Proučavanje ravnoteža u heterogenim sistemima tricikličnih antidepresiva: uticaj agregacije i sastava čvrste faze na rastvorljivost

Abstract

Cilj ove doktorske disertacije bio je razvoj metode koja će omogućiti tačno i precizno određivanje termodinamičke rastvorljivosti i definisanje ravnoteža u heterogenim sistemima nekih tricikličnih antidepresiva (desipramin, nortriptilin, imipramin i amitriptilin) u prisustvu fosfata i/ili hlorida. Rastvorljivost tricikličnih antidepresiva u zavisnosti od pH vrednosti na 25±1 ⁰ C određena je primenom pH–Ramp shake–flask metode, razvijene tokom izrade ove teze. Koncentracije jedinjenja u rastvoru određene su pomoću HPLC–UV/VIS metode. Čvrsta faza analizirana je primenom elementalne analize, termogravimetrijske analize, diferencijalne skenirajuće kalorimetrije i difrakcije X-zraka praha. Kritične micelarne koncentracije imipramina i amitriptilina određene su primenom konduktometrijskih titracija. Degradacija imipramina i amitriptilina u baznoj sredini analizirana je pomoću UV/VIS spektrofotometrije i HPLC–UV/VIS metode. Koncentracione ravnotežne konstante (Iref 0,15 M, 25 ⁰ C) – sopstvene rastvorljivosti, proizvodi rastvorljivosti soli, konstante građenja kompleksa i konstante agregacije, izračunate su pomoću programa pDISOL– XTM. Primećeno je da desipramin i nortriptilin grade katjonske i anjonske komplekse sa komponentama fosfatnog pufera, dok imipramin i amitriptilin formiraju agregate, što dovodi do povećanja rastvorljivosti tricikličnih antidepresiva. U zavisnosti od sastava suspenzije i dizajna eksperimenta triciklični antidepresivi talože se u obliku hloridnih ili fosfatnih soli ili u molekulskom obliku. Rezultati pokazuju da pH–Ramp shake–flask metoda ima veliki potencijal u proučavanju pH-zavisne rastvorljivosti i da u kombinaciji sa metodama za karakterizaciju čvrste faze može biti veoma korisna u različitim fazama dizajna i razvoja lekova.

The aim of this doctoral dissetation was development of the new method for thermodynamic solubility determination which can provide accurate and precise data and description of equilibria in tricyclic antidepressant (desipramine, nortriptyline, imipramine and amitriptyline) heterogeneous systems containing phosphate and/or chloride ions. The solubility of tricyclic antidepressant at 25±1 °C as a function of pH was determined using pH–Ramp shake–flask method, developed as a results of this dissertation. Concentration was measured by HPLC–UV/VIS method. The solid phases were characterized using elemental, thermogravimetric, differential scanning calorimetric, and powder X- ray diffraction analyses. Conductivity measurements were used for critical micelle concentration determination. Degradation of imipramine and amitriptyline in alkaline media was investigated by UV/VIS spectrophotometry and HPLC–UV/VIS method. Concentration thermodynamic constants (Iref 0,15 M, 25 ⁰ C) – intrinsic solubilities, solubility products, complexation and aggregation constants, were refined using the computer program pDISOL–XTM. Cationic and anionic phosphate complex formation was observed in heterogeneous systems of desipramine and nortriptyline, but self–aggregation was observed in heterogeneous systems of imipramine and amitriptyline, leading to increased solubility of tricyclic antidepressant. Depending on suspension composition and experimental design, tricyclic antidepressant can precipite as chloride and phosphate salts or free base. pH–Ramp shake–flask method in combination with solid state characterization methods can be powerful technique in pH-dependent solubility investigation and can provide high-quality data that can be useful in drug research.