Academic Editor: Rosa Iacovino

Received: 26 May 2020; Accepted: 17 June 2020; Published: 19 June 2020

**Abstract:** Drug concentration plays an important role in the interaction with drug carriers affecting the kinetics of release process and toxicology effects. Cyclodextrins (CDs) can solubilize hydrophobic drugs in water enhancing their bioavailability. In this theoretical study based on molecular mechanics and molecular dynamics methods, the interactions between β-cyclodextrin and piroxicam, an important nonsteroidal anti-inflammatory drug, were investigated. At first, both host–guest complexes with native β-CD in the 1:1 and in 2:1 stoichiometry were considered without assuming any initial a priori inclusion: the resulting inclusion complexes were in good agreement with literature NMR data. The interaction between piroxicam and a β-CD nanosponge (NS) was then modeled at different concentrations. Two inclusion mechanisms were found. Moreover, piroxicam can interact with the external NS surface or with its crosslinkers, also forming one nanopore. At larger concentration, a nucleation process of drug aggregation induced by the first layer of adsorbed piroxicam molecules is observed. The flexibility of crosslinked β-CDs, which may be swollen or quite compact, changing the surface area accessible to drug molecules, and the dimension of the aggregate nucleated on the NS surface are important factors possibly affecting the kinetics of release, which shall be theoretically studied in more detail at specific concentrations.

**Keywords:** β-cyclodextrin; inclusion complexes; solubilization; nanosponge; nanocarriers; pharmaceutical applications; molecular recognition phenomena; molecular dynamics simulations; drug delivery; drug concentration
