Development and Evaluation of Ternary Amorphous Solid Dispersion of Poorly Water-soluble Compounds

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Paul, Sagar Kumar
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Purpose: Ternary amorphous solid dispersion (TASD) containing an additional component compared to conventional binary ASD further enhances the effectiveness of this strategy. Recently, polyphenolic compounds such as curcumin (CUR) and resveratrol (RES) are shown to have synergistic antioxidant, chemo-preventive, chondroprotective, and anticancer activity. However, their poor aqueous solubility limits their oral application. The purpose of this study is to design, characterized, and evaluate a soluble and stable TASD containing CUR and RES with a hydrophilic polymer. Methods: Choosing an optimum polymer can be considered as one of the most crucial activities during TASD development. We carried out commonly used polymer screening studies i.e. miscibility, crystallization tendency, Flory-Huggins interaction parameter, solubility parameter, as well as advanced studies (i.e., crystallization kinetics and molecular interaction). Upon selection of the optimum polymer, TASDs were prepared by rotary evaporation. Pure drugs, their physical mixtures (PM), binary, and ternary ASDs were characterized by XRD, DSC, TGA, FTIR, and Raman spectroscopy. A 2-step in-vitro dissolution was carried out, under non-sink condition using a USP-II apparatus. Centrifuged samples were analyzed by a UV-Vis method. Finally, the long-term stability of TASDs was evaluated at room temperature. Results: The screening studies focused on the miscibility, crystallization inhibition, and interaction capability of polymer. From three different polymers (i.e., EPO, HPMCAS, and S100), the miscibility study indicated the best miscibility of CUR and RES with EPO. From the crystallization kinetics study, we inferred that EPO has a better crystallization inhibition effect than HPMCAS and S100. Finally, interaction studies confirmed that all three polymers have the potential for hydrogen bonding. Besides, EPO showed acid-base interaction with both CUR and RES. Thus, EPO was selected to formulate a stable TASD with enhanced solubility and stability. A high drug-loaded (50% w/w) TASD was prepared and characterized to be in amorphous form with a single Tg. Strong interaction was confirmed with both FTIR and Raman spectroscopy. From the in-vitro dissolution study, it was observed that the % dissolved concentration Of CUR and RES from 50% drug-loaded TASD was respectively ~197 times and ~4 times higher than the PM after 1 hour. These TASD formulations were stable at room temperature for 12 months.
Creighton University
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