TY  - CONF
AU  - Verbić, Tatjana
AU  - Avdeef, Alex
AU  - Tam, Kin Y.
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Topalović, Igor A.
AU  - Veljković, Dušan Ž.
AU  - Kathawala, Mufaddal
AU  - Serajuddin, Abu T. M.
PY  - 2023
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5993
AB  - Since the introduction of combinatorial chemistry and high-throughput screening in drug 
discovery in the early 1990s, the solubility of new chemical entities (NCE) decreased drastically 
while their lipophilicities increased greatly. Characterizing physicochemical properties of low soluble molecules can be especially challenging, since such molecules can undergo 
complicated reactions in aqueous solution, such as forming precipitates or complexes with 
buffer species or undergoing self-aggregation (dimer, trimer, etc.)1,2 or micelle formations. 
Most drugs are ionizable. Foremost to the rational interpretation of solution behavior of 
ionizable drugs in a physiologically-relevant pH domain requires an accurate aqueous pKa, 
determined by a suitable method. In a pH-dependent measurement of a property (e.g. 
solubility-, lipophilicity-, permeability-pH), when the apparent pKa value is different from the 
true aqueous pKa value, it may be an early clue that nonideal solution behavior may be taking 
place. In pharmaceutical research, it may seem cost-effective to use calculated pKa instead of 
measured values, but paradoxically, such preference can lead to inaccurate rationalization of 
the pH-dependent behavior of the drug molecule. For simple molecules, calculated values can 
be useful, but for today’s new drugs or for molecules prone to complicated solution behavior, 
the use of calculated pKas can substantially wrench the interpretation of solution properties. 
Clofazimine (CFZ), although discovered about 66 years ago, and used therapeutically for nearly 
40 years, exhibits some of the properties of relatively recent drug molecules by being 
extremely water insoluble and having variable pKa values reported. We have recently 
combined potentiometric titrations and UV/Vis spectrophotometry in methanol-water 
cosolvent media, accompanied by DFT calculations, to assess the hypothesis of CFZ free base 
dimerization. We reasoned that a soluble dimer might form from drug-drug adhesion along 
the hydrophobic molecular surface. With lessened exposure of the hydrophobic surface to 
water, the dimer would be more water soluble than the monomeric free base. In saturated 
solutions, the apparent solubility in alkaline pH would be elevated due to the presence of the 
dimer. The effect of that would be a lower pKa and reverse pKa cosolvent dependence – the 
behaviour we have noticed in CFZ aqueous solutions. These findings are of paramount 
importance for understanding of CFZ speciation and the future progress in developing its 
improved formulations which is the subject of our ongoing studies.
PB  - International Association of Physical Chemists
C3  - 10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023
T1  - Revealing the story of an orphan drug: clofazimine speciation  and solubilization as a function of pH
SP  - 15
EP  - 15
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5993
ER  - 

@conference{
author = "Verbić, Tatjana and Avdeef, Alex and Tam, Kin Y. and Marković, Olivera S. and Pešić, Miloš P. and Topalović, Igor A. and Veljković, Dušan Ž. and Kathawala, Mufaddal and Serajuddin, Abu T. M.",
year = "2023",
abstract = "Since the introduction of combinatorial chemistry and high-throughput screening in drug 
discovery in the early 1990s, the solubility of new chemical entities (NCE) decreased drastically 
while their lipophilicities increased greatly. Characterizing physicochemical properties of low soluble molecules can be especially challenging, since such molecules can undergo 
complicated reactions in aqueous solution, such as forming precipitates or complexes with 
buffer species or undergoing self-aggregation (dimer, trimer, etc.)1,2 or micelle formations. 
Most drugs are ionizable. Foremost to the rational interpretation of solution behavior of 
ionizable drugs in a physiologically-relevant pH domain requires an accurate aqueous pKa, 
determined by a suitable method. In a pH-dependent measurement of a property (e.g. 
solubility-, lipophilicity-, permeability-pH), when the apparent pKa value is different from the 
true aqueous pKa value, it may be an early clue that nonideal solution behavior may be taking 
place. In pharmaceutical research, it may seem cost-effective to use calculated pKa instead of 
measured values, but paradoxically, such preference can lead to inaccurate rationalization of 
the pH-dependent behavior of the drug molecule. For simple molecules, calculated values can 
be useful, but for today’s new drugs or for molecules prone to complicated solution behavior, 
the use of calculated pKas can substantially wrench the interpretation of solution properties. 
Clofazimine (CFZ), although discovered about 66 years ago, and used therapeutically for nearly 
40 years, exhibits some of the properties of relatively recent drug molecules by being 
extremely water insoluble and having variable pKa values reported. We have recently 
combined potentiometric titrations and UV/Vis spectrophotometry in methanol-water 
cosolvent media, accompanied by DFT calculations, to assess the hypothesis of CFZ free base 
dimerization. We reasoned that a soluble dimer might form from drug-drug adhesion along 
the hydrophobic molecular surface. With lessened exposure of the hydrophobic surface to 
water, the dimer would be more water soluble than the monomeric free base. In saturated 
solutions, the apparent solubility in alkaline pH would be elevated due to the presence of the 
dimer. The effect of that would be a lower pKa and reverse pKa cosolvent dependence – the 
behaviour we have noticed in CFZ aqueous solutions. These findings are of paramount 
importance for understanding of CFZ speciation and the future progress in developing its 
improved formulations which is the subject of our ongoing studies.",
publisher = "International Association of Physical Chemists",
journal = "10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023",
title = "Revealing the story of an orphan drug: clofazimine speciation  and solubilization as a function of pH",
pages = "15-15",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5993"
}

Verbić, T., Avdeef, A., Tam, K. Y., Marković, O. S., Pešić, M. P., Topalović, I. A., Veljković, D. Ž., Kathawala, M.,& Serajuddin, A. T. M.. (2023). Revealing the story of an orphan drug: clofazimine speciation  and solubilization as a function of pH. in 10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023
International Association of Physical Chemists., 15-15.
https://hdl.handle.net/21.15107/rcub_cherry_5993

Verbić T, Avdeef A, Tam KY, Marković OS, Pešić MP, Topalović IA, Veljković DŽ, Kathawala M, Serajuddin ATM. Revealing the story of an orphan drug: clofazimine speciation  and solubilization as a function of pH. in 10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023. 2023;:15-15.
https://hdl.handle.net/21.15107/rcub_cherry_5993 .

Verbić, Tatjana, Avdeef, Alex, Tam, Kin Y., Marković, Olivera S., Pešić, Miloš P., Topalović, Igor A., Veljković, Dušan Ž., Kathawala, Mufaddal, Serajuddin, Abu T. M., "Revealing the story of an orphan drug: clofazimine speciation  and solubilization as a function of pH" in 10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023 (2023):15-15,
https://hdl.handle.net/21.15107/rcub_cherry_5993 .

TY  - CONF
AU  - Topalović, Igor A.
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Kathawala, Mufaddal
AU  - Serajuddin, Abu T. M.
AU  - Avdeef, Alex
AU  - Verbić, Tatjana
PY  - 2023
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5994
AB  - Methods for drug solubilization have become important part of modern drug discovery and 
development due to increasing number of extremely insoluble drugs and drug candidates. 
One of such methods is acid-base supersolubilization (ABS) [1]. Clofazimine (CFZ) is weakly 
basic antibiotic and anti-inflammatory drug, most notably used in the treatment of leprosy
and tuberculosis, with recently proven inhibitory activity against several coronaviruses [2].
We have recently unraveled its aqueous pKa value and its unique cosolvent dependence [3]. 
The aim of the present study was to investigate CFZ solubilization using the ABS approach. 
Eight small organic acids were tested for the ABS effect (glutaric, malic, tartaric, citric, 
malonic, maleic, succinic, adipic) but only glutaric (GA), malic (MA), and tartaric (TA) acids 
showed some solubilization effect. The effect of their concentration (and the solution pH 
value) was further tested. The solubility of CFZ was determined in GA, MA, and TA solutions 
in wide concentration (1.0×10-2 – 5.0 M) and pH range (~0.2 – 4.8). Equilibration time was 
24 hours (6 h of stirring + 18 h of sedimentation). Phases were separated by filtration. The 
CFZ concentration in supernatant was determined by HPLC-UV/VIS. Results show that CFZ 
solubility increases as acid concentration increases: from 3.04×10-3 to 10.68 mg/mL (in GA), 
from 9.06×10-3 to 1.23 mg/mL (in MA) and from 4.76×10-3 to 0.32 mg/mL (in TA). The effect 
of CFZ solubilization is much more pronounced when the acid concentration is raised above 
2 M. These results can be used as the basis for further CFZ formulation optimization.
Furthermore, our ongoing research is focused on the type of interactions and other possible 
factors that can influence CFZ and other prectically insoluble drugs, embracing (super)solu bilization as a general methodology in drug design and development.
PB  - International Association of Physical Chemists
C3  - 10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023
T1  - Clofazimine acid-base solubilization: influence  of small organic acids’ concentration
SP  - 66
EP  - 66
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5994
ER  - 

