Studying the effects of polymers on therapeutic deep eutectic solvents' formation and stability: A thermal analysis-based approach to optimise polymer selection.

Therapeutic deep eutectic solvents (THEDES) are the liquids produced upon mixing two solid materials, where at least one of them is an active pharmaceutical ingredient. The strong hydrogen bonding (HB) between the parent materials is the reason for such profound depression in their melting points. THEDES formation can improve drugs' solubility and permeation characteristics. However, this can be limited by their encapsulation within drug delivery platforms e.g., polymeric matrices which might disrupt the HB network of THEDES by introducing new HB active sites into the mixture. Despite this, the effects of polymers on THEDES stability are not well-documented. In addition, the polymers' impact on THEDES formation during end-to-end production has not been studied. In this work, these issues were addressed by employing thermal processing of polymers and drugs. The dually active lidocaine: flurbiprofen (1:1) THEDES was utilized in addition to model polymers, namely polyethylene-co-vinyl acetate (PEVA), polyethylene oxide (PEO) and Eudragit® RL PO (EuRLPO). Firstly, probing the interaction between the polymers and the individual components of THEDES revealed that PEVA has no affinity towards both drugs while PEO can interact with flurbiprofen, and EuRLPO can interact with lidocaine. Then, to study the effect of the polymers on THEDES formation and stability, a valid in-situ method was developed to quantify THEDES in its mixture using modulated temperature differential scanning calorimetry (MTDSC). MTDSC data showed that the three polymers retarded THEDES formation in the following order PEVA < EuRLPO < PEO. This retardation was attributed to increased medium viscosity and the subsequent reduction in THEDES formation rate. Increasing the heating time led to complete THEDES formation in the case of PEVA and EuRLPO but not with PEO. This result was explained based on the polymers' interaction with THEDES parent drugs and inputs from polymers' viscoelastic properties. On the other hand, introducing the polymer after THEDES formation mitigated their viscosity effect but their interaction with the parent drugs remained an issue, where PEO and EuRLPO were able to destabilize the pre-formed THEDES to variable extents. Long-term storage stability study further confirmed this conclusion. Therefore, this study will provide valuable information regarding the interaction (or lack of) of THEDES with model pharmaceutical polymers that have been thermally processed and will provide recommendations regarding the rational choice of polymers to maintain THEDES stability.