Inclusion of the Biginelli dihydropyrimidine guest (DHPM) into β-cyclodextrin: an experimental and theoretical case study

In the present study, we obtain the inclusion compound (IC) formed between Ethyl 1,4-dihydro-2-oxo-6-methyl-4-phenyl-5-pyrimidinecarboxylate (DHPM) and β-CD by lyophilization. The guest, a Biginelli dihydropyrimidine compound, was synthesized, and the formation of ICs was characterized by spectroscopic (FTIR and 1 H NMR), thermal (DSC), and microscopic (SEM) analyses. The association constant (Ka) was determined from solubility isotherms by evaluating the influence of β-CD concentration on DHPM solubilization. Furthermore, in vitro dissolution assays were carried out to correlate time with the percentage of drug released. The formation of ICs enhanced the aqueous solubility of DHPM by 1.73-, 1.53-, and 1.43-fold at 25, 35, and 45 °C, respectively, compared to the free drug. Spectroscopic, thermal, and morphological data supported the formation of the ICs. The dissolution studies revealed a marked improvement in solubility and release rate, suggesting their potential for use in controlled drug delivery systems. Theoretical calculations of thousands of starting systems at the GFN2-xTB quantum level of theory supported the formation of the IC and the overall DHPM orientation, for which the aromatic ring of DHPM points toward the tail portion of the CD, as suggested by the 1 H NMR data.