Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs by Co-Milling Technique

Amorphous ternary solid dispersion has become one of the strategies com-monly used for improving the solubility and bioavailability of poorly water soluble drugs. Such multicomponent solid dispersion can be obtained by different techniques, this chapter provides an overview of ternary solid dispersion by co-milling method from the perspectives of physico-chemical characteristics in vitro and in vivo performance. A considerable improvement of solubility was obtained for many active pharmaceutical ingredients (e.g., Ibuprofen, Probucol, Gliclazid, Fenofibrate, Ibrutinib and Naproxen) and this was correlated to the synergy of multiple factors (hydrophilicity enhancement, particle size reduction, drug-carrier interactions, anti-plasticizing effect and complexation efficiency). This enhanced pharmacokinetic properties and bioavailability of these drug molecules (1.49 to 15-folds increase in plasma drug concentration). A particular focus was accorded to compare the ternary and binary system including Ibuprofen and highlighting the contribution of thermal and spectral characterization techniques. The addition of polyvinylpyrrolidone (PVP K30), a low molecular weight molecule, into the binary solid dispersion (Ibuprofen/ β -cyclodextrin), leads to a 1.5–2 folds increase in the drug intrinsic dissolution rate only after 10 min. This resulted from physical stabilization of amorphous Ibuprofen by reducing its molecular mobility and inhibiting its recristallization even under stress conditions (75% RH and T = 40°C for six months).


Introduction
In recent years, solid dispersion technology by milling technique was largely utilized by researchers in order to enhance dissolution rate, bioavailability and thus therapeutic efficiency of several poorly water-soluble drugs ( Table 1), as it represents a simple, economic and environmental process without using solvents [1][2][3][4][5][6][7][8][9]. In fact, millings enable particle size reduction and promote the formation of drug nanoparticles, which enhance solubility, flow properties and content uniformities of pharmaceutical dosage forms [10]. However, this process might induced drug transition from crystalline to amorphous state which is more soluble in water but physically unstable in some cases [11]. Physical stabilization of such unstable amorphous material required an optimization strategy using additives (milling time and rate, compatible carriers with optimized proportion) in order to preserve its chemical integrity (absence of degradation) and inhibiting phase transformations or polymorphic conversion towards unstable forms [11]. In some cases, the stabilization and solubilization efficiency of binary solid dispersion is weak by exhibiting limited bioavailability enhancement [12] and required a large amount of carriers. In order to further enhance drug dissolution rate, several researchers have introduced third compound in drug formulations, this led to simultaneous enhancement of drug solubility and physical stability [13][14][15][16][17][18][19]. In this chapter, the challenges and strategies in developing robust ternary solid dispersion of high stability and performance are briefly discussed.

Ternary solid dispersion: a new alternative to promote drug dissolution rate
Solubility and stability enhancement of drug molecules in ternary solid dispersion resulted from various mechanisms ( Table 2) including intermolecular interactions (drug/carrier, carrier/carrier) and synergetic effects of excipients. This required the use of appropriate carrier showing compatibility in ternary mixtures (e.g. polymer, surfactant, crosslinked polymer, adsorbent, aminoacids, cyclodextrin molecules) and reinforcing stabilization of amorphous drug by preventing its recristallization or chemical degradation. Watanabe et al. (2002) have reported the physical stabilization of amorphous Indomethacin (IM) by ternary solid dispersion using Mg (OH) 2 and SiO 2 as carriers [13]. DRIFT (Diffuse Reflectance Infrared Fourier Transform Spectroscopy) results have shown the disappearance of the OH group (carboxylic group) band of IM (Table 3) in ternary system and this was attributed to mechanical dehydration generated by ball milling in presence of Mg (OH) 2 and SiO 2 . Such dehydration leads to the increase in the acidity of the carriers and enhances the acid-base interaction which ensures the rapid amorphization of IM ( Table 3). The presence of these two carriers has increased the glass transition temperature of Indomethacin, the Tg of ternary system was higher than that of binary ground mixtures (IM-SiO 2 , IM-Mg(OH) 2 ). After storage at 30°C and 11% of RH, IM-SiO 2 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 SiO 2 -Mg (OH) 2 interface that promotes the formation of bridging bonds (Si-O-C or Mg-O-C) which inhibited the molecular mobility of amorphous drug. 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 hydroxypropylβ-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 Arginine and the hydroxyl groups of HPβCD [14].
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 and improvement in wettability and hydrophilicity of co-milled particles.
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 from HP-β-CD cavity [16].
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  Table 3.
Observed changes for Indomethacin ternary solid dispersion compared to binary mixtures [13]. 1.49-fold compared with crystalline Ibrutinib. This was attributed to wettability and hydrophilicity enhancement, as well as the presence of ionic interactions between drug and carriers as suggested by XPS (X-ray photoelectron spectroscopy) analysis showing the appearance of protonated amines (N + ) and high binding energy (+2.75 eV) in the ternary system (Ibrutinib/OXA/MCC) [17]. The combination of polymer (Kollidon® VA64) and surfactant (Cremophor®RH40) was effective for Probucol (poorly water soluble antioxidative drug/BCS II) solubility enhancement by ball milling technique (Lijia et al. 2017) [18]. This considerably enhanced in vitro dissolution and in vivo bioavailability in rats. Such enhancement was attributed to the greater hydrophilicity, increased wettability and particle size reduction. The local solubilization effect of surfactant contributed also for preventing the aggregation of drug particles during dissolution. Otherwise, pharmacokinetic study has shown an increase of maximum plasma drug concentration for the ternary co-milled system which was 6.0-folds greater than that of Probucol commercial tablets [18].
On the other hand, Fang Li et al. (2019) have shown that dissolution rate and oral absorption of Probucol can be further improved by the formation of drug nanosuspensions (planetary beads-milling technique) using ternary stabilizers mixtures (Hydroxypropyl cellulose, an anionic surfactant (Sodium dodecylsulfate, SDS) and a nonionic surfactant (Pluronic F69)) [19]. Such Probucol nanosuspensions were physically stable after storage during 7 days at 4°C or 25°C, with highest dissolution rate (more than 60% at 2 h). The in vivo pharmacokinetic study has also shown 15-folds higher value of the plasma Probucol concentration compared to that obtained for coarse Probucol suspension. Probucol dissolution enhancement was attributed to particle size reduction and the characteristics of the polymeric chain which is dependent on the nature of polymeric stabilizer used in the mixture [19].

