2.1.4. Ibuprofen Loading Procedure

Ibuprofen was loaded into MBG\_Cu2%\_SG and MBG\_Cu2%\_SD through the incipient wetness method [20]. In brief, 0.1 g of both Cu-substituted MBGs were impregnated several times by dropping consecutive small aliquots of an ibuprofen solution in ethanol (at the final concentration of 30 mg/mL) onto the powders at RT. After each impregnation, ethanol was evaporated at 50 ◦C for 10 min and the dried powder mixed with a spatula. In order to completely fill the mesopores with ibuprofen the impregnation procedure was carried out with four 100 μL aliquots. Lastly, the obtained powders were dried at 50 ◦C overnight and named as follows: MBG\_Cu2%\_SG\_Ibu and MBG\_Cu2%\_SD\_Ibu.

## *2.2. Characterization of Cu-Substituted MBGs Loaded with Ibu*

The morphology and particle size of the prepared powders were analyzed by field-emission scanning electron microscopy (FE-SEM) using a ZEISS MERLIN instrument (Oberkochen, Germany). For FE-SEM observations, 10 mg of MBG\_Cu2%\_SG\_Ibu were dispersed in 10 mL of isopropanol

using an ultrasonic bath (Digitec DT 103H, Bandelin, Berlin, Germany) for 5 min to obtain a stable suspension. A drop of the resulting suspension was put on a copper grid (3.05 mm Diam. 200 MESH, TAAB), allowed to dry and successively chromium-plated prior to imaging (Cr layer 7 nm). MBG\_Cu2%\_SD\_Ibu sample was dispersed directly onto the double face carbon tape placed on a sample stub and then coated with a Cr layer. Compositional analysis of the powders was performed by energy dispersive spectroscopy (EDS; AZtec EDS, Oxford instruments, Abingdon-on-Thames, UK). EDS spectra were acquired on powder dispersed on carbon tape by analyzing an area of 75 × 50 μm2. Nitrogen adsorption–desorption isotherms were measured by using an adsorption analyzer ASAP2020 Micromeritics (ASAP 2020 Plus Physisorption, Norcross, GA, USA) at a temperature of –196 ◦C. Before nitrogen adsorption–desorption measurements, loaded samples were outgassed at 37 ◦C for 5 h, in order to avoid the degradation of the drug. The Brunauer–Emmett–Teller (BET) equation was used to calculate the specific surface area (SSABET) from the adsorption data (relative pressures 0.04–0.2). The pore size distribution was calculated through the DFT method (density functional theory) using the NLDFT kernel of equilibrium isotherms (desorption branch). The mesopore structure was investigated by transmission electron microscopy (TEM, Fei Company, Hillsboro, OR, USA) using a FEI Tecnai G2 operated at 200 kV. The samples were prepared by suspending the powders in ethanol and drop-wise placed on carbon coated copper grids. Thermo-gravimetric analysis (TGA) of the samples was performed on a TG 209 F1 Libra instrument from Netzsch (Selb, Germany) over a temperature range of 25–600 ◦C under air flux at a heating rate of 10 ◦C min−1. The drug content was determined from the weight loss between 200 and 600 ◦C, by applying a correction for the weight loss in the same range of temperature due to the surface silanol condensation as recorded on Cu-substituted MBGs before Ibu loading. Fourier transformed infrared (FT-IR) spectra of the drug-loaded samples were collected on a Bruker Equinox 55 spectrometer (Bruker, Billerica, MA, USA) over a range of wavenumbers from 4000 to 400 cm<sup>−</sup><sup>1</sup> (resolution 2 cm<sup>−</sup>1). In order to assess the amorphous state of incorporated Ibu, X-ray patterns were collected using an X'Pert PRO, PANalytical instrument (X'Pert PRO, PANalytical, Almelo, The Netherlands) (CuK α radiation at 40 kV and 40 mA). Data were obtained from 10◦ to 80◦ (di ffraction angle 2ϑ) at a step size of 0.0130◦ and a scan step time of 60 s. Di fferential scanning calorimetry (DSC) analysis of Ibu-loaded samples was carried out with a DSC 204 F1 Phoenix (Netzsch) instrument ((Selb, Germany). The samples were heated from 37 ◦C to 200 ◦C at a heating rate of 10 ◦C min−<sup>1</sup> under N2flux.

## *2.3. Synthesis of Amphiphilic Poly(ether urethane)*
