Development of predictive tools for amorphous solid dosage forms
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Abstract
The application of amorphous solid dosage forms is one of the most promising formulation strategies to overcome the limited oral bioavailability of poorly soluble drugs. However, despite the increased interest in amorphous solid dispersions in academic and industrial research, the commercial application of this formulation strategy is still limited. This situation is mainly due to an insufficient understanding of the basic properties of amorphous solid dispersions such as their physical stability and the lack of predictive in vitro models. Therefore, the aim of the present dissertation was to contribute to the understanding and development of predictive tools for amorphous solid dispersions. The physical stability of an amorphous solid dispersion can only be fully ensured by dissolving the drug in the polymer below its equilibrium solubility (i.e. by forming a glass solution). Several methods to predict the drug–polymer solubility at room temperature have been proposed and the majority of these are based on data obtained at elevated temperature using differential scanning calorimetry (DSC) followed by extrapolation to room temperature using the Flory-Huggins model.
In order to enable a rational comparison of the solubility predictions, the confidence of the extrapolation by means of a prediction interval was introduced for the solubility curve through formal statistical analysis. This approach allowed for a range of interesting studies including a large comparative study that showed that the predicted drug-polymer solubility at room temperature is significantly influenced by the method used to obtain the solubility data at elevated temperature. In order to overcome the uncertainty associated with the temperature extrapolation performed in the established methods, a new methodology to estimate drug–polymer solubility was also developed. The method is based on the solubility of a drug in a polymer dissolved in a solvent at room temperature using a simple shake-flask approach. This new method has the potential to provide faster and possibly more precise solubility estimates than the established methods, which can save valuable time in the early drug development phase.
Besides contributing to an increased understanding of the stability of amorphous solid dispersions, different polymer properties responsible for improving both in vitro and in vivo performance were also identified. Even though the dissolution rate was found to decrease with increasing polymer molecular weight and hydrophobicity, the polymer that performed the best both in vitro and in vivo was neither the polymer with the highest or lowest molecular weight nor the most or least hydrophobic polymer. This indicates that for a given drug there is a molecular weight and hydrophobicity of a polymer where the balance between dissolution rate-enhancing and precipitation inhibiting factors is optimal. Furthermore, as the thermodynamic driving force for crystallization increased with increasing degree of supersaturation, it could be shown that both the in vitro and in vivo performance of amorphous solid dispersions were significantly influenced by the drug dose. In conclusion, this dissertation has contributed to the understanding of the thermodynamics behind amorphous solid dispersions and demonstrated that this formulation strategy presents an exciting possibility for oral delivery of poorly water-soluble drugs.