Discussion On The Universality Of Impurity Profiling Analysis Method Of Penicillin Based On The Concept Of Analytic Target Profile

The use of high performance liquid chromatography(HPLC)to control the impurity spectrum of drugs is a hot topic in current drug quality control,of which the key points are optimization of the HPLC method and structure analysis of impurities by HPLC-MS/MS.The core skeleton of penicillins is 6-amino penicilicanic acid(6-APA).The unstable 6-APA results in rich impurities,and impurity profiling of penicillins is the key to pledging clinical medication safety and efficiency.The first thing needed is a good HPLC analysis method in the process of penicillins impurity profiling.Based on the differences of drug structure,the traditional idea is to develop different chromatographic methods in order to realize effective separation of impurities.Under the guide of quality by design(QbD),the concept of analytic target profile(ATP)is concluded as below: the predefined objectives and requirements based on the structures to be analyzed.It is clear that penicillins have the same mother nucleus and similar impurities.So penicillins have similar ATP.As a result,the HPLC methods meet the ATP for penicillins impurity profiling can be similar(or different kinds of penicillins and their impurities may have similar separation performance under the same HPLC methods).The concept of universality of drug impurity profiling is proposed.Analytical method of penicillin related substances in Chinese Pharmacopoeia(Edition 2015)is created under the guide of QbD and possess high separation efficiency of penicillin related substances.In order to explore the universality of analytical method of penicillin related substances,13 penicillin drugs were tested and8 of them including Penicillin V potassium,Piperacillin and Oxacillin can be separated under this method.Then using LC-MS to analyze the structure of impurities and all the known impurities,polymer impurities,and unknown impurities can all be separated by the analytical method of penicillin related substances.We built the impurity profile of these three drugs under penicillin method.It is concluded that this method can be universally applied in the analysis of penicillins impurity profile.The degradation impurities produced by strong degradation experiments contain only part of drug impurities.Impurities that may exist in real drugs but cannot be obtained through degradation experiments are called potential impurities.In order to evaluate the separation of potential impurities by penicillin method,we need to know the retention information of potential impurities.With the help of software DiscoveryStudio 3.1,200 to 300 molecular descriptors representing molecular structural characteristics are calculated,and the key molecular descriptors are screened through the Genetic Function Approximation(GFA)method.The multiple linear regression equation of molecular descriptor and logarithm of solute retention value(logK)is also established.With this model,it is possible to predict the peak position of potential impurities(retention value),assist in judging the structure of impurities,and evaluate the separation effect of analytical methods.This thesis takes penicillin as the research object,under the guidance of the QbD concept,and studies the optimization of the analytical method of impurity profiling.Based on the similarity of species / structure of impurities in penicillin antibiotics.We established a strategy that based on the similarity of analytic target profile,and explored the universality of analysis method.8 kinds of penicillin antibiotics can be efficiently separated by the penicillin method,it is concluded that penicillin method has good universality for the analysis of penicillins.The prediction model of impurity structure-retention time is established.This model can provide retention information for potential impurities in impurity profiling.