Amorphous solid dispersions of pharmaceutical interest: influence of the polymer macromolecular architecture
Résumé
One of the current challenges facing the pharmaceutical industry is to find solutions to improve the bioavailability of new active molecules which, because of their complexity, are often poorly or not soluble in water. One way of doing this is to take advantage of the physical state and use the amorphous form of active pharmaceutical ingredients (APIs). Indeed, because of its higher Gibbs free energy, the bioavailability of the amorphous state is higher than the one of the crystalline state. But the negative counterpart is the lack of stability of that state. A strategy to improve this stability, which is gaining growing interest, is to disperse at the molecular level the active ingredient in a polymeric excipient, thereby forming an Amorphous Solid Dispersion (ASD). The role of the polymer matrix is, on the one hand, to prevent recrystallisation of the API during storage and, on the other hand, to delay its re-precipitation during the dissolution of the formulation. However, the mechanisms governing this stabilising effect are still poorly understood. The aim of the research work presented here is to better define the role played by the macromolecular architecture of the polymer excipient [1]. For this work, a model polymer, Poly(N-vinylpyrrolidone) (PVP), was synthesised in a controlled manner by RAFT/MADIX [2] (Reversible Addition-Fragmentation chain Transfer/ Macromolecular design by Interchange of Xanthates). We obtained linear PVP polymers with low dispersity, different molar masses comparable to those of commercial Kollidon@ PVPs and different chain-end functionalities. ASDs based on Curcumin (CUR) and these PVPs were then formulated and characterised by temperature modulated differential scanning calorimetry. The evolution of the glass transition temperature of the ASDs and the solubility of the CUR in the PVP as a function of the CUR content reveal the development of fairly strong attractive intermolecular interactions between CUR and PVP. This provides a better understanding of the stability conditions of CUR/PVP ASDs and the impact of PVP molar mass or chain-end functionalities. In addition, comparison of the results with those obtained for ASDs based on CUR and commercial PVP enables us to establish the particular role played by dispersity. This project has received funding from the Interreg 2 Seas programme 2014-2020 co-funding by the European Regional Development Fund under subsidy contract “Site Drug 2S07-033”. References [1] S. Samsoen, E. Dudognon, G. Le Fer, D. Fournier, P. Woisel, F. Affouard, Int. J. Pharm., 653 (2024) 123895 [2] G. Pound, PhD thesis, Stellenbosch University, 2008
