Development of an analytical method for the determination of pimavanserin and its impurities applying analytical quality by design principles as a risk-based strategy

Abstract

Pimavanserin is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. As it is a relatively new drug on the market, limited number of pharmacokinetic information and analytical methods are available. This paper presents an ultra-high performance chromatography for the simultaneous determination of pimavanserin and its four process impurities. The method was developed applying analytical quality by design (AQbD) principles as a risk-based approach. Critical method attributes (CMAs) were selected as a resolution between the worst separated compounds (impurity B and impurity C), a duration of analysis defined by the retention time of the last eluting peak (impurity D), a capacity factor of the first eluted impurity (impurity A), a tailing factor and a theoretical plate number. Risk assessment in the early stage of method development pointed out critical method parameters (CMPs): column temperature, gradient time and pH-value of the mobile phase (water phase, eluent A). Design of experiments (DoE), using DryLab®4 software, was applied to evaluate the influence of CMPs on CMAs and to determine method operable design region (MODR). Based on the risk assessment and the results of robustness and precision tests, a control strategy with system suitability criteria was proposed. Developed method was validated according to ICH Q2 (R1) guideline with respect to the selectivity, LOD, LOQ, linearity, precision, accuracy, robustness and stability. A forced degradation study was performed to provide an evidence of the stability-indicating property of the method. Degradation products of pimavanserin were identified using ultra high-performance liquid chromatography coupled to high resolution mass spectrometry (UHPLC-qTOF). Additionally, potential degradation products were assessed in silico with the help of Zeneth® software and good agreement with experimentally identified degradation products was achieved. Main degradation products were formed during acid and base hydrolysis (m/z 223.16 [M+H]+ at RRT 0.37) and under oxidative stress conditions (m/z 444.26 [M+H]+ at RRT 0.57). The results revealed that the pimavanserin undergoes degradation through acid and base hydrolysis of urea and N-oxidation of aliphatic tertiary amine.