Unit:
Κατεύθυνση Φαρμακευτική Ανάλυση - Έλεγχος ποιότηταςLibrary of the School of Science
Supervisors info:
Τσαντίλη - Κακουλίδου Άννα Καθηγήτρια Ε.Κ.Π.Α. Τμήμα: Φαρμακευτική Τομέας: Φαρμακευτική Χημεία
Γκίκας Ευάγγελος Επίκουρος Καθηγητής Ε.Κ.Π.Α. Τμήμα: Φαρμακευτική Τομέας: Φαρμακευτική Χημεία
Original Title:
ΑΝΑΠΤΥΞΗ ΚΑΙ ΒΕΛΤΙΣΤΟΠΟΙΗΣΗ ΜΕΘΟΔΩΝ ΠΡΟΣΔΙΟΡΙΣΜΟΥ ΛΙΠΟΦΙΛΙΑΣ ΦΑΡΜΑΚΕΥΤΙΚΩΝ ΕΝΩΣΕΩΝ
Translated title:
DEVELOPMENT OF NEW METHODS AND IMPROVE THEM FOR THE DETERMINATION OF LIPOPHILICITY OF DRUGS
Summary:
The present study is focused on the development of new methods and improve them in order to determine the lipophilicity of drugs. The shaking flask is still the most dominant procedure for the estimation of the distribution coefficient at water / octanol partition. Unfortunately, the problems have escalate the intrest for new methods.
The first part capitalizes on liquid chromatography and it’s advantages against traditional shaking flask for the determination of lipophilicity by the use of ABZ+ coloumn. For the estimation of chromatographic parameters such as log kw values has applied different conditions. Especially, the tested conditions are ammonium acetate – acetic acid / acetonitrile under pH 5.0 and ammonium acetate – ammonia / acetonitrile and phosphate buffer solution (saturated in octanol) / methanol (+ 0.25% octanol) for pH 7.4. Log kw values have led to considerable log D values diviations. An other approach was the insertion of φ0 values (the percentage of organic modifier required to achieve an equal distribution of compound between the mobile and stationary phase) which shows better results in the case of ammonium acetate buffers. Unfortunately, isocratic elutions are tedious and substantial solvent – consuming process. The transition from isocratic to gradient elution was obligated. The outcome was the introduction of Chromatographic Hydrophobicity Index (CHI). The CHI values demostrated more reliable results than log kw values even though φ0 parameter maintains the highest log D correlation (an exception is the phosphate buffer where the log kw values present the minor deviations for both φ0 and CHI values respecting to experimental log D values). An attempt to eliminate the abnormality of retention time where ionized acids are analyzied, was EDTA as mobile phase additive. EDTA was expected to prevent the complexation between ionized acids and metal impurities on silica surface by reducing the retention time of acids. On the contrary, the retention was increased.
The second part uses the electrospray mass spectrometry (ESI/MS) as a potential tool for determining the lipophilicity of acids and bases. For the purpose of the study, three models have been created. The first is for the acids, the second for the bases and the third combines both acids and bases. The results show a good correlation between log D and the ion intensity in electrospray mass spectrometry. The expirement performed at pH 5.0 conditions.
The third part linkage the lipophilicity of indirubin derivatives with cells membrane permeability. Crucial is the apply of biomimetic chromatography by ΙΑΜ.PC.DD2 coloumn installation. The chromatograthic results have shown prolonged retention in IAM stationary phase. The extended retentions may induce toxicity in human cells. The indirubin derivatives
4
were synthesized at University of Athens, Department of Pharmacognosy and Natural Products Chemistry
Main subject category:
Science
Keywords:
Lipophilicity, HPLC, Orbitrap, Indirubins
