Tudor Grecu

Cocrystal formation is considered as one of the most effective solid-state methods to alter the physicochemical properties of active pharmaceutical ingredients (APIs). In silico methods for cocrystal prediction are mostly based on structural and energetic considerations. We have developed a computational method that ranks the probability of cocrystal formation of APIs with large databases of crystal coformers (CCFs). This approach is based on using molecular electrostatic potential surfaces to… Mehr anzeigen

Cocrystal formation is considered as one of the most effective solid-state methods to alter the physicochemical properties of active pharmaceutical ingredients (APIs). In silico methods for cocrystal prediction are mostly based on structural and energetic considerations. We have developed a computational method that ranks the probability of cocrystal formation of APIs with large databases of crystal coformers (CCFs). This approach is based on using molecular electrostatic potential surfaces to assess molecular complementarity between two cocrystal components. The screening tool was applied to two low solubility drugs, namely griseofulvin and spironolactone. Promising coformer candidates were selected from a database of 310 pharmaceutically acceptable CCFs, and experimental screening was carried out. Novel solid forms were obtained by liquid-assisted grinding and were characterised by XRPD, DSC, TGA and IR. One new cocrystal of griseofulvin and two new cocrystals of spironolactone were identified, and the crystal structures were determined from the XRPD patterns. For these systems, phenols tend to act as successful H-bond donors in forming cocrystals, while carboxylic acids only give rise to physical mixtures of the two components. Weniger anzeigen

Formulation of solids as cocrystals offers an opportunity to modulate physical properties, so identification of cocrystal formers (CCFs) for an active pharmaceutical ingredient is an area of significant interest. Exhaustive experimental screening would be time-consuming, but we have developed a computational method for identifying CCFs that have a high chance of success based on calculated functional group interaction energies. This virtual screening tool has been applied to nalidixic acid… Mehr anzeigen

Formulation of solids as cocrystals offers an opportunity to modulate physical properties, so identification of cocrystal formers (CCFs) for an active pharmaceutical ingredient is an area of significant interest. Exhaustive experimental screening would be time-consuming, but we have developed a computational method for identifying CCFs that have a high chance of success based on calculated functional group interaction energies. This virtual screening tool has been applied to nalidixic acid cocrystals. Calculations on a library of 310 compounds identified the 44 most promising CCFs for formation of nalidixic acid cocrystals. Six of these compounds were already known to form cocrystals, and experimental work was undertaken on the remaining 38 compounds. X-ray powder diffraction (XRPD) of mixtures obtained from grinding experiments identified seven CCFs that form new solid phases with nalidixic acid. Infrared spectroscopy and differential scanning calorimetry confirm that these new solid phases are different from the pure components. Further structural characterization was not possible for the skatole, 2,4-dihydroxybenzoic acid, and 3,4-dihydroxybenzoic acid cocrystals, but X-ray crystal structures were obtained from single crystals of the 1:1 tert-butylhydroquinone cocrystal and of the 1:1 propyl gallate cocrystal and from the XRPD pattern for the 1:1 2-phenylphenol cocrystal and for the 1:2 indole cocrystal. The results suggest that success rates in cocrystal screening can be significantly improved by application of computational filters to select the most appropriate CCFs for experimental study. Weniger anzeigen