The Construction Of The PAT System For Penicillin Sodium Of Lower Allergy Rate And The Study On The Method To Control Polymers In Antibiotics

The allergic reaction of Penicillin is still the widely observed clinical adverse drug reaction (ADR). The anaphylactic reactions are of different degrees, which are depending on the patients' constitution, the administration and so on. The most serious reaction is the anaphylactic shock, AIAS. Researches showed the main reason of the allergy caused by penicillin is the high molecular weight (HMW) impurity in the drug, including residual protein and polymers. As the technology of manufacture process has been improved, the residual protein is no more the main reason of allergy. And polymers formed by drug have become the potential allergic threat.The keystone of this thesis is to set up the quality control system of production process of penicillin sodium for Process Analytical Technology, PAT. Along with the manufacture process, different penicillin samples were analyzed to find out the index impurity and to make sure where it is from. Then the production condition could be adjusted to remove the index and other high weight molecular impurities, so that the rate of allergic reaction could be reduced. Gel filtration chromatography and HPLC were applied to analyzing impurities in the drug. A7 has been confirmed as the index to guide manufacture process. It is from the product line and can be controlled. Few products without it have lower content of polymer impurities and less related substances. And the result of column switching also verified it is a high weight molecular polymer impurity. The aim is to remove A7 and to make the quality of penicillin sodium better. 2D-chromatography system has been built up for the study of HMW impurities, which is suitable for the polymer impurities evaluation of other antibiotics.The ESMOROS method for the determination of the polymer impurities content in antibiotics was invented and developed independently in our conutry. We adopted column switching to prove the composition of the polymer peak in Sephadex G10 system. And the rationality of this system in application has been complimented. Besides, some phenomena in GFC were different from the current theory about ESMOROS. In this paper the mechanism of ESMOROS has been discussed. After studying the gel Chromatographic retention behavior of different solutes, we raised an inference to explain the mechanism of the ESMOROS. The drug itself can be the external standard and the apparent molecular weight of the external standard augments is for the interaction of water molecular and the gel matrix but not for the aggregation of the small solute molecules as the current theory illustrates.