Paracetamol Molecules Research Articles

Variable temperature (100–360 K) single-crystal X-ray diffraction study of the orthorhombic polymorph of paracetamol (p-hydroxyacetanilide)

Abstract The crystal structure of the orthorhombic polymorph of paracetamol was refined in Pbca space group by single-crystal X-ray diffraction at 100, 200, 300, 360 K. Cell parameters were measured in the range between 100 and 360 K. The anisotropy of lattice strain on cooling was analysed and compared with that induced by increasing pressure. The data for the orthorhombic paracetamol were compared also with the results previously reported for the monoclinic form of the same compound. The bulk thermal expansion coefficient of the orthorhombic polymorph is larger than that for the monoclinic form. Maximum compression on cooling was observed in the direction normal to the molecular layers. The structure expanded slightly on cooling in the crystallographic a -direction. Relative compressibility of OH…O and NH…O intermolecular hydrogen bonds on cooling, as well as the changes in the intramolecular geometry of paracetamol molecules and the atomic displacement parameters were measured and analysed.

Rationalisation of Co-Crystal Formation Through Knowledge-Mining

The crystal structures of five hemiadducts of paracetamol and a related 1:1 adduct of paracetamol are described. All structures are characterised by the formation of chains of paracetamol molecules, linked either via OH-… O=C interactions [C(9) chains in graph set notation] or NH… O=C interactions [C(4) chains], depending on the presence or absence of substituent groups on the guest molecule. Throughout the series the structural rearrangement due to each guest molecule can be followed by comparison of H-bond strengths with those in the Cambridge Structural Database. In addition, the role of both molecular and space group symmetry in crystal formation can now be investigated with the help of a new relational database from the CCDC, CSD symmetry.

The formation of paracetamol (acetaminophen) adducts with hydrogen-bond acceptors.

The crystal structures of five hemiadducts of paracetamol with 1,4-dioxane, N-methylmorpholine, morpholine, N,N-dimethylpiperazine and piperazine and a related 1:1 adduct of paracetamol with 4,4'-bipyridine are described. All structures are characterized by the formation of chains of paracetamol molecules, which are linked via either OHtriplebondO=C interactions [C(9) chains in graph-set notation] or NHtriplebondO=C interactions [C(4) chains], depending on the presence or absence of substituent groups on the guest molecule. In all cases except for the morpholine and bipyridine adducts these chains are connected by hydrogen-bond interactions with the guest molecules, which reside on crystallographic inversion centres. In the bipyridine adduct this linkage also involves a pi-stacking interaction; in the morpholine adduct it is formed between the OH groups of two opposed paracetamol molecules. Most adducts (that with 4,4'-bipyridine is an exception) decompose on heating to give monoclinic paracetamol. This is the first systematic study of a series of co-crystals containing paracetamol.

Spectroscopic characterisation of the monoclinic and orthorhombic forms of paracetamol

The metastable orthorhombic form of paracetamol was prepared from the melt of the commercially available monoclinic form. Distinct differences were observed in the infrared spectra of both forms, especially in the region 1260–1225 cm −1, in which is observed three strong absorptions of approximately equal intensity in spectra of the monoclinic form, and two absorptions, one strong and one medium, in spectra of the orthorhombic form. No diagnostically useful differences were observed in the Raman spectra of the two forms. A 13C CP/MAS solid-state NMR spectrum of the monoclinic form and a spectrum of a mixture of forms prepared from a melt were obtained. A spectrum of the orthorhombic form was obtained from these spectra by difference spectroscopy. The spectra show that the carbons in the paracetamol molecules are all in unique chemical environments in both crystalline forms, and that clear well-resolved differences in the chemical shifts of particular carbons in both forms can be observed.

Molecular mobility of the paracetamol amorphous form.

The purpose of this paper is to study the molecular mobility of paracetamol molecules in their amorphous state below the glass transition temperature (Tg) in order to evaluate the thermodynamic driving force which allows the amorphous form to recrystallize under different polymorphic modifications. Samples were aged at temperatures of -15, 0, 6, and 12 degrees C for periods of time from 1 h to a maximum of 360 h. The extent of physical aging was measured by a DSC study of enthalpy recovery in the glass transition region. The onset temperature of glass transition was also determined (Tg). Enthalpy recovery (deltaH) and change in heat capacity (deltaCp) were used to calculate the mean molecular relaxation time constant (tau) using the empirical Kohlausch-Williams-Watts (KWW) equation. Enthalpy recovery and onset glass transition temperature increased gradually with aging and aging temperatures. Structural equilibrium was reached experimentally only at an aging temperature of 12 degrees C (Tg-10 degrees C), according to the deltaH(infinity) results. The experimental model used is appropriate only at lower aging temperatures, while at higher ones the complexity of the system increases and molecular polymorphic arrangement could be involved. When structural equilibrium is experimentally reached, molecules can be arranged in their lowest energy state, and the polymorphic form I formation is the one preferred.