Browsing by Subject "Pharmaceutical sciences"

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    Strength of drug-polymer interactions: Implications on molecular mobility and crystallization in amorphous dispersions
    (2016-10) Mistry, Pinal
    Amorphous solid dispersions (ASDs) provide a powerful avenue to potentially enhance the solubility of water-insoluble drugs. However, the physical instability in the amorphous state (i.e. crystallization) is a major impediment to the development ASDs as solid oral dosage forms. By identifying the key factors affecting the stability and the underlying mechanism of stabilization by the polymer, robust solid dispersions can be formulated that are resistant to crystallization. The goal of this thesis work is to (i) gain a mechanistic understanding of the stabilization brought about by drug-polymer interactions, (ii) provide guidelines for rational selection of polymers and (iii) provide simple and rapid methods for predicting crystallization times in ASDs. Overall our objectives were (i) to study the role of the strength of drug-polymer interactions on the molecular mobility and crystallization propensity (both onset time and crystallization rate) of ASDs, (ii) to study the coupling between mobility and crystallization and thereby use molecular mobility as a predictor of crystallization times in ASDs and (iii) provide an accelerated stability screening approach to predict long-term stability of ASDs. In our model systems (ketoconazole ASDs), both an increase in strength of drug-polymer interactions as well as polymer concentration resulted in a disproportionate increase in relaxation times (lowering of the molecular mobility). Stronger drug-polymer interactions translated to longer crystallization onset times and a decrease in the magnitude of crystallization rate constant, indicating enhancement in physical stability. The extent of coupling between relaxation times and crystallization times was moderate (coupling coefficient ~ 0.5) and was unaffected by the strength of drug-polymer interactions. Using molecular mobility as a determinant, a prediction model was developed to estimate crystallization times in ASDs. The predicted and experimental values were in good agreement, indicating the usefulness of the model. Additionally, water sorption was used as an accelerated stability testing approach to rank order ASDs and predict the long-term stability in glassy state. Strong drug-polymer interactions restricted the water uptake in ASDs and provided effective crystallization inhibition in presence of water.