A combined approach using differential scanning calorimetry with polarized light thermomicroscopy in the investigation of ketoprofen and nicotinamide cocrystal

Abstract

A screening of ketoprofen cocrystal with nicotinamide as a coformer was performed using the Kofler contact method and mechanochemistry. The crystallization of KET (with cocrystal formation) can occur during the heating process. However, although it is thermodynamically favorable, it was found that the kinetic reactions were slow, since the KET crystallization took about 30 days. The compounds obtained were analysed by differential scanning calorimetry (DSC), polarized light thermomicroscopy (PLTM), Fourier transform infrared spectroscopy (FTIR), and X-ray powder diffraction (XRPD). Cocrystal formation between ketoprofen and nicotinamide has great interest because the nicotinamide has FDA/GRAS status. At the adopted conditions, the achievement of cocrystal between ketoprofen and nicotinamide was not possible by mechanochemical methods However, experiments conducted by the Kofler method confirmed that ketoprofen interacted, under determined conditions, with nicotinamide giving rise to a new cocrystal. Furthermore, biological tests revealed that the KET + NA (1:1) eutectic system obtained by grinding had a greater anti-inflammatory action when compared to pure ketoprofen.

Co‐crystal Prediction by Artificial Neural Networks**

“…Members of the green, pink and blue clusters are classified as co-crystals with ahigh likelihood of actual formation, and relatively strong intermolecular interactions can indeed be imagined with ketoprofen. In fact, although lacking af ull structural characterization, it was reported by PerpØtuo et al [70] that ketoprofen and nicotinamide (green cluster, prediction value of 0.996) form aco-crystal using the Koffler method (as analyzed by polarized light thermal microscopy and FTIR), supporting the validity of our predictions.Smaller prediction values are found for the cyan cluster (on average 0.75). While the majority of the models of the ensemble recognize p-p-interactions between the clustersm olecules and ketoprofen, predictions with as maller confidence are returned.…”

Investigation and characterization by TG/DTG–DTA and DSC of the fusion of Riboflavin, and its interaction with the antibiotic norfloxacin in the screening of cocrystal

“…A cocrystal can be defined as a multicomponent crystalline solid bound by non-covalent interactions, mainly hydrogen interactions. Its aim is to improve the physicochemical properties of organic compounds, such as medications [8][9][10]. The mechanochemical method, solventassisted grinding, consists of grinding the components in the solid state with a few microliters of solvent, which acts on the kinetics of the interaction reaction between the reactants [11].…”

Hot stage microscopy and its applications in pharmaceutical characterization

“…"Birefringence is defined as the double refraction of light in a transparent, molecularly ordered material, which is manifested by the existence of orientation-dependent differences in refractive index". Amorphous compounds lack birefringence (Bergstrom 2015;Murphy et al 2019), hence can be easily distinguished from crystalline compounds. Figure 2 shows the birefringence pattern exhibited by salicylic acid:benzamide cocrystal (Zhou et al 2016).…”

“…Maria Kuhnert-Brandstätter was the first to use thermal microscopy in the field of pharmaceuticals (Stieger et al 2012). Welch in 1950s constructed a hot stage microscope with photographic capabilities (Panna et al 2016). McCrone played a very important role in further development of thermal microscopy, improving its precision and popularity (McCrone 1957;Kilbourn and McCrone 1985;McCrone et al 1993).…”

“…Perpétuo et al (Perpétuo et al 2017 ) also used a similar approach in which they melted nicotinamide and allowed it to solidify, after that melted ketoprofen was brought into the contact of solidified nicotinamide and the whole material was then kept into a desiccator for 30 days. It was also observed that ketoprofen:nicotinamide cocrystals could not be grown through conventional methods such as solvent evaporation or grinding, cocrystallization was only possible thermally.…”