Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Crystallization of Parabens: Thermodynamics, Nucleation and Processing
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena.ORCID iD: 0000-0001-7413-5571
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 [en]
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: urn:nbn:se:kth:diva-122228ISBN: 978-91-7501-723-5 (print)OAI: oai:DiVA.org:kth-122228DiVA: diva2:621416
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: 2013-05-15Bibliographically approved
List of papers
1. Nucleation of butyl paraben in different solvents
Open this publication in new window or tab >>Nucleation of butyl paraben in different solvents
2013 (English)In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 13, no 10, 4226-4238 p.Article in journal (Refereed) Published
Abstract [en]

The primary nucleation induction time of butyl paraben in pure solvents: acetone, ethyl acetate, methanol, ethanol, and propanol and in 70% and 90% ethanol aqueous mixtures has been determined. At each condition, about 100 experiments have been performed in 5 mL scale to capture the statistics of the nucleation process. The induction times at each condition show a wide variation. The data has been evaluated within the framework of the classical nucleation theory using several of the current approaches. Overall, the data obtained from the different methods of evaluation are surprisingly consistent. At comparable driving forces, nucleation is clearly fastest in acetone and slowest in propanol, with methanol, ethyl acetate, and ethanol in between. Adding water to the ethanol leads to a clear reduction in the nucleation rate. The solid-solution interfacial energy of butyl paraben in the different solvents decreases in the order: 70% ethanol > 90% ethanol > propanol > ethanol > ethyl acetate > methanol > acetone, which is surprisingly well-correlated to a decreasing solvent boiling point. It is shown that the same trend can be found for other systems in the literature. With the assumption that the stronger the bonding in the bulk phases, the higher the interfacial energy becomes, 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-solution interfacial energy.

Keyword
Aqueous mixtures, Classical nucleation theory, Different solvents, Higher melting points, Nucleation process, Nucleation rate, Primary nucleation, Solid compounds
National Category
Organic Chemistry Pharmaceutical Sciences Physical Chemistry
Research subject
SRA - E-Science (SeRC)
Identifiers
urn:nbn:se:kth:diva-122216 (URN)10.1021/cg400177u (DOI)000326300200017 ()2-s2.0-84885124771 (Scopus ID)
Funder
Swedish e‐Science Research Center
Note

QC 20131028. Updated from submitted to published.

Available from: 2013-05-14 Created: 2013-05-14 Last updated: 2017-12-06Bibliographically approved
2. Thermodynamics of molecular solids in organic solvents
Open this publication in new window or tab >>Thermodynamics of molecular solids in organic solvents
2012 (English)In: Journal of Chemical Thermodynamics, ISSN 0021-9614, E-ISSN 1096-3626, Vol. 48, 150-159 p.Article in journal (Refereed) Published
Abstract [en]

The thermodynamics of solid-solution solubility are examined using data for two different compounds: butyl paraben and benzoic acid. Solubility data in different solvents are used to estimate melting properties of the pure solid solutes, and are used to estimate the solid state Gibbs free energy relative to the super cooled melt. The relation to melting data experimentally determined is analysed, and solution activity coefficients are calculated. The work shows that there is a strong relation between solid-liquid solubility data and thermodynamic data of the pure solute. For these compounds, the melting temperature of the pure solute can be fairly accurately estimated by extrapolation of solid-liquid solubility data up to mole fraction equal unity. The estimation of the melting enthalpy is less successful showing deviations in the order of 20% to 30% from the experimental values determined by differential scanning calorimetry. For butyl paraben and benzoic acid, the best estimation of the solid state Gibbs free energy is obtained if DSC determination of melting properties is combined with an estimation of the melt-solid heat capacity difference versus temperature relation by correlation to solubility data.

Keyword
Butyl paraben, Benzoic acid, Thermodynamic, Solubility, Heat capacity, Melting temperature, Enthalpy of fusion, Correlation, Optimisation
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-87081 (URN)10.1016/j.jct.2011.12.015 (DOI)000300416700021 ()2-s2.0-84862785488 (Scopus ID)
Note
QC 20120627Available from: 2012-02-14 Created: 2012-02-14 Last updated: 2017-12-07Bibliographically approved
3. Investigation of Batch Cooling Crystallization in a Liquid-Liquid Separating System by PAT
Open this publication in new window or tab >>Investigation of Batch Cooling Crystallization in a Liquid-Liquid Separating System by PAT
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.

