4.5.1. Crystallographic Features of RIV-MAL Co

The visualization and *Eatt* methods predicted the slip along (0 0 1) plane in the RIV-MAL Co crystal structure (Figure 7 and Table 3). The visualization method showed the (0 0 1) plan to be a slip plane with a flat-layered topology (Table 4). The nature of hydrogen bonding is one-dimensional (1D) across each adjacent layer of the slip planes, with the (0 0 1) plane exhibiting the largest inter-planer distance (d-spacing) of 6.2127 Å when determined from simulated XRPD data. In addition to intramolecular H-bonding between RIV molecules, intermolecular H-bonding between RIV and MAL molecules was also observed in the crystal structure of RIV-MAL Co.

**Figure 7.** Crystal structure of RIV-MAL Co revealing the presence of flat layers topology slip plane along the (0 0 1) plane. MAL molecules are shown as "red", RIV in "black" and hydrogen bonding interaction between RIV and MAL as "cyan". The "insert" shows increased intermolecular interactions along the weakest crystallographic plane due to incorporation of MAL in the crystal lattice.


**Table 4.** Comparative assessment of molecular and supramolecular attributes of the coformer, API and cocrystal.

\* (0 0 1) plane was identified as (0 0 4) in the simulated PXRD scan of RIV.

The growth morphology model showed the (0 0 1) plane having the lowest *Eatt*, indicating that the plane along this direction may have the weakest intermolecular interactions, hence it can be a probable slip system. Using the face indexing analysis, the facet corresponding to (0 0 1) plane was identified as morphologically the largest crystal facet of RIV-MAL Co, with a relative surface contribution of 57.9% to the crystal habit [10]. These results provide experimental evidence that supports the findings of visualization and *Eatt* methods. Further, the "pop-ins" observed in the nanoindentation (*p-h*) loading curve of RIV-MAL Co crystal provided additional evidence for the presence of active slip plane system in the crystal structure (Figure 8).

**Figure 8.** The load-displacement (*p-h*) curve for RIV, MAL, and RIV-MAL Co. The pop-ins observed in crystal samples of RIV and RIV-MAL Co are shown by pointing "blue" and "black", arrows, respectively.

Pop-ins (burst in) is a result of discontinuities (a sudden increase of displacement at same load) in the load-displacement (*p-h*) curve and indicates plastic deformation mediated by the active slip planes in organic molecular solids. When indention stress is applied perpendicular to the slip plane (i.e., facet corresponding to slip plane), pop-ins can be observed due to the increased plasticity presented by the slip planes that are encountered during the penetration of nanoindenter tip. Conversely, a smooth curve without pop-in is indicative of the absence of a slip-plane system in a given crystal [29].
