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Prediction of solubility curves and melting properties of organic and pharmaceutical compounds
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.
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.

Place, publisher, year, edition, pages
2009. Vol. 36, no 2-3, 330-344 p.
Keyword [en]
Prediction of solubility, Prediction of melting properties, Temperature dependence of, solubility, Van't Hoff enthalpy of solution
National Category
Chemical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-8419DOI: 10.1016/j.ejps.2008.10.009ISI: 000262971100017Scopus ID: 2-s2.0-58149154534OAI: oai:DiVA.org:kth-8419DiVA: diva2:13733
Note
QC 20100831. Uppdaterad från submitted till published (20100831).Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Solid-liquid Phase Equilibria and Crystallization of Disubstituted Benzene Derivatives
Open this publication in new window or tab >>Solid-liquid Phase Equilibria and Crystallization of Disubstituted Benzene Derivatives
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
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:nbn:se:kth:diva-4742 (URN)978-91-7178-949-5 (ISBN)
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

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