Crystallization is a key unit operation within the pharmaceutical industry, and over 80% of drug products involve at least one crystallization step. Yet, despite its obvious importance, crystallization is still a relatively poorly understood process. Typical problems associated with crystallization include unsuitable final particle size distribution, impurity issues (including incorrect polymorph) and poor or inconsistent yield. There are also stringent regulatory commitments to which all pharmaceutical companies must adhere to ensure that the crystallization process is robust and repeatable.
However, the crystallization step offers a unique opportunity to control the size, shape, purity and yield of the final crystal product. This can be greatly facilitated by measurement of important crystallization characteristics such as the crystal size and the liquid phase concentration over the course of a batch. Ideally, these measurements should be made in situ so as to avoid the inherent difficulties associated with sampling.
The U.S. Food and Drug Administration’s (FDA’s) process analytical technology (PAT) initiative has established a framework that encourages pharmaceutical manufacturers to use in situ tools to understand how their processes behave. PAT can be applied to design, analyze and control crystallization during processing by measuring critical quality and performance attributes. In this article, we summarize some of the work that we’re doing to apply PAT to crystallization (see Table below, following Case Study 1), and present a number of case studies to illustrate how these tools can be used to improve crystallization processes.
Undesirable particle size
One of the biggest problems associated with crystallization is the formation of product with an undesirable particle size. Particle size affects such final product parameters as bioavailability and tablet strength. From a manufacturing viewpoint, poor particle size distribution can result in process bottlenecks, particularly during filtration and drying, leading to an inefficient process. Figure 1 (below) illustrates how particles can play a role in the manufacture of active pharmaceutical ingredient (API).
The final product particle size distribution is related to two key kinetic processes:
- nucleation of new crystals
- crystal growth.
By manipulating the relative magnitude of these mechanisms, it is possible to design a robust crystallization with a desirable final product particle size. For example, if small crystals are desired to increase bioavailability, or to avoid a milling step, nucleation should be favored over growth. But in a case where large crystals are desired — to reduce filtration time, for example — growth should be favored over nucleation. To understand how this can be achieved, it is vital to understand supersaturation, which drives nucleation and growth.
Supersaturation is defined as the difference between the actual solution concentration and the saturated solution concentration at a given temperature. It can be generated in many ways, including cooling, evaporation or anti-solvent addition. Cooling is the most common method used in the pharmaceutical industry.
Nucleation and growth rates are typically related to supersaturation according to Equations 1 and 2 (below). By controlling the supersaturation, one can control nucleation and growth rates and, thus, final particle size .
- B is nucleation rate (no./unit vol.)
- G is growth rate (length/unit time)
- kb and kg are kinetic nucleation and growth constants
- b and g are kinetic nucleation and growth orders
- ∆C is supersaturation (concentration units)
A simple strategy that can be used to increase the final product size is to maintain a low level of supersaturation throughout the batch. In this way, nucleation is minimized and growth will take place on the surface of existing crystals. Controlling the level of supersaturation can be achieved by employing a suitable cooling regime. This approach can also greatly enhance the final crystal size distribution. However, to do this accurately, knowledge of the solubility curve and metastable zone width (MSZW) is vital.
Case Study 1: Solubility curve and MSZW determination using FBRM 
Effective characterization of any crystallization starts with measuring the solubility curve and MSZW, which provides information on yield, suitable seeding locations and optimal zones of operation to obtain the desired particle size. FBRM can be used to measure the solubility curve and MSZW by accurately identifying the point of dissolution (point on the solubility curve) and point of nucleation (point on the MSZW) at various solute concentrations.
Here, an undersaturated solution is cooled at a fixed rate until the point of nucleation is measured with the FBRM, indicating a point on the MSZW. Next, the solution is heated slowly until the point of dissolution is measured with the FBRM indicating a point on the solubility curve. Solvent is then added to the system to change the concentration and the process is repeated. In this way, the solubility curve and MSZW can be measured rapidly over a wide range of temperatures. This process can be automated using an automated lab reactor (ALR) by introducing a feedback loop where the FBRM signal can be used to initiate the heating, cooling and dilution steps.