**4. Conclusion**

*Chitin and Chitosan - Physicochemical Properties and Industrial Applications*

As a result of physical stabilization of amorphous Ibuprofen via different factors described previously, the IB dissolution rate (**Figure 4**) in the ternary mixture (IB/βCD/PVP) in 1:1:0.5 w/w ratio was greater than that obtained in the case of the binary mixture (IB/βCD) or (IB/PVP) in 1:1 w/w ratio [29]. The formation of such a water-soluble system can be explained not only by the synergistic effect of PVP and βCD via their mutual intermolecular interactions, but also by the ability of PVP to solubilize and promote formation of βCD complexes in the solid state [29]. Loftsson et al., have shown the role of PVP as a solubilizer in the case of several βCD complexes [36]. A ternary system (salt formation) was also obtained for IB and showed a considerable improvement in drug solubility and stability compared to the IB/βCD binary system [37]. Thus, the combination of PVP and β-Cyclodextrin molecules represents a scalable alternative for dissolution enhancement of IB which weakly interacted with β-Cyclodextrin by ball milling at ambient

*Dissolution test results of co-milled mixtures (each point represents mean ± S.D., n = 3 [29]).*

**122**

**Figure 3.** *βCD molecule [29].*

**Figure 4.**

temperature [29].

In summary, the formation of physically stable ternary amorphous system by solid dispersion method using optimized ball milling technique, represents a promising alternative for drug solubility and stability enhancement. This succeeded for improving the dissolution rate of several active pharmaceutical ingredients (e.g., Probucol, Gliclazid, Fenofibrate, Ibrutinib and Naproxen). Their pharmacokinetic properties and in vivo bioavailability were considerably improved in comparison to pure drug molecules (up to 15-folds increase in plasma drug concentration). Ibuprofen dissolution rate was considerably enhanced in presence of PVP and βCD (release of 90% in 1 h), such ternary system (IB/βCD/PVP) in 1:1:0.5 w/w ratio exhibited higher drug release than binary systems (IB/PVP, IB/βCD) in 1:1 w/w ratio. This was resulted from various mechanisms (intermolecular interactions, synergetic effects of carriers, anti-plasticizing effect, hydrophilicity enhancement, particle size reduction, inclusion of IB molecules in βCD cavity) promoting stabilization of amorphous Ibuprofen even under stress conditions (75% RH and T = 40°C for six months). However, such scalable strategy requires the association of several analytical techniques in order to fully understand the solubilization and stabilization processes involved.
