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Solid-liquid Phase Equilibria and Crystallization of Disubstituted Benzene Derivatives
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena.
2008 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

The Ph.D. project compiled in this thesis has focused on the role of the solvent in solid-liquid phase equilibria and in nucleation kinetics. Six organic substances have been selected as model compounds, viz. ortho-, meta- and para-hydroxybenzoic acid, salicylamide, meta- and para-aminobenzoic acid. The different types of crystal phases of these compounds have been explored, and their respective solid-state properties have been determined experimentally. The solubility of these crystal phases has been determined in various solvents between 10 and 50 oC. The kinetics of nucleation has been investigated for salicylamide by measuring the metastable zone width, in five different solvents under different experimental conditions.

A total of 15 different crystal phases were identified among the six model compounds. Only one crystal form was found for the ortho-substituted compounds, whereas the meta-isomeric compounds crystallized as two unsolvated polymorphs. The para-substituted isomers crystallized as two unsolvated polymorphs and as several solvates in different solvents.

It was discovered that the molar solubility of the different crystal phases was linked to the temperature dependence of solubility. In general, a greater molar solubility corresponds to a smaller temperature dependence of solubility.

The generality of this relation for organic compounds was investigated using a test set of 41 organic solutes comprising a total of 115 solubility curves. A semi-empirical solubility model was developed based on how thermodynamic properties relate to concentration and temperature. The model was fitted to the 115 solubility curves and used to predict the temperature dependence of solubility. The model allows for entire solubility curves to be constructed in new solvents based on the melting properties of the solute and the solubility in that solvent at a single temperature.

Based on the test set comprising the 115 solubility curves it was also found that the melting temperature of the solute can readily be predicted from solubility data in organic solvents.

The activity of the solid phase (or ideal solubility) of four of the investigated crystal phases was determined within a rigorous thermodynamic framework, by combining experimental data at the melting temperature and solubility in different solvents and temperatures. The results show that the assumptions normally used in the literature to determine the activity of the solid phase may give rise to errors up to a factor of 12.

An extensive variation in the metastable zone width of salicylamide was obtained during repeated experiments performed under identical experimental conditions. Only small or negligible effects on the onset of nucleation were observed by changing the saturation temperature or increasing the solution volume. The onset of nucleation was instead considerably influenced by different cooling rates and different solvents. A correlation was found between the supersaturation ratio at the average onset of nucleation and the viscosity of the solvent divided by the solubility of the solute. The trends suggest that an increased molecular mobility and a higher concentration of the solute reduce the metastable zone width of salicylamide.

Place, publisher, year, edition, pages
Stockholm: KTH , 2008. , xx, 98 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2008-32
Keyword [en]
Salicylic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, salicylamide, m-aminobenzoic acid, p-aminobenzoic acid, solubility, solid-liquid equilibria, thermodynamics, activity of the solid phase, ideal solubility, activity coefficient, van't Hoff enthalpy of solution, solid state, solution properties, metastable zone width, primary nucleation, nucleation kinetics
National Category
Chemical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-4742ISBN: 978-91-7178-949-5 (print)OAI: oai:DiVA.org:kth-4742DiVA: diva2:13737
Public defence
2008-05-30, D3, D, Lindstedtsvägen 5, KTH, 10:00
Opponent
Supervisors
Note
QC 20100831Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2010-08-31Bibliographically approved
List of papers
1. Phase Equilibria and Thermodynamics of p-Hydroxybenzoic acid
Open this publication in new window or tab >>Phase Equilibria and Thermodynamics of p-Hydroxybenzoic acid
2006 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 95, no 4, 748-760 p.Article in journal (Refereed) Published
Abstract [en]

The prevalence of phases and associated solubilities of p-hydroxybenzoic acid have been investigated in methanol, acetonitrile, acetic acid, acetone, water, and ethyl acetate at temperatures from 10 to 50 degrees C. Thermodynamic data was acquired through determination of van't Hoff enthalpy of solution, enthalpy of fusion, and melting temperature. Indications of polymorphic enantiotropy were found primarily through solubility analysis and FTIR-ATR. A comprehensive thermodynamic investigation disclosed correlation between the van't Hoff enthalpy of solution and the solubility in different solvents. A higher solubility is linked to a lower van't Hoff enthalpy of solution. A thermodynamic analysis to discriminate between different solid phases is presented.

