Identification and control of a degradation product in Avapro (TM) film-coated tablet: Low dose formulation

A degradation product was formed during the long-term stability Studies (LTSS) of the low dose formulation of Avapro m film-coated tablet. The degradant was identified as the hydroxymethyl derivative (formaldehyde adduct) of the drug substance, irbesartan, based upon analysis with LC/MS, LC/MS/MS, and chromatographic comparison to the synthetic hydroxymethyl degradation product. Laboratory studies demonstrated that the interaction of individual excipients with the drug substance at elevated temperature and polyethylene glycol (PEG) used in the coating material, Opadry (TM) II White, leads to the generation of this formaldehyde adduct. Spiking of formaldehyde to the solution of drug substance gradually produced this impurity and the kinetics studies demonstrated that the reaction between formaldehyde and irbesartan is a second order reaction with a rate constant of 2.6 x 10(-4) M-1 min(-1) at 25 degrees C in an aqueous media. The redevelopment of the formulation by eliminating PEG from the Opadry (TM) II White dry-blend system was enabled by understanding the formaldehyde adduct formation.