Influence of Crystal Disorder on the Forced Oxidative Degradation of Vortioxetine HBr.

The present study investigates the impact of the solid-state disorder of vortioxetine hydrobromide (HBr) on oxidative degradation under accelerated conditions. A range of solid-state disorders was generated via cryogenic ball milling. The solid-state properties were evaluated by calorimetry, infrared-, and Raman spectroscopies. While salt disproportionation occurred upon milling, no chemical degradation occurred by milling. The amorphous fraction remained physically intact under ambient storage conditions. Subsequently, samples with representative disordered fractions were mixed with a solid oxidative stressor (PVP-H2O2 complex) and were compressed to compacts. The compacts were exposed to 40°C/75% RH for up to 6 h. The sample was periodically withdrawn and analyzed for the physical transformations and degradation. Two oxidative degradation products (DPs) were found to be formed, for which dissimilar relations to the degree of disorder and kinetics of formation were observed. The degradation rate of the major DP formation obtained by fitting the exponential model to the experimental data was found to increase up to a certain degree of disorder and decrease with a further increase in the disordered fraction. In contrast, the minor DP formation kinetics was found to increase monotonically with the increase in the disorder content. For the similar crystallinity level, the degradation trend (rate and extent) differed between the single-phase disorder generated by milling and physically mixed two-phase systems. Overall, the study demonstrates the importance of evaluating the physical and chemical (in)stabilities of the disordered solid state of a salt form of a drug substance, generated through mechano-activation.

PVP-H2O2 Complex as a New Stressor for the Accelerated Oxidation Study of Pharmaceutical Solids.

Reactive impurities, such as hydrogen peroxide in excipients, raise a great concern over the chemical stability of pharmaceutical products. Traditional screening methods of spiking impurities into solid drug-excipient mixtures oversimplify the micro-environment and the physical state of such impurities in real dosage form. This can lead to an inaccurate prediction of the long-term product stability. This study presents the feasibility of using a polyvinylpyrrolidone-hydrogen peroxide complex (PVP-H2O2) as an oxidative agent for the solid state forced degradation of a selected drug, vortioxetine HBr. The PVP-H2O2 complex was prepared and characterized using FT-IR spectroscopy. The tablet compacts were made using a mixture of solid PVP-H2O2 complex and crystalline vortioxetine HBr powder. The compacts were exposed to 40 °C/75% RH condition in open and closed states for different time intervals. The extent and the type of drug degradation were analysed using LC and LC-MS. The extent of degradation was higher in the samples stored at the open state as compared to the close state. The solution state forced oxidation was conducted to verify the peroxide induced degradation reactions. The results evidence the utility of the proposed solid-state stressor and the method for screening the sensitivity of drugs to the excipient reactive impurities involving peroxides in solid-state.