Study of equilibria in tricyclic antidepressant heterogeneous systems: influence of aggregation and the solid phase composition on solubility

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

Study of equilibria in tricyclic antidepressant heterogeneous systems: influence of aggregation and the solid phase composition on solubility

Cilj ove doktorske disertacije bio je razvoj metode koja će omogućiti tačno i preciznoodređivanje termodinamičke rastvorljivosti i definisanje ravnoteža u heterogenim sistemima nekihtricikličnih antidepresiva (desipramin, nortriptilin, imipramin i amitriptilin) u prisustvu fosfata i/ilihlorida. Rastvorljivost tricikličnih antidepresiva u zavisnosti od pH vrednosti na 25±1 ⁰ C određenaje primenom pH–Ramp shake–flask metode, razvijene tokom izrade ove teze. Koncentracijejedinjenja u rastvoru određene su pomoću HPLC–UV/VIS metode. Čvrsta faza analizirana jeprimenom elementalne analize, termogravimetrijske analize, diferencijalne skenirajuće kalorimetrijei difrakcije X-zraka praha. Kritične micelarne koncentracije imipramina i amitriptilina određene suprimenom konduktometrijskih titracija. Degradacija imipramina i amitriptilina u baznoj sredinianalizirana je pomoću UV/VIS spektrofotometrije i HPLC–UV/VIS metode. Koncentracioneravnotežne 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 sakomponentama fosfatnog pufera, dok imipramin i amitriptilin formiraju agregate, što dovodi dopovećanja rastvorljivosti tricikličnih antidepresiva. U zavisnosti od sastava suspenzije i dizajnaeksperimenta triciklični antidepresivi talože se u obliku hloridnih ili fosfatnih soli ili umolekulskom obliku. Rezultati pokazuju da pH–Ramp shake–flask metoda ima veliki potencijal uproučavanju pH-zavisne rastvorljivosti i da u kombinaciji sa metodama za karakterizaciju čvrstefaze može biti veoma korisna u različitim fazama dizajna i razvoja lekova.The aim of this doctoral dissetation was development of the new method for thermodynamicsolubility determination which can provide accurate and precise data and description of equilibria intricyclic antidepressant (desipramine, nortriptyline, imipramine and amitriptyline) heterogeneoussystems 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 resultsof this dissertation. Concentration was measured by HPLC–UV/VIS method. The solid phases werecharacterized using elemental, thermogravimetric, differential scanning calorimetric, and powder X-ray diffraction analyses. Conductivity measurements were used for critical micelle concentrationdetermination. Degradation of imipramine and amitriptyline in alkaline media was investigated byUV/VIS spectrophotometry and HPLC–UV/VIS method. Concentration thermodynamic constants(Iref 0,15 M, 25 ⁰ C) – intrinsic solubilities, solubility products, complexation and aggregationconstants, were refined using the computer program pDISOL–XTM. Cationic and anionic phosphatecomplex formation was observed in heterogeneous systems of desipramine and nortriptyline, butself–aggregation was observed in heterogeneous systems of imipramine and amitriptyline, leadingto increased solubility of tricyclic antidepressant. Depending on suspension composition andexperimental design, tricyclic antidepressant can precipite as chloride and phosphate salts or freebase. pH–Ramp shake–flask method in combination with solid state characterization methods canbe powerful technique in pH-dependent solubility investigation and can provide high-quality datathat can be useful in drug research

Biology of the deep water pink shrimp Parapenaeus longirostris (Lucas, 1846) (Crustacea, Decapoda) on the Montenegrin shelf

Jedna od najvažnijih komercijalnih vrsta dekapodnih rakova u kočarskom ribolovu na šelfu Crnogorskog primorja je kozica, Parapenaeus longirostris (Lucas, 1846). Istraživanje je obavljeno tokom dvije godine, od novembra 2006. do oktobra 2007. i od juna 2009. do maja 2010. godine pri čemu su uzorci uzimani sa kočarskih brodova mjesečnom dinamikom. Tokom prve godine je ukupno obrađeno 1979 jedinki, od kojih su 1421 (71.80%) bile ženke a 558 (28.20%) mužjaci. Odnos polova je i u drugoj godini bio u korist ženki tokom koje je analizirano 1967 jedinki, od kojih su 1304 (66.30%) bile ženke a 663 (33.70%) mužjaci. Raspon dužina karapaksa svih ulovljenih jedinki zajedno je bio manji u prvoj godini i kretao se od 15 do 37 mm (25.23 ± 4.48) dok je u drugoj taj raspon bio 11-37 mm (24.85 ± 4.48). Uočen je polni dimorfizam: ženke su u prosjeku i duže i teže od mužjaka, i u dužinskim grupama >28- 30 mm CL su 100% prisutne u ulovu. Mužjaci su u boljoj kondiciji od ženki. Vrijednosti alometrijskog koeficijenata b dužinsko-težinskog odnosa u prvoj godini iznose b = 2.58 za ukupan uzorak, b = 2.51 za ženke i b = 2.34 za mužjake; dok te vrijednosti za drugu godinu iznose b = 2.59 za ukupan uzorak, b = 2.57 za ženke i b = 2.33 za mužjake. Prva polna zrelost ženki je nastupila pri dužini karapaksa od 20.48 mm u prvoj godini, odnosno od 19.89 mm CL u drugoj godini...Parapenaeus longirostris (Lucas, 1846) is one of the most economically important decapod species in the trawl fishery on the Montenegrin shelf (southern Adriatic Sea). Despite its importance, there were no biological studies on the species for that area. Data were obtained from monthly samples taken from commercial catches realized in the southern Adriatic during the period from November 2006 to October 2007 and from June 2009 to May 2010. During the first year among the 1979 specimens, 71.80% were females and 28.20% males, while during the second year of investigation, among the 1967 specimens, 66.30% were females and 33.70% males. The overall sex ratio was in favour of females. The carapace length of all specimens ranged from 15 to 37 mm, with a mean of 25.23 ± 4.48, while during the second year the range of carapace length of all specimens was wider and ranged from 11 to 37 mm, with a mean of 24.85 ± 4.48. A marked sexual dimorphism was observed between males and females: females have a wider size range, greater size and weight. Percentage of females reached 100% in the 28-30 mm size class and beyond. Males were in better condition than females. The calculated allometric coefficient of length-weight relationships was b= 2.58 for the total sample of 2006-2007 year, b= 2.51 for females and b= 2.34 for males; while during the 2009-2010 values were b=2.59 for the total sample, b=2.57 for females and b=2.33 for males. The size at which 50% of the female population reached maturity was at a carapace length of 20.48 mm in the first year and 19.89 mm during the second year..