Keyword
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
Identifiers
urn:nbn:se:kth:diva-98946 (URN)10.1021/op200355b (DOI)000305205200005 ()2-s2.0-84862557100 (Scopus ID)
Note

QC 20120710

Available from: 2012-07-10 Created: 2012-07-05 Last updated: 2017-12-07Bibliographically approved
4. Influence of Solvent and Solid-State Structure on Nucleation of Parabens
Open this publication in new window or tab >>Influence of Solvent and Solid-State Structure on Nucleation of Parabens
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
Keyword
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:nbn:se:kth:diva-122217 (URN)10.1021/cg500449d (DOI)000340080400025 ()2-s2.0-84905686042 (Scopus ID)
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: 2017-12-06Bibliographically approved
5. Sandwich crystals of butyl paraben
Open this publication in new window or tab >>Sandwich crystals of butyl paraben
2014 (English)In: CRYSTENGCOMM, ISSN 1466-8033, Vol. 16, no 37, 8863-8873 p.Article in journal (Refereed) Published
Abstract [en]

Butyl paraben crystals having a porous layer in between two solid non-porous layers have been produced by cooling crystallization in mixtures of ethanol and water. The outer layers are transparent and fully crystalline, while the middle layer appears to be polycrystalline and is full of pores of various dimensions, down to below 0.1 mu m diameters. The thickness of the porous layer reaches about 40% of the whole crystal. The crystals contain one polymorph only and appear to be essentially fully crystalline. They are stable for more than a year when stored on the shelf at room temperature. When the crystals dissolve, the porous layer dissolves faster, leaving the outer layers for slower dissolution. The sandwich crystals are easily cleaved through the middle layer parallel to the (100) plane. This type of sandwich crystals may provide new useful properties to pharmaceutical solids, e. g. larger specific surface area, higher dissolution rates and improved compaction properties.

National Category
Pharmaceutical Sciences Organic Chemistry Analytical Chemistry
Identifiers
urn:nbn:se:kth:diva-122220 (URN)10.1039/c4ce01320d (DOI)000341359200032 ()2-s2.0-84906871652 (Scopus ID)
Note

Updated from manuscript to article.

QC 20141003

Available from: 2013-05-14 Created: 2013-05-14 Last updated: 2014-10-03Bibliographically approved
6. Solubility of Butyl Paraben in Methanol, Ethanol, Propanol, Ethyl Acetate, Acetone, and Acetonitrile
Open this publication in new window or tab >>Solubility of Butyl Paraben in Methanol, Ethanol, Propanol, Ethyl Acetate, Acetone, and Acetonitrile
2010 (English)In: Journal of Chemical and Engineering Data, ISSN 0021-9568, E-ISSN 1520-5134, Vol. 55, no 11, 5091-5093 p.Article in journal (Refereed) Published
Abstract [en]

The solubility of butyl paraben (butyl 4-hydroxybenzoate) have been determined in methanol, ethanol, propanol, acetone, ethyl acetate, and acetonitrile in the temperature range of (10 to 50) C by the gravimetric method. The order of the solubility of butyl paraben in the different solvents as mass fraction at 20 C is: methanol > ethanol > acetone > propanol > ethyl acetate > acetonitrile. In terms of mole fraction solubility, the corresponding order is acetone > propanol > ethanol > ethyl acetate > methanol > acetonitrile, which shows that both nonpolar and polar groups of the paraben molecule influence the solubility in the different solvents.

Keyword
published literature, thermodynamics, health
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-27367 (URN)10.1021/je1006289 (DOI)000284017600083 ()2-s2.0-78449307514 (Scopus ID)
Note
QC 20101214Available from: 2010-12-14 Created: 2010-12-13 Last updated: 2017-12-11Bibliographically approved
7. Ternary diagrams of ethyl paraben and propyl paraben
Open this publication in new window or tab >>Ternary diagrams of ethyl paraben and propyl paraben
(English)Manuscript (preprint) (Other academic)
National Category
Pharmaceutical Sciences Organic Chemistry Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-122224 (URN)
Note

QS 2013

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

Open Access in DiVA

Crystallization of Parabens: Thermodynamics, Nucleation and Processing(3603 kB)2280 downloads
File information
File name FULLTEXT02.pdfFile size 3603 kBChecksum SHA-512
b4c4ba39696d6ea7a4b56194c4861911ef10b8fa79027e31c3f2e41d47ca28525a7dbf666dbf01aaf9afce1645b61f223633344a0e4c0e7e4a9f2009cdc5c4ae
Type fulltextMimetype application/pdf

Authority records BETA

Huaiyu, Yang

Search in DiVA

By author/editor
Huaiyu, Yang
By organisation
Transport Phenomena
Pharmaceutical SciencesOrganic ChemistryPhysical Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 2280 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 435 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf