Quantification of Silicone Oil and Its Degradation Products in Aqueous Pharmaceutical Formulations by 1H-NMR Spectroscopy.

During the past years, there has been an increasing focus on the presence of silicone oil as a contaminant in pharmaceutical formulations kept in prefilled syringes (PFSs). As the PFSs are coated on the inner wall with silicone oil (polydimethylsiloxane), there is a potential risk that the oil can migrate from the inner surface of the primary packing material into the aqueous solution. Several studies have demonstrated that presence of silicone oil as droplets in a high-concentrated protein formulation can cause protein aggregation. Hence, because the use of silicone-coated primary packing material for protein formulations are increasing, the call for an easy and quantitative method for determination of silicone oil and its degradation products in pharmaceutical formulations is therefore needed. Several analytical techniques have in the past been developed with the aim of detecting the presence of silicone oil and degradation products hereof. Most of these methods require hydrolyzation, derivatization, and extraction steps followed by, for example, gas chromatography-mass spectrometry analysis. Applying these methods can cause a loss in detection or an overestimation of the hydrolytic degradation products of silicone oil, that is, trimethylsilanol and dimethylsilanediol. The 2 silanols are highly hydrophilic and prefers the aqueous environment. Analysis of an aqueous formulation obtained from a PFS by 1H-NMR spectroscopy provides data about the content and levels of silicone oil and the 2 silanols even in levels below 10 ppm. The 1H-NMR method offers an easy and direct, quantitative measurement of samples intended for clinical use and samples kept at elevated temperature for a prolonged time (i.e., stability studies). The result of the study presented here showed dimethylsilanediol to be the main silicone compound present in the aqueous formulation when kept in baked-on PFSs. The degradation product dimethylsilanediol, in full accordance with expected hydrolytic degradation of silicone oil, increased during storage and with elevated temperature. In addition, the method can be applied to aqueous samples where polydimethylsiloxane has been added as, for example, the major constituent of antifoam.