*3.4. Dissolution Rate Studies*

The dissolution profiles of binary and ternary PM and COE products with RAMEB and SV are shown in Figure 6.

**Figure 6.** Dissolution profiles of HCT alone (o) and from its binary and ternary systems with RAMEB and SV: Physical mixtures (PM) (blue lines) with RAMEB (), SV (♦), and both ( dotted line) and co-evaporated (COE) products (violet lines) with RAMEB (), SV (Δ), and both ( dotted line). Each value represents the mean of 3 experiments.

Binary HCT-SV systems obtained by co-evaporation revealed an increase in drug dissolution rate with respect to pure drug, more evident as compared with the simple PM, probably, due to the complete drug amorphization and its closer dispersion within the NC matrix. However, the dissolution performance of drug-SV systems was considerably worse than the corresponding binary systems with RAMEB, indicating that drug complexation with RAMEB was far more effective than NC entrapment. The simultaneous presence of both carriers in the ternary systems gave rise to a synergistic effect in improving HCT dissolution properties. This was particularly evident in the ternary COE product, which showed about a two-fold increase of the dissolved drug amount after 5 min, with respect to the binary HCT-RAMEB COE system and reached a plateau level of 12.3 ± 0.9 mg/mL. Analogous results have been previously obtained for oxaprozin [16]. However, it is necessary to evidence that, in the case of oxaprozin, the grinding technique with CDs and the cofusion technique with nanoclay resulted in the best technique to improve the drug solubility, whereas in the case of HCT, the best results were obtained with co-evaporation. These findings confirm that the combined use of cyclodextrins and nanoclays, joined with the most appropriate sample preparation technique, can be a successful strategy to strengthen the benefits related to their potential to enhane solubility and dissolution rate of lipophilic drugs. Nevertheless, it is evident that preformulation studies are important in order to find the most appropriate preparation technique.

On the basis of these findings, the HCT-SV-RAMEB COE product was selected for the development of a new tablet formulation.

#### *3.5. Tablet Formulation and Characterization*

Compatibility studies performed by DSC analysis demonstrated the complete compatibility between the drug and the selected tablet excipients, as shown in Figure S2 of Supplementary materials. Preliminary studies conducted on the excipients allowed the obtainment of the selected tablet composition. Particularly, it was necessary to bring the binder percentage up to 10% because tablets prepared with a lower content did not pass the friability test. Tablets prepared with COE HCT SV RAMEB were fully characterized according to Ph. Eur. 9th Edition and compared with the marketed product, Esidrex®and the tablet properties in terms of hardness, friability, and disintegration

time are summarized in Table 4. The batches demonstrated a good uniformity passing the tests of content (RDS < 1%), diameter (RSD < 0.3%), thickness (RSD < 1%) and weight (RSD < 3%), and uniformity. As reported, the new tablets showed higher hardness and higher disintegration time than the commercial ones, but they were within the limits of the values imposed by the Ph. Eur. 9th Edition for uncoated tablets (15 min). The SV presence was fundamental to the improvement of the powder compactability and the obtainment of tablets with acceptable hardness and low friability properties, thus, demonstrating its suitability for direct compression.


**Table 4.** Technological properties of the new tablet formulation and of the commercial reference tablet.

Dissolution studies were performed using the dispersed amount method with an excess drug amount in order to evidence the effectiveness of our formulation. As shown in Figure 7, the results clearly demonstrated the better dissolution profile of the new tablet that reached the 100% of dissolved drug within 60 min vs. about the 40% obtained with the commercial tablet.

**Figure 7.** Dissolution profiles of HCT from the new tablet formulation and from the marketed tablet. The results proved the maintenance of the synergistic effect of NC and CD in improving the dissolution behavior also in the tablet formulation. Each value represents the mean of 3 measurements.

An improved drug bioavailability can be reasonably expected as a consequence of the increased drug solubility and dissolution rate. Moreover, the permeation enhancer properties of cyclodextrins, included methyl βCD derivatives, are well documented [33–35]. In particular, other authors observed an increased HCT permeability in the presence of βCD, by performing experiments on non-everted intestinal sac model [9]. Further in vivo studies have been planned in order to demonstrate the actual improvement of therapeutic efficacy of the new tablet formulation.

## **4. Conclusions**

An exhaustive study of the interactions between HCT and several kinds of cyclodextrins, in combination with different preparation methods for binary systems resulted in the selection of the COE product with RAMEB as the most appropriate to improve drug dissolution properties, as a result of the best complexing-solubilizing ability of such CD and the complete drug amorphization achieved by co-evaporation in its presence. Solid-state studies of HCT in mixtures with three types of NCs at

different w/w ratios led to the choice of SV at the 1:4 *w*/*w* ratio as the best for establishing effective interactions with the drug. Among the different techniques used for HCT:SV binary systems preparation, the co-evaporation showed the greater ability to improve drug amorphization and dissolution.

Ternary systems prepared by co-evaporation with both selected carriers, evidenced a synergistic effect of CD and NC in enhancing drug dissolution properties, giving a two-fold and a 12-fold increase in drug solubility as compared with the binary HCT-RAMEB COE product and the pure drug, respectively, thus confirming the great potential of such a combined approach.

Tablets prepared with the selected ternary systems clearly showed a better dissolution profile as compared with a marketed formulation, with an approximate 60% increase of the drug amount dissolved at 60 min. Therefore, the new tablets give proof of their ability to strongly improve the HCT dissolution properties, thus, increasing the amount of drug available for oral absorption.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4923/12/2/104/s1, Figure S1: XRPD patterns of COE products with SBEβCD (yellow line), HPβCD (grey line) and HEβCD (orange line); Figure S2: Compatibility studies for tablet formulation.

**Author Contributions:** Conceptualization, P.M.; methodology, F.G.-V.; software, A.B.-S.; validation, F.G.-V. and A.B.-S.; formal analysis, M.C. and A.B.-S.; investigation, F.M. and A.B.-S.; resources, P.M., C.V.I.; data curation, F.M., M.C. and F.G.-V.; writing—original draft preparation, F.M. and M.C.; writing—review and editing, P.M.; visualization, M.C., F.M.; supervision, C.V.I.; project administration, C.V.I. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