@conference{
author = "Topalović, Igor A. and Marković, Olivera S. and Pešić, Miloš P. and Kathawala, Mufaddal and Serajuddin, Abu T. M. and Avdeef, Alex and Verbić, Tatjana",
year = "2023",
abstract = "Methods for drug solubilization have become important part of modern drug discovery and 
development due to increasing number of extremely insoluble drugs and drug candidates. 
One of such methods is acid-base supersolubilization (ABS) [1]. Clofazimine (CFZ) is weakly 
basic antibiotic and anti-inflammatory drug, most notably used in the treatment of leprosy
and tuberculosis, with recently proven inhibitory activity against several coronaviruses [2].
We have recently unraveled its aqueous pKa value and its unique cosolvent dependence [3]. 
The aim of the present study was to investigate CFZ solubilization using the ABS approach. 
Eight small organic acids were tested for the ABS effect (glutaric, malic, tartaric, citric, 
malonic, maleic, succinic, adipic) but only glutaric (GA), malic (MA), and tartaric (TA) acids 
showed some solubilization effect. The effect of their concentration (and the solution pH 
value) was further tested. The solubility of CFZ was determined in GA, MA, and TA solutions 
in wide concentration (1.0×10-2 – 5.0 M) and pH range (~0.2 – 4.8). Equilibration time was 
24 hours (6 h of stirring + 18 h of sedimentation). Phases were separated by filtration. The 
CFZ concentration in supernatant was determined by HPLC-UV/VIS. Results show that CFZ 
solubility increases as acid concentration increases: from 3.04×10-3 to 10.68 mg/mL (in GA), 
from 9.06×10-3 to 1.23 mg/mL (in MA) and from 4.76×10-3 to 0.32 mg/mL (in TA). The effect 
of CFZ solubilization is much more pronounced when the acid concentration is raised above 
2 M. These results can be used as the basis for further CFZ formulation optimization.
Furthermore, our ongoing research is focused on the type of interactions and other possible 
factors that can influence CFZ and other prectically insoluble drugs, embracing (super)solu bilization as a general methodology in drug design and development.",
publisher = "International Association of Physical Chemists",
journal = "10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023",
title = "Clofazimine acid-base solubilization: influence  of small organic acids’ concentration",
pages = "66-66",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5994"
}

Topalović, I. A., Marković, O. S., Pešić, M. P., Kathawala, M., Serajuddin, A. T. M., Avdeef, A.,& Verbić, T.. (2023). Clofazimine acid-base solubilization: influence  of small organic acids’ concentration. in 10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023
International Association of Physical Chemists., 66-66.
https://hdl.handle.net/21.15107/rcub_cherry_5994

Topalović IA, Marković OS, Pešić MP, Kathawala M, Serajuddin ATM, Avdeef A, Verbić T. Clofazimine acid-base solubilization: influence  of small organic acids’ concentration. in 10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023. 2023;:66-66.
https://hdl.handle.net/21.15107/rcub_cherry_5994 .

Topalović, Igor A., Marković, Olivera S., Pešić, Miloš P., Kathawala, Mufaddal, Serajuddin, Abu T. M., Avdeef, Alex, Verbić, Tatjana, "Clofazimine acid-base solubilization: influence  of small organic acids’ concentration" in 10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023 (2023):66-66,
https://hdl.handle.net/21.15107/rcub_cherry_5994 .

TY  - JOUR
AU  - Pešić, Miloš P.
AU  - Krstić, Jugoslav
AU  - Verbić, Tatjana
PY  - 2023
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5817
AB  - Molecularly imprinting technology was applied for preparing selec­tive sorbents for benzophenone-4 (BP4), an organic UV filter used in sun­screens and cosmetics. Several imprinted polymers were prepared by bulk polymerization, using BP4 as template. Combination of stability (mechanical and chemical), selectivity and robustness of the imprinted polymers with BP4 properties resulted in a successful imprinting process (imprinting factors in range 1.05–2.60). The prepared polymers were characterised by infrared spec­tro­scopy, elemental analysis, conductometric titrations and nitrogen physi­sorp­tion at 77 K. Adsorption capacities and selectivity towards 7 other organic UV filters (benzophenone-3, benzophenone-8, homosalate, butyl methoxydi­ben­zo­ylmethane, ethyl hexyl salicylate, ethyl hexyl p-dimethylamino benzoate and ethyl hexyl p-methoxycinnamate) were determined, proving high adsorption capacity and high selectivity for BP4 binding. The highest adsorption capacity was observed for 4-vinylpyridine/ethylene glycol dimethacrylate co-polymer prepared in dimethyl sulfoxide (1.108 mmol g-1). The imprinted polymer with the highest binding capacity was applied to solid phase extraction of BP4 from aqueous solutions with 98.5 % efficiency.
PB  - Belgrade : Serbian Chemical Society
T2  - Journal of the Serbian Chemical Society
T1  - Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper
VL  - 88
IS  - 1
SP  - 55
EP  - 68
DO  - 10.2298/JSC22032540P
ER  - 

@article{
author = "Pešić, Miloš P. and Krstić, Jugoslav and Verbić, Tatjana",
year = "2023",
abstract = "Molecularly imprinting technology was applied for preparing selec­tive sorbents for benzophenone-4 (BP4), an organic UV filter used in sun­screens and cosmetics. Several imprinted polymers were prepared by bulk polymerization, using BP4 as template. Combination of stability (mechanical and chemical), selectivity and robustness of the imprinted polymers with BP4 properties resulted in a successful imprinting process (imprinting factors in range 1.05–2.60). The prepared polymers were characterised by infrared spec­tro­scopy, elemental analysis, conductometric titrations and nitrogen physi­sorp­tion at 77 K. Adsorption capacities and selectivity towards 7 other organic UV filters (benzophenone-3, benzophenone-8, homosalate, butyl methoxydi­ben­zo­ylmethane, ethyl hexyl salicylate, ethyl hexyl p-dimethylamino benzoate and ethyl hexyl p-methoxycinnamate) were determined, proving high adsorption capacity and high selectivity for BP4 binding. The highest adsorption capacity was observed for 4-vinylpyridine/ethylene glycol dimethacrylate co-polymer prepared in dimethyl sulfoxide (1.108 mmol g-1). The imprinted polymer with the highest binding capacity was applied to solid phase extraction of BP4 from aqueous solutions with 98.5 % efficiency.",
publisher = "Belgrade : Serbian Chemical Society",
journal = "Journal of the Serbian Chemical Society",
title = "Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper",
volume = "88",
number = "1",
pages = "55-68",
doi = "10.2298/JSC22032540P"
}

Pešić, M. P., Krstić, J.,& Verbić, T.. (2023). Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper. in Journal of the Serbian Chemical Society
Belgrade : Serbian Chemical Society., 88(1), 55-68.
https://doi.org/10.2298/JSC22032540P

Pešić MP, Krstić J, Verbić T. Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper. in Journal of the Serbian Chemical Society. 2023;88(1):55-68.
doi:10.2298/JSC22032540P .

Pešić, Miloš P., Krstić, Jugoslav, Verbić, Tatjana, "Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper" in Journal of the Serbian Chemical Society, 88, no. 1 (2023):55-68,
https://doi.org/10.2298/JSC22032540P . .

TY  - DATA
AU  - Pešić, Miloš P.
AU  - Krstić, Jugoslav
AU  - Verbić, Tatjana
PY  - 2023
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5841
AB  - Molecularly imprinting technology was applied for preparing selec­tive sorbents for benzophenone-4 (BP4), an organic UV filter used in sun­screens and cosmetics. Several imprinted polymers were prepared by bulk polymerization, using BP4 as template. Combination of stability (mechanical and chemical), selectivity and robustness of the imprinted polymers with BP4 properties resulted in a successful imprinting process (imprinting factors in range 1.05–2.60). The prepared polymers were characterised by infrared spec­tro­scopy, elemental analysis, conductometric titrations and nitrogen physi­sorp­tion at 77 K. Adsorption capacities and selectivity towards 7 other organic UV filters (benzophenone-3, benzophenone-8, homosalate, butyl methoxydi­ben­zo­ylmethane, ethyl hexyl salicylate, ethyl hexyl p-dimethylamino benzoate and ethyl hexyl p-methoxycinnamate) were determined, proving high adsorption capacity and high selectivity for BP4 binding. The highest adsorption capacity was observed for 4-vinylpyridine/ethylene glycol dimethacrylate co-polymer prepared in dimethyl sulfoxide (1.108 mmol g-1). The imprinted polymer with the highest binding capacity was applied to solid phase extraction of BP4 from aqueous solutions with 98.5 % efficiency.
PB  - Belgrade : Serbian Chemical Society
T2  - Journal of the Serbian Chemical Society
T1  - Supplementary material for: Pešić, M. P., Krstić, J.,& Verbić, T.. (2023). Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper. in Journal of the Serbian Chemical Society Belgrade : Serbian Chemical Society., 88(1), 55-68. https://doi.org/10.2298/JSC22032540P
VL  - 88
IS  - 1
SP  - 55
EP  - 68
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5841
ER  - 

@misc{
author = "Pešić, Miloš P. and Krstić, Jugoslav and Verbić, Tatjana",
year = "2023",
abstract = "Molecularly imprinting technology was applied for preparing selec­tive sorbents for benzophenone-4 (BP4), an organic UV filter used in sun­screens and cosmetics. Several imprinted polymers were prepared by bulk polymerization, using BP4 as template. Combination of stability (mechanical and chemical), selectivity and robustness of the imprinted polymers with BP4 properties resulted in a successful imprinting process (imprinting factors in range 1.05–2.60). The prepared polymers were characterised by infrared spec­tro­scopy, elemental analysis, conductometric titrations and nitrogen physi­sorp­tion at 77 K. Adsorption capacities and selectivity towards 7 other organic UV filters (benzophenone-3, benzophenone-8, homosalate, butyl methoxydi­ben­zo­ylmethane, ethyl hexyl salicylate, ethyl hexyl p-dimethylamino benzoate and ethyl hexyl p-methoxycinnamate) were determined, proving high adsorption capacity and high selectivity for BP4 binding. The highest adsorption capacity was observed for 4-vinylpyridine/ethylene glycol dimethacrylate co-polymer prepared in dimethyl sulfoxide (1.108 mmol g-1). The imprinted polymer with the highest binding capacity was applied to solid phase extraction of BP4 from aqueous solutions with 98.5 % efficiency.",
publisher = "Belgrade : Serbian Chemical Society",
journal = "Journal of the Serbian Chemical Society",
title = "Supplementary material for: Pešić, M. P., Krstić, J.,& Verbić, T.. (2023). Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper. in Journal of the Serbian Chemical Society Belgrade : Serbian Chemical Society., 88(1), 55-68. https://doi.org/10.2298/JSC22032540P",
volume = "88",
number = "1",
pages = "55-68",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5841"
}

Pešić, M. P., Krstić, J.,& Verbić, T.. (2023). Supplementary material for: Pešić, M. P., Krstić, J.,& Verbić, T.. (2023). Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper. in Journal of the Serbian Chemical Society Belgrade : Serbian Chemical Society., 88(1), 55-68. https://doi.org/10.2298/JSC22032540P. in Journal of the Serbian Chemical Society
Belgrade : Serbian Chemical Society., 88(1), 55-68.
https://hdl.handle.net/21.15107/rcub_cherry_5841

Pešić MP, Krstić J, Verbić T. Supplementary material for: Pešić, M. P., Krstić, J.,& Verbić, T.. (2023). Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper. in Journal of the Serbian Chemical Society Belgrade : Serbian Chemical Society., 88(1), 55-68. https://doi.org/10.2298/JSC22032540P. in Journal of the Serbian Chemical Society. 2023;88(1):55-68.
https://hdl.handle.net/21.15107/rcub_cherry_5841 .

