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Investigation of Batch Cooling Crystallization in a Liquid-Liquid Separating System by PAT
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena.
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena.
2012 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 16, no 6, 1212-1224 p.Article in journal (Refereed) Published
Abstract [en]

Crystallization of butyl paraben from water-ethanol mixtures has been investigated. The liquid-liquid phase separation and the solid liquid solubility have been determined from 1 to 50 degrees C. Cooling crystallizations have been performed at different starting compositions, and the processes have been recorded by in-situ infrared spectroscopy, focused beam reflectance measurement, and particle video microscopy. In pure water the butyl paraben solubility is below 1 mg/g, while in pure ethanol the solubility is more than 3 orders of magnitude higher. While the solution saturated with butyl paraben is homogeneous at 1 degrees C, at the higher temperatures butyl paraben induces a liquid-liquid phase separation of the ethanol-water mixture, and the ternary phase diagram contains up to five different regions. The size of the liquid-liquid phase separation region increases with increasing temperature. At 50 degrees C, even the binary butyl paraben water system separates into two different liquid phases. In the cooling crystallizations, the resulting product crystals and the behavior of the process are quite different, depending on the starting composition. The largest crystals and the least agglomeration were obtained in that experiment where liquid-liquid phase separation was not occurring. In all of the other experiments the crystals were smaller and more agglomerated, and the particle size distribution was wider or more irregular. The work illustrates how Process Analytical Technology (PAT) can be used to increase the understanding of complex crystallizations.

Place, publisher, year, edition, pages
2012. Vol. 16, no 6, 1212-1224 p.
Keyword [en]
4-Hydroxybenzoate Esters Parabens, Assisted Nucleation Detection, Published Literature, Crystal-Structure, Phase-Separation, Control-Chart, Drug Solution, In-Situ, Solubility, Behavior
National Category
Chemical Engineering
URN: urn:nbn:se:kth:diva-98946DOI: 10.1021/op200355bISI: 000305205200005ScopusID: 2-s2.0-84862557100OAI: diva2:540558

QC 20120710

Available from: 2012-07-10 Created: 2012-07-05 Last updated: 2013-05-15Bibliographically approved
In thesis
1. Crystallization of Parabens: Thermodynamics, Nucleation and Processing
Open this publication in new window or tab >>Crystallization of Parabens: Thermodynamics, Nucleation and Processing
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this work, the solubility of butyl paraben in 7 pure solvents and in 5 different ethanol-water mixtures has been determined from 1 ˚C to 50 ˚C. The solubility of ethyl paraben and propyl paraben in various solvents has been determined at 10 ˚C. The molar solubility of butyl paraben in pure solvents and its thermodynamic properties, measured by Differential Scanning Calorimetry, have been used to estimate the activity of the pure solid phase, and solution activity coefficients.

More than 5000 nucleation experiments of ethyl paraben, propyl paraben and butyl paraben in ethyl acetate, acetone, methanol, ethanol, propanol and 70%, 90% ethanol aqueous solution have been performed. The induction time of each paraben has been determined at three different supersaturation levels in various solvents. The wide variation in induction time reveals the stochastic nature of nucleation. The solid-liquid interfacial energy, free energy of nucleation, nuclei critical radius and pre-exponential factor of parabens in these solvents have been determined according to the classical nucleation theory, and different methods of evaluation are compared. The interfacial energy of parabens in these solvents tends to increase with decreasing mole fraction solubility but the correlation is not very strong. The influence of solvent on nucleation of each paraben and nucleation behavior of parabens in each solvent is discussed. There is a trend in the data that the higher the boiling point of the solvent and the higher the melting point of the solute, the more difficult is the nucleation. This observation is paralleled by the fact that a metastable polymorph has a lower interfacial energy than the stable form, and that a solid compound with a higher melting point appears to have a higher solid-melt and solid-aqueous solution interfacial energy.

It has been found that when a paraben is added to aqueous solutions with a certain proportion of ethanol, the solution separates into two immiscible liquid phases in equilibrium. The top layer is water-rich and the bottom layer is paraben-rich. The area in the ternary phase diagram of the liquid-liquid-phase separation region increases with increasing temperature. The area of the liquid-liquid-phase separation region decreases from butyl paraben, propyl paraben to ethyl paraben at the constant temperature.

Cooling crystallization of solutions of different proportions of butyl paraben, water and ethanol have been carried out and recorded using the Focused Beam Reflectance Method, Particle Vision and Measurement, and in-situ Infrared Spectroscopy. The FBRM and IR curves and the PVM photos track the appearance of liquid-liquid phase separation and crystallization. The results suggest that the liquid-liquid phase separation has a negative influence on the crystal size distribution. The work illustrates how Process Analytical Technology (PAT) can be used to increase the understanding of complex crystallizations.

By cooling crystallization of butyl paraben under conditions of liquid-liquid-phase separation, crystals consisting of a porous layer in between two solid layers have been produced. The outer layers are transparent and compact while the middle layer is full of pores. The thickness of the porous layer can reach more than half of the whole crystal. These sandwich crystals contain only one polymorph as determined by Confocal Raman Microscopy and single crystal X-Ray Diffraction. However, the middle layer material melts at lower temperature than outer layer material.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2013. xvi, 67 p.
Trita-CHE-Report, ISSN 1654-1081 ; 2013:20
Nucleation, Induction time, Interfacial energy, Ethyl paraben, Propyl paraben, Butyl paraben, Methanol, Ethanol, Propanol, Acetone, Ethyl acetate, Solubility, Thermodynamics, Activity, Activity coefficient, Liquid-liquid phase separation, Ternary phase diagram, Melting point, Boiling point, Polarity, Cooling crystallization, Sandwich crystal, Porous, Particle Vision and Measurement, Focused Beam Reflectance Method, Infrared Spectroscopy, Confocal Raman Microscopy, X-Ray Diffraction, Differential Scanning Calorimetry
National Category
Pharmaceutical Sciences Organic Chemistry Physical Chemistry
Research subject
SRA - E-Science (SeRC)
urn:nbn:se:kth:diva-122228 (URN)978-91-7501-723-5 (ISBN)
Public defence
2013-05-30, K1, Teknikringen 56, KTH, Stockholm, 10:00 (English)
investigate nucleation and crystallization of drug-like organic molecules
Swedish e‐Science Research Center

QC 20130515

Available from: 2013-05-15 Created: 2013-05-14 Last updated: 2013-05-15Bibliographically approved

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