Iron(III)-Mediated Oxidative Degradation on the Benzylic Carbon of Drug Molecules in the Absence of Initiating Peroxides.
Metal ions play an important role in oxidative drug degradation. One of the most ubiquitous metal ion impurities in excipients and buffers is Fe(III). In the field of oxidative drug degradation chemistry, the role of Fe(III) has been primarily discussed in terms of its effect in reaction with trace hydroperoxide impurities. However, the role of Fe(III) acting as a direct oxidant of drug molecules, which could operate in the absence of any hydroperoxide impurities, is less common. This work focuses on Fe(III)-induced oxidation of some aromatic drug molecules/drug fragments containing benzylic C-H bonds in the absence of initiating peroxides. Alcohol and ketone degradates are formed at the benzylic carbon atom. The formation of a π-stabilized cation radical is postulated as the key intermediate for the downstream oxidation. Implications are briefly discussed.
Analytical Sciences, MRL, Merck & Co., Inc., West Point, Pennsylvania 19486. Electronic address: kausik_nanda@merck.com.
Kausik K
KK
Nanda
Analytical Sciences, MRL, Merck & Co., Inc., West Point, Pennsylvania 19486.
William D
WD
Blincoe
Analytical Sciences, MRL, Merck & Co., Inc., West Point, Pennsylvania 19486.
Leonardo R
LR
Allain
Discovery Pharmaceutical Sciences, MRL, Merck & Co., Inc., West Point, Pennsylvania 19486.
W Peter
WP
Wuelfing
Analytical Sciences, MRL, Merck & Co., Inc., West Point, Pennsylvania 19486.
Paul A
PA
Harmon
D001593:Benzyl Compounds / Q000737:chemistry* / Q000378:metabolism; D002244:Carbon / Q000737:chemistry* / Q000378:metabolism; D002712:Chlorides / Q000737:chemistry* / Q000378:metabolism; D005290:Ferric Compounds / Q000737:chemistry* / Q000378:metabolism; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010545:Peroxides / Q000737:chemistry* / Q000378:metabolism
D001593:Benzyl Compounds; D002712:Chlorides; D005290:Ferric Compounds; D010545:Peroxides; D002244:Carbon; D007501:Iron; C024555:ferric chloride
aromatic cation radical; drug degradation; iron; iron(III); oxidation