Adaptive perfusion: An in vitro release test (IVRT) for complex drug products.

In this work, adaptive perfusion, a pressure-driven separation method based on the principle of tangential flow filtration (TFF) was developed for investigating the rate and extent of drug release from drug products containing particulates, such as emulsions, suspensions, liposomes, drug-protein complexes. The TFF filters were pre-conditioned with unique conditioning solutions and processes to improve the fiber reproducibility and robustness. The adaptive perfusion method achieved size-based separation of the particulates with simultaneous analysis of the released drug as well as remaining drug. By contrast to conventional dialysis methods, the adaptive perfusion method can be used to measure the rate and extent of the drug release from drug solution, drug loaded micelles and nanoemulsions via adjustment of the filter molecular weight cutoff, feed flow rate or back-pressure. Notably, the adaptive perfusion method provided discriminatory drug release profiles for drug in solution, in micelles, and in small, medium, and large globule size nanoemulsions. The drug release profile obtained using adaptive perfusion method was found significantly faster (e.g., minutes rather than hours) and higher (e.g., >60%) than the release obtained using dialysis method. The IVRT method presented here is free from the constraints of rate-limiting factors, such as diffusion through dialysis membrane, and has potential to be extended further to examine the impact of manufacturing process on drug distribution and release characteristics of other challenging complex drug products.