Pešić, Miloš P., Krstić, Jugoslav, Verbić, Tatjana, "Supplementary material for: Pešić, M. P., Krstić, J.,& Verbić, T.. (2023). Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper. in Journal of the Serbian Chemical Society Belgrade : Serbian Chemical Society., 88(1), 55-68. https://doi.org/10.2298/JSC22032540P" in Journal of the Serbian Chemical Society, 88, no. 1 (2023):55-68,
https://hdl.handle.net/21.15107/rcub_cherry_5841 .

TY  - CONF
AU  - Marković, Olivera S.
AU  - Gajić, Brankica P.
AU  - Pešić, Miloš P.
AU  - Verbić, Tatjana
PY  - 2022
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5936
AB  - Experimental studies of solubility are important in all phases of drug design and 
development. Solubility data are used to screen out drug-like candidates, 
biopharmaceutical classification and formulation optimization. The development of oral 
and parenteral dosage forms can be challenging, especially when drugs are poorly 
soluble, ionizable, exhibiting pH-dependent solubility and when multiple counterions 
are present in drug suspension. The influence of different counterions on the existing 
equilibria and on pH-dependent drug solubility must be defined in such systems. To 
investigate the effect of multiple ions on the solubility of a model basic drug – tricyclic 
antidepressant imipramine (Im), we conducted a systematic study of the Im solubility as 
a function of pH in the presence of both chloride and phosphate ions as well as in 
chloride-free and phosphate-free suspensions. The pH–Ramp shake–flask method1,2 was 
used for solubility determination. The computer program pDISOL–X was used for data 
analysis. It is shown that distinct pH-dependent solubility profiles were obtained in 
studied systems. Depending on the pH and the total concentration of chloride and/or 
phosphate ions, Im can precipitate as chloride and phosphate salt or free base. 
Furthermore, pH values of solid phase transitions (pHmax) varied as well. For instance, 
pHmax of solid phase transition of (ImH)H2PO4(s) to (ImH)2HPO4(s) change from 5.15 
(chloride and phosphate-containing suspensions) to 5.73 (chloride-free suspensions). 
The intensive self-aggregation of Im in acidic region was suppressed by raising chloride 
or phosphate ions concentration (Iavg 1.42–1.64 M). In that way, solubility of Im was 
decreased due to the common-ion effect. This study illustrates the influence of 
competing counterions on Im solubility and on interconversions in solid phase. Hence, 
such factors must be taken into account during formulation optimization in drug 
research.
PB  - Belgrade : Serbian Chemical Society
PB  - Belgrade : Serbian Young Chemists’ Club
C3  - 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts
T1  - The influence of  competing counterions on the solubility of imipramine
SP  - 27
EP  - 27
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5936
ER  - 

@conference{
author = "Marković, Olivera S. and Gajić, Brankica P. and Pešić, Miloš P. and Verbić, Tatjana",
year = "2022",
abstract = "Experimental studies of solubility are important in all phases of drug design and 
development. Solubility data are used to screen out drug-like candidates, 
biopharmaceutical classification and formulation optimization. The development of oral 
and parenteral dosage forms can be challenging, especially when drugs are poorly 
soluble, ionizable, exhibiting pH-dependent solubility and when multiple counterions 
are present in drug suspension. The influence of different counterions on the existing 
equilibria and on pH-dependent drug solubility must be defined in such systems. To 
investigate the effect of multiple ions on the solubility of a model basic drug – tricyclic 
antidepressant imipramine (Im), we conducted a systematic study of the Im solubility as 
a function of pH in the presence of both chloride and phosphate ions as well as in 
chloride-free and phosphate-free suspensions. The pH–Ramp shake–flask method1,2 was 
used for solubility determination. The computer program pDISOL–X was used for data 
analysis. It is shown that distinct pH-dependent solubility profiles were obtained in 
studied systems. Depending on the pH and the total concentration of chloride and/or 
phosphate ions, Im can precipitate as chloride and phosphate salt or free base. 
Furthermore, pH values of solid phase transitions (pHmax) varied as well. For instance, 
pHmax of solid phase transition of (ImH)H2PO4(s) to (ImH)2HPO4(s) change from 5.15 
(chloride and phosphate-containing suspensions) to 5.73 (chloride-free suspensions). 
The intensive self-aggregation of Im in acidic region was suppressed by raising chloride 
or phosphate ions concentration (Iavg 1.42–1.64 M). In that way, solubility of Im was 
decreased due to the common-ion effect. This study illustrates the influence of 
competing counterions on Im solubility and on interconversions in solid phase. Hence, 
such factors must be taken into account during formulation optimization in drug 
research.",
publisher = "Belgrade : Serbian Chemical Society, Belgrade : Serbian Young Chemists’ Club",
journal = "8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts",
title = "The influence of  competing counterions on the solubility of imipramine",
pages = "27-27",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5936"
}

Marković, O. S., Gajić, B. P., Pešić, M. P.,& Verbić, T.. (2022). The influence of  competing counterions on the solubility of imipramine. in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts
Belgrade : Serbian Chemical Society., 27-27.
https://hdl.handle.net/21.15107/rcub_cherry_5936

Marković OS, Gajić BP, Pešić MP, Verbić T. The influence of  competing counterions on the solubility of imipramine. in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts. 2022;:27-27.
https://hdl.handle.net/21.15107/rcub_cherry_5936 .

Marković, Olivera S., Gajić, Brankica P., Pešić, Miloš P., Verbić, Tatjana, "The influence of  competing counterions on the solubility of imipramine" in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts (2022):27-27,
https://hdl.handle.net/21.15107/rcub_cherry_5936 .

TY  - CONF
AU  - Topalović, Igor A.
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Verbić, Tatjana
PY  - 2022
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5937
AB  - Nowadays, more than two-thirds of potential drugs currently being discovered are 
practically insoluble in water with solubility <100 μg/mL. Despite that, compounds with 
even lower solubility (<0.1 μg/mL) are commonly selected for further development 
which is very challenging, especially in the pharmaceutical formulation process1
. 
Clofazimine (CFZ), an anti-leprosy drug with inhibitory activity against several 
coronaviruses, has a favourable safety profile2
, but it is poorly soluble in aqueous media. 
Hence, it is important to develop a method for increasing its solubility. In this work, a 
relatively novel approach of enhancing solubility of weakly basic drugs by using weak 
acids that would not form salts with the drug (acid-base supersolubilization (ABS)) has
been applied. CFZ aqueous solubility was determined in solutions of tartaric, citric, 
malic, malonic or maleic acid: in set I acid solutions had the same concentration (2.5 
mol/L), and in the set II they were scaled to the same pH (1.0). The drug was added in 
stirred acid solution until a precipitate was noticed and, after filtration, CFZ 
concentration in samples was determined by HPLC. Based on set I, it was found that the 
solubility of CFZ had the highest value in the case of tartaric acid (0.46 mg/mL) 
compared to other acid solutions of the same concentration. In set II the highest CFZ 
concentration was determined in the malic acid solution which had the highest 
concentration (2.8 mol/L) among other acids. On contrary, maleic acid solution at 
pH=1.0 had the lowest molar concentration (0.5 mol/L) and therefore CFZ was 
minimally dissolved. Further research will be directed toward the examination of acid 
structure effect on CFZ solubility.
PB  - Belgrade : Serbian Chemical Society
PB  - Belgrade : Serbian Young Chemists’ Club
C3  - 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts
T1  - Investigation of  clofazimine acid-base supersolubilization using various weak organic acids
SP  - 37
EP  - 37
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5937
ER  - 

