Abstract

Amorphous solid dispersion (ASD) of a poorly soluble active pharmaceutical ingredient (API) in a polymeric matrix is a promising approach to increase the solubility, dissolution rate and hence bioavailability of the API. From an industrial point of view, spray-drying represents the main solvent evaporation process used for the manufacture of solid dispersions.
The aim of the present PhD thesis was to evaluate the accuracy of: i) thermodynamic models (e.g. solubility parameter and Flory-Huggins theories), ii) standard screening methodologies (e.g. solvent casting and quench cooling) and iii) novel screening approaches for predicting the miscibility of binary spray-dried solid dispersions (SDSDs) so that the best performing API-polymer systems at adequate drug-loading (DL) can be selected.
Two novel approaches for screening improvement, miniaturization and downscaling of regular spray-drying, were investigated and applied to API-polymer systems consisting of models drugs (Ibuprofen, Naproxen, Carbamazepine and Itraconazole) and seven polymers at four DLs. Screened samples were characterized using modulated differential scanning calorimetry (mDSC), X-ray powder diffraction (XRPD), thermo-gravimetric analysis (TGA) and scanning electron microscopy (SEM). Results obtained from miscibility and solid state characterization were compiled into principal components analysis (PCA) in order to qualitatively rank the screening approaches based upon their prediction accuracy. Non-sink dissolutions conditions with regard to the crystalline API were performed to assess the solubility enhancement and the extent of supersaturation of screened samples.
The two proposed screening approaches were found to provide a greater accuracy than traditional screening methodologies to predict the miscibility of SDSDs. The limitations of theoretical models and standard screening methods tested are symptomatic of the gap existing between equilibrium solid solubility to kinetic miscibility as well as the importance of the preparation method with regard to ASD properties. Therefore, the main benefits of the novel approaches rely on their capacity to better reproduce the operating mode and process conditions of regular spray-dryer, while minimizing API needs for a production, significantly. The outcome of this work favours the downscaling approach due to its improved ability to ease the transfer from
screening phases to manufacturing stage in the selection of adequate polymer and DL. In this regard, a novel three-stage decision protocol that implements spray-drying in a methodical small-scale approach for the development of ASDs during preclinical activities was developed and has successfully replaced all former practices in UCB projects.