Investigation into Intermolecular Interactions and Phase Behavior of Binary and Ternary Amorphous Solid Dispersions of Ketoconazole

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 ¹³C 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.