@conference{
author = "Topalović, Igor A. and Marković, Olivera S. and Pešić, Miloš P. and Verbić, Tatjana",
year = "2022",
abstract = "Nowadays, more than two-thirds of potential drugs currently being discovered are 
practically insoluble in water with solubility <100 μg/mL. Despite that, compounds with 
even lower solubility (<0.1 μg/mL) are commonly selected for further development 
which is very challenging, especially in the pharmaceutical formulation process1
. 
Clofazimine (CFZ), an anti-leprosy drug with inhibitory activity against several 
coronaviruses, has a favourable safety profile2
, but it is poorly soluble in aqueous media. 
Hence, it is important to develop a method for increasing its solubility. In this work, a 
relatively novel approach of enhancing solubility of weakly basic drugs by using weak 
acids that would not form salts with the drug (acid-base supersolubilization (ABS)) has
been applied. CFZ aqueous solubility was determined in solutions of tartaric, citric, 
malic, malonic or maleic acid: in set I acid solutions had the same concentration (2.5 
mol/L), and in the set II they were scaled to the same pH (1.0). The drug was added in 
stirred acid solution until a precipitate was noticed and, after filtration, CFZ 
concentration in samples was determined by HPLC. Based on set I, it was found that the 
solubility of CFZ had the highest value in the case of tartaric acid (0.46 mg/mL) 
compared to other acid solutions of the same concentration. In set II the highest CFZ 
concentration was determined in the malic acid solution which had the highest 
concentration (2.8 mol/L) among other acids. On contrary, maleic acid solution at 
pH=1.0 had the lowest molar concentration (0.5 mol/L) and therefore CFZ was 
minimally dissolved. Further research will be directed toward the examination of acid 
structure effect on CFZ solubility.",
publisher = "Belgrade : Serbian Chemical Society, Belgrade : Serbian Young Chemists’ Club",
journal = "8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts",
title = "Investigation of  clofazimine acid-base supersolubilization using various weak organic acids",
pages = "37-37",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5937"
}

Topalović, I. A., Marković, O. S., Pešić, M. P.,& Verbić, T.. (2022). Investigation of  clofazimine acid-base supersolubilization using various weak organic acids. in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts
Belgrade : Serbian Chemical Society., 37-37.
https://hdl.handle.net/21.15107/rcub_cherry_5937

Topalović IA, Marković OS, Pešić MP, Verbić T. Investigation of  clofazimine acid-base supersolubilization using various weak organic acids. in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts. 2022;:37-37.
https://hdl.handle.net/21.15107/rcub_cherry_5937 .

Topalović, Igor A., Marković, Olivera S., Pešić, Miloš P., Verbić, Tatjana, "Investigation of  clofazimine acid-base supersolubilization using various weak organic acids" in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts (2022):37-37,
https://hdl.handle.net/21.15107/rcub_cherry_5937 .

TY  - CONF
AU  - Marjanović, Nemanja Ž.
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Verbić, Tatjana
PY  - 2022
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5938
AB  - In the modern drug research the number of practically insoluble potential drugs is 
increasing. Poor aqueous solubility can cause poor oral absorption and low 
bioavailability of drugs. Hence, solubility enhancement is considered as one of the most 
important challenges in the formulation and development of the dosage forms of drugs. 
Clofazimine (CFZ) is an antibiotic drug which is used in the treatment of tuberculosis 
and leprosy. It is recently shown that CFZ has inhibitory activity against certain 
coronaviruses and can antagonize the replication of SARS-CoV-2.1 Since CFZ is highly 
lipophilic molecule with extremely low solubility, it is quite a challenge to find 
appropriate method for CFZ solubilization. The aim of this work was to investigate the 
effect of methanesulfonic (MSA) and glutaric (GA) acids on the solubility of CFZ. The 
effect of MSA on the solubility of CFZ was studied by the pH-Ramp shake-flask method 
(pH-RSF).2 The solubility of CFZ was determined in the presence of GA in two ways: 
1) by melting a mixture of CFZ and GA in different molar ratios, and then dissolving in 
water; 2) using the pH-RSF method. Interactions between CZ and GA were investigated 
by IR spectroscopy. It is shown that both MSA and GA increase the solubility of CFZ 
in acidic suspensions prepared by pH-RSF method. Also, solubility enhancement was 
observed in the molten CFZ-GA mixtures (molar ratio 1:1 and 1:4) compared to mixtures 
prepared without melting. Besides that, the IR spectra of these mixtures revealed that 
characteristic CFZ band was shifted in molted CFZ-GA mixture (molar ratio 1:1) 
probably due to CFZ-GA interactions. Preliminary results presented in this study 
illustrate that MSA and GA can be used for solubility improvement of CFZ.
PB  - Belgrade : Serbian Chemical Society
PB  - Belgrade : Serbian Young Chemists’ Club
C3  - 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts
T1  - The effect  of methanesulfonic and glutaric acids on the solubility of clofazimine
SP  - 40
EP  - 40
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5938
ER  - 

@conference{
author = "Marjanović, Nemanja Ž. and Marković, Olivera S. and Pešić, Miloš P. and Verbić, Tatjana",
year = "2022",
abstract = "In the modern drug research the number of practically insoluble potential drugs is 
increasing. Poor aqueous solubility can cause poor oral absorption and low 
bioavailability of drugs. Hence, solubility enhancement is considered as one of the most 
important challenges in the formulation and development of the dosage forms of drugs. 
Clofazimine (CFZ) is an antibiotic drug which is used in the treatment of tuberculosis 
and leprosy. It is recently shown that CFZ has inhibitory activity against certain 
coronaviruses and can antagonize the replication of SARS-CoV-2.1 Since CFZ is highly 
lipophilic molecule with extremely low solubility, it is quite a challenge to find 
appropriate method for CFZ solubilization. The aim of this work was to investigate the 
effect of methanesulfonic (MSA) and glutaric (GA) acids on the solubility of CFZ. The 
effect of MSA on the solubility of CFZ was studied by the pH-Ramp shake-flask method 
(pH-RSF).2 The solubility of CFZ was determined in the presence of GA in two ways: 
1) by melting a mixture of CFZ and GA in different molar ratios, and then dissolving in 
water; 2) using the pH-RSF method. Interactions between CZ and GA were investigated 
by IR spectroscopy. It is shown that both MSA and GA increase the solubility of CFZ 
in acidic suspensions prepared by pH-RSF method. Also, solubility enhancement was 
observed in the molten CFZ-GA mixtures (molar ratio 1:1 and 1:4) compared to mixtures 
prepared without melting. Besides that, the IR spectra of these mixtures revealed that 
characteristic CFZ band was shifted in molted CFZ-GA mixture (molar ratio 1:1) 
probably due to CFZ-GA interactions. Preliminary results presented in this study 
illustrate that MSA and GA can be used for solubility improvement of CFZ.",
publisher = "Belgrade : Serbian Chemical Society, Belgrade : Serbian Young Chemists’ Club",
journal = "8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts",
title = "The effect  of methanesulfonic and glutaric acids on the solubility of clofazimine",
pages = "40-40",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5938"
}

Marjanović, N. Ž., Marković, O. S., Pešić, M. P.,& Verbić, T.. (2022). The effect  of methanesulfonic and glutaric acids on the solubility of clofazimine. in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts
Belgrade : Serbian Chemical Society., 40-40.
https://hdl.handle.net/21.15107/rcub_cherry_5938

Marjanović NŽ, Marković OS, Pešić MP, Verbić T. The effect  of methanesulfonic and glutaric acids on the solubility of clofazimine. in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts. 2022;:40-40.
https://hdl.handle.net/21.15107/rcub_cherry_5938 .

Marjanović, Nemanja Ž., Marković, Olivera S., Pešić, Miloš P., Verbić, Tatjana, "The effect  of methanesulfonic and glutaric acids on the solubility of clofazimine" in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts (2022):40-40,
https://hdl.handle.net/21.15107/rcub_cherry_5938 .

TY  - CONF
AU  - Mrđinac, Jelena Ž.
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Verbić, Tatjana
PY  - 2022
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5939
AB  - The ionization constant (usually expressed in logarithmic form, pKa) is important 
physicochemical parameter which is used to characterize the acid-base chemistry of a 
compound. Since most drugs contain one or more ionizable functional groups, 
knowledge of pKa values is necessary in drug research. The most common techniques 
used for pKa determination are potentiometry and spectrophotometry. Potentiometry is 
a method of choice when ionization processes are overlapping, as in such case it is not 
possible to obtain the absorption spectrum of each species present in solution. The aim 
of this work was the comparative analysis of pKa determination using potentiometry and 
spectrophotometry for model compounds with overlapping ionization processes: 3-
aminobenzoic acid, 1,3,5-benzenetricarboxylic acid and tyrosine. The potentiometric
titrations were performed with pSOL Model 3 instrument (pION) equipped with pS 
software package for titration data analysis.1 Avdeef–Bucher four–parameter equation 
was used for electrode standardization.2 To overcome the above-mentioned limitation of 
spectrophotometry, the alternative approach was applied in this study. The new 
aminocaproate phosphate buffer (containing phosphoric and ε-aminocaproic acids) was 
used for the solutions preparation of the model compounds in pH range 1 – 12. This 
buffer has numerous advantages like UV-transparency, resistance to pH changes upon 
standing for several days, useful buffer capacity and constant ionic strength in the wide 
range of pH values. Absorption spectra were recorded according to specific procedure 
which was carefully designed to avoid systematic errors. Collected absorption spectra 
will be used for the development of the algorithm for the spectral deconvolution (using 
MATLAB). Such software can be very useful tool in the drug research, especially for 
the analysis of the compounds which pKa values cannot be determined by potentiometry.
PB  - Belgrade : Serbian Chemical Society
PB  - Belgrade : Serbian Young Chemists’ Club
C3  - 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts
T1  - Comparative  analysis of ionization constants determination using spectrophotometry and potentiometry: 3- aminobenzoic acid, 1,3,5-benzenetricarboxylic acid and tyrosine
SP  - 42
EP  - 42
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5939
ER  - 

