**3. Solubility enhancement of Ibuprofen by formation of physically stable amorphous ternary system (Ibuprofen, PVP, β-cyclodextrin)**

In recent years, researchers have used several techniques to improve the dissolution rate and bioavailability of Ibuprofen (IB), a non-steroidal anti-inflammatory drug (NSAID) which is poorly water soluble. The manipulation of the solid state of ibuprofen (**Figure 1**) remains a challenge for researchers because of its lower glass transition (Tg = −42 ± 1° C) and its tendency to recrystallized at room temperature [20]. The solubility improvement of ibuprofen was achieved by solid dispersion with different excipients (HPMC, Soluplus, PVP, Kaolin) [21–23], which differ in their solubilization abilities and their interactions with drug molecules. Several researchers have used complexation in the presence of βCD to improve the bioavailability of IB [24]. A water-soluble complex IB/βCD was obtained by co-precipitation or granulation (wet process) [25, 26]. Ibuprofen can also form an inclusion complex

**Figure 1.** *Ibuprofen molecule.*

*Chitin and Chitosan - Physicochemical Properties and Industrial Applications*

**Amorphization time** 60 min 60 min 10 min **DRIFT** OH (IM)/at 3377 cm−1 Decreased Decreased Disappeared

*Observed changes for Indomethacin ternary solid dispersion compared to binary mixtures [13].*

ited the molecular mobility of amorphous drug.

**Bands** Silanol group/at

**Table 3.**

3747 cm−1

OH (Mg (OH)2)/at 3377 cm−1

Arginine and the hydroxyl groups of HPβCD [14].

IM-Mg(OH)2). After storage at 30°C and 11% of RH, IM-SiO2 ground mixtures have shown rapid crystallization of amorphous Indomethacin. However, in the ternary co-grinding system, no crystallization was observed and this was attributed to higher acid–base interaction between Indomethacin and SiO2 -Mg (OH)2 interface that promotes the formation of bridging bonds (Si-O-C or Mg-O-C) which inhib-

**IM + Mg(OH)2 IM + Si(O)2 IM + Si(O)2 + Mg(OH)2**

— Disappeared Disappeared

Unchanged — Unchanged

Mura et al. (2003), have shown that aqueous dissolution of Naproxen (a poorly water-soluble anti-inflammatory drug) can be considerably enhanced by combination with hydroxypropyl- β-cyclodextrin and some aminoacids (Arginine) [14]. Such ternary system exhibited higher stability constant and drug solubility (at pH ≈ 7and T = 25°C) than binary system (Naproxen/Arginine). The synergetic effect in Naproxen solubility (a 13.4-fold increase compared to pure drug) can be attributed to the establishment of electrostatic interactions between Arginine and the carboxylic group of Naproxen, as well as hydrogen bond formation between

Lauretta et al. (2015) have shown that amorphous ternary solid dispersion of Gliclazid (poorly soluble drug used in the treatment of patients with type 2 diabetes) with crosslinked polyvinylpyrrolidone and SLS (Sodium Lauryl Sulfate) by co-milling method exhibited higher dissolution rate compared to the commercial product "Diabrezide" (Drug release of Gliclazid reached 90% in 2 h) [15]. Such solubility enhancement resulted from prevention of drug agglomeration in solution

In the case of Fenofibrate (FNB), a lipid-lowering drug (Class II) used in the treatment of hypertriglyceridemia and mixed hyperlipidemia, Xizhao Ding et al. (2018) have shown that the addition of Hydroxypropyl methylcellulose (HPMC) to the binary solid dispersion of Fenofibrate and Hydroxypropyl-β-cyclodextrin (molar ratio of 1:1), has shown a considerable enhancement of drug dissolution rate [16]. This ternary system has shown a percentage of 90% of drug release in 20 min (at 37 ± 0.5°C/pH = 7) which is higher than pure drug (24%) or binary system (60%). Such ternary solid dispersion was obtained by ball milling and led to the formation of inclusion complexes (increase in stability constants and complexation efficiency). This was attributed to the strong interactions established between FNB and HP-β-CD in presence of HPMC such as Van Der Waals dispersion forces, hydrophobic and hydrogen bonds, following the release of high-energy water molecules

Co-milling Ibrutinib (poorly water soluble antitumor drug) with oxalic acid (OXA) and microcrystalline cellulose (MCC) for six hours (Man Zhang et al. 2019) led to a simultaneous improvement in drug dissolution rate (5.33-fold higher than crystalline Ibrutinib) and physical stability of amorphous drug under stress conditions (75% RH and T = 40°C for six months) [17]. Plasma drug concentration of the ternary system (Ibrutinib, OXA, and MMC) exhibited also an increase of

and improvement in wettability and hydrophilicity of co-milled particles.

**118**

from HP-β-CD cavity [16].

with βCD mechanically [27]. It has been shown that the complexing efficiency of the IB/βCD system formed in the solid state depends on the techniques applied [28]. In our previous published work [29], binary solid dispersion of IB was achieved by comilling the drug and βCD molecules, and then PVP was added to the binary mixture (IB/βCD) in order to evaluate physico-chemical changes in solid state.
