(460a) Elucidation of Local Drug Release Dynamics in Complex Formulations with Multi-Nuclear NMR Micro-Imaging

Purpose: Concurrent visualization of liquid transport, drug mobilization and release process through complex polymer structures is of great scientific significance and challenge in the development of advanced small molecule formulations. Such elucidation of the local, non-linear dynamics of drug release not only can support formulation design and optimization, but also reveals potential risk factors for drug stability that is influenced by local transient phenomena. This work discusses the advancement of quantitative multi-nuclear (¹H and ¹⁹F) magnetic resonance imaging (MRI) and spectroscopic techniques, applied to revealing drug dissolution and mobilization dynamics inside a long-acting implant formulation in order to support formulation design and risk mitigation.

Methods: Long-acting implant samples, consisted of an active drug, MK-A, and ethylene-vinyl acetate (EVA) copolymer, were placed in dissolution media under controlled conditions and imaged periodically with a 400 MHz NMR Bruker Avance spectrometer. At each time point, ¹H NMR imaging (at 20 mm pixel resolution) and spectroscopy were used to observe water concentration and mobility;¹⁹F pulsed-field gradient (PFG) NMR spectroscopy was also used to observe drug mass transport, via its molecular self-diffusion (D^self), within the polymer matrix.

Results: Clear signals of the dissolution media were observed via ¹H MRI, showing the ingress of the media into the implant via a porous polymer structure created by dissolution of the drug. Analysis of the ¹H images reveal a dissolution medium transport diffusivity, D^T, of around 10^-13 m²s^-1.The pores are initially created as the drug dissolves into the ingressing dissolution media and thereafter provides a pathway for the drug to leave the implant. Concurrently, ¹⁹F NMR spectroscopy reveals that the solid drug dissolves into the media with a square root time dependence within the pores. D^self of the dissolution media inside the pores was found to be 2 orders of magnitude higher than the transport diffusivity, D^T. ¹⁹F PFG-NMR measurements of the dissolved drug molecules within the porous structure exhibit a similar self-diffusivity as the dissolution media, suggesting the concurrent diffusion of these mobile species in the porous system. We tentatively assert that both the transport diffusivity, D^T_, of the dissolution media ingress into the polymer matrix and the self-diffusivity, D^self, of the drug are key descriptors that govern the overall drug release rate into the surrounding dissolution medium. The characterization of such drug mobility provides a mechanistic understanding of the slow drug release as a design feature of such implants. In addition, changes in the ¹⁹F signal from within the implant with extended media exposure are indicative of recrystallization of the drug, pointing to the potential stability risks that such a slow drug release can carry.

Conclusions: The concurrent elucidation of the dynamics of both active drug and the dissolution media, made possible by advanced multi-nuclear NMR micro-imaging technology, provides unique perspectives of the local release dynamics inside the implant formulation, and greatly empowers formulation scientists to optimize the formulation design and manufacturing process based on detailed mechanistic understandings.