Study On Salt - Forming Rate Of Salt - Type Drugs Based On Mixed - Mode Chromatography And Single Crystal Diffraction

With the development of high throughput screening and synthesis technology, more and more salt drugs flowed into the market. The formation of salt drugs was a simple and effective way to modify and optimize the physical chemical properties, such as solubility, stability, impurity profiles, and bioavailability of active pharmaceutical ingredients. If drugs do not salt formation thoroughly, which will certainly cause the safety and efficacy of drugs. It is great significance that strengthen the research of salt rate.This paper was divided into three chapters, which studied the formation process and the salt ions content of salt drugs in three different and novel analysis methods.The first chapter mainly used mixed mode chromatography combined with general Charged aerosol detection to research the detection methods of salt drugs. We selected Potassium Magnesium Aspartate and Melitracen Hydrochloride as representative drugs, and established a testing method that analyzed active pharmaceutical ingredient and salt counter ions at the same time. The method established in this chapter was simple, rapid, accurate and repeatable by methodology validation. It was suitable for the quantitative detection of salt drugs, and provided methodological basis for exploring the salt degree and controlling the quality of salt drugs.The second chapter mainly used two separation ways of ion chromatography, ion suppression chromatography and ion exchange chromatography, to quantitatively detect the organic acid content of salt drugs. Fentanyl citrate injection was chosen as a representative drug. We tested the content of active pharmaceutical ingredients and citric acid in Fentanyl citrate injection. By methodology validation, both the two methods showed simpleness, environmental protection, accuracy. They were suitable for citric acid testing. And the analysis result of the two methods had no significant difference. Citric acid content in active pharmaceutical ingredients was close to the value (1:1) in theory, which proved the formation of salt drug was complete.The third chapter is mainly based on the single crystal X-ray diffraction technique. Diisopropylamine dichloroacetate, Lurasidone hydrochloride, GM-AMPL and Fentanyl citrate were selected as representative drugs. Through the crystal culture screening, diffraction testing confirmed the compound structure and analysed the principle of the structure. It is proved that the proportional relation in medicines and combination mode of the active pharmaceutical ingredients with salt.In conclusion, this paper is using three novel analysis technologies to establish a set of methods for monitoring the formation of salt drugs and detecting salt ions content of those drugs accurately, reliably and easily. According to the drug into ion detection, it could calculate the drug into salt real proportion relations. The strategy of salt formation research will be summarized to provide the method and scientific basis of the quality control of medicines research.