Crystal formation optimization

Thus, methods are now becoming available such that process systems can be designed to manufacture crystal products of desired chemical and physical properties and characteristics under optimal conditions. In this chapter, the essential features of methods for the analysis of particulate crystal formation and subsequent solid-liquid separation operations discussed in Chapters 3 and 4 will be recapitulated. The interaction between crystallization and downstream processing will be illustrated by practical examples and problems highlighted. Procedures for industrial crystallization process analysis, synthesis and optimization will then be considered and aspects of process simulation, control and sustainable manufacture reviewed. 

However, the gas flow rate must be optimized because it is inversely proportional to droplet size. Larger droplets scatter more light, thereby increasing the analytical signal and sensitivity, but they are also less prone to evaporate, thereby increasing baseline noise. Since the limit of detection is related to the signal-to-noise ratio, the chromatographer must seek the best compromise. Droplet size must be carefully controlled because it establishes the size of the dried solute particles that in turn determines the extent of the linear response. It is important to use the lowest possible evaporative temperature to allow solute crystal formation, to avoid evaporation of solute and destruction of thermo-sensitive solute. 

Examples in this chapter include sterile crystallization of a labile compound, yield enhancement by crystallization, yield and selectivity enhancement, removal of low-level impurities via crystallization from the melt, crystal formation in vials in a freeze drier, and non-equilibrium resolution of stereoisomers by crystallization. These examples represent unique crystallization processes designed for specific purposes. One lesson to be learned from examination of these nonmainstream applications is that understanding of principles can lead to inventive solutions to problems. For instance, in Examples 11-2 and 11-3, the solubility difference between starting material and desired product is used to optimize the reaction yield/selectivity by crystallizing the product and protecting it from overreaction. 

The rate equation predicts exponential growth once a critical supersaturation is attained, however, in practice, an optimal temperature exists below which the liquid is too viscous to nucleate and above which molecular motions prevent crystal formation. This was observed by Tamman (1925) for several organic salts. He found that the optimal nucieation temperature was lower than that required for maximal crystal growth. A similar observation was made by Mullin and Leci (1969) for the spontaneous nucieation of citric acid solutions and is shown in Figure 2.21. The viscous effects can be incorporated into the rate equation by taking into account the viscous free energy (Turnbull and Fisher 1949). 

The desired main crystal phase of the phlogopite type was formed at temperatures above 850°C, entirely consuming the norbergite. Fluorborite, Mg3(B03)F3 developed as a secondary crystal phase. Optimal microstructure formation, however, occurred at 950 C. 

In yet another example, a co-crystal of caffeine and adipic add [98] has been isolated by a co-crystallization methods based on a suspension/slurry containing both components of the co-crystal system. This approach provides an optimal environment for the putative co-crystal formation because the activity values of both... 

After identifying the optimal etherification conditions, our attention turned to isolation of 18 in diastereomerically pure form. Diastereomers 18 and 19 were not crystalline, but, fortunately, the corresponding carboxylic acid 71 was crystalline. Saponification of the crude etherification reaction mixture of 18 and 19 with NaOH in MeOH resulted in the quantitative formation of carboxylic acids 71 and 72 (17 1) (Scheme 7.22). Since the etherification reaction only proceeded to 75-80% conversion, there still remained starting alcohol 10. Unfortunately, all attempts to fractionally crystallize the desired diastereomer 71 from the crude mixture proved unfruitful. It was reasoned that crystallization and purification of 71 would be possible via an appropriate salt. A screen of a variety of amines was then undertaken. During the screening process it was discovered that when NEt3 was added... 

---