Logo: to the web site of Uppsala University

Combination drug therapy offers substantial clinical benefits by enhancing treatment efficacy and improving patient compliance. However, it presents complex challenges from a dosage form development perspective, particularly for drugs with low water solubility. To enhance solubility and bioavailability, amorphous formulations are an attractive formulation strategy. This thesis aimed to optimize and implement a rational design approach for amorphous multidrug formulations with a robust and predictable performance after oral administration. This was achieved by investigating the influence of drugs, formulation excipients, and biorelevant intestinal media on solution chemistry, colloidal precipitate stability, and membrane transport of drug combinations.

Dissolution, solubility, and supersaturation of drug combinations were investigated in buffer and fasted state simulated intestinal fluids (FaSSIF). The solution behavior of the drugs was the same for structurally related compounds, highlighting the impact of their molecular properties and chemical diversity on the solubility profiles. A reduction in the maximum achievable concentration of drugs in combination was observed in buffer and FaSSIF, but the extent of reduction in FaSSIF was affected by the degree of solubilization by media components. Membrane transport studies demonstrated that drug transport across membranes is dominated by the degree of supersaturation, rather than solubilization. The colloidal particles formed as a result of liquid-liquid phase separation underwent uncontrolled coarsening. Polymers, in comparison to surfactants and small molecules, were more effective in controlling the particle size of this colloidal phase. 

The mechanistic studies on multidrug combinations led to the development of a novel approach for preparing amorphous formulations using spray drying. The developed formulation successfully maintained drug supersaturation and ensured controlled colloidal particle size upon dissolution.

The undertaken scientific efforts contribute to the knowledge in the evolving field of amorphous multidrug formulations. These findings highlight the potential of particle engineering, where a mechanistically informed selection of excipients is combined with an appropriate spray drying process, to achieve stable amorphous multidrug formulations—critical for ensuring robust drug performance and enabling intestinal absorption.