Structure and Stability of Racemic and Enantiopure Pimobendan Monohydrates: On the Phenomenon of Unusually High Stability

Abstract

Study of structures and physicochemical properties of racemic (rac-H) and enantiopure (enant-H) hydrates of the active pharmaceutical ingredient pimobendan revealed that both hydrates have highly similar crystal structures and exhibit unusually high stability. Both structures contain identical two-dimensional layers and very similar conformations. The most significant difference is the stacking of these layers. The high stability of both hydrates appeared as extremely low solubility over a wide temperature range as well as an exceptionally high dehydration temperature and melting point. Study of the dehydration process showed that both hydrates have different activation energies of dehydration and kinetic model. Intermolecular interaction energy calculations showed that the dispersion interactions provide a highly significant stabilizing force in both pimobendan hydrates, while their exceptionally high stability can be associated with an efficient interplay between the hydrogen bonding and the dispersion interactions.

2-Mercaptoimidazolium halides: structural diversity, stability and spontaneous racemisation

“…3) suggests that the homochiral crystal shows a lower stability due to "weaker" stabilising intermolecular interactions and also due to a lower packing efficiency as is evident from the higher density of the racemic crystals. Thus, 6-hydroxy-1-methyl-1,5,6,7-tetrahydroimidazo[2,1b] [1,3]thiazinium chloride conforms to Wallach's rule as the racemic compound is denser than the enantiomeric crystal. 44 The relative stability difference between the homochiral and racemic crystals will be addressed in section 3.4.…”

“…The potential energy scans for the 6-hydroxy-1-methyl-1,5,6,7tetrahydroimidazo[2,1-b] [1,3]thiazinium cation, starting from two low energy ring conformations (Fig. 5a), and varying the H-O-C3-C4 dihedral angle (Fig.…”

“…1 Each of the three types of racemic solids can be polymorphic 2 or form solvates. 3 However, it is often not obvious whether two specific solidstate forms of a racemic mixture are polymorphs of the same type (e.g. two polymorphs of a racemic compound) or different types (e.g.…”

“…3 g (75 %) of (RS)-6-hydroxy-1-methyl-1,5,6,7tetrahydroimidazo[2,1-b][1,3]thiazinium bromide (1) as a white powder. Single crystals were obtained by slowly cooling a solution of compound 1 (100 mg) in a minimal amount of hot methanol to RT.…”

Investigation of the solid forms of deferasirox: solvate, co-crystal, and amorphous form

“…Different solid forms of active pharmaceutical ingredients (APIs) exhibit different physicochemical properties, such as morphology, thermodynamic property, 1 solubility, 2,3 dissolution rate, 4,5 and stability, 6,7 which affect the bioavailability, efficacy, and side effects of drugs. Therefore, scholars have focused on exploring novel solid forms of APIs, such as polymorphs, 8,9 solvates, 10,11 co-crystals, 12,13 salts, 4 and amorphous solids, 14,15 for drug development.…”