*4.3. Bulk Deformation Behaviour*

The deformation behavior of pharmaceutical materials at a bulk level is commonly studied by performing compressibility, tabletability, compactibility (CTC) profiling, as it provides a comprehensive understanding on the role of interparticulate bonding area (BA) and bonding strength (BS) [25,26,39–41]. A measure of the ability of powder material to undergo reduction in volume under the application of compaction pressure is known as "compressibility". Compressibility is represented as a plot of porosity against compaction pressure and the plot signifies the extent of increase in interparticulate bonding area (BA).

The compressibility profiles of the three solids demonstrated greater compressibility of RIV and RIV-MAL Co over MAL at a given compaction pressure (Figure 4a). Slightly higher compressibility of the cocrystal over RIV was observed at higher compaction pressure (>150 MPa) and the differences were statistically significant (*p* < 0.05). The applied compaction pressure may lead to pressure-induced phase transformation in the samples. When examined by using DSC analysis, the compacts of the three molecular solids did not show any evidence of pressure-induced phase transformation.

**Figure 4.** (**a**)–(**d**) Compressibility, tabletability, and compactibility, and Heckel plots for MAL, RIV, and RIV-MAL Co.

Compactibility is defined as "*the ability of the powder material to produce tablets of su*ffi*cient tensile strength under the e*ff*ect of densification*" [21,25]. It is represented by a plot of tensile strength against tablet porosity, and the plot signifies the bonding strength (BS) of a given material. Compactibility plots (Figure 4b) indicate a higher bonding strength of the cocrystal (RIV-MAL Co) compared with that of RIV and MAL at all compaction pressures. As shown in the compactibility plot, MAL compacts exhibited reasonably good BS at comparatively larger porosity values as compared to the porosity values of RIV and RIV-MAL Co. The inability of MAL to undergo volume reduction (i.e., lower compressibility) may be a cause of its larger porosity at comparable compaction pressures.

Tabletability is defined as "the capacity of the powder material to be transformed into a tablet of specified tensile strength under the effect of applied compaction pressure" [21,42]. The overall tabletability of a material is governed by both BA and BS. The tensile strength (σ) of all the solids increased with increasing compaction pressure from 37 to 222 MPa (Figure 4c). The tensile strength value of the compacts at higher compaction pressure (222 MPa) was comparatively lowest for MAL (σ = 1.9 MPa), intermediate (slightly higher) for RIV (σ = 2.1 MPa), and the highest for RIV-MAL Co (σ = 3.2 MPa). The tabletability order based on the tensile strength at the higher compaction pressure follows the order MAL < RIV < RIV-MAL Co. The required tensile strength for a tablet to withstand the stresses encountered during its handling and transport is 2.0 MPa, and it should be attained by compressing a material at compaction pressure ≤ 200 MPa. Interestingly, the tabletability plot for RIV-MAL Co indicated that the cocrystal could produce a tablet of sufficient tensile strength (2.3 MPa) at a relatively lower compaction pressure of 37 MPa (please refer Figure 4c). The RIV compacts demonstrated a tensile strength of 2.1 MPa at a compaction pressure of 222 MPa, while the desired tensile strength of 2 MPa could not be achieved for MAL even at a compaction pressure as high as 222 MPa. Hence, the cocrystallization led to significant improvement in the mechanical properties, despite the fact that both parent components (RIV and MAL) possessed relatively poor mechanical properties. Hence, it is interesting to unfold the supramolecular and crystallographic basis of the compaction behavior of these three solids.
