Role of oligopeptides as co-formers in stabilizing amorphous dipyridamole: mechanistic insights using molecular...

The amorphous form of poorly water-soluble drugs can be stabilized using low- molecular weight co-formers in co-amorphous systems. However, the limited choice of suitable co-formers and the need to understand the underlying stabilization mechanism remain challenging for the widespread adoption of this formulation approach. In this study, a number of commercially available and custom-designed oligo- (di/tri)-peptides were used as co-formers to prepare stable co-amorphous systems of the BCS class II drug dipyridamole (DPM), using spray drying. Feed solutions were prepared by dissolving drug and co-former in a 1:1 molar ratio in methanol-water mixtures. The spray drying process was evaluated and solid-state properties of the resulting formulations were compared to assess the effectiveness of different co-formers in preparing stable co-amorphous systems. Stability was investigated at 25 °C/60% RH and 40 °C/75% RH using non-ambient X-ray powder diffraction (XRPD), with performance quantified by the point of failure (POF), a time when co-amorphous systems exhibit crystalline peaks in the XRPD diffractograms.Spectroscopic techniques, together with molecular docking, were employed to investigate the underlying stabilization mechanisms. A direct correlation between the increasing number of amino acids in the peptide chain with the co-amorphous properties could not established within the range of co-formers investigated. It was found however that co- formers with more complex molecular structures and lower hygroscopicity were generally associated with improved stability. In addition, a correlation between higher binding affinity and increased POF time was observed, suggesting that computational screening may support the selection of suitable drug-co-former combinations prior to experimental development.