Unit:
Κατεύθυνση Φαρμακευτική Ανάλυση - Έλεγχος ποιότηταςLibrary of the School of Science
Supervisors info:
Παντερή Ειρήνη, Καθηγήτρια, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Ντότσικας Ιωάννης, Επίκουρος Καθηγητής, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Γιαγκίνης Κωνσταντίνος, Επίκουρος Καθηγητής, Τμήμα Επιστήμης Τροφίμων και Διατροφής, Πανεπιστήμιο Αιγαίου
Original Title:
Μετρήσεις λιποφιλίας σε όξινα, βασικά και ουδέτερα φαρμακευτικά μόρια με ισοκρατική και βαθμιδωτή έκλουση
Translated title:
Lipophilicity measurements of acid, basic and neutral drugs by isocratic and gradient elution chromatography
Summary:
The importance of lipophilicity in the pharmacodyamic and pharmacokinetic behaviour of drugs, as well as in their toxicity, in combination with drawbacks and limitations in partitioning experiments in the reference system octanol-water, triggered research towards the application of friendly and rapid reversed phase chromatographic techniques for the simulation of partition coefficients logP and distribution coefficients logD. Isocratic measurements at different organic modifier concentrations are used for the determination of extrapolated retention factors logkw, corresponding to 100% aqueous mobile phase. Extrapolated retention factors may lead to 1:1 correlation with logP or logD under suitable conditions. On the other hand, gradient elution chromatography has been developped for the determination of Chromatographic Hydrophobicity Index (CHI), which corresponds to the fraction of organic modifier lead to equal distribution between stationary and mobile phase. After construction of calibration equations for the chromatographic system used, the method is very rapid. However up to now, it is restricted to neutral compounds.
The present study is focused on the determination of lipophilicity in acidic, basic and neutral pharmaceutical drugs upon application of both chromatographic techniques and took place at the National and Kapodistruian University of Athens, Department of Pharmaceutical Analysis. In the first part of the experimental section the replacement of decylamine by octylamine was investigated as masking agent of the residual silanol sites present in silica based reversed phase columns, in the case of neutral and basic compounds. It was assumed that octylamine would be better for the column due to its reduced hydrophobicity. Extrapolated retention factors logkwoct were compared to corresponding logkwdec values determined earlier at our laboratory and available in literature. They were also compared to the logD7.4 of the compounds. In the second part the isocratic coditions were transferred to gradient elution chromatography in the aim to expand its application to ionizable compounds.
Our results showed that octylamine is less efficient as a masking agent and leads to increased retention, in particular in the case of protonated bases. However introduction of the term Δ(logP-logD7.4), as an expression of the effect of ionisation in lipophilicity in the logkwoct / logkwdec relationship showed similar thermodynamic balance in retention, while it leads to high quality equations, which permit the interconversion of logkw determined either by decylamine or octylamine. The transfer of the isocratic conditions to gradient elution chromatography showed that analogous retention behavior is mantained.
Gradient retention times however correlate non-linearly with the values of φ0 determined by isocratic conditions. Better results for CHI determination were obtained by a parabolic relationship. The values CHIquad correlate reasonably with logD7.4 if in the equation also the fraction protonated and the anionic fraction are included as additional parameters. Statistics are similar with those of isocratic chromatography for the logD7.4/φ0oct relationship and slightly inferior for the logD7.4/logkwoct relationship. In this aspect, the problem concerns the use of octylamine, while it is shown that conditions are tranferrable to gradient elution Chromatography. These results are encouraging for the application of gradient elution chromatography also to basic and acidic compounds.
Main subject category:
Science
Other subject categories:
Health Sciences
Keywords:
gradient elution, lipophilicity, masking agent
Number of references:
116
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ΔΙΠΛΩΜΑΤΙΚΗ ΕΡΓΑΣΙΑ-ΛΥΤΡΑ ΝΑΤΑΛΙΑ.pdf
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