Reactive impurities in PEG: A case study

Abstract

Reactive impurities in excipients are often the attributed cause of drug product instability. Development of an excipient and drug product control strategy requires detailed understanding, identification, and quantitation of the rate and extent of formation of reactive impurities in excipients. This chapter highlights some of the methodologies that can be utilized to generate such an understanding using poly(ethylene glycol) as a model excipient. A 2,4-Dinitrophenylhydrazine (DNPH) pre-column derivatization HPLC-UV method was developed to quantify levels of formaldehyde and acetaldehyde in PEG solutions. Formic acid and acetic acid were quantified by HPLC-UV. Effects of excipient source, water content, pH, trace levels of hydrogen peroxide or iron metal, and antioxidants on the formation of reactive impurities was quantitated. Formic acid was the major degradation product in nearly all cases. The presence of water increased the rate of formation of all impurities, as did the presence of hydrogen peroxide and trace metals. Acidic pH increased the formation of acetaldehyde and acetic acid. Antioxidants BHA, BHT, propyl gallate vitamin E TPGS and sodium metabisulfite were effective, while ascorbic acid and acetic acid were not. This work highlights the general methodology that can be used to study reactive impurities in excipients.