Development of a LC method for pharmaceutical quality control of the antimetastatic ruthenium complex NAMI-A.
Imidazolium trans-tetrachloro(dimethylsulfoxide)imidazoleruthenium(III) (NAMI-A) is a novel ruthenium complex with selective activity against metastases currently in Phase I clinical trials in the Netherlands. Pharmaceutical quality control of NAMI-A drug substance and lyophilized product warranted the development of an assay for determination and quantification of NAMI-A and degradation products. A high performance liquid chromatography (HPLC) method was developed, consisting of a C18 column with 0.50 mM sodium dodecylsulfate in 3% methanol at pH 2.5 (acidified using trifluoromethanesulfonic acid) as the mobile phase and UV-detection at 358 nm. The HPLC method was proven to be linear, accurate and precise. Stress testing showed that degradation products were separated from the parent compound. By combining results of nuclear magnetic resonance (NMR) and HPLC experiments, one degradation product was identified as the mono-hydroxy species of NAMI-A. HPLC analysis with off-line detection of the eluate with flameless atomic absorption spectrometry (F-AAS) showed that under most conditions, all ruthenium-containing compounds show a peak in the HPLC chromatogram and that all ruthenium applied to the column is recovered quantitatively. For completely degraded solutions of NAMI-A some ruthenium is retained on the column. Suitability of the HPLC method for the pharmaceutical quality control of NAMI-A lyophilized product was demonstrated.
Bouma
Marjan
M
Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. apmbo@slz.nl
Nuijen
Bastiaan
B
Jansen
Martine T
MT
Sava
Gianni
G
Picotti
Fabrizio
F
Flaibani
Antonella
A
Bult
Auke
A
Beijnen
Jos H
JH
D000970:Antineoplastic Agents / Q000032:analysis* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid / Q000379:methods*; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000032:analysis* / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009942:Organometallic Compounds / Q000032:analysis* / Q000627:therapeutic use; D015203:Reproducibility of Results; D017975:Ruthenium Compounds; D013054:Spectrophotometry, Atomic; D013056:Spectrophotometry, Ultraviolet
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D004121:Dimethyl Sulfoxide