Cinética de decomposição e identificação de produtos de degradação a partir de matriz de liberação osmótica contendo o fármaco paliperidona

Abstract

Paliperidone, the main active metabolite of risperidone, is an atypical antipsychotic of the chemical class of benzisoxazoles derivatives. It is commercially available as osmotic tablets, OROS® (osmotic release oral system) Push-PullTM type. This system has a semipermeable membrane containing two holes on one extremity, and an expansible polymer that helps the drug release according to concentration. Few studies about stability of paliperidona are reported, in special for OROS® system. The present study aimed to characterize the reference standard, to determine the drug on stability assay by HPLC, testing different forced conditions (acid, alkaline, oxidative, thermal and photolytic), to establish the kinetic decomposition of oxidative, photolytic and thermal conditions, with focus on reaction order, reaction constant (k), half-life time (t½) and t90%, and to identify the major degradation products by UPLC-MS. The sample preparation was evaluated comparing the disruption of tablet previously to contact with solvent on ultrasonic bath, and the treatment with solvent directly, avoiding the disruption. Paliperidone was instable when submitted to oxidative (residual concentration in 72h = 83,49%), photolytic (residual concentration in 24h = 24,64%) and thermal conditions (residual concentration in 96h = 30,12%), showing kinetics data in first order. The drug presented stability in acid medium, HCl 0,0100 mol/L, being in accordance with the procedure established for sample treatment with this solvent. For sample treatment, previous to analysis, the results indicated more reproducibility on quantitative data for samples treated directly. The analyses by UPLC-MS allowed to identify three degradation products: m/z 365, being named as (Z)-2-((((Z)-aminomethylene)amino)methylene)-4-(4-(2-(aminooxy)-4-fluorobenzyl)piperidin-1-yl)butanoic acid, detected in photolytic and thermal conditions; and another reaction route, m/z 233, being named as 3-(1-ethylpiperidin-4-yl)-2,3-dihydrobenzo[d]isoxazole, and m/z 217, named as (E)-6-((1-ethylpiperidin-4-yl)methylene)cyclohexa-2,4-dien-1-one, detected in all conditions assayed, demonstrating the importance of this decomposition route for this drug.