Keyword
p-hydroxybenzoic acid, 4-hydroxybenzoic acid, polymorphism, pseudopolymorphism, solvate, complexation, solubility, desolvation, solid state stability, van't Hoff
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8414 (URN)10.1002/jps.20569 (DOI)000236485300004 ()2-s2.0-33645991201 (Scopus ID)
Note
QC 20100831Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2010-12-17Bibliographically approved
2. Polymorphism and Thermodynamics of m-Hydroxybenzoic acid
Open this publication in new window or tab >>Polymorphism and Thermodynamics of m-Hydroxybenzoic acid
2006 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 28, no 5, 377-384 p.Article in journal (Refereed) Published
Abstract [en]

Solution and solid-state properties of m-hydroxybenzoic acid have been investigated. Two polymorphs were found where the monoclinic modification exhibits a higher stability than the orthorhombic form. The solubility of the monoclinic polymorph was determined between 10 and 50 degrees C in methanol, acetonitrile, acetic acid, acetone, water and ethyl acetate. The solubility of the orthorhombic polymorph was determined between 10 and 50 degrees C in acetonitrile, acetic acid, acetone and ethyl acetate. A thermodynamic analysis revealed a marked correlation between the molar solubility and the van't Hoff enthalpy of solution at constant temperature. In addition, in each solvent increased temperature resulted in increased van't Hoff enthalpy of solution. It is shown that the solubility data can be used to estimate melting properties for both polymorphs. The solubility ratio of the two forms and the DSC thermogram of the orthorhombic form strongly suggest that the system is monotropic. However, according to the polymorph rules of Burger and Ramberger, the estimated higher melting enthalpy and lower melting temperature of the orthorhombic form points towards an enantiotropic system. Hence, this system appears to be an exception to the Burger and Ramberger melting enthalpy rule, and the probable reason for this is found in the difference in the heat capacity of the two solid forms.

Keyword
m-hydroxybenzoic acid, 3-hydroxybenzoic acid, polymorphism, monotropy, enantiotropy, solubility, van't Hoff enthalpy of solution, thermodynamics
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8415 (URN)10.1016/j.ejps.2006.04.008 (DOI)000239682800003 ()2-s2.0-33745841320 (Scopus ID)
Note
QC 20100831Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2010-12-17Bibliographically approved
3. Solubility and Melting Properties of Salicylic acid
Open this publication in new window or tab >>Solubility and Melting Properties of Salicylic acid
2006 (English)In: Journal of Chemical and Engineering Data, ISSN 0021-9568, E-ISSN 1520-5134, Vol. 51, no 5, 1668-1671 p.Article in journal (Refereed) Published
Abstract [en]

The solubility of salicylic acid has been investigated in methanol, acetonitrile, acetic acid, acetone, water, and ethyl acetate from (10 to 50) degrees C. No new polymorphs or solvates of salicylic acid were found. The melting properties of salicylic acid were determined by differential scanning calorimetry. A correlation was observed between the solubility and the van't Hoff enthalpy of solution. A higher solubility was related to a lower van't Hoff enthalpy of solution. Water differed from the organic solvents in terms of solubility and its correlation to the van't Hoff enthalpy of solution. In addition, the morphology of salicylic acid crystals recrystallized from water differed from the other solvents.

Keyword
Ethyl acetates, Salicylic acids, Van't Hoff enthalpy
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8416 (URN)10.1021/je060134d (DOI)000240496200031 ()2-s2.0-33749824948 (Scopus ID)
Note
QC 20100831Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2010-08-31Bibliographically approved
4. Solubility and Melting Properties of Salicylamide
Open this publication in new window or tab >>Solubility and Melting Properties of Salicylamide
2006 (English)In: Journal of Chemical and Engineering Data, ISSN 0021-9568, E-ISSN 1520-5134, Vol. 51, no 5, 1775-1777 p.Article in journal (Refereed) Published
Abstract [en]

The solubility of salicylamide in methanol, acetonitrile, acetic acid, acetone, water, and ethyl acetate has been determined between (10 to 50) degrees C. The onset melting temperature and enthalpy of fusion has been determined by differential scanning calorimetry to 138.7 degrees C and 29.0 kJ center dot mol(-1), respectively. Only the monoclinic structure of salicylamide was observed at crystallization.

