Theory and Practices in Crystallisation Process

Crystallisation is important in the pharmaceutical industry as a separation process for the intermediates and often serves as the final step in the manufacture of active pharmaceutical ingredients (APIs) (Chen et al., 2011). It is responsible for 70% of all solid materials produced by the chemical industry (Giulietti et al., 2001), more than 80% of pharmaceutical products involve at least one crystallisation step in their manufacturing process (Reutzel-Edens, 2006) whilst 90% of the Active Pharmaceutical Ingredients (API’s) are found in crystalline form (Choong and Smith, 2004). The control objectives of batch crystallisation processes are defined in terms of product purity, crystal habit or morphology, average particle size, crystal size distribution (CSD), bulk density, product filterability, and dry solids flow properties (Worlitschek and Mazzotti, 2004). CSD is important for efficient downstream operations (i.e. filtration, drying, and formulation) and better product performance (i.e. dissolution rates, bioavailability, and shelf life).

This section describes the fundamentals of pharmaceutical crystallisation processes that include solubility, crystallisation mechanisms, and crystal properties. The existing techniques for characterising crystal properties are briefly reviewed. The conventional approaches for crystallisation operation and control are described. Brief reviews on process analytical technology (PAT), its tools and their application in pharmaceutical crystallisation are also included in this chapter.

2.6.1 Fundamentals and Mechanisms of Crystallisation Processes

Crystallisation is the formation of solid particles by a phase change operation like formation of solid particles from a vapour, solidification of a liquid melt, or the formation of dispersed solids from a solution. Among these, the most common approach is the production of crystals from a solution. This approach involves at least a two component system, a solute and a solvent. Hence, the concepts of solubility, supersaturation and metastable zone width (MSZW) are crucial in developing and characterising the behaviour of crystallisation system.

• Solubility

Solubility is the amount of a substance (solute) that can be dissolved in a given amount of solvent at a given temperature and pressure. A saturated solution is defined as the solution that is in equilibrium with excess of the solute present in the solution. Under certain circumstances, a solution can dissolve more solute than defined by the condition of saturation at a particular temperature which is referred to as a supersaturated solution.

Crystalline product properties like polymorphic form, shape and yield are dependent on solubility and supersaturation (Modarresi et al., 2008). Basically the selection of the type of crystallisation process, e.g. cooling or anti-solvent crystallisation is guided by the solubility of the component in selected solvents. The phase relationship between solute and solution helps to understand the mechanisms of solute crystallisation from a solution. A typical phase diagram for a crystallisation process is shown in Figure 2.7.

In Figure 2.7, AB represents the solubility curve that is determined by thermodynamics and is a function of temperature, solvent and impurities present in the system. A solution with composition laying on the equilibrium curve is called saturated; on the other hand, solutions with composition laying below and above the curve are termed as undersaturated and supersaturated respectively. Being in non- equilibrium system, the supersaturated solution tends to reach equilibrium and thereby it removes the solids in the form of nuclei, which then grow into crystals. The

generation of supersaturation is therefore regarded as the first step in the crystallisation process.

Figure 2.7: Supersaturation in crystallisation processes.

• Supersaturation

As mentioned earlier, supersaturation is the driving force for the crystallisation process (Mullin, 2001). It is defined as the difference between the concentration of the solute (C) and the saturation concentration at a particular temperature (C_sat) as given by Equation 2.17, sat C C C S =Δ = − (2.17)

with units consistent with the units of the concentrations (e.g. kg solute/kg solvent or kg solute/kg solution). It is essential to control the extent of the supersaturation during crystallisation process since the size, shape, and solid-state properties of the product crystals are decided by the supersaturation profile achieved during the crystallisation process.

• Nucleation

When the supersaturation moves far enough from the solubility, eventually a point is reached where the formation of nuclei occurs spontaneously. The nucleation curve is

Metastable Region Temperature Concentration Undersaturated Region Labile Region A C Equilibrium Solubility Curve Nucleation Curve B D

designated as the line CD in phase diagram in Figure 2.7. The formation of nuclei is an attempt of the system to reach equilibrium. The process of forming nuclei is called nucleation that can be termed as the first step towards the formation of a solid phase (Jones, 2002). The region above the solubility curve where the nucleation starts to occur is called the metastable zone. The width of this metastable zone depends on kinetic variables, such as the rate at which supersaturation was created, the agitator speed, and the presence of impurities (Tititz-Sargut and Ulrich, 2002). Knowledge of the metastable zone width (MSZW) is important in crystallisation because it provides information on nucleation kinetics, so that the nucleation behaviour of a system can be understood (Myerson, 2002).

Nucleation is commonly classified into two types, e.g. primary nucleation and secondary nucleation. However, it can be further divided as shown in Figure 2.8. Primary nucleation is the formation of a solid phase from a clear liquid and it is more prevalent in unseeded crystallisation (Hardenberg et al., 2004). Primary nucleation is further classified as homogeneous and heterogeneous nucleation. Nucleation that occurs spontaneously from a clear pure solution is called homogeneous nucleation, whereas one stimulated by foreign particles or surfaces is called a heterogeneous nucleation (Rawlings et al., 1993).

Figure 2.8: Types of nucleation.

Secondary nucleation takes place when a supersaturated solution is in contact with

Nucleation

Primary

(absence of solute crystals ) (presence of solute crystals)Secondary

Homogeneous (spontaneous)

Heterogeneous (induced by foreign

chance present in the system. These seed crystals catalyse the nucleation process and as a result, nucleation takes place at a relatively lower supersaturation than that for the primary nucleation. As a result, the secondary nucleation can be controlled more easily (Rawlings et al., 1993).

Crystal growth

After formation, nuclei grow with time by addition of solute molecules from a supersaturated solution to the crystal surface (Rodriguez-Hornedo and Murphy, 1999). Crystal growth is generally a two-step process. In the first stage, mass transfer involves the diffusion of solute molecules from the bulk liquid through the solution boundary layer adjacent to the crystal surface. In the next stage, the adsorbed solute molecules at the crystal surface are then integrated into the crystal lattice by surface reaction. However, several researchers have added heat transfer as the third step that occurs in parallel with the other two steps (Hixson and Knox, 1951).

Aggregation

The next significant phenomenon in the crystallisation process is aggregation. It is the particle size enlargement process by which fines are joined together in an assembly. Therefore, the particle characteristics obtained in the product depend on the mechanism of aggregation as well. Researchers and scientists have extensively studied and modelled the aggregation processes (Yu et al., 2005).

Dissolution

Crystal dissolution cannot be defined exactly as the reverse process of the crystal growth because dissolution does not require the surface integration step; rather it is completely controlled by the solute diffusion. Crystal dissolution rate is of first order with respect to supersaturation and the dissolution occurs at all levels of undersaturation (Mullin and Gaska, 1969). The coefficient for the dissolution rate is a function of the diffusion coefficient, crystal size, and local hydrodynamics.

Breakage and Attrition

Particle breakage initiates the formation of new smaller particles of varying sizes. The breakage occurs due to different types of collisions like particle-particle collisions, collisions of particles with the walls of the container, inserted probes, and impeller. When a crystal is fractured into two or more pieces it is called breakage, whereas attrition is the fracture of a crystal into many small fragments. Therefore, these phenomena can impose a strong impact on the CSD and the median crystal size (Qu, 2007). Breakage processes have also got significant attention by the researchers and gone through intense analysis by (Soos et al., 2006).

2.6.2 Measurement Techniques for State Variables

Generally, three types of measurement techniques are required for batch chemical processes these are,

1. On-line measurements to provide information during the course of the batch.