4.5.3. Crystallographic Features of MAL

The visualization of the crystal structure of MAL revealed the presence of interlocked 3D hydrogen bonding between MAL molecules (resembling isotropic interactions) (Figure 10). The possibility of slip (glide) is not likely in the MAL crystal structure owing to the presence of strong intermolecular interactions across all three crystallographic axes (x, y, and z). The lowest attachment energy was observed for (1 0 0) plane in the MAL crystal structure (*Eatt* = −13.3 kcal/mol) (Table 3). The slip system prediction using attachment energy calculations assumes any plane with the least *Eatt* as a slip plane [47,48,50]. However, this assumption may provide erroneous predictions as it does not consider the role of the strong hydrogen bonding interactions commonly present in a crystal structure with 3D interlocked molecules. Some planes in the 3D interlocked structure would obviously have lower interactions energies than other planes, hence one may consider the least attachment energy plane as the "slip plane" based on the calculated *Eatt*. Therefore, prediction of slip planes in a 3D interlocked crystal structure only based on Eatt calculations can be erroneous. For 3D interlocked crystal structure, one should rely on either visualization method or other experimental techniques such as nanoindentation. The visualization method indicated the absence of a slip plane in the crystal structure of MAL. Additionally, the smooth (*p-h*) loading curve (without pop-ins) verified the absence of slip planes in the MAL crystal structure (Figure 8).

**Figure 10.** Crystal structure of MAL illustrating 3D hydrogen bonding network with strong intermolecular interactions.

### *4.6. Decoding the Basis of Bulk Deformation Behavior: Impact of Crystallographic and Supramolecular Features*

### 4.6.1. Impact of Crystallographic Features on Plasticity

Based on the compressibility plots and mean yield pressures, the order of plasticity (i.e. BA) for the three solids is MAL < RIV < RIV-MAL Co. Thus, the observed plastic deformation can be qualitatively written as "good" for RIV-MAL Co (Py of 83 MPa), "average" for RIV (Py of 133 MPa) and "poor" for MAL (Py of 323 MPa).

The greater plasticity of the cocrystal can be ascribed to the presence of the (0 0 1) active slip plane, which facilitates the facile slip in a direction perpendicular to the applied compaction pressure. Moreover, the higher inter-planar distance (d-spacing, 6.217 Å) in the slip plane of the cocrystal crystal structure as compared to the slip plane in RIV crystal structure (d-spacing, 4.4850 Å) could help in better slippage of the planes (higher plasticity) in the cocrystal system.

The crystal structure evaluation of RIV unveiled the presence of two slip planes, i.e., (0 0 1) and (1 0 2) and one-dimensional hydrogen bonding (Table 4). It was expected that RIV would have excellent plasticity owing to the presence of the multiple slip systems. However, RIV was less plastic than RIV-MAL Co. This behavior can be explained by the presence of corrugated or zigzag topology of the secondary slip plane (1 0 2).

The corrugated topology has an adverse impact on plastic deformation due to possible intertwisting (interlocking) of these planes during gliding over other nearest plane(s). The unfavorable impact of corrugated slip planes on plastic deformation of materials was also reported in crystal systems like paracetamol Form I, sulfathiazole Form IV and sucrose [49]. The presence of corrugated slip planes may facilitate a new hydrogen bond formation during slippage (gliding) process. On one hand, the intermolecular interaction is weaker due to separation of layers, while on the other hand, the intertwisting (interlocking) brings two layers close enough for formation of new hydrogen bonds. The likelihood of interlocking depends upon the degree of interlayer separations [51]. The inter-planar distance, i.e., d-spacing, can be a good indicator of interlayer separation between two planes [49]. A lower value of d-spacing indicates lesser interlayer separation and vice versa. In the case of RIV, a low value of d-spacing (3.8752 Å) for (1 0 2) plane signifies less interlayer separation and increased chances of interdigitation. The plastic deformation due to the primary slip plane (0 1 1) could be adversely affected by the resistance offered by the corrugated slip planes (10-2). Hence, the overall plasticity of RIV is governed by the presence of primary (flat layers topology slip) and secondary (corrugated topology slip) planes. Thus, RIV is a unique crystal system wherein both flat layers and

corrugated slip planes are observed in the same system, and the BA is governed by both slip planes. Moreover, the higher elastic recovery of RIV crystals (demonstrated by nanoindentation) could have reduced the available BA during bulk deformation.

