Abstract by Jingwen Liu

Over the past decades, co-amorphous drug delivery systems have been widely investigated to overcome the poor aqueous solubility challenge of many new drug candidates. Three main critical quality attributes (CQA) are to be considered in the development and evaluation of co-amorphous systems, i.e., co-formability, physical stability and dissolution behavior. Despite of the more than 10 years of research from all over the world in the co-amorphous area, there are still some crucial but unexplored topics remaining to obtain a comprehensive understanding of co-amorphous systems.

This thesis aims to deepen the understanding of the important CQA of co-amorphous systems and to fill the remaining gaps for the rational development and optimization of these systems. Four specific topics have been investigated, i.e., (i) the correlation between surface diffusion and the physical stability of co-amorphous systems, (ii) the physical stability of co-amorphous systems with various mixing ratios at both dry and non-dry conditions, (iii) the methods to determine the optimal mixing ratio of drug and co-former to achieve the highest physical stability, and (iv) the feasibility of optimizing dissolution performance by designing ternary co-amorphous systems.

In the first section of the thesis, for the first time, surface diffusion of co-amorphous systems was investigated and linked to the physical stability. The results showed that the addition of a small amount of L-aspartic acid (ASP) (i.e., ≤ 5% w/w) could already significantly slow down drug surface diffusion and improve the physical stability of pure amorphous model drug carvedilol (CAR). In addition, a good correlation between surface diffusion and the physical stability was revealed, indicating the important role of surface diffusion on the stabilization of co-amorphous systems.

The second section of the thesis expanded physical stability tests of CAR-ASP co-amorphous systems towards two aspects, i.e., various co-former concentrations and different humidity levels during storage, to identify the optimal mixing ratio of drug to co-former to achieve the highest stability under both, dry and non-dry storage conditions. Although CAR and ASP were expected to interact with each other at equimolar ratio, the strongest interactions and the highest physical stability was unexpectedly observed at the CAR to ASP molar ratio of 1:1.5 at dry conditions. The results emphasizes the utmost importance of molar ratio optimization in the development of co-amorphous systems. Moisture from the storage conditions however, could result in a change in the drug to co-former ratio for the most stable system. In contrast to the CAR to ASP molar ratio of 1:1.5 obtained at dry conditions, the system with the 1:1 molar ratio showed the highest physical stability at non-dry conditions. In addition, moisture also disturbed the molecular interactions between CAR and ASP and caused salt disproportionation.

Based on the findings of different optimal mixing ratios at dry and non-dry conditions, practical approaches were developed in the third part of this thesis to determine the optimal ratio of co-amorphous systems already at an early time point during storage. At dry conditions, a data fitting method based on the experimental T_gs of the co-amorphous systems was applied to determine the optimal mixing ratio for strongly interacting co-amorphous systems, and application of multivariate analysis on FTIR spectra was used to determine the optimal ratio for both, strongly and non-strongly interacting co-amorphous systems. At non-dry conditions, morphology changes of co-amorphous systems were tracked after one week of storage and the extent of morphology deformation in the co-amorphous systems at various mixing ratios could be used to predict the relative physical stability of the co-amorphous systems. In addition, variable temperature XRPD (vtXRPD) analysis on the stored co-amorphous systems indicated that the excess components existing in a system (compared to the system at the optimal ratio) could result in an earlier recrystallization of this component at a lower temperature after one week of storage at non-dry conditions, highlighting the potential of obtaining the optimal mixing ratio of co-amorphous systems by using the vtXRPD measurements.

The last section of this thesis investigated the feasibility of optimizing the dissolution behavior of co-amorphous systems by co-formulation with a small amount of polymer. The results demonstrated that the addition of 10% (w/w) HPMC to the CAR-ASP co-amorphous systems decreased the initial drug dissolution rate and achieved a longer period of maintaining super-saturation compared to the corresponding polymer free co-amorphous systems. Consequently, the areas under the dissolution curves in CAR-ASP-HPMC systems were significantly larger compared to the corresponding CAR-ASP systems. No influence of HPMC addition was observed on the molecular interactions between CAR and ASP, and no negative influence of HPMC addition was detected on the physical stability of CAR-ASP systems at dry conditions for at least seven months. Therefore, design and preparation of ternary co-amorphous systems by co-formulating a small amount of polymer shows its potential to optimize the dissolution profile of drug from binary co-amorphous systems without sacrificing the physical stability advantages.

In summary, this thesis expands the understandings of co-formability (especially molar ratio optimization), physical stability (especially including non-dry storage conditions) and dissolution performance (especially in the presence of a small amount of polymer) of co-amorphous systems, which also provides fundamental and practical knowledge to realize the goal of rational design and optimization of co-amorphous systems.