Abstract
The model compounds benzocaine (BENZ) and lidocaine (LIDO) exhibited amorphous phase instability, evident by the absence of measurable glass transition temperatures (Tg) during differential scanning calorimetric (DSC) analysis; this was associated with their high propensity to crystallise upon cooling. Through formation of co-amorphous mixtures (CAMs) with each other and ketoprofen (KETO), this instability was minimised with some instances of glass solution formation. Stability enhancement by these means enabled TgCAM measurements, followed by modelling neat drug Tg through rearranged and modified forms of the Fox and Gordon-Taylor (GT) equations. Despite its simplicity, the rearranged form of the Fox equation (R-Fox) led to predicted Tg of - 30.3 and - 68.5 degrees C for BENZ and LIDO, respectively, which were comparable to literature values of - 31.0 and - 63.4 degrees C. The more complex modified GT equation (M-GT) led to similar Tg predictions of - 34.3 and - 64.8 degrees C and allowed for Tg interpolation with respect to non-ideal mixing effects. It was then possible to determine the optimal ratio of BENZ:LIDO as 5:5 mol/mol, with a GT model deviation of + 8.2 degrees C and + 7.5 degrees C for the R-Fox and M-GT predicted neat Tg values, respectively. This outcome affirmed these models as successful Tg predictors of poor glass forming compounds. Observed deviations from literature were contextualised by recognising the role of intermolecular interactions and their relationship with pKa, rotatable bonds, molecular mass, aromatic rings, and number of hydrogen bond donors and acceptors.