Insight into nucleation kinetics and other nucleation parameters can be obtained from probability distributions of induction time measurements in combination with the classical nucleation theory. In this work, induction times of crystallization were recorded using a robust and automated methodology involving a focused beam reflectance measurement probe. This methodology is easily interchangeable between different crystallizers which allowed us to investigate the effects of scale-up on the kinetics of crystal nucleation of paracetamol from 2-propanol in four different crystallizers, ranging from small magnetically stirred 10 mL solutions to overhead-stirred solutions of 680 mL. The nucleation rate was an order of magnitude faster in the magnetically stirred crystallizer as compared to the crystallizers involving overhead stirring. The thermodynamic part of the nucleation rate expression did not significantly change the nucleation rate, whereas the kinetic nucleation parameter was found to be the rate-determining process when the crystallization process was scaled-up. In particular, the shear rate was rationalized to be the part of the kinetic parameter that changes most significantly when the crystallization process was scaled-up. The effect of shear rate on the nucleation kinetics decreases with increasing volume and plateaus when the volume becomes too large. In this work, the nucleation mechanism was also investigated using the chiral sodium chlorate system. These experiments showed that the single nucleus mechanism is the underlying nucleation mechanism in all four tested crystallization setups when supersaturation remains the same. When the supersaturation was changed continuously through cooling, crystallization was driven by a multinucleus mechanism. The automated and robust method used to measure induction times can easily be extended to other crystallizers, enabling the measurement of induction times beyond small crystallizer volumes.
A multitude of ultrathin crystal needles are formed during the evaporation of saturated aqueous NaCl solution droplets in the presence of amide containing additives. The needles are as small as 300 nm wide and 100–1000 μm in length. Heating experiments, X-ray diffraction, and energy dispersive X-ray spectroscopy showed that the needles are cubic sodium chloride crystals with the needle length direction pointing toward [100]. This shape, not expected for the 43̅m point group symmetry of NaCl, has been explained using a model, based on tip formation by initial morphological instability followed by time dependent adsorption of additive molecules blocking the growth of the needle side faces. The latter also suppresses side branch formation, which normally occurs for dendrite growth.
The striking ability of impurities to significantly influence crystallization processes is a topic of paramount interest in the pharmaceutical industry. Despite being present in small quantities, impurities tend to considerably change a crystallization process as well as the final crystalline product. In the present work, the effect of two markedly different impurities 4-nitrophenol and 4′-chloroacetanilide on the solubility, nucleation, and crystallization of paracetamol is described. In the first part of this work, the fundamentals are outlined and show that, although each impurity led to a small increase in solubility of paracetamol, their effect as a nucleation inhibitor was much more pronounced. Induction time experiments were used in conjunction with the classical nucleation theory to show that the impurities did not affect the solid−liquid interfacial energy but instead significantly reduced the kinetic factor, overall resulting in reduced nucleation rates. Intriguingly, both impurities influenced the solubility and nucleation of paracetamol in a similar fashion despite their significant differences in terms of molecular structure, solubility, and ability to incorporate into the crystal structure of paracetamol. In the second part of this work, the incorporation of 4′-chloroacetanilide into the solid phase of paracetamol was investigated. The presence of 4′-chloroacetanilide in the solid phase of paracetamol significantly increased the compressibility of paracetamol, resulting in improved processability properties of paracetamol. The compressibility efficiency of paracetamol could be controlled using the amount of incorporated 4′-chloroacetanilide. Therefore, an experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. Intriguingly, the number of carbon atoms in the aliphatic chain of the alcohol solvent strongly correlated to the impurity incorporation efficiency. As a result, it was feasible to accurately control the compressibility and the amount of 4′-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the solvent for crystallization. Thus, the present work comprehensively shows how different impurities impact the key crystallization mechanisms and properties of a pharmaceutical product. Rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored specifications.
Organothiol monolayers on metal substrates (Au, Ag, Cu) and their use in a wide variety of applications have been extensively studied. Here, the growth of layers of organothiols directly onto muscovite mica is demonstrated using a simple procedure. Atomic force microscopy, surface X‐ray diffraction, and vibrational sum‐frequency generation IR spectroscopy studies revealed that organothiols with various functional endgroups could be self‐assembled into (water) stable and adaptable ultra‐flat organothiol monolayers over homogenous areas as large as 1 cm2. The strength of the mica–organothiol interactions could be tuned by exchanging the potassium surface ions for copper ions. Several of these organothiol monolayers were subsequently used as a template for calcite growth.
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