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This work describes the crystal structures of phenylbutazone 2:1 solvates with benzene, cyclohexane, 1,4-dioxane, tetrahydrofuran, tetrachloromethane, and chloroform. These solvates are isostructural, with the exception of the chloroform solvate. The solvent molecules are located in channels from which they can escape. Solvent incorporation causes an increase in volume of the unit cell to an extent that depends on the volume of the solvent molecule and the strength of the phenylbutazone-solvent interactions. The van der Waals interactions contribute most to the lattice energy in all these solvates. The volume available to the solvent correlates with the increase of the unit cell parameters. The quality of the crystallographic data of the chloroform solvate is poor as a result of twinning. Crystallographic differences of the chloroform solvate may result from hydrogen bonding between the chloroform molecules and the carbonyl oxygens of the phenylbutazone molecules.

The article describes the effect of degree of supersaturation, σ, on the crystallization of specific polymorphs of phenylbutazone from its methanolic solution at 20°C. At low initial supersaturation, σ ≤ 2.0, the fraction of the metastable α polymorph in the crystallized product exceeds that of the δ polymorph, while at σ ≥ 5.0, the fraction of the stable δ polymorph increases in the crystallized product. The results are explained by the effect of supersaturation on the relative rates of nucleation and crystal growth of the polymorphs. Furthermore, the mechanism of nucleation and crystal growth also change with supersaturation. Supersaturated methanolic solutions of phenylbutazone exhibit a critical temperature at which the nucleation rates of the polymorphs decrease drastically. This effect is partly explained by the decreased mobility of phenylbutazone molecules at lower temperatures. Nucleation is most rapid when the crystallization temperature is close to the transition temperature, T t (α↔δ), between the polymorphs, α and δ. The nucleation rate decreases as the temperature difference between T t (α↔δ) and the crystallization temperature increases.

A new method is developed to estimate the time of onset of nucleation from supersaturated solutions using molecular dynamics simulation and knowledge of the solubility of the solute and the density of the saturated solution. Calculations are based on the dynamics of pairs of solute molecules at extreme supersaturations instead of dynamics of molecular aggregates at practical supersaturations. First, the characteristic radial distance (CRD) specific to each solute-solvent system is identified. Next, the time evolution of the radial distribution function (RDF), g(r), at CRD is evaluated. The onset of the nucleation is taken as the time after which g(r) at the CRD remains constant. Finally, the estimated relative nucleation times are compared with those measured experimentally. The calculated and experimental nucleation times in various solvents are related linearly and by rank order. However, the ratio of the calculated to the experimental nucleation time is on the order of 10 -16 for sulfamerazine and 10 -14 for phenylbutazone. This discrepancy arises from the underlying assumptions that are necessarily imposed by the limitation in the number of atoms the computation can treat.

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