Crystallization Development A – QbD Approach to PSD Control using Modelling


An approach to crystallization development is described, based on a mixture of theoretical modelling and experimentation that provides a deep understanding of the process factors that influence PSD and improves efficiency in development and …


Nearly all synthetic steps in industrial chemical manufacturing end with a crystallization. This is because it is almost always the most efficient method to purify and isolate the material. While most chemists are proficient at formulating a basic procedure, when it comes down to the fine details, often crystallization is seen as a mysterious process and subject to factors beyond our control. Various quality attributes may be important: purity, residual solvents, filtration speed, polymorph, crystal habit and particle size distribution (PSD). An in-depth understanding of the crystallization process will help reduce risks on scale-up. In this article we discuss the use of modelling tools for solubility and supersaturation and how they can aid crystallization development, with an emphasis on PSD.

Basic Concepts

A crystallization consists mainly of two basic processes: crystal growth and nucleation. Other factors such as attrition and agglomeration may also play a role, and should be considered, but first we need to understand growth and nucleation. These two processes occur throughout the crystallization with rates that depend on many factors including supersaturation, crystal surface area, collision rate, viscosity and temperature. Several of these factors are changing throughout the crystallization and therefore, the relative rates of growth and nucleation that determine the final PSD are also variable throughout the process. The fundamental driving force for crystallization is supersaturation. In simple terms this is defined as how far the solution concentration is from the thermodynamic equilibrium or solubility.

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