@conference{
author = "Mrđinac, Jelena Ž. and Marković, Olivera S. and Pešić, Miloš P. and Verbić, Tatjana",
year = "2022",
abstract = "The ionization constant (usually expressed in logarithmic form, pKa) is important 
physicochemical parameter which is used to characterize the acid-base chemistry of a 
compound. Since most drugs contain one or more ionizable functional groups, 
knowledge of pKa values is necessary in drug research. The most common techniques 
used for pKa determination are potentiometry and spectrophotometry. Potentiometry is 
a method of choice when ionization processes are overlapping, as in such case it is not 
possible to obtain the absorption spectrum of each species present in solution. The aim 
of this work was the comparative analysis of pKa determination using potentiometry and 
spectrophotometry for model compounds with overlapping ionization processes: 3-
aminobenzoic acid, 1,3,5-benzenetricarboxylic acid and tyrosine. The potentiometric
titrations were performed with pSOL Model 3 instrument (pION) equipped with pS 
software package for titration data analysis.1 Avdeef–Bucher four–parameter equation 
was used for electrode standardization.2 To overcome the above-mentioned limitation of 
spectrophotometry, the alternative approach was applied in this study. The new 
aminocaproate phosphate buffer (containing phosphoric and ε-aminocaproic acids) was 
used for the solutions preparation of the model compounds in pH range 1 – 12. This 
buffer has numerous advantages like UV-transparency, resistance to pH changes upon 
standing for several days, useful buffer capacity and constant ionic strength in the wide 
range of pH values. Absorption spectra were recorded according to specific procedure 
which was carefully designed to avoid systematic errors. Collected absorption spectra 
will be used for the development of the algorithm for the spectral deconvolution (using 
MATLAB). Such software can be very useful tool in the drug research, especially for 
the analysis of the compounds which pKa values cannot be determined by potentiometry.",
publisher = "Belgrade : Serbian Chemical Society, Belgrade : Serbian Young Chemists’ Club",
journal = "8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts",
title = "Comparative  analysis of ionization constants determination using spectrophotometry and potentiometry: 3- aminobenzoic acid, 1,3,5-benzenetricarboxylic acid and tyrosine",
pages = "42-42",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5939"
}

Mrđinac, J. Ž., Marković, O. S., Pešić, M. P.,& Verbić, T.. (2022). Comparative  analysis of ionization constants determination using spectrophotometry and potentiometry: 3- aminobenzoic acid, 1,3,5-benzenetricarboxylic acid and tyrosine. in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts
Belgrade : Serbian Chemical Society., 42-42.
https://hdl.handle.net/21.15107/rcub_cherry_5939

Mrđinac JŽ, Marković OS, Pešić MP, Verbić T. Comparative  analysis of ionization constants determination using spectrophotometry and potentiometry: 3- aminobenzoic acid, 1,3,5-benzenetricarboxylic acid and tyrosine. in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts. 2022;:42-42.
https://hdl.handle.net/21.15107/rcub_cherry_5939 .

Mrđinac, Jelena Ž., Marković, Olivera S., Pešić, Miloš P., Verbić, Tatjana, "Comparative  analysis of ionization constants determination using spectrophotometry and potentiometry: 3- aminobenzoic acid, 1,3,5-benzenetricarboxylic acid and tyrosine" in 8th Conference of Young Chemists of Serbia, Belgrade, Serbia, 29th October, 2022. In: Book of Abstracts (2022):42-42,
https://hdl.handle.net/21.15107/rcub_cherry_5939 .

TY  - CONF
AU  - Marković, Olivera S.
AU  - Gajić, Brankica P.
AU  - Pešić, Miloš P.
AU  - Verbić, Tatjana
PY  - 2022
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5940
AB  - Cilj ovog rada bio je proučavanje ravnoteža u heterogenim sistemima tricikličnog 
antidepresiva amitriptilina (Am) koji sadrže hloride i/ili fosfate. Rastvorljivost Am u 
uslovima povećane jonske sile određena je pH–Ramp shake–flask metodom.1, 2 Veća 
rastvorljivost Am u kiseloj sredini od očekivane, posledica je agregacije – analiza 
eksperimentalnih podataka pomoću programa pDISOL–XTM ukazuje na verovatno 
građenje pentamera Am5H5
5+. Kritična micelarna koncentracija i stepen disocijacije 
agregata određeni su primenom konduktometrijskih titracija. U baznoj sredini primećena je 
delimična degradacija Am. Eksperimentalno dobijeni podaci o rastvorljivosti biološki 
aktivnih supstanci i postojećim ravnotežama u heterogenim sistemima važni su u svim 
fazama dizajna i razvoja lekova.
AB  - The aim of this work was to study the equilibria in tricyclic antidepressant amitriptyline 
(Am) heterogeneous systems containing chloride and/or phosphate ions. Solubility of Am 
in high ionic strength conditions was determined using pH–Ramp shake–flask method.1, 2
Higher solubility of Am than expected in an acidic media is a consequence of self aggregation – pentamer formation (Am5H5
5+) according to pDISOL–XTM analysis. Critical 
micelle concentration and the degree of the aggregate dissociation were determined by 
conductometric titrations. Partial degradation of Am in alkaline suspensions was observed. 
Experimental studies of solubility as well as the existing equilibria in heterogeneous 
systems of biologically active compounds are important at all stages of drug design and 
development.
PB  - Beograd : Srpsko hemijsko društvo
C3  - 58. Savetovanje Srpskog hemijskog društva, Kratki izvodi radova, Beograd 9. i 10. jun 2022. godine
T1  - Proučavanje ravnoteža u heterogenim sistemima tricikličnog  antidepresiva amitriptilina
SP  - 53
EP  - 53
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5940
ER  - 

@conference{
author = "Marković, Olivera S. and Gajić, Brankica P. and Pešić, Miloš P. and Verbić, Tatjana",
year = "2022",
abstract = "Cilj ovog rada bio je proučavanje ravnoteža u heterogenim sistemima tricikličnog 
antidepresiva amitriptilina (Am) koji sadrže hloride i/ili fosfate. Rastvorljivost Am u 
uslovima povećane jonske sile određena je pH–Ramp shake–flask metodom.1, 2 Veća 
rastvorljivost Am u kiseloj sredini od očekivane, posledica je agregacije – analiza 
eksperimentalnih podataka pomoću programa pDISOL–XTM ukazuje na verovatno 
građenje pentamera Am5H5
5+. Kritična micelarna koncentracija i stepen disocijacije 
agregata određeni su primenom konduktometrijskih titracija. U baznoj sredini primećena je 
delimična degradacija Am. Eksperimentalno dobijeni podaci o rastvorljivosti biološki 
aktivnih supstanci i postojećim ravnotežama u heterogenim sistemima važni su u svim 
fazama dizajna i razvoja lekova., The aim of this work was to study the equilibria in tricyclic antidepressant amitriptyline 
(Am) heterogeneous systems containing chloride and/or phosphate ions. Solubility of Am 
in high ionic strength conditions was determined using pH–Ramp shake–flask method.1, 2
Higher solubility of Am than expected in an acidic media is a consequence of self aggregation – pentamer formation (Am5H5
5+) according to pDISOL–XTM analysis. Critical 
micelle concentration and the degree of the aggregate dissociation were determined by 
conductometric titrations. Partial degradation of Am in alkaline suspensions was observed. 
Experimental studies of solubility as well as the existing equilibria in heterogeneous 
systems of biologically active compounds are important at all stages of drug design and 
development.",
publisher = "Beograd : Srpsko hemijsko društvo",
journal = "58. Savetovanje Srpskog hemijskog društva, Kratki izvodi radova, Beograd 9. i 10. jun 2022. godine",
title = "Proučavanje ravnoteža u heterogenim sistemima tricikličnog  antidepresiva amitriptilina",
pages = "53-53",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5940"
}

Marković, O. S., Gajić, B. P., Pešić, M. P.,& Verbić, T.. (2022). Proučavanje ravnoteža u heterogenim sistemima tricikličnog  antidepresiva amitriptilina. in 58. Savetovanje Srpskog hemijskog društva, Kratki izvodi radova, Beograd 9. i 10. jun 2022. godine
Beograd : Srpsko hemijsko društvo., 53-53.
https://hdl.handle.net/21.15107/rcub_cherry_5940

Marković OS, Gajić BP, Pešić MP, Verbić T. Proučavanje ravnoteža u heterogenim sistemima tricikličnog  antidepresiva amitriptilina. in 58. Savetovanje Srpskog hemijskog društva, Kratki izvodi radova, Beograd 9. i 10. jun 2022. godine. 2022;:53-53.
https://hdl.handle.net/21.15107/rcub_cherry_5940 .

Marković, Olivera S., Gajić, Brankica P., Pešić, Miloš P., Verbić, Tatjana, "Proučavanje ravnoteža u heterogenim sistemima tricikličnog  antidepresiva amitriptilina" in 58. Savetovanje Srpskog hemijskog društva, Kratki izvodi radova, Beograd 9. i 10. jun 2022. godine (2022):53-53,
https://hdl.handle.net/21.15107/rcub_cherry_5940 .

