Exploring the Solubility of the Carbamazepine–Saccharin Cocrystal: A Charge Density Study

Abstract

Carbamazepine (CBZ) is used in the treatment of multiple neurological conditions. Although efficacious, its potential has been limited by its poor solubility, which means that patients are required to take very large doses to gain the desired effect. Co-crystals have been proposed as a means of improving the physicochemical properties of pharmaceutical compounds while maintaining their efficacy. CBZ cocrystallized with saccharin (SAC) and nicotinamide (NIC) have previously been studied, with the CBZ-SAC crystal being more soluble than the commercially available product Tegretol, which only contains CBZ, while the nicotinamide cocrystal was found to be less soluble. High-resolution X-ray crystallography has been carried out on the CBZ-SAC cocrystal and its individual constituents to determine which features of the electron density distribution contribute to the differing physical properties. The number of hydrogen bonds found for the CBZ, SAC, and CBZ-SAC systems were 8, 5, and 10, respectively. Homosynthons (interactions between a pair of identical functional groups) are the primary bonding motif in CBZ and SAC, while a heterosynthon is also present in the cocrystal. Molecular electrostatic potential (MEP) maps show that cocrystallization results in changes in distribution around the carboxamide group, thus accommodating heterosynthon formation and leading to subsequent charge redistribution across the CBZ molecule. Additional lattice energy calculations were not able to provide a definitive answer as to which system was most stable. Solid state entropy calculations revealed that the CBZ-SAC cocrystal had a higher entropy, providing explanations for the lower melting point and improved dissolution profile previously described. These investigations at an electronic level help to explain the greater solubility of the CBZ-SAC cocrystal compared to CBZ alone.

Hydrogen and chalcogen bonds in crystals of chalcogenadiazolecarboxylic acids – competition or cooperation?

“…The lower (the more negative) the value, the more stable and usually less soluble the crystal of a given compound, due to the greater amount of energy needed to break the interactions, although the dissociation process also releases some energy. 68…”

“…The lower (the more negative) the value, the more stable and usually less soluble the crystal of a given compound, due to the greater amount of energy needed to break the interactions, although the dissociation process also releases some energy. 68 During the characterisation of the final chalcogenadiazolecarboxylic acids we observed that 3 Se clearly differs in its physical properties from the other compounds. It has a much higher melting point (286-287 °C), which is relatively rare for an organic compound with such a low molecular weight, and additionally it has markedly reduced solubility in common organic solvents.…”

Enhanced luminescence of single-benzene fluorescent molecules through halogen bond cocrystals

“…In order to fundamentally understand the driving force behind the formation of the cocrystals, especially the electronic properties of the atoms involved in weak interactions, 31 the molecular electrostatic potential of DMCAT and the two co-formers were calculated and visualized by Multiwfn and VMD software, as shown in Fig. S3 †.…”

Crystal engineering, electron density analysis, andin situvariable temperature studies on co-crystal between nicotinic acid and gallic acid sesquihydrate

“…This is mainly due to the reason that co-crystals usually do not diffract to very high resolutions. There are few reports in the literature on the electron density analysis of co-crystals, such as nicotinamide-salicylic acid and oxalic acid, 36 melamine–barbital co-crystal, 37 piroxicam–saccharin co-crystal, 38 carbamazepine–saccharin co-crystal, 39 carbamazepine–aspirin co-crystal, 40 NAPY, 26 antipyrene-2,4 dihydroxy benzoic acid, 41 which highlight the significance of electron-density-based topological analysis in the co-crystal assembly. Highly diffracting co-crystals of NAGA allow a thorough multipolar modeling of the electron density to derive electrostatic properties.…”