Amorphous phases of active pharmaceutical ingredients (APIs) generally possess greater solubility than the crystalline counterparts. This presents them as attractive candidates for enhancing the bioavailability of the sparingly soluble drugs, while the unstable nature of them makes it challenging to reliably evaluate their potential improvement in solubility and utilize them in drug formulations. We have investigated the anodic aluminum oxide (AAO) substrates with nanopores to establish a simple system to examine the solubility increase accompanied by the decrease of the API crystallinity, using ibuprofen (IBU) as a model compound. The fabricated AAO substrates had the average pore diameters: 25, 55, and 370 nm. The AAO substrates with nanopores allowed the solidification of IBU with lower crystallinity. Also, the release behavior directly from the AAO substrates made it possible to estimate the accompanying solubility increase. The amorphous IBU in the 25-nm pores possessed solubility about 6 times higher than the bulk crystalline phase. The present study demonstrated that the nanoporous AAO substrates could be utilized as a straightforward tool to investigate the solubility and stability of the amorphous phases of APIs.
Some polymeric additives were studied to understand their effects on the amorphous phase of ibuprofen (IBU), used as a poorly water soluble pharmaceutical model compound. The amorphous IBU in bulk, as well as in nanopores (diameter ~24 nm) of anodic aluminum oxide, was examined with the addition of poly(acrylic acid), poly(N-vinyl pyrrolidone), or poly(4-vinylphenol). Results of bulk crystallization showed that they were effective in limiting the crystal growth, while the nucleation of the crystalline phase in contact with water was nearly instantaneous in all cases. Poly(N-vinyl pyrrolidone), the most effective additive, was in specific interaction with IBU, as revealed by IR spectroscopy. The addition of the polymers was combined with the nanoscopic confinement to further stabilize the amorphous phase. Still, the IBU with addition of polymeric additives showed sustained release behavior. The current study suggested that the inhibition of the crystal nucleation was probably the most important factor to stabilize the amorphous phase and fully harness its high solubility.
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