An increasing proportion of drug candidates in the pharmaceutical pipeline have significant aqueous solubility issues. Amorphous Solid Dispersions are a growing and innovative advancement to the field of drug formulation tackling this problem; however many issues remain unresolved, impacting their widespread adoption. The most notable issue is poor dissolution performance, attributed to the phase separation of the blend into drug-rich and polymer-rich phases on contact with water, called amorphous-amorphous phase separation (AAPS).
This work is the first to study ASDs with the Quartz Crystal Microbalance (QCM). This work used the model compounds Ritonavir and Copovidone and performed gravimetric water sorption experiments. Thin films were cast, sub 300 nm, allowing for the better deconvolution of the water sorption and phase separation mechanisms. Furthermore, the QCM’s dissipation monitoring capability was able to detect the earliest signs of AAPS in films shown in the literature. The equilibrium water sorption kinetics were modelled using a Fickian based relaxation−diffusion model to highlight the impact of the inclusion of a hydrophobic drug in a hydrophilic carrier. All work on the QCM was corroborated with orthogonal techniques including the TEM-EDX, confocal microscopy, and AFM. The last was crucial in demonstrating that AAPS onset led to surface roughening and was related to the dissipation increase. It also showed further insights into the molecular mechanisms of AAPS growth mimicking that of spinodal decomposition.
The work offered definitive proof that AAPS was a thermodynamic limited event and not a kinetic one, as sometimes debated in the literature; however, the amount of water plasticizing the ASD would determine the kinetics of AAPS growth. This miscibility drug loading limit was in line with results from literature dissolution performance data for the same ASD, reinforcing the impact of AAPS on dissolution. It was found that the inclusion of surfactants could improve the miscibility of the ASD but increase the speed of AAPS growth. This work also showed the importance of properly identifying and controlling the nanoconfinement effects due to the presence of interfacial regions in such thin amorphous films. This was done by comparing kinetic and equilibrium sorption uptake data based on thickness. This is also crucial in selecting the correct QCM model for measuring the actual mass uptake.
The results show that maintaining miscibility is crucial to properly functioning ASD formulations. Furthermore, the work has shown that surfactants could be an ideal solution for resolving such issues. Finally, the QCM could be used for the rapid mass screening of ASDs for the appearance of AAPS when performing polymer-drug paired selections. This data could be valuable in the development of models for the rational pairing of both components.