The solubility behaviour and thermodynamic relations of the three forms of Venlafaxine free base.

The polymorphic and solubility behaviour of the active pharmaceutical ingredient Venlafaxine free base, which is used as an antidepressant, is studied. Using differential scanning calorimetry and slurry experiments, an enantiotropic relation between the three forms was found. Transition temperatures were determined using solubility data and compared with calculated transition temperatures based on the melting enthalpies and temperatures of the different forms. The solubility of Venlafaxine in heptane, toluene and methanol shows a large deviation from ideal behaviour. The deviations are to a large extent determined by the temperature dependence of the difference in fusion enthalpy of the undercooled melt and the solid.

Experimental and computational morphology of three polymorphs of the free base of Venlafaxine: a comparison of morphology prediction methods.

In this paper the experimental and the computational studies of the morphology of three polymorphs of the free base of Venlafaxine ((N,N-dimethyl)-2-(1-hydroxy cyclohex-1-yl)-2-(4-methoxyphenyl) ethylamine) are reported. The morphology of all polymorphs has been predicted using the Bravais-Friedel-Donnay-Harker method, the attachment energy method and kinetic Monte Carlo growth simulations and these predictions have been compared with experimental observations. The Monte Carlo simulations allow for a detailed simulation of the growth process, including driving force and growth mechanism, which leads to a semi-quantitative prediction of the growth morphologies of all three phases. For phase I two distinct growth habits are found experimentally under the same conditions. This is explained by the occurrence of a spiral growth mechanism in one of the two, which was observed using AFM and which is also supported by the Monte Carlo simulations. The habit of phase II could only be explained from simulations when a spiral growth mechanism is assumed; the shape of phase III could not be modeled accurately from the Monte Carlo simulations. Although the shape of the crystal is reproduced accurately, some of the indices of the faces predicted are not in agreement with the indices measured. The deviations are interpreted to be due to the presence of domains in the crystals as a result of the layered structure.

Solubility of molecular crystals: polymorphism in the light of solubility theory.

The thermodynamic theory of solubility of molecular crystals in solvents is reviewed with an emphasis on solutes showing polymorphism as in case of many pharmaceuticals. The relation between solubility and binary phase diagrams of the solute solvent system is treated. The astonishing variety of possible solubility curves as a function of temperature is explained using simple models for the solution thermodynamics assuming no mixing between the solvent and solute in the solid phase, though including the case of solvates or pseudo polymorphs. In passing a new method is introduced that allows to estimate the transition temperature of enantiotropically related polymorphs from melting temperatures and enthalpies of the polymorphs.

Interlacing of growth steps on crystal surfaces as a consequence of crystallographic symmetry.

During crystal growth, concentric steps of unit-layer thickness [= dhklu with the surface's hkl Miller indices corrected according to the selection rules for non-primitive lattices] are often found to split into lower steps in a regular fashion [Frank (1951). Phil. Mag. 42, 1014-1021]. These 'interlaced' step patterns are introduced by a stacking of two or more growth layers, with different lateral anisotropy in step velocity within each unit layer. In this paper, a general relation between the symmetry of the crystal surface and the configuration of the concentric step patterns thereon is derived and is used to give theoretical shapes of spirals, growth hillocks and etch pits. It is shown that many of the interlaced patterns and their details are imposed by the presence of screw axes and/or glide planes perpendicular to the crystal surface. Finally, the results are compared with the patterns of unit-layer height and lower steps observed by optical and atomic force microscopy on crystals such as SiC, GaN, potash alum, garnet and NiSO4*6H2O.

On the prediction of crystal morphology. III. Equilibrium and growth behaviour of crystal faces containing multiple connected nets.

In this paper, the equilibrium and growth behaviour of faces (hkl) with more than one connected net is studied. It is shown that for these types of orientation different surface phases exist under equilibrium conditions as a function of temperature. Depending on the exact bonding topology at the surface, flat, rough or disordered flat phases are found. Moreover, the growth rate R(hkl) of such faces can differ significantly from the usually calculated relative growth rates based on the attachment energy. Monte Carlo simulations confirm the results from the Hartman-Perdok analyses and offer a tool for the prediction of the crystal habit as a function of supersaturation.