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Influence of Solvent and Solid-State Structure on Nucleation of Parabens
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena. Strathclyde Institute of Pharmacy and Pharmaceutical Sciences, University of Strathclyde3, United Kingdom .ORCID iD: 0000-0001-7413-5571
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena. Department of Chemical and Environmental Science, Materials and Surface Science Institute, University of Limerick, Ireland .ORCID iD: 0000-0002-6647-3308
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena. Department of Chemical and Environmental Science, Materials and Surface Science Institute, University of Limerick, Ireland .
2014 (English)In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 14, no 8, 3890-3902 p.Article in journal (Refereed) Published
Abstract [en]

In the present work, the induction time for nucleation of ethyl paraben (EP) and propyl paraben (PP) in ethanol, ethyl acetate, and acetone has been measured at different levels of supersaturation. The induction time shows a wide variation among repeat experiments, indicative of the stochastic nature of nucleation. The solid-liquid interfacial energy and the size of the critical nucleus have been determined according to the classical nucleation theory. Combined with previous results for butyl paraben (BP), the nucleation behavior is analyzed with respect to differences in the solid phase of the three pure compounds, and with respect to differences in the solution. The results indicate that the difficulty of nucleation in ethanol and acetone increases in the order BP < PP < EP but is approximately the same in ethyl acetate. For each of the three parabens, the difficulty of nucleation increases in the order acetone < ethyl acetate < ethanol. The Gibbs energy of melting increases in the order BP < PP < EP, but the crystal structures are quite similar resulting in the basic crystal shape being very much the same. The solid-liquid interfacial energy is reasonably well correlated to the solvation energy, and even better correlated to the deformation energy, of the solute molecule within the first solvation shell as obtained by density functional theory calculations.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2014. Vol. 14, no 8, 3890-3902 p.
Keyword [en]
Acetone, Ethanol, Interfacial energy, Parabens, Solvation, Stochastic systems, Classical nucleation theory, Deformation energy, Nucleation behavior, Solid-liquid interfacial energy, Solid-state structures, Solute molecules, Solvation energy, Stochastic nature
National Category
Pharmaceutical Sciences Organic Chemistry Physical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-122217DOI: 10.1021/cg500449dISI: 000340080400025Scopus ID: 2-s2.0-84905686042OAI: oai:DiVA.org:kth-122217DiVA: diva2:621397
Funder
Swedish Research Council, 621-2010-5391
Note

Updated from manuscript to article in journal.

QC 20161024

Available from: 2013-05-14 Created: 2013-05-14 Last updated: 2018-01-11Bibliographically 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.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2013:20
Keyword
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)
Identifiers
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)
Opponent
Supervisors
Projects
investigate nucleation and crystallization of drug-like organic molecules
Funder
Swedish e‐Science Research Center
Note

QC 20130515

Available from: 2013-05-15 Created: 2013-05-14 Last updated: 2018-01-11Bibliographically approved

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