TY  - JOUR
AU  - Pešić, Miloš P.
AU  - Todorov, Miljana D.
AU  - Becskereki, Gergely
AU  - Horvai, George
AU  - Verbić, Tatjana
AU  - Tóth, Blanka
PY  - 2020
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/3951
AB  - A novel method is successfully tested for non-covalent imprinting. Conditions are used which practically exclude the formation of prepolymerization complexes. The template is cholesterol, and no so-called functional monomer is used. The polymers contain only an acrylic diester crosslinker. The porogen isopropanol prevents even hydrogen bonding between the template and the monomer in the prepolymerization solution. Despite of these apparently very disadvantageous conditions, appreciable imprinting factors for cholesterol and imprinted selectivity against some other steroids are observed, similar to other cholesterol MIPs with proven analytical usefulness.
PB  - Elsevier
T2  - Talanta
T1  - A novel method of molecular imprinting applied to the template cholesterol
VL  - 217
SP  - 121075
DO  - 10.1016/j.talanta.2020.121075
ER  - 

@article{
author = "Pešić, Miloš P. and Todorov, Miljana D. and Becskereki, Gergely and Horvai, George and Verbić, Tatjana and Tóth, Blanka",
year = "2020",
abstract = "A novel method is successfully tested for non-covalent imprinting. Conditions are used which practically exclude the formation of prepolymerization complexes. The template is cholesterol, and no so-called functional monomer is used. The polymers contain only an acrylic diester crosslinker. The porogen isopropanol prevents even hydrogen bonding between the template and the monomer in the prepolymerization solution. Despite of these apparently very disadvantageous conditions, appreciable imprinting factors for cholesterol and imprinted selectivity against some other steroids are observed, similar to other cholesterol MIPs with proven analytical usefulness.",
publisher = "Elsevier",
journal = "Talanta",
title = "A novel method of molecular imprinting applied to the template cholesterol",
volume = "217",
pages = "121075",
doi = "10.1016/j.talanta.2020.121075"
}

Pešić, M. P., Todorov, M. D., Becskereki, G., Horvai, G., Verbić, T.,& Tóth, B.. (2020). A novel method of molecular imprinting applied to the template cholesterol. in Talanta
Elsevier., 217, 121075.
https://doi.org/10.1016/j.talanta.2020.121075

Pešić MP, Todorov MD, Becskereki G, Horvai G, Verbić T, Tóth B. A novel method of molecular imprinting applied to the template cholesterol. in Talanta. 2020;217:121075.
doi:10.1016/j.talanta.2020.121075 .

Pešić, Miloš P., Todorov, Miljana D., Becskereki, Gergely, Horvai, George, Verbić, Tatjana, Tóth, Blanka, "A novel method of molecular imprinting applied to the template cholesterol" in Talanta, 217 (2020):121075,
https://doi.org/10.1016/j.talanta.2020.121075 . .

TY  - JOUR
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Shah, Ankita V.
AU  - Serajuddin, Abu T.M.
AU  - Verbić, Tatjana
AU  - Avdeef, Alex
PY  - 2019
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2924
AB  - Although solubility-pH data for desipramine hydrochloride (DsHCl) have been reported previously, the aim of the present study was to critically examine the aqueous solubility-pH behavior of DsHCl in buffer-free and buffered solutions, in the presence of physiologically-relevant chloride concentration, using experimental practices recommended in the recently-published “white paper” (Avdeef et al., 2016). The computer program pDISOL-X was used to design the structured experiments (pH-RSF method), to process the data, and to refine the equilibrium constants. Low-to-high and high-to-low pH assays (using HCl, H 3 PO 4 , or NaOH to adjust pH) were performed on phosphate-buffered (0.12‑0.15 M) saturated solutions of DsHCl in the pH 1.3–11.6 range. After equilibration (stirring 6 h, followed by 18 h stir-free sedimentation), filtration or centrifugation was used for phase separation. Concentration was measured using HPLC with UV/VIS detection. The 2:1 drug-phosphate solubility product (K sp 2:1 = [DsH + ] 2 [HPO 4 2− ]) was determined from data in the pH 4–9 region. The free base of desipramine was prepared and used to determine the K sp 1:1 ([DsH + ][H 2 PO 4 − ]) in chloride-free acidified suspension. In addition, phosphate-free titrations were conducted to determine the intrinsic solubility, S 0 , and the 1:1 drug-chloride solubility product, K sp DsH [rad] Cl = [DsH + ][Cl − ]. Under the assay conditions, only the phosphate-free solutions showed some supersaturation near pH max 8.0. In phosphate-containing solutions, pH max was indicated at higher pH (8.8–9.6). Oils mixed with solids were observed to form in alkaline solutions (pH > 11). Notably, soluble drug-phosphate complexes appeared to form below pH 3.9 and above pH max in saturated phosphate‑containing saline solutions. This was indicated by the systematic pH shift to higher values in the log S-pH curve in alkaline solution than expected from the Henderson-Hasselbalch equation. For pH < 3.9, saturated phosphate-containing saline solutions exhibited elevated solubility, with drug-hydrochloride as the sole precipitate. Salt solubility products, intrinsic solubility, and complexation constants, which rationalized the data, were determined. Elemental, thermogravimetric (TGA), differential scanning calorimetric (DSC), and powder X-ray diffraction (PXRD) analyses were used to characterize the precipitates isolated from suspensions at different pH.
PB  - Elsevier
T2  - European Journal of Pharmaceutical Sciences
T1  - Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates
VL  - 133
SP  - 264
EP  - 274
DO  - 10.1016/j.ejps.2019.03.014
ER  - 

@article{
author = "Marković, Olivera S. and Pešić, Miloš P. and Shah, Ankita V. and Serajuddin, Abu T.M. and Verbić, Tatjana and Avdeef, Alex",
year = "2019",
abstract = "Although solubility-pH data for desipramine hydrochloride (DsHCl) have been reported previously, the aim of the present study was to critically examine the aqueous solubility-pH behavior of DsHCl in buffer-free and buffered solutions, in the presence of physiologically-relevant chloride concentration, using experimental practices recommended in the recently-published “white paper” (Avdeef et al., 2016). The computer program pDISOL-X was used to design the structured experiments (pH-RSF method), to process the data, and to refine the equilibrium constants. Low-to-high and high-to-low pH assays (using HCl, H 3 PO 4 , or NaOH to adjust pH) were performed on phosphate-buffered (0.12‑0.15 M) saturated solutions of DsHCl in the pH 1.3–11.6 range. After equilibration (stirring 6 h, followed by 18 h stir-free sedimentation), filtration or centrifugation was used for phase separation. Concentration was measured using HPLC with UV/VIS detection. The 2:1 drug-phosphate solubility product (K sp 2:1 = [DsH + ] 2 [HPO 4 2− ]) was determined from data in the pH 4–9 region. The free base of desipramine was prepared and used to determine the K sp 1:1 ([DsH + ][H 2 PO 4 − ]) in chloride-free acidified suspension. In addition, phosphate-free titrations were conducted to determine the intrinsic solubility, S 0 , and the 1:1 drug-chloride solubility product, K sp DsH [rad] Cl = [DsH + ][Cl − ]. Under the assay conditions, only the phosphate-free solutions showed some supersaturation near pH max 8.0. In phosphate-containing solutions, pH max was indicated at higher pH (8.8–9.6). Oils mixed with solids were observed to form in alkaline solutions (pH > 11). Notably, soluble drug-phosphate complexes appeared to form below pH 3.9 and above pH max in saturated phosphate‑containing saline solutions. This was indicated by the systematic pH shift to higher values in the log S-pH curve in alkaline solution than expected from the Henderson-Hasselbalch equation. For pH < 3.9, saturated phosphate-containing saline solutions exhibited elevated solubility, with drug-hydrochloride as the sole precipitate. Salt solubility products, intrinsic solubility, and complexation constants, which rationalized the data, were determined. Elemental, thermogravimetric (TGA), differential scanning calorimetric (DSC), and powder X-ray diffraction (PXRD) analyses were used to characterize the precipitates isolated from suspensions at different pH.",
publisher = "Elsevier",
journal = "European Journal of Pharmaceutical Sciences",
title = "Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates",
volume = "133",
pages = "264-274",
doi = "10.1016/j.ejps.2019.03.014"
}

Marković, O. S., Pešić, M. P., Shah, A. V., Serajuddin, A. T.M., Verbić, T.,& Avdeef, A.. (2019). Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates. in European Journal of Pharmaceutical Sciences
Elsevier., 133, 264-274.
https://doi.org/10.1016/j.ejps.2019.03.014

Marković OS, Pešić MP, Shah AV, Serajuddin AT, Verbić T, Avdeef A. Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates. in European Journal of Pharmaceutical Sciences. 2019;133:264-274.
doi:10.1016/j.ejps.2019.03.014 .

Marković, Olivera S., Pešić, Miloš P., Shah, Ankita V., Serajuddin, Abu T.M., Verbić, Tatjana, Avdeef, Alex, "Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates" in European Journal of Pharmaceutical Sciences, 133 (2019):264-274,
https://doi.org/10.1016/j.ejps.2019.03.014 . .

TY  - JOUR
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Shah, Ankita V.
AU  - Serajuddin, Abu T.M.
AU  - Verbić, Tatjana
AU  - Avdeef, Alex
PY  - 2019
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2925
AB  - Although solubility-pH data for desipramine hydrochloride (DsHCl) have been reported previously, the aim of the present study was to critically examine the aqueous solubility-pH behavior of DsHCl in buffer-free and buffered solutions, in the presence of physiologically-relevant chloride concentration, using experimental practices recommended in the recently-published “white paper” (Avdeef et al., 2016). The computer program pDISOL-X was used to design the structured experiments (pH-RSF method), to process the data, and to refine the equilibrium constants. Low-to-high and high-to-low pH assays (using HCl, H 3 PO 4 , or NaOH to adjust pH) were performed on phosphate-buffered (0.12‑0.15 M) saturated solutions of DsHCl in the pH 1.3–11.6 range. After equilibration (stirring 6 h, followed by 18 h stir-free sedimentation), filtration or centrifugation was used for phase separation. Concentration was measured using HPLC with UV/VIS detection. The 2:1 drug-phosphate solubility product (K sp 2:1 = [DsH + ] 2 [HPO 4 2− ]) was determined from data in the pH 4–9 region. The free base of desipramine was prepared and used to determine the K sp 1:1 ([DsH + ][H 2 PO 4 − ]) in chloride-free acidified suspension. In addition, phosphate-free titrations were conducted to determine the intrinsic solubility, S 0 , and the 1:1 drug-chloride solubility product, K sp DsH [rad] Cl = [DsH + ][Cl − ]. Under the assay conditions, only the phosphate-free solutions showed some supersaturation near pH max 8.0. In phosphate-containing solutions, pH max was indicated at higher pH (8.8–9.6). Oils mixed with solids were observed to form in alkaline solutions (pH > 11). Notably, soluble drug-phosphate complexes appeared to form below pH 3.9 and above pH max in saturated phosphate‑containing saline solutions. This was indicated by the systematic pH shift to higher values in the log S-pH curve in alkaline solution than expected from the Henderson-Hasselbalch equation. For pH < 3.9, saturated phosphate-containing saline solutions exhibited elevated solubility, with drug-hydrochloride as the sole precipitate. Salt solubility products, intrinsic solubility, and complexation constants, which rationalized the data, were determined. Elemental, thermogravimetric (TGA), differential scanning calorimetric (DSC), and powder X-ray diffraction (PXRD) analyses were used to characterize the precipitates isolated from suspensions at different pH.
PB  - Elsevier
T2  - European Journal of Pharmaceutical Sciences
T1  - Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates
VL  - 133
SP  - 264
EP  - 274
DO  - 10.1016/j.ejps.2019.03.014
ER  - 

