From molecular crystals to salt co-crystals of barbituric acid via the carbonate ion and an improvement of the solid state properties

Co-crystals formed by neutral barbituric acid (HBA) molecules and alkaline barbiturate salts have been prepared by solvent-free mechanochemical treatment of solid HBA and alkaline carbonates or bicarbonates. During the reaction the carbonate salts release CO2 and H2O, affording the corresponding barbiturate salts which then co-crystallize with the neutral molecule. These "salt co-crystals" have the general formula M x+(BA-)x\ub7HBA\ub7nH 2O with (M = Na and K). The compounds can be obtained in a single step, by directly grinding HBA with M2CO3 (4:1 ratio) or MHCO3 (2:1 ratio), or, alternatively, in two steps: the preparation of the BA salt followed by a further grinding process or crystallization of the resulting salts with a stoichiometric amount of neutral HBA. All compounds have been characterized by means of single-crystal and powder XRD, solid-state NMR (1H MAS, 13C and 15N CPMAS), vibrational spectroscopies and thermal methods (DSC and TGA). A series of BA- salts (either hydrated or anhydrous) of formula Mx +(BA-)x\ub7nH2O (M = Na, K, Mg and Ca) have also been prepared and reported for comparison

Using salt cocrystals to improve the solubility of niclosamide

This Article reports the solvent-free synthesis and characterization of a number of different crystal forms of niclosamide (HNic), which is an API belonging to the Salicilamide class. The synthesized compounds are four new salt cocrystals (KNic.HNic.H2O, KNic.HNic.3H(2)O, NaNic.HNic.3H(2)O, NaNic.HNic.2H(2)O), a classic cocrystal with imidazole (IM) (HNic.IM), and two sodium salts, (NaNic.DMSO.H2O and NaNic.DMSO.2H(2)O). The peculiarity of these salt cocrystals is the APIs concomitant presence as both a neutral component and as a salt coformer and the fact that they interact via hydrogen bond formation. HNics poor aqueous solubility makes the enhancement of its dissolution rate via the modulation of its physical properties extremely important. All samples have been investigated using a combination of solid-state experimental techniques which provide complementary information on powdered samples. These techniques are X-ray powder diffraction, solid-state NMR, IR, and Raman. Single crystals were only obtained for KNic.HNic.H2O and NaNic.DMSO.2H(2)O. The nature of the adducts (whether salt or cocrystal), their stoichiometry and the presence of independent molecules in the unit cell of the other samples were thus all determined by means of solid-state NMR and the comparative analysis of C-13 and N-15 CPMAS (Cross-Polarization Magic Angle Spinning) and 1H MAS spectra. Furthermore, differential scanning calorimetry, thermogravimetric analysis and intrinsic dissolution rate measurements completed the characterization and enabled us to evaluate the effects of microscopic changes (molecular packing, weak interactions, conformations, etc.) on the macroscopic properties (thermal stability and bioavailability) of the multicomponent forms. The results obtained indicate that the formation of salt cocrystals provides a reliable method with which to improve the HNic intrinsic dissolution rate