Lipid mesophases-nanoconfined water rules crystal symmetry during in-meso crystallization

Polymorphism plays a critical role in the pharmaceutical industry, as it directly influences the solubility, stability, and bioavailability of drug compounds. In this work, nanoconfinement via cubic lipid mesophases (Ia3¯d and Pn3¯m geometries) has been used to study the polymorphism of the model drugs theophylline, paracetamol and caffeine. By exploiting the interactions of the drug with nanoconfined water and lipid head groups, this approach drives the nucleation towards polymorphs that are otherwise not stable at ambient conditions. In the lipid mesophases, theophylline crystallizes as metastable forms I and III, along with two previously unknown forms; paracetamol produced a mixture of metastable single crystals - including forms III, VII, and hydrate forms - and one original polymorph; caffeine crystallized in its metastable α form, normally observed only at high temperatures. These results highlight the key role of nanoconfined water and drug-lipid interactions on the establishment of original and unconventional polymorphs of the drug crystals, and set phytantriol-water mesophases as a biocompatible potential toolbox to optimize pharmacokinetics in pharmaceutical formulations.