Mechanistic understanding of the stability of amorphos pharmaceuticals by molecular dynamics simulation

One of the promising approaches to improve the bioavailability of poorly soluble therapeutic compounds is to render such drugs to be in an 'amorphous' state. There exists a significant gap in the molecular level understanding of the factors governing the stability and performance of amorphous formulations. The goal of this research was to develop novel molecular dynamics (MD) based approaches and utilize them in conjunction with experimental techniques to gain mechanistic understanding of the stability of amorphous systems.;A MD simulations based technique was developed, that utilizes COMPASS forcefield and isochoric-isothermal/isobaric-isothermal ensembles, to compute the solubility parameter (a) of indomethacin, polyethylene oxide, glucose and sucrose. The magnitude of Aa was used to predict the miscibility of drug-carrier matrices: i.e. favorable miscibility between indomethacin/polyethylene oxide, borderline miscibility between indomethacin/sucrose and immiscibility between indomethacin/glucose. Further, the in-silico predictions were experimentally verified by thermo-analytical techniques. Differential scanning calorimetry showed melting point depression of polyethylene oxide with increasing levels of indomethacin accompanied by peak broadening confirming miscibility. In contrast, distinctive thermal events seen for blends of indomethacin with sucrose and glucose were indicative of overall immiscibility.;The research also encompassed development of MD based approaches for the prediction of the glass transition temperature (Tg); the investigation of the plasticizer effect on Tg;; and finally, the characterization of intermolecular interactions using radial distribution function (RDF). The gradual decrease in specific volume of sucrose was effectively simulated as the system was quenched. The characteristic 'kink' observed in volumetemperature curves defined the Tg. The MD computed Tg values were 367 K, 352 K and 343 K for amorphous sucrose containing 0%, 3% and 5% w/w water, respectively. The MD technique simulated the plasticization effect of water and the results were in reasonable agreement with theoretical models and literature reports. The RDF measurements revealed strong interactions between sucrose hydroxyl-oxygens and wateroxygen. Steric effects led to weak interactions between sucrose acetal-oxygens and water-oxygen. MD is thus a powerful predictive tool for probing temperature, plasticizer and microenvironment effects in amorphous systems. Knowledge gained from MD modeling, in conjunction with experimental data, can aid in the rational selection of excipients and the development of robust amorphous drug products.