Investigating Crystallization tendency, Miscibility and Molecular interactions of drug-polymer systems for the development of amorphous solid dispersions.

摘要

This project aims to characterize the crystallization tendencies, miscibility and molecular interaction in drug-polymer systems of poorly soluble drugs and correlate it with the performance of prepared or reported SDs (solid dispersions). Crystallization tendencies of five different drugs [i.e. Curcumin (CUR), indomethacin (IND), flutaminde (FLU), dipyridamole (DIP), griseofulvin (GRI)] in absence and presence of four different polymers [i.e. polyethylene glycol (PEG), eudragit EPO (EPO), hydroxypropyl methylcellulose (HPMC) and polyvinyl pyrrolidone (PVP)] in various drug-polymer ratios were determined by using modulated differential scanning calorimetry (MDSC). Thermal analysis i.e. glass transition temperature (Tg), crystallinity and melting point depression along with theoretical calculations such as solubility parameter were performed to study drug polymer miscibility. Molecular interactions were predicted by using Tg deviations and molecular modeling. Physical states of drug in the SDs were characterized by X-ray diffraction (XRD) and MDSC. IR (Infrared) and Raman were used in selected systems (i.e. CUR, DIP and GRI systems) to explore the role of drug polymer interactions in amorphization of SDs. Dissolution studies using USP apparatus II and physical stability study at room temperature were performed for selected systems. Based on the absence and presence of endothermic and exothermic peaks (heat-cool-heat cycle) in MDSC, the crystallization tendency of pure drugs was categorized as low, moderate and high. In presence of selected polymers, crystallization tendency of all the drugs can be modified albeit high polymer concentration was required for drugs with high crystallization tendency i.e. DIP and GRI (> 50%w/w). Polymers showing greater effect on crystallization tendency of drugs were found to have higher drug-polymer miscibility and stronger molecular interactions. For example, FLU-PVP system showed good miscibility and no remarkable Tg deviation. This is reflected in its ability to change the crystallization tendency of FLU. Further, the results correlated well with the physical state, dissolution and stability of prepared/reported SDs. The developed approach has significant potential to be a rational screening method for the development of amorphous SDs.