Evaluation of hydroperoxides in common pharmaceutical excipients.
While the physical properties of pharmaceutical excipients have been well characterized, impurities that may influence the chemical stability of formulated drug product have not been well studied. In this work, the hydroperoxide (HPO) impurity levels of common pharmaceutical excipients are measured and presented for both soluble and insoluble excipients. Povidone, polysorbate 80 (PS80), polyethylene glycol (PEG) 400, and hydroxypropyl cellulose (HPC) were found to contain substantial concentrations of HPOs with significant lot-to-lot and manufacturer-to-manufacturer variation. Much lower HPO levels were found in the common fillers, like microcrystalline cellulose and lactose, and in high molecular weight PEG, medium chain glyceride (MCG), and poloxamer. The findings are discussed within the context of HPO-mediated oxidation and formulating drug substance sensitive to oxidation. Of the four excipients with substantial HPO levels, povidone, PEG 400, and HPC contain a mixture of hydrogen peroxide and organic HPOs while PS80 contains predominantly organic HPOs. The implications of these findings are discussed with respect to the known manufacturing processes and chemistry of HPO reactivity and degradation kinetics. Defining critical HPO limits for excipients should be driven by the chemistry of a specific drug substance or product and can only be defined within this context.
Wasylaschuk
Walter R
WR
Pharmaceutical Analysis Chemistry, Merck Research Laboratories, Merck & Co., Inc., P.O. Box 4, WP78-210, West Point, PA 19486, USA. walter_wasylaschuk@merck.com
Harmon
Paul A
PA
Wagner
Gabriella
G
Harman
Amy B
AB
Templeton
Allen C
AC
Xu
Hui
H
Reed
Robert A
RA
D002482:Cellulose / Q000031:analogs & derivatives / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D004304:Dosage Forms; D004340:Drug Contamination; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry* / Q000592:standards; D005989:Glycerides / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000032:analysis* / Q000737:chemistry; D007785:Lactose / Q000737:chemistry; D008353:Mannitol / Q000737:chemistry; D010545:Peroxides / Q000032:analysis; D004364:Pharmaceutical Preparations / Q000737:chemistry; D020442:Poloxamer / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011136:Polysorbates / Q000737:chemistry; D011205:Povidone / Q000737:chemistry; D011786:Quality Control; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods
D004304:Dosage Forms; D005079:Excipients; D005989:Glycerides; D010545:Peroxides; D004364:Pharmaceutical Preparations; D011136:Polysorbates; D020442:Poloxamer; D008353:Mannitol; D011092:Polyethylene Glycols; D002482:Cellulose; C008079:hydroxypropylcellulose; D006861:Hydrogen Peroxide; D011205:Povidone; D007785:Lactose; C109691:microcrystalline cellulose