From Batch to Continuous Crystallisation: Nucleation and Growth Under Various Flow Conditions

Crystallisation processes are widely used for separation and purification in chemical and pharmaceutical industries. In order to develop continuous crystallisation of desired polymorphic forms, it is crucial to better understand the influence of mixing and flow conditions on nucleation of various polymorphs from supersaturated solution. For example, both supersaturation and post-mixing flow conditions can be used to control competitive nucleation of polymorphic forms in reactive crystallisation of L-Glutamic acid at constant temperature. We investigated various flow units for treatment of supersaturated L-Glutamic acid solutions prepared under identical initial mixing conditions in either reactive or antisolvent crystallisation. 

We obtained respective crystal forms of L-Glutamic acid (either metastable α or stable β) by exposing supersaturated solutions to various flow units, such as a stirred tank, a magnetically stirred crystalliser, a peristaltic pump recycle loop or an oscillatory baffled crystalliser, operating at constant temperature. Using suitable flow units as nucleators to produce seeding suspensions of desired polymorphs, we designed a continuous crystallisation process by connecting a mixing unit (such as a static or in-line mixer) with a nucleator unit (a flow unit) and a continuous crystal growth unit (based on cooling crystallisation in a continuous oscillatory baffled crystalliser). 

This set up was successfully used for continuous crystallisation of the stable β polymorph of L-Glutamic acid, achieving a good control over the final crystal size with a narrow particle size distribution.