Protein crystals are of interest for several fields of science and technology. Their formation underlies several human pathological conditions. An example is the crystallization of hemoglobin C and the polymerization of hemoglobin S that cause, respectively, the CC and sickle cell diseases (Charache et al. 1967; Hirsch et al. 1985; Eaton and Hofrichter 1990; Vekilov 2007). The formation of crystals and other protein condensed phases of the so-called crystallines in the eye lens underlies the pathology of cataract formation (Berland et al. 1992; Asherie et al. 2001). A unique example of benign protein crystallization in humans and other mammals is the formation of rhombohedral crystals of insulin in the islets of Langerhans in the pancreas. The suggested function of crystal formation is to protect the insulin from the proteases present in the islets of Langerhans and to increase the degree of conversion of the soluble proinsulin (Dodson and Steiner 1998).

Crystallization from solutions is a complex process completed in several stages. The first stage is the formation of supersaturated solution because the spontaneous appearance of a new phase can occur only when a system is in a nonequilibrium condition. In the next stage, molecules dissolved in solution begin to aggregate to relieve the supersaturation and move the system toward equilibrium. The molecular aggregation process eventually leads to the formation of nuclei that can act as centers of crystallization. A nucleus can be defined as the minimum amount of a new phase capable of independent existence (Khamskii 1969). The nature of nuclei (i.e., whether they are amorphous particles or tiny crystals) is still unknown. The birth of these small nuclei in an initially metastable phase is called nucleation, which is a major mechanism of first-order phase transition. Kashchiev and van Rosmalen (2003) describe nucleation as the process of fluctuational appearance of nanoscopically small clusters of the new crystalline phase, which can grow spontaneously to macroscopic sizes. The growth stage, which immediately follows nucleation, is governed by the diffusion of particles, called growth units, to the surface of the existing nuclei and their incorporation into the structure of the crystal lattice (Khamskii 1969). This stage continues until all the solute in excess of saturation is consumed for the development of mature crystals. The initial stages of crystallization, which can be defined as the period between the achievement of supersaturation and the formation of nuclei, plays a decisive role in determining properties of the resulting solid phase, such as purity, crystal structure, and particle size. Thus higher levels of control over crystallization cannot be achieved without understanding the fundamentals of nucleation.

Mixing determines the environment in which crystals nucleate and grow and is therefore intrinsic to industrial crystallization. Individual nucleating and growing crystals respond directly to their microenvironment and not in a simple way to the macroenvironment, often thought of as the bulk or average environment. Because the growing crystal removes solute from solution and the dissolving crystal releases it, the solute concentration and therefore the supersaturation is in general different at the crystal surface than in the bulk. Crystals grow when the microenvironment is supersaturated, stop when it is just saturated, and dissolve when it is undersaturated. In most cases, impurities are rejected by growing crystals; therefore, each growing crystal face creates a zone of locally higher impurity concentration immediately adjacent to it. The growth rate and amount of impurity taken up by the growing crystal are functions of the impurity concentration where growth is occurring – at the crystal face itself. Mixing is the family of processes that links this local microenvironment to the macroscopic scale of the crystallizer by affecting the mass transfer between crystal and the larger environment and the dynamics of crystal suspension flow in the crystallizer. Mixing, therefore, to a large extent creates the crystal microenvironments. Furthermore, it determines the homogeneity of the macroenvironment, both temporally and spatially. Inhomogeneity in the macroenvironment affects the microenvironments around crystals, causing temporal variations as the crystals circulate from one zone to another inside the crystallizer. This is particularly important because local values of key variables such as supersaturation and solids concentration are often much more important in crystallization than the bulk or global averages of these quantities, as discussed below.

There are many components in foods that crystallize, either partially or completely (Hartel 2001). Most important are sugars (i.e., sucrose, lactose, glucose, and fructose), ice, lipids and starches, although crystallization of salts, sugar alcohols, organic acids, proteins, and emulsifiers may be important in certain applications. Crystallization in the food industry differs to some extent from that in other fields in that, for the most part, the crystals form an integral part of the food. Although separation of crystals is important in certain food applications, crystalline structures within the food itself often define the characteristics of that product.

Crystallization is a separation and purification technique employed to produce a wide variety of materials. Crystallization may be defined as a phase change in which a crystalline product is obtained from a solution. A solution is a mixture of two or more species that form a homogeneous single phase. Solutions are normally thought of in terms of liquids, but solutions may include solids and even gases. Typically, the term solution has come to mean a liquid solution consisting of a solvent, which is a liquid, and a solute, which is a solid, at the conditions of interest. The term melt is used to describe a material that is solid at normal conditions and is heated until it becomes a molten liquid. Melts may be pure materials, such as molten silicon used for wafers in semiconductors, or they may be mixtures of materials. In that sense, a homogeneous melt with more than one component is also a solution, but it is normally referred to as a melt. A solution can also be gaseous; an example of this is a solution of a solid in a supercritical fluid.

