This paper discusses theoretical and experimental considerations of organic molecules nucleating inside tubular reactors or nucleators. Temperature evolution of these liquid systems is experimentally shown for different flow rates as a function of distance when these nucleators are immersed into a water bath set at spontaneous nucleating conditions. When different restrictions in the flow path are introduced before the cooling phase of the liquid; important differences on the nucleation rates are observed. For this study, Aspirin was dissolved in a blend of water and ethanol in a 50/50 vol%. At a concentration of 200 mg/mL and a nucleation temperature of 10 °C, demonstrated to be close to the metastable zonewidth, these flow restrictions show an antagonistic effect on the nucleation rate. One restriction, placed right before the nucleator enters the cooling bath, induces a reduction in nucleation rate. Putting more restrictions into the flow path with an equal separation of 5 cm in between, the nucleation recovers back to its initial value when a second restriction of an expansion ratio 2 is applied. Restrictions with an expansion ratio of 4 exceed this nucleation rate up to an order of magnitude when more than 2 restrictions are put in place.
At a higher kinetic driving force defined KDF, at a concentration of 300 mg/mL of Aspirin, the influence of the restriction becomes invariant as a function of the expansion ratio. For all experiments, the nucleation rates is highly increased with the number of restrictions introduced into the flow path. A thermal gradient difference by using the restrictions on the cooling rate of the liquid flowing inside the tubing was not observed experimentally. Therefore only hydrodynamic changes of the flow seems a plausible cause for this nucleation rate - restriction dependence as it is expected that finite amplitude perturbations, amplified by the use of restrictions, cause vortex shedding in current experimental setup.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Schaber SD, Gerogiorgis DI, Ramachandran R, JMB E, Barton PI, Trout BL (2019) Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing: A Case Study. Ind. Eng. Chem. Res. 50:10083
Paul EL, Tung HH, Midler M (2005) Organic crystallization processes. Powder Technol 150:133–143
Adamo A, Beingessner RL, Behnam M, Chen J, Jamison TF, Jensen KF, Monbaliu JCM, Myerson AS, Revalor EM, Snead DR, Stelzer T, Weeranoppanant N, Wong SY, Zhang P (2016) On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science 352:61–67
Lawton S, Steele G, Shering P, Zhao L, Laird I, Ni XW (2009) Continuous Crystallization of Pharmaceuticals Using a Continuous Oscillatory Baffled Crystallizer. Org. Process Res.Dev. 13:1357–1363
Wang T, Lu H, Wang J, Xiao Y, Zhou Y, Bao Y, Hao H (2017) Recent progress of continuous crystallization. J. Indust.Eng. Chem. 54:14–29
Baxendale IR, Braatz RD, Hodnett BK, Jensen KF, Johnson MD, Sharratt P, Sherlock JP, Florence AJ (2015) Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance. J.Pharmaceut. Sci. 104:781–791
Eder RJP, Radl S, Schmitt E, Innerhofer S, Maier M, Gruber-Woelfler H, Khinast JG (2010) Continuously Seeded, Continuously Operated Tubular Crystallizer for the Production of Active Pharmaceutical Ingredients. Cryst.Growth Des 10:2247–2257
Eder RJP, Schmitt EK, Grill J, Radl S, Gruber-Woelfler H, Khinast JG (2011) Seed loading effects on the mean crystal size of acetylsalicylic acid in a continuous-flow crystallization device. Cryst. Res. Technol. 46:227–237
Malet-Sanz L, Susanne F (2012) Continuous Flow Synthesis. A Pharma Perspective. J. Med. Chem. 55:4062–4098
Alvarez AJ, Singh A, Myerson AS (2011) Crystallization of Cyclosporine in a Multistage Continuous MSMPR Crystallizer. Cryst. Growth Des. 11:4392–4400
Borissova A, Dashova Z, Lai X, Roberts KJ (2004) Examination of the Semi-Batch Crystallization of Benzophenone from Saturated Methanol Solution via Aqueous Antisolvent Drowning-Out as Monitored In-Process Using ATR FTIR Spectroscopy. Cryst. Growth Des. 4:1053–1060
Hohmann L, Gorny R, Klaas O, Ahlert J, Wohlgemuth K, Kockmann N (2016) Design of a Continuous Tubular Cooling Crystallizer for Process Development on Lab-Scale. Chem. Eng. Technol. 39:1268–1280
Cogoni G, de Souza B, Frawley P (2015) Particle Size Distribution and yield control in continuous Plug Flow Crystallizers with recycle. Chem. Eng. Sci. 138:592–599
Besenhard MO, Hohl R, Hodzic A, Eder RJP, Khinast JG (2014) Modeling a seeded continuous crystallizer for the production of active pharmaceutical ingredients: Modeling a seeded continuous crystallizer. Cryst. Res. Technol. 49:92–108
Besenhard MO, Neugebauer P, Ho CD, Khinast JG (2015) Crystal Size Control in a Continuous Tubular Crystallizer. Cryst. Growth Des. 15:1683–1691