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][22][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 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.

Milling method
Ibuprofen was milled in presence of β-Cyclodextrin and then PVP at different weight ratios, physical mixtures (PM) were prepared by homogenization of pure components using ceramic mortar. Milling procedure was performed in a planetary ball mill (Pulverisette 7, Fritsch) using two milling jars (45 cm3)/7 balls (⌀ = 1 cm) in ZrO 2 . The rotation rate was set to 300 rpm and the ball/sample weight ratio was 82.5:1. The milling procedure was optimized for 10 h at room temperature (≈298 K) constituted by 20 min milling periods with pause periods (10 min) in order to minimize the overheating of the sample.

Results
In the case of the binary system (IB/βCD), the X-ray diffraction results showed the complete amorphization of the βCD (Figure 2), while the crystallinity of the IB has been slightly modified [29]. Amorphization of βCD by milling at room temperature is predictable, as milling is carried out at a temperature sufficiently below the Tg of βCD (Tg ≈ 292°C) [30]. The enlargement of the Bragg peaks is explained by the reduction in the size of the crystallites and slight distortions of the crystal lattice generated by ball milling. As shown by SEM micrographs (Figure 2), the birefringence and the crystallinity of drug particles were moderately affected in the binary system (IB/ βCD). By adding 20% of PVP to this binary mixture, the formation of amorphous agglomerations can be observed [29]. This aspect is similar to that obtained in the case of inclusion complexes between IB and βCD by different methods (co-precipitation, lyophilization) [31]. As shown by X-ray diffraction results (Figure 2), the ternary mixture (IB/βCD/PVP) was totally amorphous and showed physical stability after storage under stress conditions at RH: 75% and T = 40° C for 6 months, while the quenched IB (Figure 2) recrystallized at room temperature after few minutes [29].  Different mechanisms were involved in the physical stabilization of amorphous IB in the ternary system, this required the use of several techniques (XRD, FTIR, SEM, DSC, and NMR) according to ICH recommendations [32]. Noticeable changes were resumed in Tables 4 and 5. In the case of the binary mixture (IB/βCD), the frequency shift of the carbonyl group of IB (Table 4) [29], could be attributed to the breaking of certain intermolecular bonds (hydrogen bonds) associated with IB dimmers, largely described in the literature [33]. The shift of the CO (primary alcohol) band and the OH (associated) band of βCD compared to physical mixtures, as well as the disappearance of the NMR proton of the carboxylic group of IB and the hydroxyls peaks of βCD (2, 3, 6) suggested the presence of hydrogen bonds between the carboxylic group of IB and hydroxyl groups of βCD [29]. DSC results ( Table 5) have shown that the ternary mixture (IB/βCD/PVP) exhibited higher glass transition temperature (Tg˃250°C). This effect contributed to the reduction of molecular mobility of amorphous drug molecules and prevented its recristallization [29]. The addition of PVP to the binary system (IB/βCD) generated higher shifts for several infrared bands of IB, PVP and βCD ( Table 4), this was accompanied also by an upfield shift of proton peaks of IB and βCD (located inside and outside the cavity), and a downfield shift of carbonyl peaks of IB and PVP [29]. All these changes can be attributed to the formation of multiple hydrogen bonds between the carboxylic group of IB and the carbonyl group and nitrogen of the pyrrolidone ring of PVP [34], as well as intermolecular hydrogen bonds between βCD (Figure 3) and PVP that were frequently observed in ternary systems [29,35].  • Upfield shift of IB protons (higher than binary system) Table 5. NMR and DSC characterization of co-milled mixtures (IB/βCD, IB/βCD/PVP) [29].
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 temperature [29].

Conclusion
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.

Perspectives
A development of stability assay method should be performed to evaluate the absence of drug impurities in the ternary system. Moreover, it is necessary to further investigate the nature of interactions between drug molecules and carriers in such complex system.