**1. Introduction**

Hydrochlorothiazide (HCT) is a thiazide diuretic drug widely used in the treatment of heart failure, hypertension, hypovolemic shock, or edema [1]. HCT is a class IV drug, according to the Biopharmaceutical Classification System (BCS), characterized by low aqueous solubility and low permeability [2]. Due to these factors, this drug is poorly absorbed in the gastrointestinal tract, thus, resulting in a variable and low bioavailability after oral administration [3]. Moreover, HCT can be easily hydrolyzed in an aqueous environment, which also poses stability problems [4].

Cyclodextrins (CDs) are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity used as complexing agents to increase aqueous solubility of poorly soluble drugs and to increase their bioavailability and stability. The natural CDs, named α−, β−, and γCD consist of six, seven, or eight glucopyranose units and among them, βCD usually demonstrates the higher complexing ability toward drugs [5]. Cyclodextrins (CDs) have been successfully used as carriers to improve the solubility and bioavailability of antihypertensive agents such as HCT [6]. CD complexation can provide additional advantages, including taste masking, increased drug stability, and drug permeation, thus, leading to dose lowering and reduction of side effects [7]. Mendes et al., 2016 showed the capacity of βCD to increase HCT solubility, protect the drug from hydrolysis and enhance the in vivo effect [8]. Moreover, the effectiveness of βCD in increasing drug permeability across the small intestine of rats was recently demonstrated by Altamimi et al., 2018 [9]. However, βCD has relatively low solubility and often cannot be used at concentrations suitable for pharmaceutical applications. For these reasons several modified βCDs have been prepared, and now its hydroxypropyl, methyl, and sulfobutylether derivatives have been commercially used as new pharmaceutical excipients.

Clay minerals can be used as excipients in several medicinal products and can be effectively used in the development of new formulations. Nanoclays (NCs) are fibrous inorganic matrices that are able to entrap little molecules and release them in particular conditions and have aroused particular interest as drug carriers due to their biocompatibility, high drug loading power, low cost, and very poor toxicity [10,11]. Moreover, their ability to enhance the dissolution properties and, then, the bioavailability of poorly soluble drugs has been reported [12,13].

Tablets are still the most used solid dosage form in the market due to their manufacturing efficiency, good stability, and good patient acceptance [14]; and CD and fibrous clays used as excipients for tablet formulation is well recognized and consolidated [13,15]. Recently, "drug-in-CD-in-NC" hybrid systems have been developed and used to prepare tablets of oxaprozin, a poorly water-soluble NSAID, with improved dissolution properties and enhanced therapeutic effect on rats [16,17]. Taking these considerations into account, the aim of this work was to assess the effectiveness of such a particular approach, based on the combined use of CDs and NCs as drug carriers, for the development of a powerful tablet formulation for oral delivery of HCT. With this purpose, the solubilizing effect of different CDs and NCs towards the drug was first investigated, in order to select the best carriers. In fact, it is not possible to determine in advance which kind of CD or NC better improves the drug dissolution properties, as well as it is not possible to predict the effect of drug-CD complexation on the nanoclay interaction and entrapment. Moreover, in order to evaluate the influence of the preparation technique in establishing effective drug-carrier interactions, binary and ternary combinations of the drug with CDs and NCs were prepared by different methods and characterized for solid-state (by differential scanning calorimetry and X-ray powder diffractometry) and dissolution properties. The best CD and NC carriers and the most effective preparation method were then selected to obtain the hybrid ternary system, which was used for the development of tablets. These were suitably evaluated for technological properties and tested for dissolution behavior and compared with a marketed tablet formulation.
