Effect of metal oxide foams as additives during the crystallization of pharmaceuticals

Here we explored the use of porous metal oxide foams as additives for the supramolecular control of active pharmaceutical ingredients (APIs) during crystallization. Supramolecular control of APIs is critical as it influences the physicochemical properties and manufacturability of pharmaceutical products. As a result, crystal engineers have developed various techniques (e.g., quench cooling, spray drying, milling, or co-precipitation) to control the crystallization of APIs and maximize their bioavailability. In this work, we proposed to laverge the functionalities of zinc oxide (ZnO) foams to induce changes in the crystallization of a model API system.
As a case study, a porous ZnO foam was immersed in a solution of paracetamol, metacetamol, water and isopropanol. Following solvent evaporation amorphous crystal paracetamol were retrived from the pores of the ZnO foam. Through zeta potential measurements, we identified the presence of an electrical double layer, formed at the surface of ZnO. This electrical double layer coupled with the spatial restriction of the crystallization media (pore confinement) were found to be critical factors to produce amorphous paracetamol. Certainly, amorphous structures display a higher bioavailability than native crystal forms due to the lack of hydrogen bonds that restrict solvation. We complemented the experimental findings with relevant molecular dynamic simulations that assessed the average partial density profiles of both APIs in solution inside a ZnO nanopore. This analysis led to two major insights: (1) the nucleation of paracetamol was inhibited when the supersaturated solution was subject to in-pore crystallization; and (2) paracetamol interacted with with the oxygen of the ZnO surface - an effect that appears to hinder hydrogen bonding. Our experimental/simulation approach demonstrate that metal oxide foams can be used as an alternative process to control the supramolecular structure of pharmaceuticals and therefore modernize current drug manufacturing processes.