**1. Introduction**

Glyburide (GLY) belongs to the second generation of sulfonylurea antidiabetic drugs, and it is one of the most widely utilized oral hypoglycemic agents [1]. Moreover, its ability to prevent cerebral ischemia and hemorrhagic stroke has been recently proved [2,3], and from 2015 it has been included in the model list of Essential Medicines of World Health Organization [4]. Due to its high permeability but very low aqueous solubility [5], GLY is classified as a class II drug according to the biopharmaceutical classification system [6]. As known, the dissolution rate of poorly water-soluble drugs often represents the main limiting factor in their absorption rate [6,7]. Clinical studies evidenced a variable in vitro dissolution, in vivo bioavailability, and the hypoglycaemic effect of GLY from different commercial tablets [8]. Problems of bio-inequivalence among pharmaceutically equivalent dosage forms of the drug were confirmed by a multinational post-market comparative study of various marketed products of the drug [9]. Such findings were found to be related to the unsatisfactory and variable dissolution behavior of GLY, further supporting the previously reported problems of formulation-dependent oral absorption of the drug [10].

Despite the fact that several strategies have been investigated in an effort to improve the dissolution performance of GLY, including complexation with cyclodextrins [11–13], solid dispersions in hydrophilic carriers [14–16], micellar solubilization [17], and formulation of self-micro-emulsifying drug delivery systems (SMEDDS) [18–20], at present, there are no commercial GLY products arising from such approaches. As a result, the development of effective GLY tablets with optimized dissolution behavior and ease of manufacture with industrial scale-up feasibility still remains a challenge and would be an important and useful result.

The liquisolid technique is a recent and promising alternative approach for improving the dissolution properties of poorly soluble drugs. This technique was initially used to transform liquid or semi-solid drugs into free-flowing, non-adherent, and readily compressible powders by simple mixing with suitable solid excipients [21]. Subsequently, the possibility of preparing liquisolid systems of solid poorly soluble drugs by dissolving them in a non-volatile water-miscible solvent, and then converting the liquid system in an apparently dry, well flowable powder, suitable for tableting, by mixing with proper solid excipients referred as carrier and coating materials [22,23] has been considered. The non-volatile solvents would remain on the carrier surface, so that the drug is kept within the powder substrate in a solubilized, almost molecularly dispersed state, with a great increase in both its wetting properties and surface area available for dissolution, and thus a consequent improvement in release rate and bioavailability is expected [22,24,25]. The actual effectiveness of this technique in improving the dissolution performance [26–30] and, consequently, the bioavailability [31–33] of several poorly-soluble drugs has been shown. Moreover, in addition to its drug release enhancement ability, the liquisolid strategy is particularly interesting and attractive because of the manufacturing process simplicity, low production costs, and ease of scale-up to industrial tablet production. Compounds such as various grades of cellulose derivatives, starch, and lactose are mainly used as carrier materials, while Aerosil is the most used coating material [26–29,31].

Mesoporous clays and silicas represent interesting and versatile pharmaceutical excipients, due to their numerous attractive features, such as large surface area and great loading ability, good flow and tableting properties, joined to very low toxicity, and low cost [34–36]. The multifaceted applications of clay materials in the pharmaceutical field have been carefully reviewed [37,38]. In particular, their effective use as drug delivery systems to modulate, extend, and/or target drug release has been widely described [39–43]. Furthermore, they also proved their effectiveness in enhancing the dissolution behavior, and then the bioavailability of scarcely water-soluble drugs [44–46]. Mesoporous clays and silicas can thus be considered as potentially suitable materials for liquisolid systems preparation.

Therefore, based on all these premises, we considered it worthy of interest to investigate the effectiveness of the liquisolid approach in the development of fast dissolving tablets of GLY with improved drug dissolution performance, by replacing the mixture of carrier and coating materials commonly used for their formulation with suitable mesoporous silicas or clays which would be able to simultaneously perform both such functions.

This novel strategy should enhance the applicability of the liquisolid technique in the pharmaceutical field, making it possible to decrease the necessary amount of adsorbent material, and, consequently, reducing the tablet final weight, known as the main limiting factor of this approach [47]. At the same time, it should facilitate the formulation scale-up from laboratory to industrial production, enabling the simplification of liquisolid tablet development by decreasing the number of formulation components (and the problems of their proper choice and of their relative w/w ratios).

With this aim, after selection of the most suitable non-volatile water-miscible solvent, based on its better solubilizing power towards GLY, the efficacy as carrier-coating materials of two different mesoporous silicas (i.e., Aeroperl®300/30 and Zeopharm®5170) and a mesoporous clay (Neusilin®US2) was investigated. Various liquisolid systems were then prepared and fully characterized for solid-state properties, flowability, compressibility, morphology, particle size, specific surface area, and then used for the preparation of directly compressed tablets. The obtained liquisolid tablets were tested for technological properties (mean weight, crushing strength, disintegration time) and their drug

dissolution profile was compared to those of a reference conventional tablet formulation containing the drug as such and of a commercial tablet (Gliboral®).
