Miniaturized Measurement of Drug-Polymer Interactions via Viscosity Increase for Polymer Selection in Amorphous Solid Dispersions.

Abstract

Drug-polymer interactions have a substantial impact on stability and performance of amorphous solid dispersions (ASD) but are difficult to analyze. Whereas there are many screening methods described for polymer selection based for example on glass forming ability, drug-polymer miscibility, supersaturation, or inhibition of recrystallization, the distinct detection of physico-chemical interactions mostly lacks miniaturized techniques. This work presents an interaction screening assessing the relative viscosity increase between highly concentrated polymer solutions with and without the model drug ketoconazole (KTZ). The fluorescent molecular rotor 9-(2-carboxy-2-cyanovinyl)julolidine was added to the solutions in a miniaturized setup in μL-scale. Due to its environment-sensitive emission behavior, the integrated fluorescence intensity can be used as a viscosity dye within this screening approach (FluViSc). Differences in relative viscosity increases through addition of KTZ were proposed to rank polymers regarding KTZ-polymer interactions. Absolute viscosities were measured with a cone-plate rheometer as a complimentary method and supported the results acquired by the FluViSc. Solid-state nuclear magnetic resonance (ss-NMR) relaxation time measurements and Raman spectroscopy were utilized to investigate drug-polymer interactions at a molecular level. Whereas Raman spectroscopy was not suited to reveal KTZ-polymer interactions, ss-NMR relaxation time measurements differentiated between the selected polymeric carriers hydroxypropylmethylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone vinyl acetate 60:40 (PVP-VA64). Interactions were detected for HPMCAS/KTZ ASD while there was no hint for interactions between KTZ and PVP-VA64. These results were in correlation with the FluViSc. The findings were correlated with the dissolution performance of ASD and found to be predictive for supersaturation and inhibition of precipitation during dissolution.