Revealing the Role of Structural Features in Bulk Mechanical Performance of Ternary Molecular Solids of Isoniazid.

Mechanical performance in ternary (3n) molecular solids has been rarely studied, and hence it is an interesting topic of investigation in the direct compression method of tableting. The structural features of 3n-eutectic (3n-Eu: INZ-ADP-NIC) and 3n-cocrystal (3n-Co: INZ:SUC:NIC) were explored to understand the bonding area-bonding strength (BA-BS) interplay. Higher compressibility and lower values of the Heckel parameter of 3n-Co as compared to 3n-Eu suggested its better deformation behavior, with BA being the predominant factor. The higher tensile strength and Walker analysis indicated a higher compressibility coefficient ( W) and lower pressing modulus ( L) for 3n-Eu, which was consistent with its better tabletability over 3n-Co. The higher compressibility and plastic energy, and higher value of L of 3n-Co, were attributed to the facile propagation (⟨-1' 0' 5'⟩) of the shearing molecular slip (-1 0 5) when subjected to the external mechanical stress. Thus, the overall higher tableting performance of 3n-Eu over 3n-Co was found due to the predominant BS and limited contribution of BA. The latter was the dominant factor in 3n-Co. Cohesive interactions, like the 3D mechanically interlocked structure of conglomerates of 3n-Eu, contributed toward the higher BS. Moreover, the prediction of better tabletability solely based on crystallographic feature slip planes (0D/1D/2D H-bonded layer (h k l) ⊥ vdW interactions) is warranted in pharmaceutical molecular solids. Eutectics with varying microstructural variants ( nLα + nLß + nLγ) may open up the opportunity to manipulate the physicomechanical performance.

Molecular Understanding and Implication of Structural Integrity in the Deformation Behavior of Binary Drug-Drug Eutectic Systems.

In eutectic, a lamellar microstructure offers better tableting than that of the nonreacted physical mixture. However, bulk deformation remains elusive in two binary eutectics. We hypothesized that the binary eutectic of a drug with different components, having different H-bonding dimensionalities and crystal structure, shall allow the understanding of the structural integrity in the bulk deformation behavior. The shearing molecular solid (FXT Q) shared a common composition with the viscoelastic crystal (ASP I) and brittle (PCM I), forming EM-1 (ϕ1 = 41.27:58.73% w/w) and EM-2 (ϕ2 = 41.10:58.90% w/w), respectively. The excess thermodynamic functions were contributed by high energy microstructures (nonbonding interactions) along incoherent phase boundaries (visualized under CLSM). The energy dispersive analysis enabled the recognition of the relative distribution of higher atoms over the heterogeneous surface. EM-1 (FXT Q-ASP I) demonstrated higher compressibility, tensile strength, and compactibility (CTC profile) compared to those of EM-2 (FXT Q-PCM I) over a range of applied compaction pressures. The lower true yield strength (σ0(EM-1) = 138.66 MPa) of EM-1 as compared to that of EM-2 (σ0(EM-2) = 166.66 MPa) suggested a better deformation performance and incipient plasticity quantified from the "out-of-die" Heckel analysis. From Ryshkewitch analysis, the tensile strength at zero porosity (τ01 = 3.83 MPa) was predicted to be higher for EM-1 than EM-2 (τ02 = 2.54 MPa). The higher bonding strength of EM-1 was contributed to the additional influence of true density and isotropic van der Waals interactions of ASP I (0D). In contrast, EM-2 demonstrated lower compressibility and compactibility, having herringbone molecular packing of PCM I (1D) with a common shearing component (FXT Q (1D)). This study confirmed that the intrinsic deformational and chemical nature of the second component defined the compressibility and compactibility tendency to a greater extent in the tableting performance of conglomerates of crystalline solid solution.