Su Q, Benyahia B, Nagy ZK, Rielly CD (2015) Mathematical Modeling, Design, and Optimization of a Multisegment Multiaddition Plug-Flow Crystallizer for Antisolvent Crystallizations. Org. Process Res. Dev. 19:1859–1870
Sultana M, Jensen KF (2012) Microfluidic Continuous Seeded Crystallization: Extraction of Growth Kinetics and Impact of Impurity on Morphology. Cryst. Growth Des. 12:6260–6266
Wong SY, Cui Y, Myerson AS (2013) Contact Secondary Nucleation as a Means of Creating Seeds for Continuous Tubular Crystallizers. Cryst. Growth Des. 13:2514–2521
Jiang M, Zhu Z, Jimenez E, Papageorgiou CD, Waetzig J, Hardy A, Langston M, Braatz RD (2014) Continuous-Flow Tubular Crystallization in Slugs Spontaneously Induced by Hydrodynamics. Cryst. Growth Des. 14:851–860
Mendez del Rio JR, Rousseau RW (2006) Batch and Tubular-Batch Crystallization of Paracetamol: Crystal Size Distribution and Polymorph Formation. Cryst. Growth Des. 6:1407–1414
Alvarez AJ, Myerson AS (2010) Continuous Plug Flow Crystallization of Pharmaceutical Compounds. Cryst. Growth Des. 10:2219–2228
Rimez B, Debuysschère R, Conté J, Lecomte-Norrant E, Gourdon C, Cognet P, Scheid B (2018) Continuous-Flow Tubular Crystallization To Discriminate between Two Competing Crystal Polymorphs. 1. Cooling Crystallization. Cryst. Growth Des. 18:6431–6439
Rimez B, Conté J, Lecomte-Norrant E, Cognet P, Gourdon C, Scheid B (2018) Continuous-Flow Tubular Crystallization To Discriminate between Two Competing Crystal Polymorphs. 2. Antisolvent Crystallization. Cryst. Growth Des 18:6440–6447
Rimez B, Septavaux J, Debuysschère R, Scheid B (2019) The creation and testing of a fully continuous tubular crystallization device suited for incorporation into flow chemistry setups. J Flow Chem. https://doi.org/10.1007/s41981-019-00042-z
Rimez B, Septavaux J, Scheid B (2019) The coupling of in-flow reaction with continuous flow seedless tubular crystallization. React. Chem. Eng. 4:516–522
Liu J, Rasmuson C (2013) Influence of Agitation and Fluid Shear on Primary Nucleation in Solution. Cryst. Growth Des. 13:4385–4394
Mura F, Zaccone A (2016) Effects of shear flow on phase nucleation and crystallization. Phys. Rev. E 93:042803
Forsyth C, Mulheran PA, Forsyth C, Haw MD, Burns IS, Sefcik J (2015) Influence of Controlled Fluid Shear on Nucleation Rates in Glycine Aqueous Solutions. Cryst. Growth Des. 15:94–102
Sreenivasan KR (1983) An instability associated with a sudden expansion in a pipe flow. Phys.Fluids 26:2766–2769
Tsai CH, Chen HT, Wang YN, Lin CH, Fu LM (2006) Capabilities and limitations of 2- dimensional and 3-dimensional numerical methods in modeling the fluid flow in sudden expansion microchannels. Microfluid.Nanofluid 3:13–18
Forrester S, Evans G (1997) Computational modelling study of the hydrodynamics in a sudden expansion—tapered contraction reactor geometry. Chem. Eng. Sci. 52:3773–3785
Sanmiguel-Rojas E, Mullin T (2012) Finite-amplitude solutions in the flow through a sudden expansion in a circular pipe. J.Fluid Mech. 691:201–213
Back LH, Roschke EJ (1972) Shear-Layer Flow Regimes and Wave Instabilities and Reattachment Lengths Downstream of an Abrupt Circular Channel Expansion. J.Appl. Mech. 39:677–681
Park JS, Song SH, Jung HI (2009) Continuous focusing of microparticles using inertial lift force and vorticity via multi-orifice microfluidic channels. Lab Chip 9:939–948
Mersmann A (ed.), Crystallization technology handbook, 2nd edn. (Marcel Dekker, New York (2001)
Mullin JW, Crystallization, 4th edn. (Butterworth-Heinemann, Oxford ; Boston (2001)
Latornell DJ, Pollard A (1986) Some observations on the evolution of shear layer instabilities in laminar flow through axisymmetric sudden expansions. Phys. Fluids 29:2828–2835
Boujo E, Gallaire F (2015) Sensitivity and open-loop control of stochastic response in a noise amplifier flow: the backward-facing step. J. Fluid Mech. 762:361–392
Vekilov PG (2010) Nucleation. Cryst. Growth. Des. 15:5007–5019
Vekilov PG (2005) Two-step mechanism for the nucleation of crystals from solution. J.Cryst. Growth. 275:65–76
Richard D, Speck T (2015) The role of shear in crystallization kinetics: From suppression to enhancement. Sci Rep 5:14610
This work was executed thanks to the Walloon Region and its financial support during the MecaTech-Legomedic project. B.Scheid thanks the F.R.S.- FNRS for financial support.
Part of the study falls under the information added to European patent application EP 18171018.7.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Rimez, B., Debuysschère, R. & Scheid, B. On the effect of flow restrictions on the nucleation behavior of molecules in tubular flow Nucleators. J Flow Chem 10, 241–249 (2020). https://doi.org/10.1007/s41981-019-00069-2
- Tubular nucleator
- Spontaneous nucleation
- Flow restrictions