**1. Introduction**

Oral solid dosage forms (such as tablets and capsules) represent the most popular delivery system amongs<sup>t</sup> various pharmaceutical dosage forms, as they o ffer many benefits in terms of cost, stability, ease of handling, and patient compliance [1]. The mechanical properties of active pharmaceutical ingredients (APIs) play a critical role in the manufacturing of solid dosage form, as poor mechanical properties can cause di fficulties during processing. With the emergence of crystal engineering, cocrystallization has become a useful strategy in the design of pharmaceutical materials with desired properties [2–5]. Cocrystallization has received significant attention because it can be employed for altering physicochemical properties of the APIs such as solubility [6], dissolution [7,8], stability [9],

hygroscopicity [10,11], and mechanical properties [12,13]. Many reports sugges<sup>t</sup> that cocrystallization can improve [14,15], deteriorate [16,17] or have no impact on modulation of mechanical properties of organic molecular solids including APIs. Understanding the role of crystallographic/supramolecular features, in modulating mechanical properties, remains an area of significant interest.

Tabletability is represented by tensile strength as a function of applied compaction pressure. It has been commonly used to compare the compaction performance of organic molecular solids and is particularly useful in studying bulk deformation behavior [18,19]. The tensile strength of the compacts is governed by interparticulate bonding area (BA) as well as interparticulate bonding strength (BS) [20]. Therefore, a thorough understanding of tabletability can be developed by a quantitative model, based on the concept of interparticulate bonding area and bonding strength (BABS model) [21,22]. Increased BA is achieved on irreversible (plastic) deformation of organic molecular solid and this deformation behavior is known as plasticity [21]. Crystallographic features such as slip systems are responsible for plasticity (increase in BA) in single component polymorphs [19,23] and multicomponent cocrystals [14,24]. The degree of intermolecular interactions and true density contribute to the BS of the crystal form [19,20,25,26]. It is worthwhile mentioning that "plasticity" only contributes to BA, and hence the role of BS also needs to be considered while evaluating bulk deformation (compaction) behavior.

Nano-mechanical parameters such as elastic modulus (E), indentation hardness (H) and elastic recovery (determined from load-displacement (*P–h*) curves) provide useful insights on the mechanical behavior of solids at a particle (crystal) level [27–29]. It is noteworthy that nanoindentation focuses on particle mechanical properties, but other factors such as particle size, particle shape and distribution, inter-particle interaction can have a significant e ffect when translating these properties to the bulk deformation (compaction). Interestingly, nanoindentation is useful for interpolation of particle-level behavior to crystallographic features [30], thereby furthering our understanding of crystal structure-mechanical property relationships. As demonstrated by Wendy and Duncan-Hewitt [31], and recently by our research group [32], the indentation hardness to elastic modulus (H/E) ratio is a predictor of compaction behaviour of materials undergoing deformation. The higher the value of H/E, the higher are the residual stresses after compaction (higher elastic recovery) and vice-versa. Another predictor of elastic recovery is (*hmax*-*hp*), wherein *hp* is the permanent indentation depth after removal of the test load and *hmax* is indentation depth at a maximum load; both are computed from the (*P–h*) curve.

Crystal anisotropy is responsible for distinct variations of the plastic deformation within the same structural class. Consequently, deformation processes in molecular solids cannot be labelled in simple terms and each molecular solid has to be evaluated individually [29,33]. It is well accepted that the presence of active slip planes in molecular solids leads to "plastic" deformation. A higher plasticity confers improved tabletability, because of increased BA. Therefore, slip planes have been increasingly used to describe "plasticity" and have also been used to correlate to the deformation behavior of molecular solids. However, the existing literature lacks descriptions of how a molecular solid undergoes deformation when its crystal structure contains more than one active slip system with two di fferent surface topologies (flat and zigzag topologies).

In the present work, we reveal the role of crystallographic features such as slip planes, slip plane topology, intermolecular interactions (nature of hydrogen bonding: 1D, 2D, or 3D) and largest d-spacing on "plasticity" and interparticulate bonding strength of the model systems—rivaroxaban (RIV), malonic acid (MAL) and 2:1 rivaroxaban-malonic acid cocrystal (RIV-MAL Co). In particular, we focus on how the materials deform when their crystal structures contain a single active slip plane system (RIV-MAL Co), more than one slip plane system (RIV) and devoid of active slip planes (MAL). In this study, the nanoindentation technique was employed to uncover "crystal level" deformation behavior, while "bulk level" deformation was studied using Compressibility-Tabletability-Compactibility (CTC) profiling. Slip plane systems were predicted by visualization as well as attachment energy calculations, and further experimentally confirmed by nanoindentation studies.