Keyword
Melting temperature, Monoclinic structure, Salicylamide
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8417 (URN)10.1021/je060178m (DOI)000240496200050 ()2-s2.0-33749865149 (Scopus ID)
Note
QC 20100831Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2010-08-31Bibliographically approved
5. Determination of the Activity of the Solid phase of Molecular Compounds
Open this publication in new window or tab >>Determination of the Activity of the Solid phase of Molecular Compounds
(English)Article in journal (Other academic) Submitted
Abstract [en]

The activity of the solid phase of an organic molecular compound is often defined using the melt at the same temperature as the thermodynamic reference. However, far below the melting temperature, the properties of this reference state cannot be determined experimentally, and different simplifications and approximations are normally adopted. In the present work, a novel method is presented to determine the activity of the solid phase (= ideal solubility) and the heat capacity difference between the supercooled melt and solid. The approach is based on rigorous thermodynamics, using standard experimental thermodynamic data at the melting temperature of the pure compound and solubility measurements in different solvents at various temperatures. The method is illustrated using data for ortho-, meta-, and para-hydroxybenzoic acid, salicylamide and paracetamol. The results show that complete neglect of the heat capacity terms may lead to estimations of the activity that are incorrect by a factor of 12. Other commonly used simplifications may lead to estimations that are only one third of the correct value.

Keyword
Solid-state activity, ideal solubility, heat of fusion, heat capacity, supercooled liquid
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8418 (URN)
Note
QS 20120328Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2012-03-28Bibliographically approved
6. Prediction of solubility curves and melting properties of organic and pharmaceutical compounds
Open this publication in new window or tab >>Prediction of solubility curves and melting properties of organic and pharmaceutical compounds
2009 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 36, no 2-3, 330-344 p.Article in journal (Refereed) Published
Abstract [en]

The relationships between solubility, temperature dependence of solubility, melting temperature and melting enthalpy are investigated for the purpose of finding relations that can significantly reduce the need for experimental work in the selection of the solvent for processing of organic fine chemicals and pharmaceuticals. The relationships are investigated theoretically and by evaluation of experimental data for 41 organic and pharmaceutical compounds comprising a total of 115 solubility curves in organic and aqueous solvents. The work considers (i) selection of the equation for correlation of solubility data based on thermodynamic considerations and ability to predict melting properties of the solute from solubility data, (ii) prediction of the temperature dependence of solubility, and (iii) prediction of solubility curves in new solvents. While it is a simple task to find an equation to obtain a decent fit of experimental solubility data, it is more challenging to find relations that are sufficiently sound thermodynamically to allow for extrapolation to the melting temperature. However, with a proper choice of equation it is shown that the melting temperature of the solute can readily be predicted from solubility data in organic solvents (average accuracy of -5K, standard deviation of 26 K). Relationships are identified by which the entire solubility curve can be predicted of the compound in a new solvent using only the melting properties and a single solubility data point in that solvent.

Keyword
Prediction of solubility, Prediction of melting properties, Temperature dependence of, solubility, Van't Hoff enthalpy of solution
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8419 (URN)10.1016/j.ejps.2008.10.009 (DOI)000262971100017 ()2-s2.0-58149154534 (Scopus ID)
Note
QC 20100831. Uppdaterad från submitted till published (20100831).Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2010-08-31Bibliographically approved
7. Metastable Zone Width of Salicylamide
Open this publication in new window or tab >>Metastable Zone Width of Salicylamide
(English)Manuscript (Other academic)
Keyword
Salicylamide, metastable zone width, supersaturation, primary nucleation, nucleation kinetics
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8420 (URN)
Note
QC 20100831Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2010-08-31Bibliographically approved
8. (2/1) p-Aminobenzoic acid-Acetone Solvate
Open this publication in new window or tab >>(2/1) p-Aminobenzoic acid-Acetone Solvate
(English)Manuscript (Other academic)
Keyword
p-aminobenzoic acid, solvate, adducts, complex, solubility
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8421 (URN)
Note
QC 20100831Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2010-08-31Bibliographically approved
9. (2/1) p-Hydroxybenzoic acid-1,4-Dioxane Solvate
Open this publication in new window or tab >>(2/1) p-Hydroxybenzoic acid-1,4-Dioxane Solvate
(English)Manuscript (Other academic)
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8422 (URN)
Note
QC 20100831Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2010-08-31Bibliographically approved

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