1:1 and 2:1 Urea−Succinic Acid Cocrystals: Structural Diversity, Solution Chemistry, and Thermodynamic Stability

Abstract

The aim of this work was to study the crystal structures of 1:1 and 2:1 urea−succinic acid (U-SA) cocrystals and to investigate the role of solution chemistry in the formation and stability of different stoichiometric cocrystals. The structural diversity of other urea−dicarboxylic acid cocrystals is also discussed. The 1:1 U-SA cocrystal was stabilized by an acid−amide heterosynthon while acid−amide heterosynthons and amide−amide homosynthons stabilized the 2:1 cocrystals. The hydrogen bonding motifs in 1:1 and 2:1 U-SA cocrystals were consistent with other urea−dicarboxylic acid systems with similar stoichiometries. The 1:1 cocrystals were transformed to 2:1 cocrystals upon slurrying in various solvents at 25 °C. The phase solubility diagram was used to define the stability regions of different solid phases in 2-propanol at 25 °C. While no phase stability region for 1:1 cocrystal could be found, the stable regions for the 2:1 cocrystals and their pure components were defined by eutectic points. The solubility of the 2:1 cocrystals was dependent on the concentration of the ligand in the solution and explained by the solubility product and 1:1 solution complexation. The mathematical models predicting the solubility of the 2:1 cocrystals were evaluated and found to fit the experimental data.

Hydrogen Bond Synthons in the Interplay of Solubility and Membrane Permeability/Diffusion in Variable Stoichiometry Drug Cocrystals

“…14 The effects of crystallization solvent on the composition of urea•succinic acid (1:1 & 2:1) cocrystals has been demonstrated. 20,21 The solid stoichiometric interconversion, solvent-mediated conversion for pyrazinamide•pnitrobenzoic acid with two stoichiometric cocrystals in 1:1 and 2:1 ratio are also reported. 15 -III IC CC-VI Dioxane 1:1 IC IC IC 1:2 IC IC IC 2:1 IC IC IC Diethyl ether 1:1 IC IC IC 1:2 IC IC IC 2:1 IC IC IC Dichloromethane 1:1 IC CC-V VI 1:2 IC CC-V* CC-VI* 2:1 IC CC-V* CC-VI* Chloroform 1:1 IC CC-V* IC 1:2 IC CC-V* IC 2:1 IC CC-V* IC Acetone 1:1 IC IC IC 1:2 IC IC IC 2:1 IC IC IC Acetic acid 1:1 IC IC IC 1:2 IC IC IC 2:1 IC IC IC Tetrahydrofuran 1:1 IC IC IC 1:2 IC IC IC 2:1 IC IC IC 1-Propanol 1:1 CC-I CC-V CC-VI …”

Co-crystal/salt crystal structure disorder of trichloroacetic acid–N-methylurea complex with double system of homo- and heteronuclear O–H···O/N–H···O hydrogen bonds: X-ray investigation, ab initio and DFT studies

“…There are known many acid-urea multicomponent crystal structures among them are neutral complexes and ionic structures as well [35][36][37][38][39][40][41][42]. Moreover, the urea is of interest in experimental and theoretical investigations because of simplicity of its molecule [43][44][45][46], interesting highly symmetrical crystal structure [47,48] or physical properties [49,50].…”

Two Isostructural Explosive Cocrystals with Significantly Different Thermodynamic Stabilities

“…Furthermore, DADP/TBTNB failed to form reliably via many commonly employed crystallization methods, such as solvent-mediated transformation (slurries). [15] The behavior of DADP/TBTNB demonstrates it to be unstable relative to its pure components under equilibrium conditions at room temperature. Though incongruently saturating systems can complicate the behavior of cocrystals in slurry, [13] the behavior of DADP/TBTNB is distinct in that the cocrystal disappeared completely in the slurry and both pure components emerged; this indicates that there is no region of cocrystal stability on the DADP-solvent-TBTNB phase diagram at room temperature.…”

“…To our knowledge no cocrystal has been reported previously that is unstable relative to the pure solid forms of its components. [15] The behavior of DADP/TBTNB demonstrates it to be unstable relative to its pure components under equilibrium conditions at room temperature. DADP, TBTNB, and seeds of DADP/TBTNB were each added to vials and sealed beneath solutions co-saturated with both DADP and TBTNB in various solvents (see Supporting Information).…”