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

Abstract

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.

Identification of a new cocrystal of citric acid and paracetamol of pharmaceutical relevance

“…18 Also, Myz et al have studied a 1 : 1 citric acid-meloxicam cocrystal. 19 A number of paracetamol cocrystals have been reported to date; [20][21][22] Lemmerer et al have studied cocrystal of citric acid and nicotinamide formation of four hydrogen bonding heterosynthons in one cocrystal; 23 Schantz et al have studied citric acid anhydrous and paracetamol, prepared as crystalline physical mixtures using solid-state NMR, 24 but a systematic synthesis and vibrational spectroscopy characterization of the citric acid-paracetamol (CIT-Pa) cocrystal have not to our knowledge been studied hitherto.…”

Etching patterns on the monoclinic and orthorhombic paracetamol

“…20 This can explain why during etching of paracetamol by morpholine and methylmorpholine the reaction front is directed normally to [001]. During etching of paracetamol II, the differences in the shapes of the etching pits formed at the faces parallel to the molecular layers, and the sharpness of their angles, are less pronounced, due to weaker hydrogen bonds 18 and, hence, a lower selectivity of dissolution and a less pronounced anisotropy of etching. The almost square shape of the etching pits formed at the face normal to the molecular layers, in case of etching paracetamol II with dioxane, morpholine, and methylmorpholine (molecules with the two donor centers) reflects the location of the neighbouring paracetamol molecules at the face (110) of paracetamol II activated during dissolution.…”

“…, 3 the anisotropy of structure compression on cooling 14 and with increasing hydrostatic pressure 8,15,16,17,18 were considered.…”

Pharmaceutical Cocrystals: An Overview

“…High temperature stress can also be used to predict the physical and chemical stability based on accelerated stability conditions. Few researchers reported about thermal stability [49,50] . Paracetamol cocrystals with 4,4-bipyridine showed the better stability than other coformers upon heating by DSC [49] .…”

“…Few researchers reported about thermal stability [49,50] . Paracetamol cocrystals with 4,4-bipyridine showed the better stability than other coformers upon heating by DSC [49] . Thermal stability of cocrystals (L-883555, a phosphodiesterase IV inhibitor) with tartaric acid was studied in different stoichiometries ranging from 0.3:1.0 to 0.9:1.0.…”