Supersolubility measurement

To confirm the occurrence of the polymorphic transition predicted in the section 4 and to elucidate the mechanism, it is primarily necessary to clarify the enantiomeric assembly mode in the first-formed metastable crystal prior to the polymorphic transition and compare it with the stable crystal structure after the polymorphic transition with respect to a compound showing Preferential Enrichment. Since it is very possible that the stable molecular assembly structure in solution would be retained in the crystalline phase first-formed by crystallization from the same solvent,20 at first, we have investigated the enantiomeric association mode in solutions of the racemates showing Preferential Enrichment. Consequently, in our case, the variable temperature H NMR technique proved to be inapplicable to deciding which molecular association mode is more stable in solution, homochiral or heterochiral.21 Instead, the combined use of the solubility and supersolubility measurements under various conditions and the number-averaged molecular weight measurement by vapor pressure osmometry turned out to become a potent tool for this objective. 

When the nuclei of the precursor to be precipitated interact significantly with the surface of the support, the rate of precipitation is measurable at much lower concentrations. Accordingly it is possible to perform precipitation exclusively on the surface of the support by maintaining the concentration of the precursor between that of the solubility and supersolubility curve. Control of the concentration of catalytically active precursors within the above range is the basis of the deposition-precipitation procedure. With sparingly soluble solids, the concentration difference between the solubility and supersolubility curves is small. The concentration therefore has to be controlled fairly accurately. 

Interaction with the support is a prerequisite to achieve the desired dense and uniform coverage of the surface of the support with the precursor of the active component. Precipitation from a homogeneous solution without interaction with the support leads usually to relatively large precipitated crystallites. The interaction with the support can be easily assessed by measuring the pH as a function of time or of the amount of alkali injected both with and without a suspended support. If there is a significant interaction with the support. the level of the pH remains with a suspended support considerably below that of the pH measured without a suspended support. Without a support, the concentration of the supersolubility curve is often apparent from the pH curve passing through a maximum. 

Using this formula for a measured solubility at low temperatures immediately gives an idea about potential yield and about the feasibility of a cooling crystallization process. In the metastable zone no nucleation is observed even though the solution is supersaturated. Spontaneous nucleation will only occur when the supersolubility curve is reached. 

The supersaturation before the addition of seeds should be adjusted according to the solubility curve and the supersolubility curve (cf. Figure 10.2). Typically, seeding at 4—5 K below saturation temperature is fine. Of course, the metastable zone width has to be considered here and the seeding point should be closer to the solubility curve than to the supersolubility curve. It should be kept in mind that the metastable zone width is not thermodynamically determined, but strongly depends on plant properties and process parameters, such as cooling rate. If the metastable zone width is very narrow, for the sake of process robustness temperature control has to be improved or even an inline measurement of the supersaturation (e.g., by NIR) may have to be used to detect supersaturation close to the solubility curve and to avoid spontaneous nudeation or unwanted dissolving of the seed crystals. In such cases, special care has to be taken that no crystals are present in the crystallizer from the previous batch. 

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