Phase Behavior and Membrane Transport of Supersaturated Solutions in Complex Media
Supersaturating delivery systems, as a solubility enhancement strategy for poorly aqueous soluble drugs, are gaining increasing interest due to their ability to generate solution concentration of the drug in excess of its crystalline solubility, which can ultimately lead to an enhancement in oral bioavailability. Highly supersaturated solutions of hydrophobic compounds can undergo liquid-liquid phase separation (LLPS), wherein the concentration of the continuous solution phase is equal to the amorphous solubility and the dispersed phase is composed of excess amorphous drug that exists as nano-sized droplets. LLPS can occur both in vivo and in vitro . It has been suggested that, unlike crystallization, LLPS can be advantageous for oral absorption. Here, absorption across the intestinal membrane can take place from the continuous solution phase while the amorphous nanodroplets can serve as a drug reservoir, dissolving rapidly to replenish drug that has been lost due to absorption. This reservoir effect of the nanodroplets is experimentally demonstrated in this work. Current studies investigating LLPS have focused on the characterization of this phenomenon in simple media, in particular aqueous buffer solutions. However, gastrointestinal fluids are more complex. The variation in pH can impact the extent of supersaturation of ionizable drugs. Additionally, surfactants such as bile salts and phospholipids that are present in biorelevant dissolution media or in the intestinal fluids can also influence supersaturated systems. Amorphous solid dispersions (ASDs) are typically composed of an amorphous drug molecularly mixed with a polymer. However, formulators may also incorporate additives such as surfactants in the ASD to improve its wetting and dissolution. Addition of a surfactant can change the thermodynamics of the system. These surfactants can impact the solubility of the drug, the supersaturation that can be attained in the solution, as well as the crystallization kinetics in both the ASD and the solution generated by its dissolution. Although solubilization of crystalline drugs by pH and surfactants has been widely explored, there is little knowledge about their impact on either amorphous solubility or supersaturated solutions. This research aims to bridge the knowledge gap by studying the impact of pH on supersaturation and providing molecular understanding of the influence of surfactants on solubilization mechanisms of supersaturating systems. As surfactants in the biorelevant media can impact crystallization from supersaturated systems, the impact of biorelevant media composition on crystallization of drugs from supersaturated systems is also a focus of this study. LLPS can also occur due to dissolution of ASDs, leading to formation of nanodroplets. However, mechanisms leading to the formation of nanodroplets are still uncertain. In this research, the mechanism of nanodroplet generation was elucidated using isotope labelling. The understanding of phase behavior of supersaturated systems in complex media obtained through this research can aid in designing robust supersaturating formulations as well as predicting and modelling their in vivo performance.
Taylor, Purdue University.
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