In the area of industrial crystallization, population balances are used to model how the number and properties of the crystals in a crystallizer are generated and eventually appear as the solid product. A population balance is a mathematical description of conservation of number of particles, and accounts for how the number of particles having a particular set of properties (e.g., size, shape, density) may change during the process. The population balance has the same format as a mass balance or an energy balance. However, while mass and energy are conserved, particles having specific properties are not, and the population balance aims to account for how various mechanisms lead to changes. Traditionally, a population balance is a number balance, accounting for the number of particles of each particular size. Even though linear size is by far the most common particle characteristic on which the balance is based, other independent variables of the particle phase space can be of interest and modeled. By particle phase space is meant the multidimensional space of various particle properties. The population balance can also be formulated with more than one independent variable describing different particle properties. For example, if two linear dimensions of the particle are used in its characterization and are included in the modeling, we obtain a balance that also contains a description of shape changes, not only size changes.

In previous chapters, the simple case of two-component systems, i.e., one single solute crystallizing in a solvent (or solvent mixture), was mainly considered. However, because crystallization is most often employed as a purification process, numerous impurities resulting from the upstream part of the process are necessarily present in solution, such as buffer components, residual reactants, intermediates, or by-products. These impurities may affect the crystallization process and the resulting crystal properties, even at low concentration. Besides, additives are sometimes placed intentionally in solution with a view to tuning certain crystal properties. The mechanisms by which impurities and additives dissolved in solution affect the crystallization process can be rationalized in a common framework, so they will both be placed under the umbrella of foreign species in this chapter. The species to be purified will instead be referred to as the host species.

Precipitation and crystallization are the key production steps for shaping the application properties of pigments. Although the technical features of the particle-formation technologies and process design considerations applied for pigment synthesis are quite similar to those for other sparingly soluble substances, some unique differences exist. These differences are to a large extent related to the special application properties of pigments, that is, the coloristic quality of pigments; pigment stability toward light, weather, heat, and chemicals; and their dispersability in application media. To facilitate a better understanding of how the operating conditions applied during precipitation and crystallization control the application properties, this chapter starts with a detailed discussion on the different types of pigments and their properties in Section 16.2. In particular, the discussion is focused on color. Some theoretical background on color perception and color systems is given with the aim of providing the fundamentals for understanding the quality characteristics of pigments. Moreover, it is discussed in some detail how pigment coloristic properties can depend on particle size, and some aspects of the influence of particle size, particle size distribution, and particle morphology on color are also discussed. However, a thorough understanding of these influences is not fully established, and this is still an important field of ongoing research that is aimed at providing solid and rational foundations to pigment particle technology.

Crystallization is one of the most important separation and product-formation technologies in the chemical industry. Typical advantages of crystallization are the low energy consumption, mild process conditions, and high product purity that can be obtained in a single separation step. The future impact of crystallization is even expected to increase further because many new high-added-value products are often in crystalline form. However, future crystalline products are also subject to increasingly stringent product quality requirements related to, for example, flowability, filterability, bioavailability, stability, and dissolution behavior. Product quality requirements for crystalline products typically vary strongly depending on the field of application.

Crystallization is one of the main separation and purification processes in the pharmaceutical, biotechnology, food, microelectronics, fine and bulk chemicals industries. The production of more than 70 percent of all solid products involves at least one crystallization as a key processing step, which can have a significant effect on the overall performance of the entire production process and the properties of the final product. The control of crystallization processes is challenging because of the highly nonlinear dynamics, large variations in length and time scales at which the various simultaneous mechanisms occur, variations in crystallization rates over time owing to variations in the impurity profiles of chemical feedstocks, unexpected polymorphic transformations, and nonideal mixing conditions.

Most crystallizations in the pharmaceutical industry are not carried out by crystallization scientists. The Cambridge Structure Database (CSD) contains over 850,000 crystal structures, and the number of organic molecules that have been isolated as solids is much larger. In many cases these isolations have not been repeated or scaled up. Yet this task, namely the development of robust, reproducible crystallization processes, is the main topic of this chapter. By way of introduction, meet the types of molecules, the types of people, and the nature of the industry.

Crystallization can be regarded as a self-assembly process in which randomly organized molecules in a fluid come together to form an ordered three-dimensional molecular array with a periodic repeating pattern. It is vital to many processes occurring in nature and manufacturing. Geologic crystallization is responsible from huge deposits of carbonates, sulfates, and phosphates that often grow in mountains and quarries. This process occurs over long periods of time, often at high temperatures and pressures, and results in large and usually highly ordered crystals such as diamond.

Batch crystallization is different from continuous crystallization in that the withdrawal of crystal product for the batch system is made only once at the end of the batch run. Batch crystallization may also include the semibatch system, in which one or more feed solutions are added to the crystallizer at a constant or variable rate throughout all or part of the batch.

Batch crystallization is different from continuous crystallization in that the withdrawal of crystal product for the batch system is made only once at the end of the batch run. Batch crystallization may also include the semibatch system, in which one or more feed solutions are added to the crystallizer at a constant or variable rate throughout all or part of the batch.