The onset of crystal nucleation was studied for seeded semibatch experiments in aqueous solutions in which either the feed rate, the seed size, or seed amount was varied. The results of these experiments show that the nucleation behavior of polycrystalline vaterite features striking similarities with monocrystalline particles in general. Investigations of the nucleation rate of vaterite during spontaneous precipitation experiments have revealed that it would take orders of magnitude higher supersaturation values to obtain the particle numbers required for a proposed nanoaggregation process. The subunit "size" of polycrystalline vaterite is markedly different from particle to particle in seeded semibatch experiments in which nucleation occurred. Differences in the subunit "size" of particles formed under the same process conditions can hardly be explained by aggregation of precursor particles, as nanoaggregation would lead to a uniform distribution of nanoparticles among all particles. Crystal growth, on the other hand, can explain this phenomenon as it may depend on the underlying crystal surface and on the spherulite size. This points at spherulitic growth as the underlying particle enlargement mechanism. The same could be shown for spherulites of calcite for which the particle growth mechanism has been found to be dependent on the crystal surface structure. The current study suggests furthermore the performance of further studies concerning other substances forming polycrystalline particles to establish the correct particle enlargement mechanism.

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The present example illustrates the application of a consistent process development strategy to ascertain reproducible active pharmaceutical ingredient (API) polymorph manufacture. Key methodologies are illustrated using a Novartis API and carbamazepine as model substances. In the present example, the Novartis API was synthesized in the final chemical step by hydrolysis followed by acidification. The process was investigated in four steps: First, solid-liquid equilibrium studies were carried out in several solvents and yielded two polymorphs that were characterized by X-ray powder diffraction. Reliable solubility data and the transition temperature (45 °C) were extracted from these experiments as well. Second, based on the knowledge of the enantiotropic behavior of the system, a procedure was developed that crystallized the stable polymorphswhich was chosen for developments reproducibly by seeding at low supersaturation below 45 °C, followed by cooling at a moderate rate. The absence of metastability with respect to the undesired polymorphic form throughout the process was confirmed by applying ATR-FTIR. Third, reaction conditions were modified to obtain the API in solution at undersaturated conditions. Subsequently, the API could be crystallized in a controlled manner as described above. Fourth, filtration, washing, and drying conditions were investigated to avoid scale-up problems. Constant pressure filtration yielded low compressibility of the filter cake allowing a nutsche or centrifuge as appropriate equipment for isolation. On the basis of vacuum thermogravimetry, fast drying kinetics could be determined. Bench scale paddle dryer experiments illustrated an unacceptable increase of bulk density at permanent rotation. Therefore, intermittent rotation was successfully used at production scale. Thus, the presented process development strategy leads to a robust process scale-up from lab to pilot and production plant, yielding the desired product quality with respect to physical properties as well as chemical purity. Using solid-liquid equilibrium studies, the solubility and the transition temperature (79 °C) between forms I and III of carbamazepine could be determined in 2-propanol. These results correspond well with findings of other authors. On the basis of vacuum thermogravimetry, fast drying kinetics of 2-propanol from carbamezepine is illustrated. Near-complete drying can be achieved at any pressure below the solvent vapor pressure, which points to solvent free from interactions with the solid drug substance.

A quartz oscillator, operated with one of its faces in contact with a liquid, can be used as a highly sensitive microbalance. When used together with an electronic driver circuit, frequency changes will not only reflect changes of vibrating rigid mass but also detect changes of the surface microstructure. Using impedance spectroscopy we have analyzed the influence of the surface microstructure on the frequency changes. A liquid that is rigidly coupled to the surface by inclusion into voids or narrow channels can be discerned from a liquid that is viscously coupled to the surface. This analysis is shown for silver surfaces, roughened by several oxidation and reduction cycles, in chloride ion containing solutions.

We use a vector analyzer to investigate the impedance of a quartz oscillator, one face of which is exposed to a liquid. An aqueous LiCl – solution can be used to vary density and viscosity of the liquid over a wide range. The solution acts as an additional impedance with as well a real as an imaginary part. Furthermore, different electrical driver circuits have been used to excite the crystal vibrations. In most cases, our experimental results deviate from the predicted dependence of the crystal frequency from density and viscosity. These deviations are different for different driving circuits, but they do not change with the properties of the liquid.

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