Development of Amorphous Ternary Solid Dispersions of a Novel Anti-Tubercular Indole-2-Carboxamide Derivative with Curcumin/Clofazimine for Tuberculosis Treatment

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Borde, Shambhavi
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This research presents novel amorphous ternary (drug-drug-hydrophilic polymer) solid dispersions to simultaneously enhance the aqueous solubility of incorporated poorly soluble drugs. A highly potent novel anti-tubercular drug (i.e., Indole-2-carboxamide derivative (North 2)) was combined with an antioxidant (i.e., curcumin) and an anti-tubercular drug, clofazimine. Binary and ternary amorphous dispersions of North 2- Curcumin and North 2-Clofazimine were prepared with hydrophilic polymers, namely polyvinylpyrrolidone (PVP), Eudragit® EPO® (EPO), and hydroxypropyl methylcellulose (HPMC), at 1:1w/w (for binary solid dispersions) and at 1:1:2 w/w/w (for ternary solid dispersions) ratios. The binary and ternary solid dispersions and their respective physical mixtures were characterized for their crystallinity by X-ray diffraction (XRD) and differential scanning (DSC). Infrared spectroscopy (IR), solution nuclear magnetic resonance (NMR), and molecular modeling studies (docking studies using MOE with the MMFF94x forcefield) were utilized to understand the interaction between compounds and polymers. In the case of ternary solid dispersions, North 2: CUR: EPO at 1:1:2 w/w/w, North 2: CUR: HPMC at 1:1:2 w/w/w, and North 2: CUR: PVP at 1:1:2 w/w/w, North 2:Clofazimine:EPO at 1:1:2 w/w/w were confirmed to be amorphous by XRD and DSC. Significant peak shifts indicating molecular interactions such as hydrogen bonding were observed in the IR data of binary and ternary dispersions compared to physical mixtures, indicating potential North 2- polymer, Curcumin-polymer, and Clofazimine-polymer interactions. These interactions mainly involved carbonyl group of both compounds, indole NH of North 2 and Phenolic OH of Curcumin and NH amide of clofazimine with the polymer chain. These interactions were confirmed by solution NMR and molecular modeling studies in case of North 2-Curcumin and EPO combination. For North 2-Curcumin, the dissolution studies showed that the concentrations of the compounds released from all the ternary solid dispersions were significantly higher than their physical mixtures. Out of the three hydrophilic polymers, EPO enhanced the solubility by 55 and 59 times for North 2 and CUR, respectively, within 12 hours. For North 2-Clofazimine, amorphous ternary solid dispersion of North 2:Clofazimine:EPO (1:1:2) found to be enhance the solubility of North 2 and clofazimine by 84 and 47 folds as compared to physical mixtures . For North 2-Curcumin and North 2:clofazimine:EPO ternary solid dispersions, XRD stability data of the ternary solid dispersions showed that they were stable over 90 days at room temperature.
Creighton University
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