Crystallization diagram for antisolvent crystallization of lactose: using design of experiments to investigate continuous mixing- induced supersaturation

Pól Macfhionnghaile, Vaclav Svoboda, John McGinty, Alison Nordon, Jan Sefcik

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This study investigates the effects of key process parameters of continuous mixing-induced supersaturation on the antisolvent crystallization of lactose using D-optimal Design of Experiments (DoE). Aqueous solutions of lactose were mixed isothermally with antisolvents using a concentric capillary mixer. Process parameters investigated were the choice of antisolvent (acetone or isopropanol), concentration of lactose solution, total mass flow rate, and the ratio of mass flow rates of lactose solution and antisolvent. Using a D-optimal DoE a statistically significant sample set was chosen to explore and quantify the effects of these parameters. The responses measured were the solid state of the lactose crystallized, induction time, solid yield and particle size. Mixtures of α-lactose monohydrate and β-lactose were crystallized under most conditions with β-lactose content increasing with increasing amount of antisolvent. Pure α-lactose monohydrate was crystallized using acetone as the antisolvent, with mass flow ratios near 1:1, and near saturated solutions of lactose. A higher resolution DoE was adopted for acetone and was processed using multivariate methods to obtain a crystallization diagram of lactose. The model was used to create an optimized process to produce α-lactose monohydrate and predicted results agreed well with those obtained experimentally, validating the model. The solid state of lactose, induction time, and solid yield were accurately predicted.
Original languageEnglish
Pages (from-to)2611-2621
Number of pages11
JournalCrystal Growth and Design
Issue number5
Early online date28 Mar 2017
Publication statusPublished - 3 May 2017



  • continuous mixing-induced supersaturation
  • antisolvent crystallization
  • lactose
  • concentric capillary mixer
  • D-optimal design of experiments
  • induction time
  • solid yield

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