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Molecular descriptors influencing melting point and their role in classification of solid drugs
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
2003 In: Journal of Chemical Information and Computer Sciences, Vol. 43, no 4, 1177-1185 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2003. Vol. 43, no 4, 1177-1185 p.
URN: urn:nbn:se:uu:diva-90860OAI: oai:DiVA.org:uu-90860DiVA: diva2:163363
Available from: 2003-09-30 Created: 2003-09-30Bibliographically approved
In thesis
1. Computational and Experimental Models for the Prediction of Intestinal Drug Solubility and Absorption
Open this publication in new window or tab >>Computational and Experimental Models for the Prediction of Intestinal Drug Solubility and Absorption
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

New effective experimental techniques in medicinal chemistry and pharmacology have resulted in a vast increase in the number of pharmacologically interesting compounds. However, the number of new drugs undergoing clinical trial has not augmented at the same pace, which in part has been attributed to poor absorption of the compounds.

The main objective of this thesis was to investigate whether computer-based models devised from calculated molecular descriptors can be used to predict aqueous drug solubility, an important property influencing the absorption process. For this purpose, both experimental and computational studies were performed. A new small-scale shake flask method for experimental solubility determination of crystalline compounds was devised. This method was used to experimentally determine solubility values used for the computational model development and to investigate the pH-dependent solubility of drugs. In the computer-based studies, rapidly calculated molecular descriptors were used to predict aqueous solubility and the melting point, a solid state characteristic of importance for the solubility. To predict the absorption process, drug permeability across the intestinal epithelium was also modeled.

The results show that high quality solubility data of crystalline compounds can be obtained by the small-scale shake flask method in a microtiter plate format. The experimentally determined pH-dependent solubility profiles deviated largely from the profiles predicted by a traditionally used relationship, highlighting the risk of data extrapolation. The in silico solubility models identified the non-polar surface area and partitioned total surface areas as potential new molecular descriptors for solubility. General solubility models of high accuracy were obtained when combining the surface area descriptors with descriptors for electron distribution, connectivity, flexibility and polarity. The used descriptors proved to be related to the solvation of the molecule rather than to solid state properties. The surface area descriptors were also valid for permeability predictions, and the use of the solubility and permeability models in concert resulted in an excellent theoretical absorption classification. To summarize, the experimental and computational models devised in this thesis are improved absorption screening tools applicable to the lead optimization in the drug discovery process.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 65 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 295
Pharmaceutics, aqueous drug solubility, melting point, intestinal drug permeability, pH-dependent solubility, multivariate data analysis, molecular descriptors, molecular surface area, in silico modeling, drug absorption, Galenisk farmaci
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-3593 (URN)91-554-5747-9 (ISBN)
Public defence
2003-10-24, B42, Uppsala Biomedicinska Centrum, Uppsala, 13:00
Available from: 2003-09-30 Created: 2003-09-30Bibliographically approved

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