| Simethicone is the mixture of polydimethylsiloxane(PDMS)and colloidal silicon dioxide.Both dimethicone and simethicone can act as antifoaming agents,but the defoaming activity of simethicone is much stronger than that of dimethicone.Simethicone has the capacity to reduce the surface tension of bubbles in the digestive tract and excrete the air of bubbles,which is totally a physical process.Therefore,therapeutic effect of simethicone is to help people ease flatulence.At present,one kind of simethicone emulsion(trade name:Percy)is on sale in China,and it has two clinical uses:for one thing,it can alleviate discomfort of flatulence,for another thing,it can be used as contrast agent adjuvant for imaging examinations,such as X-ray,ultrasound gastroscope examination,and so on.Being a macromolecular substance,simethicone is inert in pharmacology and physiology,besides,it is not absorbed in the gastrointestinal tract,and the results of acute toxicity test and long-term toxicity test on rats show that simethicone is not poisonous.Dimethicone is fully methylated linear siloxane polymers,which means that dimethicone is a mixture of PDMS with different degree of polymerization.Colloidal silicon dioxide is a kind of highly pure,inert,flavorless,white,free-flowing powder particle,and it has the advantage of large specific surface area and tiny particle size in comparison with common silicon dioxide.When PDMS and colloidal silicon dioxide tend to transform into complex,they form a two-layer structure,which includes the adsorbed layer and the restricted layer.The adsorbed layer mainly consists of colloid silicon dioxide particles and the adsorbed PDMS chains on their surface,while the restricted layer is formed of the interwined PDMS chains.Being an active ingredient,simethicone is recorded both in USP and EP.but it is not included in ChP 2015 and none of Chinese pharmaceutical companies has the qualification to manufacture simethicone.ChP records quality control methods of dimethicone and colloidal silicon dioxide.In order to deeply investigate the quality characteristics of simethicone and its synthesis process,this paper are divided into four parts:The first part is about quality analysis of the original drug.By consulting relative literature,we got to know the quality standards of simethicone and their respective quality control results.In order to fully understand the inner quality characteristics of the original drug,we tested the size distribution and the viscosity of the original simethicone,its 10%,50%,90%cumulative particle size distribution were 2.36±0.27?m,7.05±1.79?m,25.22±6.89?m respectively,and its viscosity was 579.2±3.3cP.Furthermore,we analyzed the quality characteristics of a kind of dimethicone,which is the starting material of the original simethicone.Besides getting the hang of the quality control standards of dimethicone,we measured molecular weight of this dimethicone through a newly established and validated method.The peak molecular weight(Mp)of the starting material was 23318±158,weight average molecular weight(Mw)of it was 35896±1460,and this was a precise standard of dimethicone that we used later for material choosing.The main content of the second part is the investigation in the related substances of simethicone and dimethicone,and the purpose of this part is to figure out the type and content of related substances in simethicone and dimethicone,especially to control the content of the toxic oligomers.Gas chromatography(GC)was employed for qualitative analysis and quantitative analysis of low-molecular polymers,and the method was validated to be good for required test.Determination of the oligomers in dimethicone and simethicone is based on the internal standard method without calibration factor.According to the detection results of original simethicone and its starting material dimethicone,we set the limits of the low-molecular polymers in dimethicone and simethicone:the content of the single oligomer is no more than 0.02%,the total content of the oligomers is no more than 0.1%.Because dimethicone and colloidal silicon dioxide transform into simethicone just like a one-step process,and by strictly controlling the quality of dimethicone,we can have a better understanding of the impact of the synthesis process on the simethicone quality,and then we are more likely to prepare simethicone product with higher quality and safety.The third part is about the research of simethicone synthetic process.At first,we undertook preliminary research on the synthesis processing route,and found out the impact of stirring,heating,grinding process on the inner quality of lab-made simethicone.Second.we determined to adopt the method to mix the starting materials roughly by stirring and heating simultaneously,and then grinding the rough mixture to produce simethicone.At last.we optimized the critical parameters through the synthetic processing routine.By using single-factor test,an optimized synthesis process of simethicone was determined:the weight ratio of dimethicone and colloidal silicon dioxide was 96:4,and the starting substances were mixed by stirring at the temperature of 150?160? for 2.5 h,finally the mixture was ground for 35 min and simethicone was prepared.The last part is about quality check of lab-made simethicone and its starting materials.According to ChP 2015,we established company internal control standard of dimethicone and colloidal silicon dioxide,the detection of low-molecular polymers in dimethicone was added into the standard of dimethicone,but the items in internal standard of colloidal silicon dioxide are same with the ones in ChP 2015.As for the internal quality standard of simethicone,it includes all the items in USP and EP as well as the detection of low-molecular polymers.Firstly,two starting materials were tested to be qualified according to the company internal standard.Then,three-batch simethicone samples were synthesized by the optimized method.Finally,the quality of the lab-made simethicone samples was examined to be not only qualified but also not worse than the original drug. |
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