Conventionally, amorphous solid dispersions (ASDs) have been formulated as a binary matrix, but in recent years a new class of ASDs has emerged, where generally a second polymer is also added to the formulation. Having the presence of a second polymer necessitates a comprehensive solid-state characterization to study the intermolecular interactions and phase behavior on a molecular level. With this goal in mind, ketoconazole (KET) was selected as a model drug, and hydroxypropyl methyl cellulose (HPMC) and poly(acrylic acid) (PAA) were chosen as polymeric carriers. The binary and ternary ASDs were characterized by differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, and powder X-ray diffraction (PXRD). The binary KET:HPMC dispersions lacked any specific interactions, whereas binary KET:PAA dispersions and ternary KET:PAA:HPMC dispersions showed evidence for ionic and hydrogen bonding interactions. The 13 C SSNMR deconvolution study established a comparison for molecular interactions between the binary KET:PAA and ternary KET:PAA:HPMC dispersions, with the binary KET:PAA system showing higher prevalence of ionic and hydrogen bonds than the ternary KET:PAA:HPMC system. Moreover, individual binary and ternary ASDs were found to be homogeneous on a nanometric level, implying the presence of a second polymer did not impact the phase homogeneity. In addition, a stronger interaction in binary KET:PAA and ternary KET:HPMC:PAA systems translated to better physical stability at different storage conditions. Through this case study it is recommended that a comprehensive investigation is needed to study the impact of using two polymers in ASD formulations in terms underlying intermolecular interactions and physical stability.

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