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

Abstract

Cocrystals have been increasingly recognized as an attractive alternative delivery form for solid drug products. In this work, Raman spectroscopy, X-ray powder diffraction/X-ray crystallography, and differential scanning calorimetry have been used to study the phenomenon of cocrystal formation in stoichiometric mixtures of citric acid with paracetamol. Raman spectroscopy was particularly useful for the characterization of the products and was used to determine the nature of the interactions in the cocrystals. It was observed that little change in the vibrational modes associated with the phenyl groups of the respective reactants took place upon cocrystal formation but changes in intensities of the vibrational modes associated with the amide and the carboxylic acid groups were observed upon cocrystal formation. Several new vibrational bands were identified in the cocrystal which were not manifest in the raw material and could be used as diagnostic features of cocrystal formation. An understanding of the effects of cocrystal formation on the vibrational modes was obtained by the complete assignment of the spectra of the starting materials and of the cocrystal component. The results show that the cocrystals was obtained in a 2 : 1 molar ratio of paracetamol to citric acid. The asymmetric unit of the crystal contains two paracetamol molecules hydrogen-bonded to the citric acid; one of these acts as a phenolic-OH hydrogen bond donor to the carbonyl of a carboxylic acid arm of citric acid. In contrast, the other phenolic-OH acts as a hydrogen bond acceptor from the quaternary C-OH of citric acid.

Synthesis and structure of a 1:1 co-crystal of hexamethylenetetramine carboxyborane and acetaminophen

“…The first is an N6-H6NÁ Á ÁO1 hydrogen bond (HÁ Á ÁO = 2.00 Å ) found between the N-H group of acetaminophen and the C=O acceptor from CORCB-1-APAP. This type of bond has been previously reported in the acetaminophen co-crystal with citric acid (Elbagerma et al, 2011). Pure acetaminophen crystals typically only form hydrogen bonds between N-HÁ Á ÁO-H and O-HÁ Á ÁO=C.…”

Rational Coformer or Solvent Selection for Pharmaceutical Cocrystallization or Desolvation

“…Thus, a screening is done for several hundred compounds within minutes. Figure 3 shows an enrichment plot (rocking plot) for both drugs which have been screened against this list including known coformers of paracetamol 42,48,49,50,51 and meloxicam. 40,52,53 The plot has been generated just by ordering the results according to the excess enthalpy H ex of each API conformer pair.…”

Insight into Concept and Progress on Pharmaceutical Co-Crystals: An overview

“…P-Hydroxyacetanilide (paracetamol PA) is the most popular API used as analgesic 183,184 which exhibits poor compatibility and belongs to BCS Class-III. 185 PA cocrystals formed with different co-formers PA-Pherazine, 186 PA-trimethyl glycine, 187 PA-citric acid 188 and others 189 results in improved physiochemical, mechanical and pharmaceutical properties. Ethenzamide (2-etoxy benzamide, ET) is a commonly used non-steroidal anti-inflammatory drug belongs to BCS Class-II, whose water solubility is low and some of the modifications may improve the property.…”