Investigation of molecular interactions between active pharmaceutical substances and polymers in amorphous solid dispersions
Year: 2026
Type: dissertation
Abstract: This study investigates the complex relationship between the active substances cinnarizine and trimethoprim and various polymers, as well as the influence of their molecular interactions on the performance of binary and ternary amorphous solid dispersions (ASDs). Through a systematic evaluation of manufacturing methods such as melt quenching, hot melt extrusion (HME) and spray drying, supplemented by analyses of residual crystallinity, phase diagrams and NMR titrations, important insights into the stabilisation of amorphous states and dissolution behaviour are gained. The results show that acidic polymers such as hypromellose acetate succinate and methacrylic acid-ethacrylate copolymer (MAE-A) are most effective at stabilising the amorphous state in the solid. Using 1H-NMR titration, applied for the first time to drug-polymer systems, significant molecular interactions with the weak bases cinnarizine and trimethoprim have been demonstrated. In addition to acid-base interactions, the melting behaviour, glass transition temperature and melt viscosity of the polymers significantly influence the incorporation of the active ingredient into the matrix. With regard to long-term stability, initially crystalline ASDs tend to undergo further crystallisation, whilst recrystallisation from completely amorphous, homogeneous systems rarely occurs. At low drug loadings, the dissolution behaviour is primarily determined by the properties of the polymer; this is confirmed in particular for MAE-A, copovidone and povidone at different drug loadings of 10% and 50% (m/m). Furthermore, the choice of manufacturing method plays a crucial role in stability and drug release. Whilst HME enables the formation of ASDs with higher active ingredient loads and superior physical stability, spray-drying usually results in higher crystallinity; however, in trimethoprim formulations, it leads to rapid initial dissolution and high supersaturation levels. This illustrates that the success of a formulation does not depend solely on amorphousness, and that conventional markers such as XRPD analysis do not always correlate with drug release. Computer-predicted pKa values explain the pH-dependent solubility behaviour and identify protonation sites. Molecular dynamics simulations demonstrate in detail that, in non-polar systems, it is primarily the polymer content that disrupts API interactions, whilst for polar APIs, the functional groups of the polymer are decisive. Taken together, this study provides a detailed picture of the diverse factors influencing ASD performance. The combination of experimental and modelling approaches illustrates how drug-polymer interactions, physicochemical properties and process parameters collectively shape stability and dissolution behaviour.
Author: Sandhöfer, Selina
Language: English
Subfield: Pharmaceutical Science
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7224143583