Abstract
The enhancement of aqueous solubility of poorly water-soluble drugs is a challenge. Additional hurdle is to enhance the solubility of more than one drugs in same formulation for the combination therapy. This research paper presents the development of novel amorphous ternary (drug-drug-hydrophilic polymer) solid dispersions to simultaneously enhance the aqueous solubility and stability of two poorly soluble drugs. The ternary amorphous solid dispersions in the study contains the combination of a highly potent and novel anti-tubercular agent, Indole2-carboxamide derivative (North 2) and anti-oxidant, curcumin (CUR). Binary and ternary amorphous dispersions of North 2 and CUR were prepared using hydrophilic polymers, namely polyvinylpyrrolidone (PVP), Eudragit EPO® (EPO), and hydroxypropyl methylcellulose (HPMC), at 1:1 w/w (for binary solid dispersions) and at 1:1:2 w/w/w (for ternary solid dispersions) ratios. Differential scanning calorimetry (DSC) studies showed that North 2 has high crystallization tendency and formed an amorphous binary solid dispersion with only EPO, whereas CUR was characterized as low crystallization tendency compound and formed amorphous binary solid dispersions with EPO, PVP, and HPMC. All the three polymers formed amorphous ternary solid dispersions at 1:1:2 w/w/w ratios. Fourier transform infrared spectroscopy (FTIR) data showed significant peak shifts in both binary and ternary dispersions of North 2/CUR indicating molecular interactions. These interactions mainly involved the carbonyl group of both compounds, indole –NH of North 2 and phenolic –OH of CUR with the polymer chain. These interactions were confirmed by solution NMR and molecular modeling studies. In dissolution studies, out of the three hydrophilic polymers, EPO showed maximum solubility enhancement with and increased solubility by 55 and 59 times for North 2 and CUR, respectively, within 12 h. XRD stability data of the ternary solid dispersions showed that they were stable over 90 days at room temperature. The aqueous solubility of North 2 and curcumin was enhanced successfully with 50% loading of the drugs. Hence, this study shows the potential of designing ternary dispersions to achieve the solubility enhancement of a combination of poorly soluble drugs by utilizing a molecularly interacting hydrophilic polymer.