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.