The model-based estimation of primary nucleation rates from the probability distribution of induction time measurements has been used extensively in the literature; however, there has been no experimental validation of this approach via direct measurements of nucleation rates. In this work, we compared the nucleation rates obtained from the probability distribution model against that measured from in situ optical reflectance measurement (ORM) with p-aminobenzoic acid and l-glutamic acid as model compounds. Results reveal that the primary nucleation rates obtained from stochastic models are several orders of magnitude lower than those measured from a direct particle-counting technique. Although differences in fluid dynamics due to agitation and crystallizer geometry may have an effect, this tremendous discrepancy provides strong evidence that primary nucleation rates obtained from induction time measurements are not scalable and should not be used for interpretation of nucleation rates in industrial applications.

Three approaches for estimation of nucleation rates from induction time and metastable zone width (MSZW) were validated based on directly measured nucleation rates for paracetamol in ethanol. To quantitatively predict nucleation kinetics using Kubota's methods it is necessary to know the minimum detectable number concentration of nuclei. This was found by determination of light transmission of a series of diluted suspensions of newly nucleated crystals where the size had already been assessed by optical reflection measurement (ORM). The measured nucleation rates strongly depended on both temperature and supersaturation. The Nyvlt method predicted nucleation rates in this system reasonably well; however, it gave slightly low estimates for all temperatures. The methods of Kubota provided nucleation rates that were low by an order of magnitude.

The phase diagrams of tetragonal hen egg white lysozyme containing besides thermodynamic (solubility) also kinetic (nucleation) data were determined for pH values of 4.4, 5.0, and 6.0, 3 to 7 wt % sodium chloride concentrations and lysozyme concentrations from 5 to 70 mg/mL by the use of a turbidity technique. This new technique offers a rapid, precise and reliable determination of nucleation and solubility points. These points can be obtained simultaneously within 6 h. The errors of measurements are less than ±0.9 °C for the solubility temperature and less than ±1.0 °C for the nucleation temperature. The solubility data obtained could be extended and described by a good correlation with literature data. The solubility of lysozyme was found to decrease with increasing salt concentration while the nucleation points were observed more early with respect to salt addition; as a consequence the metastable zone is more narrow. The solubility of lysozyme is slightly reduced at higher values of the pH, and the nucleation point is observed later in time. The result is an increase of the metastable zone width.

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The solubility, secondary nucleation threshold, and growth kinetics of (RS)-ibuprofen have been studied in an aqueous ethanol solvent. The metastable zone for secondary nucleation is very narrow at lower temperatures in this range, but greatly enlarged at higher temperatures. The crystal growth kinetics not only display significant dispersion of growth rates, but also a dead zone that is dependent on the growth rates of the crystals. Faster growing crystals display almost no dead zone, whereas the smallest crystals have a large dead zone. The size of the dead zone is largely responsible for the dispersion of crystal growth rates, perhaps due to differences in the thermodynamic stability of the different crystals. The mechanism of growth rate dispersion relates to that of the dead zone.