**3.2 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].

**121**

**Table 5.**

**Mixtures/ infrared bands**

**Table 4.**

**Binary system**

**Ternary system**

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

PVP that were frequently observed in ternary systems [29, 35].

*Shifts of Infrared Bands compared to physical mixtures [29].*

• A decrease of melting temperature Tf (IB)

• Disappearance of IB melting event

• Tg (glass transition temperature) >250°C

*NMR and DSC characterization of co-milled mixtures (IB/βCD, IB/βCD/PVP) [29].*

**C=O(IB) C=O(PVP) OH/associated** 

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

**Shifts**

**C-O/ secondary alcohol (**β**CD)**

**C-O/ primary alcohol (**β**CD)**

• Upfield shirt of IB carbon peaks (Δδ [0.04:0.08] ppm)

• Downfield shift of carbonyl peaks of IB

and PVP

**C-N (PVP)**

**(**β**CD)**

**Binary system** 8 cm−1 — 11 cm−1 2 cm−1 3 cm−1 — **Ternary system** 12 cm−1 5 cm−1 22 cm−1 5 cm−1 6 cm−1 12 cm−1

**DSC RMN 1H RMN 13 C**

(2, 3, 6)

• Disappearance of the proton peaks of IB carboxylic group and hydroxyl groups of βCD

• Upfield shift of all proton peaks of βCD (located inside and outside the cavity) except hydroxyl peak (6) which

downfielded

system)

• Upfield shift of IB protons (higher than binary

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

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

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].


#### **Table 4.**

*Chitin and Chitosan - Physicochemical Properties and Industrial Applications*

(IB/βCD) in order to evaluate physico-chemical changes in solid state.

**3.1 Milling method**

**3.2 Results**

minimize the overheating of the sample.

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

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 ZrO2. 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

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].

**120**

**Figure 2.**

*X-ray diffraction results and SEM micrographs of binary and ternary system [29].*

*Shifts of Infrared Bands compared to physical mixtures [29].*


**Table 5.**

*NMR and DSC characterization of co-milled mixtures (IB/βCD, IB/βCD/PVP) [29].*

**Figure 3.** *βCD molecule [29].*

**Figure 4.** *Dissolution test results of co-milled mixtures (each point represents mean ± S.D., n = 3 [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].

**123**

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

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 stabiliza-

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

The authors thank Pr. Abdessalem Ben Haj Amara (Faculty of Sciences of Bizerte, Tunisia) for his considerable inputs and helpful discussions. On the other hand, the authors confirmed that this research Work did not receive any specific

The authors declare that they have no conflict of interest.

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

**4. Conclusion**

tion processes involved.

in such complex system.

**Acknowledgements**

**Conflict of interest**

funding.

**5. Perspectives**

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