend to develop is consistent with the primary drug,the specification is 500mL large-volume sterilization injection.To provide a basis for evaluating the quality of the newly developed multiple electrolytes injection(?)and the quality of the products of the listed German Braun,the stability of its preparation process is studied and the quality standard is established also.This paper mainly includes the following aspects:1.The first aspect:the establishment of determination method of drug contents and the related substances for multiple electrolytes injection(?)Content and related substances are one of the important quality indicators for measuring the safety and effectiveness of a pharmaceutical preparation.In this part,the content of each component in the prescription of multiple electrolytes injection(?)and the determination method of related substances were established,and then the methodological verification was carried out.The results showed that the HPLC method was used to determine the content of acetate,L-malic acid and the related substances in the prescription of multiple electrolytes injection(?).The content of chlorine was determined by indicator titration.Polyvinyl alcohol is added during the titration to prevent precipitation;and the contents of sodium,potassium,calcium and magnesium are determined by atomic absorption spectrophotometry.The specificity of the method,system suitability,limit of quantitation and detection limit,linearity and range,precision,accuracy(recovery),solution stability,durability,etc.can meet the content of multiple electrolytes injection(?)and related substances.The measurement requirements are met at the same time as the standard requirements.2.The second aspect:the study of the preparation process of multiple electrolytes injection(?)According to the primary drug to determine the specifications and prescription composition of the product.Through the screening of the source of the drug substance,the screening of the source and amount of the prescription components,the order of addition,the pH value of the solution,the temperature of the solution,the compatibility of the filter material,the amount of medicinal carbon,nitrogen protection and sterilization temperature to determine the optimal formulation composition and process parameters.The bulk-sterilized injection with a specification of 500mL was selected.The final composition was determined to be(sodium chloride,potassium chloride,calcium chloride,magnesium chloride,sodium acetate,L-malic acid,sodium hydroxide,activated carbon);the order of addition was Sodium chloride,L-malic acid,sodium acetate,potassium chloride,magnesium chloride,calcium chloride,sodium hydroxide,activated carbon input amount of 0.1%(W/V);pH range(5.3?5.7);0.22 ?m filter was finely filtered and the sterilization condition was 121 °C for 15 min.According to the results of prescription and process research,three batches of pilot samples were prepared.After inspection,the properties of traits,pH value,clarity and color,osmotic pressure,heavy metals,related substances and contents,and various investigation items of self-products and original research products were investigated.The results are basically the same.It shows that the prescription design is reasonable and the preparation process is stable.3.The third aspect:the study of quality standards of multiple electrolytes injection(?)In order to ensure the safety and effectiveness of the products,the scientific and reasonable quality standards and testing methods including traits,pH,clarity and color,osmotic pressure,heavy metals,related substances,content and other items were developed based on comprehensive quality research referring to the "Chinese Pharmacopoeia of 2015" and the import drug registration standards of multiple electrolytes injection(?).The chlorine content was titrated with the indicator method and the specificity,precision,accuracy(recovery),linearity and extent of the method were verified.Determination of sodium,potassium,calcium and magnesium by atomic absorption spectrophotometry and the specificity,linearity and range,precision and accuracy(recovery)of the method were verified.Acetate and L-malic acid were determined by high performance liquid chromatography and the specificity,system suitability,solution stability,and durability,linearity and range,precision and accuracy(recovery rate)were verified.At the same time,the relevant substances of this product are tested according to the chromatographic conditions of the determination method of acetate and L-malic acid content,and the specificity,system suitability,limit of quantitation and detection limit,linearity and range,precision,accuracy(recovery),solution stability,durability were verified.Method verification results are in line with acceptable standards,indicating that the method is suitable for this Determination of the relevant substances,the specificity is good.4.The fourth aspect:the stability study of multiple electrolytes injection(?)On the basis of the scientific quality standard research,according to the requirements of the pharmacopoeia appendix,the stability of the influencing factor test,the accelerated test and the long-term sample test were carried out on the sample simulation package.The product was placed under the conditions of the influencing factors for 30 days,accelerated test conditions for 6 months,and long-term test conditions for 24 months.There was no significant change in each item,and all met the requirements of quality standards.The research results provide theoretical basis and reference for the preparation process design,quality standard and effective period of multiple electrolytes injection(II).