Crystal structure evaluation of MAL was carried out to investigate the cause of its profoundly lower plasticity. MAL molecules form multiple hydrogen bonds across all three crystallographic axes forming a 3D network of hydrogen bonds (Figure 10). The lower plastic deformation (Py of 323 MPa) could be a result of the absence of slip plane (Table 4) and the rigid crystal structure of MAL. The 3D hydrogen bonding network of MAL o ffers a closer crystal packing which confers a dense crystalline structure and the same is evidenced by its higher crystal packing density (crystallographic true density is 1.621 g/cm2). Closer packing of the molecules along with strong intermolecular interaction (3D hydrogen bonding network) presented a rigid structure, which resists deformation under compaction pressure, resulting in the poor compressibility (poor plastic flow) of MAL. Therefore, MAL exhibited lower densification and higher yield pressure at a given pressure. The MAL possessed a lower plasticity and this material could be brittle in nature based on its high mean yield pressure (Py).

### 4.6.2. Impact of Crystallographic Features on BS

The measured BS in terms of σ0 was found to be higher in MAL (<sup>σ</sup>0 = 2.75 MPa) than RIV (<sup>σ</sup>0 = 2.58 MPa), while the highest BS was observed for RIV-MAL Co (<sup>σ</sup>0 = 3.21 MPa). The crystal systems devoid of slip planes showed a direct relationship between true density and compactibility (BS) and the inverse relationship between true density and compressibility (BA). This relationship holds true for the series of crystal systems studied in our lab [19,25,26] and is largely applicable to other systems [20,52]. Closely packed crystal systems have a higher crystallographic density (true density) and exhibit higher intermolecular interactions as compared to the crystal systems with an open structure and lower true density. Therefore, higher true density enables greater intermolecular contacts during compaction, resulting in higher BS. At the same time, the systems having higher true density resist densification under the applied compaction pressure and hence exhibit higher yield pressure and poor compressibility (low BA).

MAL crystal structure is devoid of slip planes and contains higher intermolecular interactions across all three axes (3D interlocked) that give rise to its higher true density of 1.621 g/cm3. The reasonably good BS and poor compressibility (poor plasticity) of MAL were thus attributed to its higher true density. Many reported studies have considered only slip plane or plasticity (increasing BA) as key to govern tabletability and have neglected the role of BS. It is necessary to understand the role of BS in governing tabletability of molecular solids, and also considering "true density" as an important parameter, as it has a direct correlation with BS.

In crystal systems with active slip planes, BS is expected to be directly proportional to the strength of intermolecular interactions across the lowest energy slip plane in the corresponding crystal form [24,31]. In the crystal structure of RIV-MAL Co, MAL molecules form additional intermolecular hydrogen bonding interactions between the carbonyl (C=O) group of morpholinone in RIV (H-bond acceptor) and hydroxyl (-OH) in MAL (H-bond donor) [10]. Thus, cocrystallization of RIV with MAL led to the increased extent of intermolecular interactions in the crystal structure of RIV-MAL Co along the lowest energy slip plane (0 0 1). Thus, the significantly higher BS (<sup>σ</sup>0 = 3.21 MPa) of the cocrystal over RIV (<sup>σ</sup>0 = 2.58 MPa) can be attributed to the increased strength of intermolecular interaction. A summary of the key findings of the present work is pictorially captured in Figure 11.

**Figure 11.** Pictorial depicting a summary of the key findings of present work. The observed values of interparticulate bonding strength (BS), bonding area (BA), and tabletability are expressed in "+" symbol. For the purpose of comparison, "+++" indicate "high"; "+" indicate "low"; and "+ +" represents "intermediate" value.
