Bis(paracetamol) pyridine – a new elusive paracetamol solvate: from modeling the phase diagram to successful single-crystal growth and structure–property relations

Abstract

Multi-component crystals -salts, co-crystals, or solvates -are usually designed based on the analysis of complementarity of functional groups and intermolecular interactions of the components. However, no crystal design can do without a practical method of crystal growth. Not all compounds that should be 10 expected to exist based on the "synthon approach" can be prepared in real experiments. This paper aims to illustrate that, in addition to the synthon approach, it is equally important to take into account phase diagrams when searching for practical methods of crystallising multi-component crystals, either as single crystals or as fine particles. Here, we describe the crystallization of bis(paracetamol) pyridine solvate from a glass-like metastable phase produced by quench-freezing of the paracetamol-pyridine solution 15 with subsequent low-temperature annealing. These procedures must be carried out strictly within the boundaries of the two-phase region "solid solvate + liquor", which was found only as a result of modelling the phase diagram. The crystal structure was solved by single-crystal X-ray diffraction and compared with co-crystals of paracetamol found in Cambridge Structural Database. The structureforming role of the intermolecular interactions and their characteristics were studied by variable-20 temperature experiments over the range of 100-275 K. This was compared with the structures of pure paracetamol polymorphs and other solvates and co-crystals at ambient and non-ambient conditions.

Pressure–Temperature Phase Diagrams and Transition Mechanisms of Hybrid Organic–Inorganic NH···N Bonded Ferroelectrics

“…High pressure can influence the course of crystallization of materials and the weak hydrogen bonds are relevant for the formation of new polymorphs or solvates. − For all dabco salts studied at high-pressure conditions, either new phases or solvates were formed. − Likewise, we have found that dabcoHBF 4 forms a hydrate at 1.06 GPa, when crystallized from water solution. No other solvates have been obtained, although recrystallizations of dabcoHBF 4 from methanol or ethanol or their 1:1 or 3:1 mixtures with water in isochoric conditions were tried.…”

Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

“…† Solvates of paracetamol have been reported in 1,4-dixoane 88 and pyridine. 89 Therefore, these solvents were excluded from the solvent screen as the target polymorph was the monoclinic form I.…”

Functional materials based on molecules with hydrogen-bonding ability: applications to drug co-crystals and polymer complexes

“…In both co-crystals, the 1D hydrogenbonded chains stack to form layered structures. Additional cases of synthon diversity with PCA have been demonstrated in other co-crystals and numerous hydrate and solvate structures [51][52][53][54][55][56].…”