**2. 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 SiO2 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 SiO2. 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-SiO2,

**117**

**Drug molecules** **Indomethacin**

**Ibrutinib** **Probucol**

HPC, pluronic P6g and SDS

Kollidon® VA64, Cremophor®

RH40

**Naproxen** **Fenofibrate**

Hydroxypropyl-β-cyclodextrin,

hydroxypropyl methylcellulose

(HPMC)

**Gliclazid**

**Table 2.**

Sodium lauryl sulfate, crosslinked

Prevention of drug

—

—

90% in 2 h

[19]

agglomeration, wettability and

hydrophilicity enhancement

*Specificities of several ternary systems involving poorly water soluble drugs (Indomethacin, Ibrutinib, Probucol, Naproxen, Fenofibrate, and Gliclazid).*

polyvinylpyrrolidone

Hydroxypropyl-β-cyclodextrin,

Hydrogen bond formation,

—

—

—

90% in 20 min

[18]

[17]

Electrostatic interactions

Formation of inclusion

—

complexes

arginine

Micelle solubilization, increase

15-folds higher than that of

coarse Probucal suspension

6.0-folds higher than

—

30% at 2 h (commercial

[16]

tablets was only 0.68%

at 2 h)

commercial tablet

in hydrophilicity

Hydrophilicity, wettability and

particle size reduction

Oxalic acid (OXA)/

Ionic Interactions

1.49-fold greater than

crystalline Ibrutinib

microcrystalline cellulose (MCC)

Mg(OH)2/SiO2

Acid–base interaction and formation of C - O -Si bridging bond

—

At 30°C and

—

11% RH for

2 months

At 75% RH

5.33-folds higher than

[14]

crystalline Ibrutinib

and T-40°C for

6 months

7 days at 4 °C or

About 40% at 2 h

[15]

25 °C

**Carriers**

**Mechanisms**

**Pharmacokinetic properties (plasma drug concentration)**

**Physical stability**

**Drug release (at 37.0 ± 0.5°C)**

**Authors**

*Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs…*

*DOI: http://dx.doi.org/10.5772/intechopen.95518*

[13]


*Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs… DOI: http://dx.doi.org/10.5772/intechopen.95518*

**Table 2.**

 *Specificities of several ternary systems involving poorly water soluble drugs (Indomethacin, Ibrutinib, Probucol, Naproxen, Fenofibrate, and Gliclazid).*

*Chitin and Chitosan - Physicochemical Properties and Industrial Applications*

**Drug molecules Authors**

Piroxicam Anna Penkina et al. [1] Praziquantel Alessio Gaggero et al. [2] Telaprevir Xinnuo Xiong et al. [3] Hydrochlorothiazide Sakib M. Moinuddin et al. [4] Indomethacin Georgia Kasten et al. [5] Nifedipine Pooja J. Patel et al. [6] Ibuprofen Amjad Hussain et al. [7] Bicalutamide Joanna Szafraniec et al. [8] Celecoxib Zhuang Ding et al. [9]

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 [13–19]. In this chapter, the challenges and strategies in developing robust ternary solid dispersion of high

*Some examples of drug molecules exhibiting solubility enhancement by binary solid dispersion using co-milling* 

stability and performance are briefly discussed.

recristallization or chemical degradation.

**dissolution rate**

**Table 1.**

*technique [1–9].*

**2. Ternary solid dispersion: a new alternative to promote drug** 

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

Watanabe et al. (2002) have reported the physical stabilization of amorphous Indomethacin (IM) by ternary solid dispersion using Mg (OH)2 and SiO2 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 SiO2. 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-SiO2,

**116**


#### **Table 3.**

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

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 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 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 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

**119**

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

*Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs…*

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) analy-

oxidative 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

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].

**3. Solubility enhancement of Ibuprofen by formation of physically stable** 

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

**amorphous ternary system (Ibuprofen, PVP, β-cyclodextrin)**

) and high binding energy

*DOI: http://dx.doi.org/10.5772/intechopen.95518*

that of Probucol commercial tablets [18].

sis showing the appearance of protonated amines (N<sup>+</sup>

(+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 anti*Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs… DOI: http://dx.doi.org/10.5772/intechopen.95518*

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<sup>+</sup> ) 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].
