Silanization Treatment Of Glass Containers For Pharmaceutical Packaging

In recent years,the development of vaccines has driven the diversified growth of biological therapies,which is mainly reflected in various novel drugs,such as lipid-based drugs,m RNA vaccines,and antibody-drug conjugates.These drugs are sensitive to their storage environment,posing a significant challenge to the biocompatibility of drug packaging.The primary components of pharmaceutical packaging include three parts:the vial for storing the drug,the sealing plug for sealing the vial,and the pre-filled glass syringe(PFS).The drug undergoes long-term storage in the vial,which may lead to drug degradation.The vial is made of hydrophilic borosilicate glass,and long-term storage of the drug solution in the vial may cause the leaching of metal elements from the glass surface,which can affect drug quality and potentially cause immunogenicity.Due to the unique Si-O-Si structure of silicones,which is extremely similar to that of glass,and its advantages such as low surface energy,lubricity,and good biocompatibility,it is considered an ideal reagent for treating the glass surface.Currently,silanization reagents used for pharmaceutical glass container packaging mainly include DC360 silicone oil,DC365,and DC366 silicone oil emulsion produced by Dow Corning Corporation,and high-temperature baking is the main silanization method.However,numerous studies have shown that this silanization system can cause quality problems in drug solutions.During the transportation of drugs,drug proteins will adsorb onto the surface silicone oil layer to form protein-silicone oil gels,which will detach under shear forces from bubbles and mix into the drug solution;incomplete silanization;and leaching of metal elements from the packaging glass container.This thesis addresses these issues and conducts the following research:(1)Short-chain siloxane R-Si-O-Si-R was selected and the end groups were modified to improve the reactivity and curing ability of the surface silicone oil layer under high-temperature baking.Three different silane agents,namely hexamethyldisiloxane,1,1,3,3-tetramethyldisiloxane,and tetramethyldivinylsiloxane,were chosen to perform silanization treatment on the inner surface of vials under high-temperature conditions.The microstructure before and after the silanization treatment was observed by scanning electron microscopy(SEM),and the elements and bonding modes on the surface were characterized by energy-dispersive X-ray spectroscopy(EDS)and Fourier transform infrared spectroscopy(FT-IR),respectively.The leaching of Na~+in the solution stored in the vials was determined by high-performance ion chromatography(HPIC).The results showed that the water contact angle(WCA)of the inner surface of the vials treated with the three different agents could reach 100°～110°.The surface microelements changes were confirmed by EDS,indicating the state of the silanization coating.The staining experiment with methylene blue showed that the silanization treatment was uniform.The quantitative analysis with n-hexane extraction showed that 1,1,3,3-tetramethyldisiloxane and tetramethyldivinylsiloxane were more firmly adsorbed on the glass surface under high temperature.Even after 100times of tape peeling,the WCA on the inner surface of the vials could still reach 100°,and after 2 hours of n-hexane extraction,the highest WCA on the surface was still 90°.The silanization treatment effectively reduces the risk of p H increase and Na~+leaching in the solution stored in the vials,and the study found that siloxane and the glass inner surface can form chemical bonding under high-temperature conditions.(2)Under low-temperature conditions,the internal surface of a vial is silanized using N,O-bis(trimethylsilyl)trifluoroacetamide(BSTFA)and Q7-9180 medical dispersant(hexamethyldisiloxane)as a solvent,which has good biocompatibility.The water contact angle of the silanized vial surface can reach 100°～110°.The uniformity of the silanization treatment and the necessity of hydroxyl activation on the glass surface were confirmed by methylene blue staining.After being extracted with n-heptane for 2 hours,the water contact angle of the vial surface remained between100°～110°,demonstrating the successful silanization of the vial with BSTFA at low temperature.This silanization method effectively reduces the risk of p H increase and Na~+leaching when storing solutions in the vial.