Scientific Publications by FDA Staff

AAPS PharmSciTech 2020 Jan 2;21(2):40

Assessing drug release from manipulated abuse deterrent formulations.

Feng X, Zidan A, Kamal NS, Xu X, Sun D, Walenga R, Boyce H, Cruz CN, Ashraf M

There is a need to develop in vitro dissolution methods that discriminate for particle size of the manipulated abuse deterrent formulation (ADF) and that can be used for in vivo predictive models since dissolution methods developed for intact formulation might not be suitable for manipulated ones. A vertical diffusion cell (VDC) and United States Pharmacopeia (USP) Apparatus 1, 2, and 4 were evaluated for measuring the dissolution of intact and manipulated metoprolol succinate tablets with abuse deterrent-like properties. These tablets were physically manipulated to produce fine (106-500 mum) and coarse (500-1000 mum) powder samples. The VDC method was not able to discriminate the effect of particle size on drug release with varied stirring rate (200 to 800 rpm), molecular weight cut-off (MWCO, 3-5 kDa to 12-14 kDa) of the diffusion membrane, or composition and ionic strength (0.45% and 0.9%) of receiver medium. Standard and modified USP Apparatus 1 and 2 methods were assessed; however, large variations (RSD > 20%) were observed with USP Apparatus 1 for manipulated product dissolution and floating powder samples caused failure of auto-sampling when using standard USP Apparatus 2. For the USP Apparatus 4 dissolution method, packing configuration (1, 3, 8 layers and blend), ionic strength of dissolution medium (0.017, 0.077, and 0.154 M additional NaCl), and flow rate (4, 8, 16 mL/min) were studied to discriminate the effect of particle size on release. The USP Apparatus 4 dissolution method was optimized by using a packaging configuration of 8 layers with 8 mL/min flow rate which exhibited low variability and complete drug release and it could be used for in vivo predictive models. The dissolution method variables can be optimized for a specific product for desirable reproducibility and discriminatory power when using USP Apparatus 4.