| Polypropylene and polyethylene are commonly used in the production of infusion bottles,infusion films(bags),eye drops bottles,oral solid bottles and oral liquid bottles.When in direct contact with the drug,some components will migrate to the drug and may enter the body along the route of administration,posing a threat to medication safety and health.Therefore,the National Pharmaceutical Packaging Standard limits the substances of soluble from polypropylene and polyethylene,that is,the substances extracted by water,ethanol and n-hexane must not exceed the prescribed limits.However,in the actual detection of drug packaging materials,it was found that the unqualified rate of the substances soluble in hexane from polypropylene and polyethylene was higher,which was a risk point of great concern,and the research on the substances of soluble from polypropylene and polyethylene was very few.Therefore,it is necessary to strengthen the research on the substances of soluble from polypropylene and polyethylene and raise the attention.In this study,the substances soluble in hexane from polypropylene and polyethylene were characterized comprehensively,including chemical structure analysis and quantitative characterization.It was found that about 96.19% of the substances soluble in hexane from polypropylene was oligomer,3.81% was additive,95.75% of the substances soluble in hexane from polyethylene was oligomer,and4.25% was additive.For the characterization of oligomers,molecular weight and distribution,chemical structure and thermal properties were characterized by GPC,IR,HT-NMR,DSC and TGA.The molecular weight of the substances soluble in hexane from polypropylene ranged from 5214 to21226,the morphology is amorphous,and the structural regularity is low.The molecular weight of the substances soluble in hexane from polyethylene is about 730-3746,which has certain regularity and crystalline morphology.In order to carry out in-depth and detailed analysis of the substances soluble in hexane,taking the substances soluble in hexane from polypropylene as an example,five components with different molecular weights were prepared by preparative chromatography for in-depth study.For characterization of molecular weight and distribution,two analytical columns PL gel MIXED-B(300 *7.5mm,10 micron)with pre-column PL gel Guard 10 micron in series were used as chromatographic columns,column temperature 150 ?,mobile phase 1,2,4-trichlorobenzene solution containing250mg/L antioxidant BHT.Standard curves were established using molecular weight reference substances of polypropylene,and differential refractive detector was used.The molecular weight of component 1 is 21226 and its distribution index is 1.66;the molecular weight of component 2 is 14462 and its distribution index is 1.70;the molecular weight of component 3 is 8257 and its distribution index is 2.21;the molecular weight of component 4 is 6264 and its distribution index is 3.19;and the molecular weight of component 5 is 5214 and its distribution index is 3.70.The chemical structure was characterized by IR and HT-NMR.It was found that the regularity of substances soluble in hexane from polypropylene was low.With the decrease of molecular weight,the random insertion of ethylene increased and the structural regularity decreased.DSC and TGA were used to characterize the thermal properties,it was found that the substances soluble in hexane from polypropylene was amorphous,and the transition temperature and thermal degradation temperature decreased with the decrease of molecular weight,that is,the structural regularity and thermal stability decreased.For the analysis of additives,the quantitative characterization by HPLC showed that the substances soluble in hexane from polypropylene contained additives: the content of antioxidant 1010 was 1.48%,the content of antioxidant 168 was 2.33%,and the total content was 3.81%.The substances soluble in hexane from polyethylene contained additives: the content of antioxidant 1010 was 0 0.54%,the content of antioxidant 1076 was 3.09%,and the content of antioxidant 168 was 0.62%,and the total content was 4.25%.In this study,the safety of substances soluble in hexane from polypropylene and polyethylene was studied.On the one hand,the cytotoxicity was evaluated and no cytotoxicity was found.On the other hand,the insoluble particles in 0.9% sodium chloride injection and 5% glucose injection packaged by polypropylene were determined.It was found that after sterilization under high temperature and pressure,the insoluble particles with small size increased significantly,the content of insoluble particles at 2-5 ?m in 0.9% sodium chloride injection increased from 103.60/ml to169.80/ml,accounting for about 98.81%;the content of particulates at 5-10 ?m increased from 18.80/ml to 19.40/ml,accounting for about 0.90%;the content of insoluble particulates greater than 10 ?m increased from 0.50/ml to 0.70/ml,accounting for about 0.30%;the content of insoluble particulates at 2-5 ?m in 5%glucose injection increased from 49.70/ml to 283.90/ml,accounting for about 83.43%;the content of insoluble particulates at 5-10 ?m increased from 4.00/ml to 46.70/ml,accounting for about 15.21%;the content of insoluble particles greater than 10 ?m increased from 0.30/ml to 4.10/ml,accounting for about 1.35%.In summary,the research shows that after sterilization under high temperature and high pressure,the injections packaged by polypropylene produce the largest number of insoluble particles with small particle size less than 10 microns.In the National Pharmacopoeia Packaging Standard,only three control points of 5?m,10?m and 25?m are set up.No strict and reasonable control is carried out on the insoluble particles with small size.These particles enter the systemic circulation along the route of administration,and cause tissue embolism and necrosis,which seriously increases the risk of clinical use.In summary,the main components of the substances soluble in hexane from polypropylene and polyethylene are oligomers,and a few components are additives.The higher the amount of the substances soluble in hexane from polypropylene and polyethylene,the higher the risk of introducing insoluble particles with small particle size into the drug solution.These particles are easy to enter the blood circulation along with the drug delivery route,resulting in hidden dangers of drug safety.The idea of research and analysis established in this paper provides a method for effectively and accurately characterizing the chemical structure and safety assessment of migrants from plastic packaging materials,lays a foundation for further promoting the improvement of the quality of pharmaceutical packaging materials,and then guarantees the safety,effectiveness and quality controllability of medicines.Therefore,the research of this paper has certain theoretical guiding significance and practical application value. |
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