Interpreting in vitro Release Performance from Long-Acting Parenteral Nanosuspensions using USP-4 Dissolution and Spectroscopic Techniques.

Injectable sustained release dosage forms have emerged as desirable therapeutic routes for patients that require life-long treatments. The prevalence of drug molecules with low aqueous solubility and bioavailability has added momentum towards the development of suspension based long-acting parenteral (LAP) formulations; the previously undesirable physicochemical properties of BCS Class II/IV compounds are best suited for extended release applications. Effective in vitro release (IVR) testing of crystalline suspensions affirms product quality during early-stage development and provides connections with in vivo performance. However, before in vitro-in vivo correlations (IVIVC) can be established, it is necessary to evaluate formulation attributes that directly affect IVR properties. In this work, a series of crystalline LAP nanosuspensions were formulated with different stabilizing polymers and applied to a continuous flow-through (USP-4) dissolution method. This technique confirmed the role of salt effects on the stability of polymer-coated nanoparticles through the detection of disparate API release profiles. The polymer stabilizers with extended hydrophilic chains exhibited elevated intra-polymer activity from the loss of hydrogen bond cushioning in dissolution media with heightened ionic strength, confirmed through 1D (1)H NMR and 2D NOESY experiments. Thus, steric repulsion within the affected nanosuspensions was limited and release rates decreased. Additionally, the strength of interaction between hydrophobic polymer components and the API crystalline surface contributed to suspension dissolution properties, confirmed through solution- and solid-state spectroscopic analyses. This study provides a perspective on the dynamic interface between the crystalline drug and aqueous micro-environment during dissolution.