@article{
author = "Marković, Olivera S. and Pešić, Miloš P. and Shah, Ankita V. and Serajuddin, Abu T.M. and Verbić, Tatjana and Avdeef, Alex",
year = "2019",
abstract = "Although solubility-pH data for desipramine hydrochloride (DsHCl) have been reported previously, the aim of the present study was to critically examine the aqueous solubility-pH behavior of DsHCl in buffer-free and buffered solutions, in the presence of physiologically-relevant chloride concentration, using experimental practices recommended in the recently-published “white paper” (Avdeef et al., 2016). The computer program pDISOL-X was used to design the structured experiments (pH-RSF method), to process the data, and to refine the equilibrium constants. Low-to-high and high-to-low pH assays (using HCl, H 3 PO 4 , or NaOH to adjust pH) were performed on phosphate-buffered (0.12‑0.15 M) saturated solutions of DsHCl in the pH 1.3–11.6 range. After equilibration (stirring 6 h, followed by 18 h stir-free sedimentation), filtration or centrifugation was used for phase separation. Concentration was measured using HPLC with UV/VIS detection. The 2:1 drug-phosphate solubility product (K sp 2:1 = [DsH + ] 2 [HPO 4 2− ]) was determined from data in the pH 4–9 region. The free base of desipramine was prepared and used to determine the K sp 1:1 ([DsH + ][H 2 PO 4 − ]) in chloride-free acidified suspension. In addition, phosphate-free titrations were conducted to determine the intrinsic solubility, S 0 , and the 1:1 drug-chloride solubility product, K sp DsH [rad] Cl = [DsH + ][Cl − ]. Under the assay conditions, only the phosphate-free solutions showed some supersaturation near pH max 8.0. In phosphate-containing solutions, pH max was indicated at higher pH (8.8–9.6). Oils mixed with solids were observed to form in alkaline solutions (pH > 11). Notably, soluble drug-phosphate complexes appeared to form below pH 3.9 and above pH max in saturated phosphate‑containing saline solutions. This was indicated by the systematic pH shift to higher values in the log S-pH curve in alkaline solution than expected from the Henderson-Hasselbalch equation. For pH < 3.9, saturated phosphate-containing saline solutions exhibited elevated solubility, with drug-hydrochloride as the sole precipitate. Salt solubility products, intrinsic solubility, and complexation constants, which rationalized the data, were determined. Elemental, thermogravimetric (TGA), differential scanning calorimetric (DSC), and powder X-ray diffraction (PXRD) analyses were used to characterize the precipitates isolated from suspensions at different pH.",
publisher = "Elsevier",
journal = "European Journal of Pharmaceutical Sciences",
title = "Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates",
volume = "133",
pages = "264-274",
doi = "10.1016/j.ejps.2019.03.014"
}

Marković, O. S., Pešić, M. P., Shah, A. V., Serajuddin, A. T.M., Verbić, T.,& Avdeef, A.. (2019). Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates. in European Journal of Pharmaceutical Sciences
Elsevier., 133, 264-274.
https://doi.org/10.1016/j.ejps.2019.03.014

Marković OS, Pešić MP, Shah AV, Serajuddin AT, Verbić T, Avdeef A. Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates. in European Journal of Pharmaceutical Sciences. 2019;133:264-274.
doi:10.1016/j.ejps.2019.03.014 .

Marković, Olivera S., Pešić, Miloš P., Shah, Ankita V., Serajuddin, Abu T.M., Verbić, Tatjana, Avdeef, Alex, "Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates" in European Journal of Pharmaceutical Sciences, 133 (2019):264-274,
https://doi.org/10.1016/j.ejps.2019.03.014 . .

TY  - DATA
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Shah, Ankita V.
AU  - Serajuddin, Abu T.M.
AU  - Verbić, Tatjana
AU  - Avdeef, Alex
PY  - 2019
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2926
PB  - Elsevier
T2  - European Journal of Pharmaceutical Sciences
T1  - Supplementary data for the article: Marković, O. S.; Pešić, M. P.; Shah, A. V.; Serajuddin, A. T. M.; Verbić, T. Ž.; Avdeef, A. Solubility-PH Profile of Desipramine Hydrochloride in Saline Phosphate Buffer: Enhanced Solubility Due to Drug-Buffer Aggregates. European Journal of Pharmaceutical Sciences 2019, 133, 264–274. https://doi.org/10.1016/j.ejps.2019.03.014
DO  - 10.1016/j.ejps.2019.03.014
ER  - 

@misc{
author = "Marković, Olivera S. and Pešić, Miloš P. and Shah, Ankita V. and Serajuddin, Abu T.M. and Verbić, Tatjana and Avdeef, Alex",
year = "2019",
publisher = "Elsevier",
journal = "European Journal of Pharmaceutical Sciences",
title = "Supplementary data for the article: Marković, O. S.; Pešić, M. P.; Shah, A. V.; Serajuddin, A. T. M.; Verbić, T. Ž.; Avdeef, A. Solubility-PH Profile of Desipramine Hydrochloride in Saline Phosphate Buffer: Enhanced Solubility Due to Drug-Buffer Aggregates. European Journal of Pharmaceutical Sciences 2019, 133, 264–274. https://doi.org/10.1016/j.ejps.2019.03.014",
doi = "10.1016/j.ejps.2019.03.014"
}

Marković, O. S., Pešić, M. P., Shah, A. V., Serajuddin, A. T.M., Verbić, T.,& Avdeef, A.. (2019). Supplementary data for the article: Marković, O. S.; Pešić, M. P.; Shah, A. V.; Serajuddin, A. T. M.; Verbić, T. Ž.; Avdeef, A. Solubility-PH Profile of Desipramine Hydrochloride in Saline Phosphate Buffer: Enhanced Solubility Due to Drug-Buffer Aggregates. European Journal of Pharmaceutical Sciences 2019, 133, 264–274. https://doi.org/10.1016/j.ejps.2019.03.014. in European Journal of Pharmaceutical Sciences
Elsevier..
https://doi.org/10.1016/j.ejps.2019.03.014

Marković OS, Pešić MP, Shah AV, Serajuddin AT, Verbić T, Avdeef A. Supplementary data for the article: Marković, O. S.; Pešić, M. P.; Shah, A. V.; Serajuddin, A. T. M.; Verbić, T. Ž.; Avdeef, A. Solubility-PH Profile of Desipramine Hydrochloride in Saline Phosphate Buffer: Enhanced Solubility Due to Drug-Buffer Aggregates. European Journal of Pharmaceutical Sciences 2019, 133, 264–274. https://doi.org/10.1016/j.ejps.2019.03.014. in European Journal of Pharmaceutical Sciences. 2019;.
doi:10.1016/j.ejps.2019.03.014 .

Marković, Olivera S., Pešić, Miloš P., Shah, Ankita V., Serajuddin, Abu T.M., Verbić, Tatjana, Avdeef, Alex, "Supplementary data for the article: Marković, O. S.; Pešić, M. P.; Shah, A. V.; Serajuddin, A. T. M.; Verbić, T. Ž.; Avdeef, A. Solubility-PH Profile of Desipramine Hydrochloride in Saline Phosphate Buffer: Enhanced Solubility Due to Drug-Buffer Aggregates. European Journal of Pharmaceutical Sciences 2019, 133, 264–274. https://doi.org/10.1016/j.ejps.2019.03.014" in European Journal of Pharmaceutical Sciences (2019),
https://doi.org/10.1016/j.ejps.2019.03.014 . .