Analytical and numerical method of velocity fields for the explosively formed projectiles

Ovaj rad predstavlja analitički i numerički pristup procenu performansi brzine za Eksplozivno Formirane Projektile (EFP). Predložene analitičke metode matematički razvijaju parametre brzina pojedinačnih segmenata za EFP disk pogonjen eksplozivnim procesom. Ovaj model baziran je na dobro poznatim teorijskim pristupima distribucije energije na plastičnim telima u dinamičkim uslovima formiranjem integralnih rešenja za konačnu brzinu projektila. Paralelno sa analitičkim takođe je razvijen i numerički metod u cilju obezbeđenja procene ponašanje projktila u toku vrmena procesa formiranja EFP-a pogonjenog eksplozivom. Oba modela su validna za procenu performansi EFP bojevih glava i projektnih podatka za optimalno projektivanje oblika EFP-a. Simulacije su podržane softverima Matlob i Autodin kako za ananlitičko tako i numeričko modeliranje. Dobijeni numerički i analitički rezultati upoređeni su sa raspoloživivim eksperimentalnim rezultatima. PR Projekat Ministarstva nauke Republike Srbije, br. III-47029.The current paper presents analytical and numerical approaches of velocity performances estimations for the EFP (Explosively Formed Projectiles). The proposed analytical methods mathematically develop velocities parameters of a particular segment for EFP liner propelled by explosive process. This model is based on the well-known theoretical approaches of energy distribution on plastic body in dynamical conditions providing integral solution for projectile final velocity. The redundant to analytical, the numerical method is also developed, to provides estimations about behavior of projectile vs. time in the EFP forming process powered by explosion. Both models are valid for performances estimations of EFP warheads and design data for optimal EFP configuration. Simulations are supported by the software Matlab and Autodyn for analytical and numerical modeling respectively. The obtained numerical and analytical results are compared with the available experimental data

A new simple liquid chromatographic assay for gentamicin in presence of methylparaben and propylparaben

Gentamicin sulfate is a potent broad spectrum aminoglycoside antibiotic which is used against Gram- positive and Gram-negative bacteria. A simple, isocratic HPLC method for separation, identification and determination of gentamicin and parabens (methylparaben and propylparaben) was developed and validated. To our knowledge there is no report about simultaneous determination of those three ana- lytes in pharmaceutical products. The optimum chromatographic conditions were achieved on CN column with a mobile phase consisting of 0.15% triethylamine in 10 mM KH 2 PO4 aqueous solution (final pH 3.0 adjusted with H 3 PO 4 ) and methanol in the ratio 70:30 (v/v), providing selective quan- tification of analytes within 5 min. The method was successfully validated according to ICH guidelines acceptance criteria in terms of selectivity, linearity, accuracy, precision and robustness. The linearity of the method was proved in defined concentrations ranges for gentamicin (0.32–1.04 mg mL1 ), meth- ylparaben (0.0072–0.0234 mg mL1 ) and propylparaben (0.0008–0.0026 mg mL1 ). Relative standard deviations calculated for all analytes in precision testing were <2% (analysis repeatability) and <3% (intermediate precision). Recovery values were between 98.87% and 101.67%. Chromatographic pa- rameters are not significantly influenced by small variations of column temperature, pH and molarity of KH2 PO 4 . Finally, the method was successfully applied for quantitative determination of gentamicin and parabens in commercially available solution for injection. Proposed HPLC method is found to be promising in terms of simplicity, analysis times and non-use of derivatization and ion-pair agents

Analytical and numerical method of velocity fields for the explosively formed projectiles

