The techniques for seeding of a desired polymorph during crystallisation from solutions are reviewed. The basic information about the type of polymorphism needed to consider seeding strategies is discussed first. The development of seeding strategies is facilitated by certain data on the system. Their relevance as well as techniques for the determination are given. Reflections on the choice, characterisation, and preparation of the seed are followed by a discussion of techniques for the determination and optimisation of the seeding, that is, the rate of crystallisation and amount of seed added. Scale-up issues from the well-controlled environment of the laboratory to the plant sum up this point. The discussion of published as well as unpublished results of seeding strategies serve as illustration of the theoretical and practical considerations made.

We report here on a new, straightforward, and effective method for insulating etched and cut Pt/Ir scanning tunneling microscopy (STM) tips for in situ electrochemical studies. The coating was formed by electrophoretic painting and subsequent heating. It covered all but the very end of the tip, which may be attributed to shrinking of the polymer during heating. We have characterized these tips by voltammetric methods, scanning electron microscopy, and by in situ STM imaging.

Abecarnil, a partial agonist of the benzodiazepine receptor, crystallizes in three modifications, A, B, and C. Depending on the solvent, the form crystallized in an unseeded process is one of the two metastable forms A or B. Isopropyl acetate was chosen as solvent for the crystallization of the drug substance Abecarnil, yielding the B form for an unseeded crystallization. However, the crystals undergo a slow solution-mediated phase transformation into the stable C form. More readily observed is a partial phase transformation into the A modification. The rate of transformation depends sensitively on the purity of the material. To access this second metastable form quantitatively, reproducibly and irrespective of the purity of the material, a seeding strategy for a batch cooling crystallization from isopropyl acetate is developed. The technique is optimized under laboratory conditions and transferred to pilot plant scale. The physicochemical data necessary for the effective development are given and their relevance is discussed.

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Experimental data on the effects that different antisolvents and antisolvent addition strategies have on nucleation behavior in antisolvent crystallization is very limited, and our understanding of these effects is sparse. In this work we measured the metastable zone width for the isothermal antisolvent crystallization of glycine from water utilizing methanol, ethanol, and dimethylformamide as antisolvents. We then investigated induction times for glycine crystallization across these metastable zones using the same three antisolvents. Supersaturated solutions were prepared by mixing of an antisolvent with undersaturated aqueous glycine solutions, either by batch rapid addition or using a continuous static mixer. Induction times were then recorded under agitated isothermal conditions in small vials with the use of webcam imaging and vary from apparently instant to thousands of seconds over a range of compositions and different mixing modes. Well-defined induction times were detected across most of the metastable zone, which shows that primary nucleation is significant at supersaturations much lower than those identified in conventional metastable zone width measurements. As supersaturation increases toward the metastable zone limit, crystal growth and secondary nucleation are likely to become rate-limiting factors in the observed induction times for antisolvent crystallization. Furthermore, the observed induction times were strongly dependent on the mode of mixing (batch rapid addition vs continuous static mixing), which demonstrates an interplay of antisolvent effects on nucleation with their effects on mixing, leading to crossover of mixing and nucleation time scales. This shows that appropriate mixing strategies are crucial for the rational development of robust scalable antisolvent crystallization processes.

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