*2.5. Solid-State Characterization*

Thermal analysis of pure components, drug–CD and drug-SV binary systems obtained with the different techniques was performed by a Mettler TA 4000 Stare system (Mettler Toledo, Greifensee, Switzerland). About 5 to 10 mg of each sample were accurately weighed by a MX5 Microbalance (Mettler-Toledo, Greifensee, Switzerland), placed in sealed aluminum pans with pierced lid, and scanned at a heating rate of 10 ◦C min−<sup>1</sup> under static air atmosphere, at a temperature in the range 30–300 ◦C. The instrument was calibrated using Indium as a standard (99.98% purity, melting point 156.61 ◦C, and fusion enthalpy 28.71 J/g).

The relative degree of drug crystallinity (RDC) in the samples was calculated according to Equation (3) [17]:

$$RDC = \frac{\Delta H \text{sample}}{\Delta H drug} \times 100\% \tag{3}$$

where Δ*H sample* and Δ*H drug* are, respectively, the heat of fusion of the drug in the sample (normalized to the drug content) and of the pure drug. Measurements were performed in triplicate and the relative standard deviation of crystallinity data was about ±4% to 5%.

The X-ray powder diffraction analysis (XRPD) was conducted at room temperature (2θ = 5 to 30◦ and scan rate = 0.05◦/s) with Bruker D8-advance apparatus (Silberstreifen, Germany) at a 40 mV voltage and 55 mA current using a Cu Kα radiation and a graphite monochromator.

#### *2.6. Dissolution Rate Studies*

Dissolution rate studies of HCT as such and from its different binary and ternary systems as well as from the final tablets were performed according to the dispersed amount method.

Powder samples, containing a fixed amount of drug, were sieved and the selected granulometric fraction (75 to 150 μm) was placed into a 150 mL beaker containing 75 mL of pH 5.5 phosphate buffer solution. In the beaker, thermostated at 37 ± 0.5 ◦C, a three-blade paddle (1.5 cm radius) was centrally placed and rotated at 100 rpm. Drug content was determined as described above (Section 2.1) in samples (3 mL) periodically withdrawn and filtered with a syringe-filter (pore size 0.45 μm). Fresh medium was added to replace the sampling and a correction was made for the cumulative dilution.

Each test was repeated four times (C.V. < 5%). All data were analyzed by ANOVA (one-way analysis of variance) (GraphPad Prism version 4.0 program, Inc. San Diego, CA, USA). Differences were considered statistically significant when *p* values were <0.05.

#### *2.7. Tablet Formulation and Characterization*

Flat tablets containing 25 mg of drug were prepared with the selected ternary system (COE HCT-RAMEB-SV). In order to obtain mixtures with proper flowability, disintegration, and compactability properties, 4% sodium starch glycolate (Explotab®) as superdisintegrant, 10% of polyvinylpirrolidone (PVP K30) as binder, and 1% of Mg stearate as lubricant were combined to the drug or drug-carrier systems. After a mixing of 15 min in a turbula mixer, the powders were compressed

at 2.5 tons for 3 min using a hydraulic press. Uniformity of content, weight, diameter, thickness, hardness, friability, and disintegration tests were performed according to European Pharmacopoeia (Ph. Eur.) 9th Edition. In order to obtain results comparable with the powders, dissolution studies were instead performed according to the method described above (Section 2.5).

The same test was also performed on Esidrex®, an HCT tablet formulation present on the market.
