Evaluating PAA/PVA thermal crosslinking process during the preparation of in-situ high-drug loading amorphous solid dispersions

Novel high drug loading amorphous solid dispersions (HDASDs) based on the in situ thermal crosslinked polymeric carriers/matrices have been recently introduced as an upcoming class of drug delivery systems. In this set framework, the present article extends the work of previously published studies by scrutinizing the processes and mechanisms involved during the preparation of indomethacin (IND) HDASDs via in-situ thermal crosslinking of poly(acrylic acid) (PAA) and poly(vinyl alcohol) (PVA). Specifically, the implementation of ATR-FTIR spectroscopy made the elucidation of the thermal crosslinking process feasible revealing that the crosslinking reaction follows a remarkably different pattern when different crosslinking temperatures are used; namely the utilization of elevated temperature leads to a higher degree of crosslinking in the case of neat PAA/PVA matrices. Interestingly, the presence of IND in the system subverts the data, since a slightly higher degree of crosslinking is achieved in the case of the lower annealing temperature (i.e., 150 °C instead of 170 °C). The progress of PAA/PVA crosslinking in the presence or absence of IND was also evaluated with the aid of isothermal thermogravimetric analysis (TGA). The results of TGA studies concerning the dependence of crosslinking density on the selected annealing temperature were in agreement with the ATR-FTIR findings. Nevertheless, a discordance between the ATR-FTIR spectroscopy and TGA results presented, as far as, the progress of the annealing process is concerned. Additionally, given the indisputable correlation between viscosity and the API's molecular mobility, and hence its recrystallization tendency, the rheological behavior of the prepared systems was addressed. Finally, in order to gain an insight into the of elastic mechanical properties of the developed HDASDs, molecular dynamics (MD) simulation models were utilized as realistic representations of the actual systems.