Polymorphism crystallization dynamics

The thermomicroscopic differentiation between two phases that are known to be related either by polymorphism or dynamic isomerism is elegantly straightforward. The two phases should be melted side by side between a microscope slide and a cover slip, and then allowed to crystallize. Two possibilities exist for the subsequent crystallization events. In the case of polymorphism, the crystal fronts from the two melts will grow at a constant velocity until they come into contact, at which point one phase will grow through the other, due to a solid-solid transformation to the stable phase at that temperature. In the case of dynamic isomerism, the two crystal fronts would slow down as they approach each other, and in the so-called zone of mixing (McCrone 1965) a eutectic could appear. 

H NMR spectroscopy combined with different techniques (see Section 4.05.3.6) has been used to perform the dynamic characterization of fananserin 35, an anxiolytic drug which can be crystallized as four different polymorphs. The dynamics were monitored by measuring the spin-lattice relaxation and line-shape evolution temperature dependence <2006MI798>. 

Within routine studies of new chemical entities, the initial focus is to explicate a comprehensive description of the drug. The aim is to provide specific information on its physical aspects such as morphological form, polymorphism, crystal habit and solvate state. This information is combined with data from other techniques such as dynamic vapour sorption (DVS), particle size analysis, XRPD (x-ray powder diffraction), solid state NMR, IR spectrophotometry and Raman spectroscopy. 

Parrinello M and Rahman A 1981 Polymorphic transitions In single crystals a new molecular dynamics method J. Appl. Phys. 52 7182-90... 

In 2007, in a very exhaustive paper, Paradies and coworkers carried out a comprehensive structural characterization of the colorless and yellow forms of Af-hydroxyphthalimide (NHPI) by means of single-crystal X-ray diffraction, FTIR and Raman spectroscopies and scanning electron microscopy. In the yellow form, the Af-hydroxyl group is significantly out of the plane (1.19°), but the Af-hydroxyl group in the colorless form is only 0.06° out of the plane. The irreversible conversion of the colorless crystalhne form to the yellow crystalhne form is more like a dynamic isomerism than a polymorphic transformation. 

PREFERENTIAL ENRICHMENT A DYNAMIC ENANTIOMERIC RESOLUTION PHENOMENON CAUSED BY POLYMORPHIC TRANSITION DURING CRYSTALLIZATION... 

Preferential Enrichment is a secondary phenomenon caused by a polymorphic transition occurring during crystallization from a highly supersaturated solution. This unique dynamic enantiomeric resolution phenomenon has proved to be observable for a fairly ordered racemic mixed crystal showing a polymorphism a solvent-assisted solid-to-sohd type of polymorphic transition from the kinetically-formed metastable crystalline phase comprising homochiral R and S chains into the thermodynamically stable crystalline phase consisting of a heterochiral 2D sheet structure during crystallization is responsible for this phenomenon. That is, it is essential that homochiral R and S ID chain structures are stable in solution while a heterochiral 2D sheet structure is stable in the crystal. 

It was found that is a function of temperature but the model was found to give a better fit than analytical expressions like the Avrami model or the modified Gompertz model (Kloek, Walstra and Van Vliet 2000). The main advantage of this model is that as it is formulated as a differential equation, it can be used to predict isothermal as well as dynamic crystallization. However, this model does not consider the polymorphism of the material which is a critical point in the crystallization of cocoa butter. Another contribution is the model of Fessas et al. (Fessas, Signorelli and Schiraldi 2005) which considers all the transitions possible between each... 

At first glance this definition seems straightforward. What are some of the complications For flexible molecules McCrone would include conformational polymorphs, wherein the molecule can adopt different conformations in the different crystal structures (Corradini 1973 Panagiotopoulis et al. 1974 Bernstein and Hagler 1978 Bernstein 1987). But this is a matter of degree dynamic isomerism or tautomerism... 

McCrone (1965) notes that polymorphs, existing only in the solid, can convert at least in one direction without going through the melt. On the other hand Curtin and Engelman (1972) observed that the equilibrium in melt or in solution between the two configurational isomers may be shifted by crystallization or by chemical reaction to form a derivative of one of the isomers. In solution, the two isomers will have different solubilities, in the same way that different polymorphs can have different solubilities (Sections 3.2 and 7.3.1). The solubility curves may cross, and with a change in temperature the solution can become saturated with one form. This is apparently what happens in the case of l-I, as the C form is obtained from the room temperature crystallization, while at lower temperatures, a mixture of A and B is obtained. Dynamic isomers exist in both the melt and the solid state. Each isomer can exist in polymorphic forms, which is true for forms B and C. Details on the experimental techniques and observations are given in Chapter 4. 

First, it is necessary to eliminate tautomerism or dynamic isomerism by determining that the two materials give identical melts. X-ray diffraction can determine that crystal strain (which can be mistaken for polymorphism) is not a factor. Then, McCrone... 

Gavezzotti, A., Flippini, G., Kroon, J., van Eijck, B. P. and Klewinghaus, P. (1997). The crystal polymorphism of tetrolic acid (CHsC CCOOH) a molecular dynamics study of precursors in solution, and in crystal structure generation. Chem. Fur. J., 3, 893-9. [183]... 

Some indirect experimental evidence exists for the liquid-liquid critical point hypothesis from the changing slope of the melting curves, which was observed for different ice polymorphs (30, 31). A more direct route to the deeply supercooled region, by confining water in nanopores to avoid crystallization, has been used more recently by experimentalists. These researchers applied neutron-scattering, dielectric, and NMR-relaxation measurements (32-35). These studies focus on the dynamic properties and will be discussed later. They indicate a continuous transition from the high to the low-density liquid at ambient pressure. The absence of a discontinuity in this case could be explained by a shift of the second critical point to positive pressures in the confinement. This finding correlated with simulations, which yield such a shift when water is confined in a hydrophilic nanopore (36). 

Unfortunately, a rigorous derivation of stochastic pure-state dynamics is still lacking. Nevertheless it is gratifying that such stochastic dynamics are important and in fact form the basis of a quantum theory of individual (quantum) objects. One hint in this direction comes from single-molecule spectroscopy (SMS), where single molecule always is to be understood as a single molecule embedded into a polymorphic matrix or a crystal.The example used in Fig. 9 is a single... 

M. Parrinello and A. Rahman,/. Appl. Phys., 52, 7182 (1981). Polymorphic Transitions in Single Crystals A New Molecular Dynamics Method. 

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