Proučavanje ravnoteža u heterogenim sistemima tricikličnih antidepresiva: uticaj agregacije i sastava čvrste faze na rastvorljivost
Study of equilibria in tricyclic antidepressant heterogeneous systems: influence of aggregation and the solid phase composition on solubility
Метаподаци
Приказ свих података о дисертацијиСажетак
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 solub...ilities, 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.