Ovaj rad predstavlja analitički i numerički pristup procenu performansi brzine za Eksplozivno Formirane Projektile (EFP). Predložene analitičke metode matematički razvijaju parametre brzina pojedinačnih segmenata za EFP disk pogonjen eksplozivnim procesom. Ovaj model baziran je na dobro poznatim teorijskim pristupima distribucije energije na plastičnim telima u dinamičkim uslovima formiranjem integralnih rešenja za konačnu brzinu projektila. Paralelno sa analitičkim takođe je razvijen i numerički metod u cilju obezbeđenja procene ponašanje projktila u toku vrmena procesa formiranja EFP-a pogonjenog eksplozivom. Oba modela su validna za procenu performansi EFP bojevih glava i projektnih podatka za optimalno projektivanje oblika EFP-a. Simulacije su podržane softverima Matlob i Autodin kako za ananlitičko tako i numeričko modeliranje. Dobijeni numerički i analitički rezultati upoređeni su sa raspoloživivim eksperimentalnim rezultatima. PR Projekat Ministarstva nauke Republike Srbije, br. III-47029.The current paper presents analytical and numerical approaches of velocity performances estimations for the EFP (Explosively Formed Projectiles). The proposed analytical methods mathematically develop velocities parameters of a particular segment for EFP liner propelled by explosive process. This model is based on the well-known theoretical approaches of energy distribution on plastic body in dynamical conditions providing integral solution for projectile final velocity. The redundant to analytical, the numerical method is also developed, to provides estimations about behavior of projectile vs. time in the EFP forming process powered by explosion. Both models are valid for performances estimations of EFP warheads and design data for optimal EFP configuration. Simulations are supported by the software Matlab and Autodyn for analytical and numerical modeling respectively. The obtained numerical and analytical results are compared with the available experimental data

Simulation of changes in temperature and pressure fields during high speed projectiles forming by explosion

The research in this paper considered the temperatures fields as the consequently influenced effects appeared by plastic deformation, in the explosively forming process aimed to design explosively formed projectiles. As the special payloads of the missiles, used projectiles are packaged as the metal liners, joined with explosive charges, to design explosive propulsion effect. Their final form and velocity during shaping depend on distributed temperatures in explosively driven plastic deformation process. Developed simulation model consider forming process without metal cover of explosive charge, in aim to discover liner's dynamical correlations of effective plastic strains and temperatures in the unconstrained detonation environment made by payload construction. The temperature fields of the liner copper material are considered in time, as the consequence of strain/stress displacements driven by explosion environmental thermodynamically fields of pressures and temperatures. Achieved final velocities and mass loses as the expected explosively formed projectiles performances are estimated regarding their dynamical shaping and thermal gradients behavior vs. effective plastic strains. Performances and parameters are presented vs. process time, numerically simulated by the Autodyne software package

Application of graphene quantum dots in heavy metals and pesticides detection

Graphene Quantum Dots (GQDs) were produced using electrochemical oxidation of graphite rods. Obtained GQDs were gamma-irradiated in the presence of the N atoms source, ethylenediamine. Both structural and morphological changes were investigated using UV-Vis, X-ray photoelectron and photoluminescence (PL) spectroscopy as well as atomic force microscopy. The ability of both types of dots to change PL intensity in the presence of pesticides such as malathion and glyphosate, as well as copper (II) ions was detected. These preliminary results indicated a high potential of produced GQDs to be applied as non-enzymatic PL sensors for the detection of selected pesticides and metal ions

N-doped graphene quantum dots for detection of palladium(II) ions and carbofuran

We produced Graphene Quantum Dots (GQDs) by electrochemical oxidation of graphite rods and exposed them to gamma irradiation at a dose of 200 kGy, in the presence of ethylenediamine. Before irradiation, oxygen was removed from the GQDs dispersion by purging with Ar. These conditions induced both chemical reduction as well as the incorporation of N atoms in the structure of GQDs. Thus, N-doped GQDs were produced. The morphology of dots was investigated using atomic force microscopy. UV-Vis and photoluminescence spectroscopy were used to investigate the optical properties of modified GQDs. The changes in the intensities of PL emission spectra were studied in the presence of different concentrations of Pd2+ and pesticide carbofuran. We observed promising results for the application of N-doped GQDs for non-enzymatic PL detection of selected metal ions and molecules of pesticide

Reproduction of the Caramote prawn, Melicertus kerathurus (Forskål, 1775) (Decapoda, Penaeidae) in Boka Kotorska bay, Montenegro (South-eastern Adriatic)

The aim of this study was to investigate for the first time some aspects of the reproductive activity of the Caramote prawn, Melicertus kerathurus, in Montenegrin waters. This species is considered a target species in the small-scale fishery in Boka Kotorska Bay, being a species of high commercial value. Sampling was carried out on a monthly basis from April 2019 to December 2019 by trammel nets. The spawning season was estimated based on monthly changes in the gonadosomatic index, condition factor and gonadal maturity stages. The main spawning season for females extends from April-May to September, with a clear peak in June. The total sex ratio (males/females) was 1:1. Sexual differences related to the length-weight relationship were noted