Abstract
The present work aims to understand the crystallographic basis of the mechanical behavior of rivaroxaban-malonic acid cocrystal (RIV-MAL Co) in comparison to its parent constituents, i.e., rivaroxaban (RIV) and malonic acid (MAL). The mechanical behavior was evaluated at the bulk level by performing “out of die” bulk compaction and at the particle level by nanoindentation. The tabletability order for the three solids was MAL < RIV < RIV-MAL Co. MAL demonstrated “lower” tabletability because of its lower plasticity, despite it having reasonably good bonding strength (BS). The absence of a slip plane and “intermediate” BS contributed to this behavior. The “intermediate” tabletability of RIV was primarily attributed to the differential surface topologies of the slip planes. The presence of a primary slip plane (0 1 1) with flat-layered topology can favor the plastic deformation of RIV, whereas the corrugated topology of secondary slip planes (1 0 2) could adversely affect the plasticity. In addition, the higher elastic recovery of RIV crystal also contributed to its tabletability. The significantly “higher” tabletability of RIV-MAL Co among the three molecular solids was the result of its higher plasticity and BS. Flat-layered topology slip across the (0 0 1) plane, the higher degree of intermolecular interactions, and the larger separation between adjacent crystallographic layers contributed to improved mechanical behavior of RIV-MAL Co. Interestingly, a particle level deformation parameter H/E (i.e., ratio of mechanical hardness H to elastic modulus E) was found to inversely correlate with a bulk level deformation parameter σ0 (i.e., tensile strength at zero porosity). The present study highlighted the role of cocrystal crystallographic properties in improving the tabletability of materials.
Highlights
Oral solid dosage forms represent the most popular delivery system amongst various pharmaceutical dosage forms, as they offer many benefits in terms of cost, stability, ease of handling, and patient compliance [1]
Increased bonding area (BA) is achieved on irreversible deformation of organic molecular solid and this deformation behavior is known as plasticity [21]
We reveal the role of crystallographic features such as slip planes, slip plane topology, intermolecular interactions 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)
Summary
Oral solid dosage forms (such as tablets and capsules) represent the most popular delivery system amongst various pharmaceutical dosage forms, as they offer many benefits in terms of cost, stability, ease of handling, and patient compliance [1]. Many reports suggest 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. 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]. Nanoindentation is useful for interpolation of particle-level behavior to crystallographic features [30], thereby furthering our understanding of crystal structure-mechanical property relationships. Fgoenr enraanteodin,daenndtattiohne ecxrpyesrtaimllieznattsi,ornelamtievtehloydlaorlgoegry-sifzoerd scarmysetalhsas been were gentheroartoeudg,halnyddtihsceucsrsyesdtailnlizoautriornecmenetthpoudbolilcoagtyiofnor[1s0a]m. e has been thoroughly discussed in our recent publication [10]
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