*4.5. Identification of Crystallographic Features*

Crystallographic features such as slip planes, topology of slip planes, crystallographic density, molecular packing and nature of intermolecular interactions predominantly govern the deformation behavior at both crystal as well as bulk level. The crystallographic factors influencing the bulk deformation behavior can be divided into two categories—(1) those contributing to increasing BA (plasticity) include—slip planes, topology and numbers of slip planes; (2) those contributing to BS include—the strength of interactions along the weakest crystallographic planes and true density or crystallographic true density. It is well reported that the presence of active slip planes is responsible for plastic deformation (increasing BA) of organic molecular solids including pharmaceutical solids [13,47,48]. Slip planes are defined as "*crystallographic planes in the crystal structure which contain the weakest interaction between the adjacent planes and are accounted by the highest molecular density and largest d-spacing, as compared to the other planes in that crystal*" [23,47,49].

The slip plane identification based on *Eatt* calculation assumes that a plane with the least absolute attachment energy would have the weakest interaction between the adjacent planes and could slip (glide) over one another more easily than other planes in the crystal. The crystal morphology predictions by the "growth morphology" method assumes that the planes with lower attachment energies will grow at a slower rate and hence will be manifested as the larger faces of the crystal habit and vice versa. Typically, the slip plane in a crystal structure is likely to be the one with the least *Eatt* and may manifest as the "largest" face within the crystal habit. The largest surface face (facet) has the highest surface area contribution to the crystal habit, and hence can be experimentally identified by either simple microscopic analysis or more accurately by face indexation analysis. Further, nanoindentation of the crystal provides experimental evidence of the presence or absence of slip planes when the stress is applied normal to the most predominant facet of a crystal (i.e., probable slip plane).

A combination of visualization and attachment energy calculations (*Eatt*) could provide a more accurate prediction of the slip system compared to either individual method. Therefore, both visualization and *Eatt* calculations methods were employed for reliable identification of slip systems (Table 3). *Eatt* values obtained from COMPASS II force field method are presented in Table 3. The results of *Eatt* calculations using "Dreiding force field method" are provided in the Supplementary Materials file. The presence and absence of slip planes in the molecular solids was experimentally confirmed by the nanoindentation study and the face indexation data previously reported by the authors [10].


**Table 3.** Identification of slip plane using visualization, *Eatt* calculation and nanoindentation studies.

> *Eatt* values reported here are from COMPASS II force field method.
