Forced degradation studies of ivabradine and in silico toxicology predictions for its new designated impurities

Marzena Jamrógiewicz; Piotr Pikul; Joanna Nowakowska; Weronika Hewelt-Belka; Krzesimir Ciura

doi:https://doi.org/10.3389/fphar.2016.00117

Forced degradation studies of ivabradine and in silico toxicology predictions for its new designated impurities

Abstrakt

All activities should aim to eliminate genotoxic impurities and/or protect the API against
degradation. There is a necessity to monitor impurities from all classification groups,
hence ivabradine forced degradation studies were performed. Ivabradine was proved
to be quite durable active substance, but still new and with insufficient stability data.
Increased temperature, acid, base, oxidation reagents and light were found to cause its
degradation. Degradation products were determined with the usage of HPLC equipped
with Q-TOF-MS detector. Calculations of pharmacological and toxicological properties
were performed for six identified degradation products. Target prediction algorithm
was applied on the basis of Hyperpolarization-activated cyclic nucleotide-gated cation
channels, as well as more general parameters like logP and aqueous solubility. Ames
test and five cytochromes activities were calculated for toxicity assessment for selected
degradation products. Pharmacological activity of photodegradation product (UV4),
which is known as active metabolite, was qualified and identified. Two other degradation
compounds (Ox1 and N1), which were formed during degradation process, were found
to be pharmacologically active