The Role of Cocrystallization-Mediated Altered Crystallographic Properties on the Tabletability of Rivaroxaban and Malonic Acid

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.

Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs

“…It is important to improve the oral bioavailability of RIV to reduce dosing frequency and thus to improve patient compliance. Recently, several techniques have been utilized to improve the solubility and bioavailability of RIV such as cocrystals ( Kale et al, 2020 ), amorphous solid dispersions ( Metre et al, 2018 ), microemulsions ( Wingert et al, 2018 ), self-nanoemulsifying drug delivery system ( Xue et al, 2018 ), and micelles ( Cao et al, 2016 ). Among these strategies, cocrystals have attracted great interest and are a promising strategy to modify the physical-chemical properties of solid-state materials.…”

“…RIV is a Biopharmaceuticals Classification System (BCS) Class II drug with low oral bioavailability ( Kushwah et al, 2021 ). Rivaroxaban-malonic acid cocrystal (RIV-MAL) could improve the tabletability and increase the water sorption of RIV ( Kale et al, 2020 ; Kale et al, 2019 ). However, to the best of our knowledge, the study and application of improved permeability and bioavailability of RIV by cocrystals has not yet been reported ( Grunenberg et al, 2011 ).…”

Enhancement of Dissolution Rate and Bioavailability of Nifedipine by Chitosan Based Cocrystallization Technique

“…There are various practical approaches to improve the solubility of these include the use of particle size manipulation via micronization and nanonization, use of complexing agents such as cyclodextrins. The preparation of high energy drug states related to polymorphic or amorphic transformations use of co-solvents, micellar solutions and lipid based systems for lipophilic drugs are also one of the techniques to improve the solubility behaviour [8,9].…”

The crystal packing and slip plane analysis in mechanical properties improvement of mefenamic acid by cocrystallization with nicotinamide coformer

“…Some researchers investigated a relationship between crystal structure and mechanical properties [13][14][15][16][17][18][19][20]. Kale et al reported a better tableting performance of rivaroxaban-malonic acid (2:1) cocrystal than that of rivanoxaban due to the presence of flat slip plane that enhances the plasticity of rivaroxaban-malonic acid cocrystal [21]. To continue to improve the solubility of the current cocrystal, herein we reported the performance of the mechanical properties of mefenamic acid (MFA) : nicotinamide (NIC) cocrystal.…”