TY  - CONF
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Shah, Ankita V.
AU  - Serajuddin, Abu T. M.
AU  - Avdeef, Alex
AU  - Verbić, Tatjana
PY  - 2019
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5941
AB  - Optimal experimental design to measure the aqueous equilibrium solubility of an ionizable 
substance requires a number of critical considerations. The aqueous medium to which the 
substance is added usually contains a buffer to help control the pH. 
The solution behavior of desipramine hydrochloride (DsHCl) in phosphate-buffered and 
unbuffered solutions is evidently complicated and only tentatively understood. The computer 
program pDISOL-X was used to design the structured pH-ramp shake flask experiments (pH RSF method), to process the data, and to refine the equilibrium constants. Specifically, 
solubility was measured: a) using state-of-the-art experimental design, as recommended in a 
recently published white paper on solubility [1], b) performing solubility titrations in two 
directions, pH 11.6→1.3 as well as 1.3→11.6, c) using both DsHCl and Ds (free base), as 
starting solids, d) performing titrations in chloride-containing media, without any phosphate, e) 
performing the converse measurements (phosphate-containing, chloride-free media), 
f) isolating solids at critical log S-pH points and performing solid state characterizations using 
elemental, thermogravimetric, differential scanning calorimetric, and powder X-ray diffraction 
analyses. Concentration was measured using HPLC with UV/VIS detection. 
Under the assay conditions, only the phosphate free solutions showed some supersaturation 
near pHmax 8.0. In phosphate-containing solutions, pHmax was indicated at higher pH (8.8–
9.6). Oils mixed with solids were observed to form in alkaline solutions (pH>11). Notably, 
soluble drug-phosphate complexes appeared to form below pH 3.9 and above pHmax in 
saturated phosphate‑containing saline solutions. This was indicated by the systematic pH 
shift to higher values in the log S-pH curve in alkaline solution than expected from the 
Henderson-Hasselbalch equation. For pH<3.9, saturated phosphate-containing saline 
solutions exhibited elevated solubility, with drug-hydrochloride as the sole precipitate. Salt 
solubility products, intrinsic solubility, and complexation constants, which rationalized the 
data, were determined [2].
PB  - International Association of Physical Chemists
C3  - 8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery  & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019
T1  - Desipramine solubility studies: enhanced solubility due to drug-buffer aggregates
SP  - 17
EP  - 17
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5941
ER  - 

@conference{
author = "Marković, Olivera S. and Pešić, Miloš P. and Shah, Ankita V. and Serajuddin, Abu T. M. and Avdeef, Alex and Verbić, Tatjana",
year = "2019",
abstract = "Optimal experimental design to measure the aqueous equilibrium solubility of an ionizable 
substance requires a number of critical considerations. The aqueous medium to which the 
substance is added usually contains a buffer to help control the pH. 
The solution behavior of desipramine hydrochloride (DsHCl) in phosphate-buffered and 
unbuffered solutions is evidently complicated and only tentatively understood. The computer 
program pDISOL-X was used to design the structured pH-ramp shake flask experiments (pH RSF method), to process the data, and to refine the equilibrium constants. Specifically, 
solubility was measured: a) using state-of-the-art experimental design, as recommended in a 
recently published white paper on solubility [1], b) performing solubility titrations in two 
directions, pH 11.6→1.3 as well as 1.3→11.6, c) using both DsHCl and Ds (free base), as 
starting solids, d) performing titrations in chloride-containing media, without any phosphate, e) 
performing the converse measurements (phosphate-containing, chloride-free media), 
f) isolating solids at critical log S-pH points and performing solid state characterizations using 
elemental, thermogravimetric, differential scanning calorimetric, and powder X-ray diffraction 
analyses. Concentration was measured using HPLC with UV/VIS detection. 
Under the assay conditions, only the phosphate free solutions showed some supersaturation 
near pHmax 8.0. In phosphate-containing solutions, pHmax was indicated at higher pH (8.8–
9.6). Oils mixed with solids were observed to form in alkaline solutions (pH>11). Notably, 
soluble drug-phosphate complexes appeared to form below pH 3.9 and above pHmax in 
saturated phosphate‑containing saline solutions. This was indicated by the systematic pH 
shift to higher values in the log S-pH curve in alkaline solution than expected from the 
Henderson-Hasselbalch equation. For pH<3.9, saturated phosphate-containing saline 
solutions exhibited elevated solubility, with drug-hydrochloride as the sole precipitate. Salt 
solubility products, intrinsic solubility, and complexation constants, which rationalized the 
data, were determined [2].",
publisher = "International Association of Physical Chemists",
journal = "8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery  & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019",
title = "Desipramine solubility studies: enhanced solubility due to drug-buffer aggregates",
pages = "17-17",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5941"
}

Marković, O. S., Pešić, M. P., Shah, A. V., Serajuddin, A. T. M., Avdeef, A.,& Verbić, T.. (2019). Desipramine solubility studies: enhanced solubility due to drug-buffer aggregates. in 8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery  & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019
International Association of Physical Chemists., 17-17.
https://hdl.handle.net/21.15107/rcub_cherry_5941

Marković OS, Pešić MP, Shah AV, Serajuddin ATM, Avdeef A, Verbić T. Desipramine solubility studies: enhanced solubility due to drug-buffer aggregates. in 8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery  & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019. 2019;:17-17.
https://hdl.handle.net/21.15107/rcub_cherry_5941 .

Marković, Olivera S., Pešić, Miloš P., Shah, Ankita V., Serajuddin, Abu T. M., Avdeef, Alex, Verbić, Tatjana, "Desipramine solubility studies: enhanced solubility due to drug-buffer aggregates" in 8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery  & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019 (2019):17-17,
https://hdl.handle.net/21.15107/rcub_cherry_5941 .

TY  - CONF
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Avdeef, Alex
AU  - Verbić, Tatjana
PY  - 2019
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5942
AB  - Amphiphilic tricyclic bases are surface-active, sparingly-soluble drugs, which can exhibit 
complicated aqueous solution chemistry. New pH-Ramp Shake-Flask method was 
previously applied to desipramine hydrochloride solubility studies and described in the 
literature [1]. Solubility was measured using state-of-the-art experimental design, 
recommended in the white paper on equilibrium solubility measurements [2]. The aim of 
this study was to examine solubility-pH behavior of desipramine structural analogues: 
imipramine and amitriptyline hydrochlorides (Figure 1). Imipramine and amitriptyline are 
tricyclic antidepressants, which are used in the treatment of mental illnesses. pH-Ramp 
Shake-Flask method was applied. Appearance of aggregates (trimer, around pH 4 in imipramine case), which lead to slow 
sedimentation, and oil forms make solubility determination extremely challenging. Oils 
which are more soluble than crystalline forms are formed in alkaline solutions (above pH 
7.8 in imipramine case). Sometimes in such cases, pH adjustment in that pH region can be 
unpredictable. Furthermore, oil sticks to electrode making pH measurement difficult, 
especially in amitryptiline case. Concentration was measured using HPLC with UV/Vis 
detection. Different techniques were used for solid phase characterization. Solid phase 
characterization is particularly important in complicated systems like this.
PB  - International Association of Physical Chemists
C3  - 8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019
T1  - pH-Dependent  solubility profiles of imipramine and amitriptyline hydrochlorides
SP  - 51
EP  - 51
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5942
ER  - 

@conference{
author = "Marković, Olivera S. and Pešić, Miloš P. and Avdeef, Alex and Verbić, Tatjana",
year = "2019",
abstract = "Amphiphilic tricyclic bases are surface-active, sparingly-soluble drugs, which can exhibit 
complicated aqueous solution chemistry. New pH-Ramp Shake-Flask method was 
previously applied to desipramine hydrochloride solubility studies and described in the 
literature [1]. Solubility was measured using state-of-the-art experimental design, 
recommended in the white paper on equilibrium solubility measurements [2]. The aim of 
this study was to examine solubility-pH behavior of desipramine structural analogues: 
imipramine and amitriptyline hydrochlorides (Figure 1). Imipramine and amitriptyline are 
tricyclic antidepressants, which are used in the treatment of mental illnesses. pH-Ramp 
Shake-Flask method was applied. Appearance of aggregates (trimer, around pH 4 in imipramine case), which lead to slow 
sedimentation, and oil forms make solubility determination extremely challenging. Oils 
which are more soluble than crystalline forms are formed in alkaline solutions (above pH 
7.8 in imipramine case). Sometimes in such cases, pH adjustment in that pH region can be 
unpredictable. Furthermore, oil sticks to electrode making pH measurement difficult, 
especially in amitryptiline case. Concentration was measured using HPLC with UV/Vis 
detection. Different techniques were used for solid phase characterization. Solid phase 
characterization is particularly important in complicated systems like this.",
publisher = "International Association of Physical Chemists",
journal = "8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019",
title = "pH-Dependent  solubility profiles of imipramine and amitriptyline hydrochlorides",
pages = "51-51",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5942"
}

Marković, O. S., Pešić, M. P., Avdeef, A.,& Verbić, T.. (2019). pH-Dependent  solubility profiles of imipramine and amitriptyline hydrochlorides. in 8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019
International Association of Physical Chemists., 51-51.
https://hdl.handle.net/21.15107/rcub_cherry_5942

Marković OS, Pešić MP, Avdeef A, Verbić T. pH-Dependent  solubility profiles of imipramine and amitriptyline hydrochlorides. in 8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019. 2019;:51-51.
https://hdl.handle.net/21.15107/rcub_cherry_5942 .

Marković, Olivera S., Pešić, Miloš P., Avdeef, Alex, Verbić, Tatjana, "pH-Dependent  solubility profiles of imipramine and amitriptyline hydrochlorides" in 8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019 (2019):51-51,
https://hdl.handle.net/21.15107/rcub_cherry_5942 .

TY  - DATA
AU  - Pešić, Miloš P.
AU  - Todorov, Miljana D.
AU  - Drakulić, Branko J.
AU  - Juranić, Ivan O.
AU  - Verbić, Tatjana
AU  - Zloh, Mire
AU  - Cvijetić, Ilija
PY  - 2018
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/3050
PB  - Springer/Plenum Publishers, New York
T2  - Structural Chemistry
T1  - Supplementary material for the article: Cvijetić, I. N.; Pešić, M. P.; Todorov, M. D.; Drakulić, B. J.; Juranić, I. O.; Verbić, T. Ž.; Zloh, M. Tautomerism of 4-Phenyl-2,4-Dioxobutanoic Acid. Insights from PH Ramping NMR Study and Quantum Chemical Calculations. Structural Chemistry 2018, 29 (2), 423–434. https://doi.org/10.1007/s11224-017-1039-3
UR  - https://hdl.handle.net/21.15107/rcub_cherry_3050
ER  - 

@misc{
author = "Pešić, Miloš P. and Todorov, Miljana D. and Drakulić, