Observation of Ɛ-AlKeggin-Oligonucleotide Complexes in Analytical Sample Solutions.

Complexes formed between aluminum cluster molecules that adopt a Ɛ-Al-Keggin structure and antisense oligonucleotides were observed as new impurity peaks during drug product stability testing. The Ɛ-Al-Keggin molecules were determined to be artifacts of the analysis, originating from contact between antisense oligonucleotide drug product solution and aluminum weigh boats used to prepare the analytical sample solutions The presence of the Ɛ-Al-Keggin molecules was confirmed through synthesis of the Keggin molecule through an established route and subsequent spiking studies. Binding affinity studies revealed that the Ɛ-Al-Keggin bound to oligonucleotide sequences of various lengths (10 to 20 bases) and base compositions, though there is some evidence for preferential binding to 5-methylcytosine-containing sequences. Modification of the sample preparation procedure to use polypropylene or glass weighing funnels eliminates the potential for Ɛ-Al-Keggin-oligonucleotide complex formation in analytical sample solutions.