Enhancing sustainability in crystallization and isolation by recovery of pharmaceuticals from crystallization mother liquors

   Department of Chemical and Process Engineering

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  Prof Chris Price, Prof J Sefcik  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Losses in yield in the final API isolation play a disproportionately large role in lowering the overall sustainability of an API manufacturing process. This is a consequence of long synthetic paths and the resources consumed in reaching the final stage. The final API crystallization and subsequent isolation pose a challenge, in addition to achieving a high yield they must also deliver both consistent purification and control of API particle attributes. Focusing on yield in the current crystallize once approach necessitates a hold period for the supersaturation to be depleted to an acceptable level prior to isolation. A series of economic break points need to be considered; the cost of increased plant occupancy vs increased yield, for cooling crystallization the cost of further temperature reduction vs increased yield and for anti-solvent crystallization, the cost of additional solvent, increased volumes to filter and hazardous waste to dispose of. A significant sustainability benefit would be achieved if residual API in the mother liquors is recovered and recycled back into the process. This will allow the yield constraint can be relaxed allowing the primary API crystallization to focus almost exclusively on controlling API physical attributes and purity. In a conventional process, purity may be enhanced at the expense of yield, and focusing on control of API physical attributes requires tight control of crystallization conditions which tends to disfavour very high starting solution concentrations which would enhance yield. In terms of API quality, the least critical factor is yield. A classical non-pharmaceutical approach to this problem is to recover product from mother liquors and subject it to a rework process. However, in current pharmaceutical manufacturing practice, this is not favoured because of concerns that the recovered API would have a marginally different purity profile or slightly different physical properties which would impact drug product quality.

The aim of this PhD program will be to identify and evaluate alternative process topologies with recycle streams that address the objective of recovering API from crystallization mother liquors. The approach will combine multi-objectve optimisation of process topologies, pathways and conditions using software tools including Aspen and gPROMS with experimental investigation, with the ultimate objective of demonstration and validation of the optimisation approach in a continuous operation. The multi-objective optimisation will be targeted to suitable technoeconomic and sustainability objectives. The project will start with an existing (model) crystallization process conducted using a starting solution with a defined impurity loading, the API will be isolated by classical filtration, washing and drying. The filtrates will be collected and concentrated by vacuum distillation to generate additional supersaturation to drive further crystallization. Process topology will be an important parameter as a suitably concentrated stream can be recycled either directly into an existing continuous process or subject to additional crystallisation and isolation steps. This will in turn require further process optimisation compared to the original (presumably already originally optimised) process. A range of distillation end points will be explored for their potential to recover API from the concentrated stream and the level of purification attained.

In addition to undertaking cutting edge research, students are also registered for the Postgraduate Certificate in Researcher Development (PGCert), which is a supplementary qualification that develops a student’s skills, networks and career prospects.

Information about the host department can be found by visiting:



Chemistry (6) Engineering (12) Mathematics (25)

Funding Notes

Students applying should have (or expect to achieve) a minimum 2.1 undergraduate degree in a relevant engineering/science discipline, and be highly motivated to undertake multidisciplinary research. Funding for this project will be announced in due course.

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