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

Abstract

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.

Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

“…For comparison, the carboxylic dimers between two indomethacin molecules could not be observed any more as the polymer concentration increased to 50% w/w. In a recent study, Sarpal et al used the SS-NMR technique to compare the molecular interactions in amorphous ketoconazole (KET), KET binary dispersions, and KET ternary dispersions [60]. A detailed 13 C SS-NMR deconvolution study showed that binary KET and poly (acrylic acid) (PAA) system exhibits higher prevalence of ionic and hydrogen bonds in comparison with its ternary system containing hydroxypropyl methyl cellulose (HPMC) [60].…”

“…In a recent study, Sarpal et al used the SS-NMR technique to compare the molecular interactions in amorphous ketoconazole (KET), KET binary dispersions, and KET ternary dispersions [60]. A detailed 13 C SS-NMR deconvolution study showed that binary KET and poly (acrylic acid) (PAA) system exhibits higher prevalence of ionic and hydrogen bonds in comparison with its ternary system containing hydroxypropyl methyl cellulose (HPMC) [60]. In recent studies, two-dimensional (2D) ss-NMR was also developed to identify the type and strength of various drug-polymer interactions in ASDs with enhanced sensitivity and resolution [61,62].…”

Effect of Storage Humidity on Physical Stability of Spray-Dried Naproxen Amorphous Solid Dispersions with Polyvinylpyrrolidone: Two Fluid Nozzle vs. Three Fluid Nozzle

“…Interestingly, 3FN shows a similar 1 H T 1 of the two components but distinct 1 H T 1rho values, suggesting a partially homogeneous system. It is worth mentioning that 2FN and 3FN have identical one-dimensional 13 C spectra (data not shown), suggesting that the two ASDs do not have distinctly different molecular structures and interactions, regardless of the level of mixing [ 28 , 30 ].…”

“…In recent years, ssNMR has been utilized to assess the homogeneity of drug substances and polymer in ASDs at a high-resolution and to successfully correlate such microscopic attributes to the formulation processes [23,[26][27][28][29]. 1 H T 1 and T 1rho values of individual components were measured as described in the method section and were compared to evaluate the homogeneity.…”

New Development in Understanding Drug–Polymer Interactions in Pharmaceutical Amorphous Solid Dispersions from Solid-State Nuclear Magnetic Resonance

“…The capability of NMR to characterize this complex ternary ASD has been demonstrated using KTZ-HPMC-PAA ASD. 52 While no changes in chemical shift were highlighted in the 13 C spectra for the binary system KTZ-HPMC ASDs (Figure 3a) and the possibility of an interaction between the compounds was excluded, 13 C spectroscopic data for both KTZ-PAA and KTZ-HPMC-PAA dispersions (Figure 3b,c) showed some interesting similar spectral features. In both systems, the intensity of the peak corresponding to the PAA dimer form (at 182 ppm) decreases with respect to the free form (at 177 ppm); the intensity across the drug loading changes and, interestingly, a new peak at 172 ppm emerges, which corresponds to hydrogen bonded KTZ.…”