Crystallization is a critical process for the purification and isolation of chemical compounds in the manufacture of many fine chemical and pharmaceutical products. The results of the crystallization step have far reaching impacts on overall process efficiency and final product quality. Crystallization is also a very difficult process to effectively optimize and control. Crystallization is inherently complicated simply by being a process involving the creation and formation of solid particles.
Timothy A. Bell, of DuPont Engineering Research and Technology, wrote a review of the challenges of scaling-up particulate processes where he stated:
“Studies by the Rand Corporation in the 1980s identified substantial differences in the scale-up and start-up performance of plants processing particles versus those processing liquids or gases. These differences were inevitably unfavorable. Particulate process plants take longer to start up and are less likely to achieve desired production rates… These problems generally relate to an inadequate understanding of the behavior of particle systems. Many of these behaviors are sensitive to process scale or process history in ways that would not be expected by engineers familiar only with liquid or gas systems.”1
Tim went on to identify crystallization as one of the most complicated particulate processes to scale-up (or scale-down) due to the significant impact of typical scale-up parameters – such as agitation – on the size distribution of the crystal product.
The implications of a well-designed crystallization process are considerable:
- Critical product parameters – such as product dissolution rates – and critical process parameters– such as powder bulk density, compressibility, and flowability – can be directly modified and controlled through effective crystallization process design.
- Achieving a target crystal size specification can significantly reduce cycle –time – sometimes by an order of magnitude – by eliminating bottlenecks in filtration and drying to improve downstream process efficiency.
- Improving the repeatability of the crystallization process – by reducing batch –to batch variability – improves the ability to design and fully utilize downstream processing equipment by avoiding the need to over design capacity for filtration, drying and milling equipment.
- Producing crystals that can be easily isolated from the mother liquor and — used directly in the final product, or compressed directly into a granulated or tableted product, can avoid additional unit operations such as milling or wet granulation that can significantly reduce overall yield.
For all these reasons, crystallization continues to be an area in which incremental improvement in efficiency and yield can often have a significant impact on the overall production efficiency and product profitability. The use of Process Analytical Technology (PAT) for optimization, scale-up, and ultimately control can help to quickly develop and capture the benefits of a more efficient crystallization process.
This is an excerpt from the white paper – A Guide to Scale-up of Batch Crystallization from Lab to Plant.
If you are interested in discussions with others working and interested in crystallization, consider joining the 500+ member LinkedIn Crystallization Community.
Terry Redman, MSc, MBA
Benjamin Smith, BSC
Mark Barrett BE, PhD
1. T. A. Bell, Challenges in the scale-up of particulate processes—an industrial perspective, Powder Technology, 150 (2): 60-71 (2004).