Crystal Design Approaches for the Synthesis of Paracetamol Co-Crystals

Crystal engineering principles were used to design three
new co-crystals
of paracetamol. A variety of potential co-crystal formers were initially
identified from a search of the Cambridge Structural Database for
molecules with complementary hydrogen-bond forming functionalities.
Subsequent screening by powder X-ray diffraction of the products of
the reaction of this library of molecules with paracetamol led to
the discovery of new binary crystalline phases of paracetamol with trans-1,4-diaminocyclohexane (1); trans-1,4-di­(4-pyridyl)­ethylene (2); and 1,2-bis­(4-pyridyl)­ethane
(3). The co-crystals were characterized by IR spectroscopy,
differential scanning calorimetry, and 1H NMR spectroscopy.
Single crystal X-ray structure analysis reveals that in all three
co-crystals the co-crystal formers (CCF) are hydrogen bonded to the
paracetamol molecules through O–H···N interactions.
In co-crystals (1) and (2) the CCFs are
interleaved between the chains of paracetamol molecules, while in
co-crystal (3) there is an additional N–H···N
hydrogen bond between the two components. A hierarchy of hydrogen
bond formation is observed in which the best donor in the system,
the phenolic O–H group of paracetamol, is preferentially hydrogen
bonded to the best acceptor, the basic nitrogen atom of the co-crystal
former. The geometric aspects of the hydrogen bonds in co-crystals 1–3 are discussed in terms of their electrostatic
and charge-transfer components.