Progressing conformational analysis to drug-excipient interactions - a study of co-amorphous systems with macrocycles

Macrocyclic drugs are of increasing interest in modern drug discovery; however, they exhibit biopharmaceutical challenges, such as poor aqueous solubility. Owing to their size, there is often a particular complexity in existing conformations with possible chameleonicity. Currently, there is little research on co-amorphous mixtures of macrocyclic drugs and an even more complex conformational landscape of drug and co-former remains to be explored. The present study uses a new stochastic global geometry optimization algorithm (GOAT) coupled with semi-empirical quantum chemical calculations to study the conformational landscape of the model drugs rapamycin and cyclosporine A with a given co-former, revealing insights into patterns of intramolecular vs. intermolecular hydrogen bonding between drug and coformer. Gallic acid was selected as coformer based on an initial screening of calculated excess enthalpy of mixing with each drug. A linear light scattering method with an ultrafast laser was used for kinetic solubility study and as a stoichiometric optimization method for the drug to coformer ratios. In the case of rapamycin, a 1:1 and 1:2 drug to coformer ratios increased the apparent solubility. Subsequently, solid dispersions of gallic acid with each of the model compounds were prepared by solvent evaporation. The solid-state characterization by X-ray powder diffraction and differential scanning calorimetry revealed a complete amorphization of both drugs in the mixtures. Such molecular insights from computational methods have the potential to guide future co-former selection for amorphous drug delivery systems.