*3.4. Preparation and Characterization of Liquisolid-Tablets*

Preformulation studies, performed to select the most suitable excipients to use, in mixture with the liquisolid systems, for obtaining direct-compressed tablets with the proper characteristics of hardness and disintegration time, enabled the selection of two kinds of microcrystalline cellulose (Avicel®PH102 and Ceolus®KG802) as binders, in virtue of their high flowability and compressibility, and of Explotab® (sodium starch glycolate) as super-disintegrant. The composition and properties of the examined tablets are reported in Table 2. For each tablet formulation, the lowest compression force allowing to obtain tablets with suitable hardness and tensile strength was used (Table 2). A conventional tablet containing the drug as such was also prepared as a reference, by using the same excipients present in liquisolid tablets, except the solvent, replaced by an equivalent quantity by weight of Avicel®PH102. A GLY commercial tablet at the same drug dosage (Gliboral®) was also used as a further reference.


**Table 2.** Composition and properties of glyburide (GLY) liquisolid tablets.

All tablets complied with the USP friability test (weight loss in all cases less than 0.2%) and weight uniformity and showed short disintegration times, always less than 2 min.

Dissolution test was performed under the same experimental conditions (900 mL of pH 7.4 buffer solution) used in our previous studies aimed at the development of GLY fast-dissolving tablets [12,15,16,20], in order to obtain comparable results. Moreover, these conditions of medium volume and pH are those indicated by FDA and USP (test 5, Revision Bulletin 2010, 1st Supplement USP 34-NF 29) for the dissolution test of GLY (micronized) tablets. The dissolution profiles of GLY from liquisolid-tablets are shown in Figure 7, in comparison with those from the conventional reference and the marketed tablets, while their dissolution parameters, in terms of percentage drug dissolved and Dissolution Efficiency (DE) at 10 min and 60 min, indicative, respectively, of the rate and of the totality of the process, are collected in Table 3.

**Figure 7.** Dissolution profiles of glyburide (GLY) from liquisolid tablets (LS 1–4) and from the commercial tablet (Gliboral®) and the reference conventional tablet (CT).

**Table 3.** Dissolution parameters of glyburide from liquisolid (LS) and conventional (CT) tablets in terms of percent dissolved (PD) and dissolution efficiency (D.E.) at 10 and 60 min.


\* For the composition of tablet batches, see Table 2.

As is evident, all liquisolid tablets exhibited a marked enhancement of the GLY dissolution performance, with respect to both the reference tablet containing the plain drug and the commercial tablet. In fact, the percentage of drug dissolved at 60 min from the conventional reference and from the commercial tablets reached only 40% and 50%, respectively, while it exceeded 90% for all liquisolid systems. The observed improvement in dissolution rate can be attributed to the increased wetting properties and to the larger surface area of drug particles exposed to the dissolution medium, in virtue of its almost molecular dispersion within the liquisolid matrix [26–28]. However, interestingly, tablets with liquisolid systems containing 2-PYR as solvent showed a slightly better dissolution profile, particularly in terms of percentage dissolved at 10 min (*p* < 0.05), than those containing DMA, despite the slightly higher solubility of GLY in DMA than in 2-PYR (see Figure 1). Nevertheless, this result may be somehow connected to the tablet formulation and/or compression process. In fact, dissolution experiments performed directly on the plain liquisolid systems as powders, exhibited an inverted behavior, with a slight, even not significant, better performance of those containing DMA as solvent (see Figure 6).

On the other hand, no significant differences (*p* > 0.05) in the drug dissolution behavior were instead observed between systems with Neusilin®US2 or Aeroperl®300. However, as can be seen in Table 2, when comparing liquisolid formulations containing the same solvent (LS1 vs. LS2, or LS3 vs. LS4), Neusilin®US2 allowed to obtain tablets with similar or even better hardness, than those with Aeroperl®300, but using lower compression force. This is considered a desirable property, since tablets of suitable hardness, necessary to avoid breakage problems, should be ideally obtained without applying excessive compression force, in order to can be easily disintegrated when in contact with the dissolution medium. In fact, tablets prepared under large compression force will have a reduced porosity and will require more time for water penetration into the compact, thus resulting in prolonged disintegration times [27].

A comparison between the drug dissolution properties from the new liquisolid tablets and those from the previously developed GLY fast-dissolving tablets based on other different formulation approaches, showed that the new technology was actually more effective in enhancing the GLY dissolution properties than the formation of binary or ternary solid dispersions [15,16], cyclodextrin complexation [12] or simple adsorption on mesoporous silicas [46]. The performance of the new GLY liquisolid tablets resulted comparable only to that of fast-dissolving tablets based on solid-self-microemulsifying systems (SMEDDS) [20]. However, the new liquisolid-tablets presented the strong advantage of a simpler and faster formulation development and of a lower production cost. In fact, they did not require the time-consuming construction of pseudo-ternary phase diagrams to select the best surfactant and co-surfactant and to define the zone of microemulsion existence, which are instead necessary for the SMEDDS development. On the contrary, their very basic preparation procedure should assure an easy and economic industrial scale-up feasibility.

Finally, ESEM analyses were performed on final liquisolid tablets (Figure 8). The results further confirmed the better technological performance of tablets containing Neusilin®US2, whose whole surface appeared highly porous but perfectly homogeneous (Figure 8A); on the contrary, some horizontal fracture lines and thin fissures were observed on the surface of tablets containing Aeroperl®300, indicative of not optimal technological properties of the formulation and of a potential tablet delamination process (Figure 8B).

**Figure 8.** ESEM images of the surface of glyburide liquisolid tablets LS1 (**A**) and LS2 (**B**).
