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A method is presented for optimizing the cooling strategy and seed loading simultaneously. Focused beam reflectance measurement (FBRM) was used to determine the approximating optimal cooling profile. Using these results in conjunction with constant growth rate assumption, modified Mullin-Nyvlt trajectory could be calculated. This trajectory could suppress secondary nucleation and has the potential to control product's polymorph distribution. Comparing with linear and two step cooling, modified Mullin-Nyvlt trajectory have a larger size distribution and a better morphology. Based on the calculating results, the optimized seed loading policy was also developed. This policy could be useful for guiding the batch crystallization process.

Continuous crystallization is a widely viewed topic as it has many advantages in industrial production. However, it is very resource intensive and time-consuming to determine operation conditions through trial and error. Computer simulation appears to an effective method in continuous crystallization design. The continuous cooling crystallization of paracetamol in a 5 L crystallizer was modeled to investigate the effect of mixing on the particle size distribution (PSD). A novel coupled computational fluid dynamics−population balance equation (CFD−PBE) simulation was developed in which the PBE was discretized using a high-resolution central scheme and solved simultaneously with CFD equations in ANSYS FLUENT 15.0 utilizing user-defined scalars. The influences of both internal grid and external (spatial) grid on the final PSD were studied, and an appropriate grid was chosen. The spatial distribution of velocity, temperature, slurry density, and nucleation rate were simulated. The continuous cooling crystallization under different stirrer speeds, bath temperatures, and residence times was investigated. It was found that (a) higher stirrer speeds lead to uniform distribution but smaller PSD, and (b) as the average temperature gets higher, or the residence time gets longer, the influence of mixing on final PSD gets smaller.

Continuous crystallization has gained growing interest in the pharmaceutical industry due to its high productivity and consistency of the product quality. Significant progress on the control of mixed-suspension mixed-product removal (MSMPR) product properties with the aspects of crystal size distribution, polymorphism, and crystal shape has been achieved. This review aims to summarize different property control methods and put forward new viewpoints on process control by applying a secondary nucleation mechanism. The review begins with a brief introduction to the characteristics and mechanisms of secondary nucleation, followed by an attempt to investigate the underlying phenomena involved in secondary nucleation. Then, the steadystate conditions of continuous crystallization from mathematical and mechanism analyses are discussed. Subsequently, the focus is on a variety of approaches that have been implemented in continuous crystallization processes to enable crystals to meet different critical quality attributes. Among them, by applying a secondary nucleation mechanism, new design strategies for crystal size and polymorph control in continuous crystallization are proposed. Furthermore, the possible relationship between the secondary nucleation threshold and crystal shape distribution is elaborated using a theoretical analysis and selecting supporting experimental evidence from the literature.

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A strategy for the formation of antimony‐carbon bond was developed by nickel‐catalyzed cross‐coupling of halostibines. This method has been applied to the synthesis of various triaryl‐ and diarylalkylstibines from the corresponding cyclic and acyclic halostibines. This protocol showed a wide substrate scope (72 examples) and was compatible to a wide range of functional groups such as aldehyde, ketone, alkene, alkyne, haloarenes (F, Cl, Br, I), and heteroarenes. A successful synthesis of arylated stibine 3 a in a scale of 34.77 g demonstrates high synthetic potential of this transformation. The formed stibines (R3Sb) were then used for the palladium‐catalyzed carbon–carbon bond forming reaction with aryl boronic acids [R−B(OH)2], giving biaryls with high selectivity, even the structures of two organomoieties (R and R′) are very similar. Plausible catalytic pathways were proposed based on control experiments.

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