CHAPTER 2: CONCEPTUAL DESIGN OF CRYSTALLISATION PROCESSES
2.3 Physical processes during crystallisation
2.3.1 Nucleation 38
Nucleation is the starting point of crystal formation. This may occur through one of the following mechanisms
• Primary nucleation is the formation of a new solid phase from a clear liquid. This type of nucleation can be further subdivided into homogeneous and heterogeneous nucleation. In heterogeneous nucleation, nucleation starts on foreign substrates of mostly microscopic particles, dust or dirt particles. If such substrates are absent, new phase formation takes place by statistical fluctuations of solute entities clustering together, a mechanism referred to as homogeneous primary nucleation. It requires very high supersaturation conditions, as in the labile zone shown in Figure 2.2. (Jones, 2002 and Beckmann, 2013).
• Secondary nucleation is induced only when previously crystallized material is available. This nucleation mechanism generally occurs at much lower supersaturations than in primary nucleation. There are various types of secondary nucleation, but the most important source of secondary nuclei in crystallisation is contact nucleation, and occurs as a result of crystal collisions (Mullin, 2001).
2.3.2. Crystal growth and dissolution
Crystal growth is a desired phenomenon in crystallisation and it results from the addition of more solute molecules to the nucleation site or crystal lattice. Besides increasing crystal size, crystal growth also largely determines the key qualities of the crystal: crystal morphology, surface structure and purity of the crystal. Crystal growth is a three-step process, consisting of mass transfer, surface integration and heat transfer. Mass transfer and surface integration occur sequentially and in parallel with heat transfer. Mass transfer involves the diffusion of growth units (molecules, atoms or ions) to the crystal surface. Surface integration consists of surface diffusion, orientation and the actual incorporation into the lattice. The latent heat of crystallisation is released and transported to the crystal and solution.
39 2.3.3. Agglomeration and Breakage
An agglomerate is defined as the mass formed by the cementation of individual particles, probably by inter-particle forces during the collision of particles. Agglomerates are usually undesirable because they contain mother liquor between the primary crystals that form the agglomerate. This liquor is hard to remove during drying, and promotes caking of the product during storage.
Breakage, as the fracture of a particle into one slightly smaller particle and many much smaller fragments, is defined as attrition. Breakage involves the fracture of a particle into two or more pieces.
Control strategies for crystallisation are primarily used to determine whether nucleation or growth should be the dominant process, depending on which of these process objectives is most critical for the desired overall outcome. The demand for increasing control of physical attributes, for final bulk pharmaceuticals, has necessitated a shift in emphasis from control of nucleation to control of growth (Tung , 2009). Both nucleation and growth are dependent on the degree of supersaturation, and hence, maintaining the degree of supersaturation within the metastable zone is crucial. This desired zone of operation is shown in Figure 2.3, which shows how the primary, secondary and growth rates vary with supersaturation. In the next section we will examine the various ways of generating and maintaining the required supersaturation.
Figure 2.3. The influence of supersaturation on growth and nucleation rates (adapted from Moyers and Rousseau, 1987).
2.4. Modes of Crystallisation
The technique employed to generate supersaturation in a solution, for crystal formation, is referred to as the mode of operation. The mode chosen is dependent on the phase-equilibrium characteristics of the system. The usual techniques for generating supersaturation include:
cooling, solvent evaporation, chemical reaction, anti-solvent addition, and common ion addition.
40
The choice of the mode of crystallisation is normally dependent on the system properties (e.g.
solubility, heat of solvent vaporisation, feed stream composition, etc.); and sometimes, a combination of processes is employed to maximize the yield.
In this section, a qualitative discussion is presented on the processes that are used to create and maintain supersaturation conditions that promote crystallisation. These procedures are classified by the manner in which supersaturation is generated. They are briefly described in Table 2.1, and some are illustrated on a solubility curve, as shown in Figure 2.4.
Table 2.1. Methods of Supersaturation Generation.
Mode of Crystallisation
Description
Cooling Crystallisation is achieved by cooling solvent from a high temperature to a low temperature at constant solvent composition. This mode is applicable to systems where the solubility has a strong temperature dependence. Since the solubility decreases with temperature, the solution becomes supersaturated.
Anti-solvent Crystallisation is achieved by adding an anti-solvent to a solvent in which the solute is soluble. The anti-solvent is used to reduce solubility of the solute in the mixed solvent, and hence the mixed solvent becomes supersaturated.
Reactive Crystallisation is achieved by changing the compound ionically or structurally through reaction. The reactants are often soluble with the product being insoluble.
Reaction is used to change the concentration of the product above the solubility limit
Evaporative Crystallisation is achieved by the evaporation of solvent that increases the solute concentration above the solubility limit, resulting in supersaturation. The evaporation of the solvent can be through flashing or heating.
Figure 2.4. Solubility Diagram showing how the different modes of crystallisation influence supersaturation (adapted from Jones, 2002).
41
The processing implications of the various modes of supersaturation generation are briefly described below.