Studies On Analytical Methods Of Related Substances In3Chemical Drugs

Any component of the drug substance that is not the chemical entity is defined as thedrug impurity. Organic impurities can arise during the manufacturing process and/orstorage of the new drug substance. They can be identified or unidentified, volatile ornon-volatile, also named related substances. The existence of these impurities influencesthe safety of the drugs and the people’ health. Some of related substances in impuritieseven cause the long term drug misadventures. Thus researches and controls of theidentified and unidentified impurities decrease the risk of the adverse drug reaction andbecome the priorities in research and development (R&D) of new drugs and listed drugreevaluation. However, it is difficult to detect the related substances because of traceamount and uncertainty of their structures. With the rapid development of techniques inchromatography and spectroscopy, a growing number of multiple techniques have beenapplied in drugs quality control, especially in related substances’ structure identification,degradation path and assay.Based on the modern analytical techniques and new concepts of impurity research,the article chose the memantine hydrochloride tablets, nifedipine extended-release tabletsand amikacin sulfate injection to represent the new drug, commonly used medicine,―olddrug‖. The analytical methods were established to detect the related substances inchemical drugs. Influencing factors of related substances’ formation in memantinehydrochloride tablets were investigated. Article mapped out the evaluation procedure ofconsistency between generic drugs and original drugs by using the example of nifedipineextended-release tablets according to the concept of impurity profiles. Development ofthe derivatization method for detecting the kanamycin in amikacin sulfate injectionpromotes the development of quality standard. The results can provide the methods andmodes for drugs’quality development, quality evaluation and R&D.PART Ⅰ Research of the related substances in memantine hydrochloridetabletsFour known impurities in memantine hydrochloride tablets, a new drug withoutultraviolet absorption, were detected by gas chromatography (GC). Used the Agilent19091Z-213HP-1(30m×0.32mm，0.25μ m)as chromatography column to separatememantine and4known impurities. The present method, with good linear, accuracy,precision, sensibility, can be used for detecting the related substances in memantinehydrochloride tablets.A HPLC-TOF/MS method was used for evaluating the Maillard reaction betweenmemantine and excipients. A high performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD) was used for detecting the product of the Maillardreaction.A mobile phase of0.05%trifluoroacetic acid (A) and acetonitrile (B) was used withgradient elution and flow rate was1ml/min. The temperature of drift tube was40℃andthe nebulizer nitrogen press was3.5bar, gain was7. The present method, with goodlinear accuracy precision sensibility, can be used for detecting the product of Maillardreaction.The two methods can guarantee the safety, effective, quality control of memantinehydrochloride tablets systematically and complementarily.PART Ⅱ The quality consistency evaluation of impurity profile in nifedipineextended-release tablets (Ⅱ)Based on the concept of impurity profile, the evaluation procedure of consistencybetween generic drugs and original drugs was established by treating the wholeimpurities as object. The classical chemometrics method (correlation coefficient, vectorcosine, principal component analysis, hierarchical clustering,) in traditional Chinesemedicine fingerprint were used to evaluate the quality difference between6generic drugsand an original drug. The evaluation procedure includes: method of screening, assay anddate acquisition, consistency of inter-batch, consistency of generic drugs, consistency ofweight.PART Ⅲ A sensitive pre-column derivatization LC-UV method for assayingkanamycin in amikacin sulfate injectionIt is the listed drugs that we also should focus on its safety. Narrower limitation ofthe related substances is one of the methods in development of quality standard. In thearticle, the stability of samples was extended after the development method for detectingthe known impurity Kanamycin. The new method guaranteed the accuracy of detection.The results of this article, from assay of a single related substance, systemicresearch of the related substances in new drug to consistency of the whole relatedsubstances, will provide the reliable analytical methods and research ideas for the safetyand effectiveness of the drugs. From new drug, commonly used medicine to―old drug‖,the results of this article can nearly reflected the different emphasizes of investigation ofrelated substances in drugs’ whole life.