*3.3. Characterization of Drug–NC Binary Systems*

DSC analyses were then performed on HCT binary systems with three different nanoclays (SV, PHC, and VHS) at three different drug:NC *w*/*w* ratios (1:1, 1:2, and 1:4) in order to find the nanoclay that more strongly interacts with the drug and the most suitable weight ratio between the components. The results, as summarized in Table 2, show evidence that no interaction occurred between HCT and VHS, as indicated by the absence of variations in drug melting peak or enthalpy. Evidently, on the one hand, the typical lamellar stratified structure of VHS, despite having proven to effectively entrap

molecules by cation, exchange with the hydrated cations present in its interlayers [10] showed limited interaction with a lipophilic molecule as HCT. On the other hand, the typical fibrous structure of SV and PHC, consisting in hollow nanotubes, seemed to be more suitable to entrap lipophilic drugs. SV proved to have a greater interaction ability towards HCT, raising to the highest reduction in drug crystallinity at the 1:4 *w*/*w* ratio (RDC 37%) as a consequence of its better dispersion into the nanoclay structure. The higher interaction ability of SV than PHC towards HCT probably could be related to the different dimensions of their channels (0.37 × 1.06 nm for SV and 0.37 × 0.64 nm for PHC) [32]. Moreover, these findings were in accordance with those previously obtained with another lipophilic drug, oxaprozin, where SV provided the best results in terms of NC–drug interactions [16].


**Table 2.** Thermal parameters and % residual drug crystallinity (% RDC) of hydrochlorothiazide (HCT) alone or in the presence of the different examined nanoclays (NCs).

SV was then selected in order to test the effect of different preparation methods and experimental conditions (such as use of solvent, stirring rate, temperature, etc.) on the performance of drug-nanoclay systems. Binary systems at 1:4 *w*/*w* drug:SV ratio were prepared by co-evaporation (COE), co-fusion (COF), co-grinding (GR), solvent-heating (SH), solvent-sonication (SS), and solvent magnetic stirring (SMS) techniques. The products obtained were submitted to DSC analyses and the results are summarized in Table 3 in terms of drug melting temperature and enthalpy and percent of residual drug crystallinity (RDC %).

**Table 3.** Thermal parameters and % residual drug crystallinity (% RDC) of hydrochlorothiazide (HCT) alone or in the different 1:4 *w*/*w* systems with sepiolite prepared by physical mixing (PM), solvent-sonication (SS), solvent magnetic stirring (SMS), co-grinding (GR), co-fusion (COF), solvent-heating (SH), and co-evaporation (COE).


Even if all the used techniques gave rise to a marked reduction of intensity of the drug melting peak, with the trend PM < SS = SMS < GR < COF < SH, its complete disappearance was obtained just with the COE.

The XRPD patterns of pure components, PM and COE product are reported in Figure 5. SV showed a typical crystalline pattern clearly recognizable in the PM and still detectable in the COE product with the drug. However, the crystallinity peaks of HCT were well visible in the PM and in the other binary systems (data are reported just for PM as example) while they completely disappeared in the COE product.

**Figure 5.** Patterns of HCT, SV, and their 1:4 *w*/*w* binary systems obtained by physical mixing (PM) and co-evaporation (COE).

On the basis of these results, ternary systems were prepared by physical mixture and co-evaporation with RAMEB (HCT-RAMEB 1:1 molar ratio) and SV (HCT-SV 1:4 *w*/*w* ratio) and compared with the corresponding binary systems. X-ray diffractograms, performed on ternary PM and COE products confirmed the complete drug amorphization in the COE product, thus, confirming the DSC results.
