Transition metal-induced degradation of a pharmaceutical compound in reversed-phase liquid chromatographic analysis.
Drug degradation that occurs in HPLC analysis, during either sample preparation or chromatographic separation, can greatly impact method robustness and result accuracy. In this work, we report a case study of drug dimerization in HPLC analysis where proximate causes were attributed to either the LC columns or the HPLC instrument. Solution stress studies indicated that the same pseudo-dimeric degradants could also be formed rapidly when the compound was exposed to certain oxidative transition metal ions, such as Cu(II) and Fe(III). Two pseudo-dimeric degradants were isolated from transition metal stressed samples and their structures were elucidated. A degradation pathway was proposed, whereby the degradation was initiated through transition metal-induced single electron transfer oxidation. Further studies confirmed that the dimerization was induced by trace transition metals in the HPLC flow path, which could arise from either the stainless steel frits in the LC column or stainless steel tubing in the HPLC instrument. Various procedures to prevent transition metal-induced drug degradation were explored, and a general strategy to mitigate such risks is briefly discussed.
Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903, USA. Electronic address: qinggang.wang@bms.com.
Qinggang
Q
Wang
Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903, USA.
Brian Lingfeng
BL
He
Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903, USA.
Jin
J
Zhang
Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903, USA.
Yande
Y
Huang
Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903, USA.
Brent
B
Kleintop
Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903, USA.
Thomas
T
Raglione
D002851:Chromatography, High Pressure Liquid / Q000379:methods; D056148:Chromatography, Reverse-Phase / Q000379:methods; D004355:Drug Stability; D005290:Ferric Compounds / Q000737:chemistry; D007477:Ions / Q000737:chemistry; D008670:Metals / Q000737:chemistry*; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012996:Solutions / Q000737:chemistry; D013193:Stainless Steel / Q000737:chemistry; D028561:Transition Elements / Q000737:chemistry*
D005290:Ferric Compounds; D007477:Ions; D008670:Metals; D004364:Pharmaceutical Preparations; D012996:Solutions; D028561:Transition Elements; D013193:Stainless Steel
HPLC; Pharmaceutical analysis; Stainless steel column frits; Stainless steel tubing; Transition metal-induced degradation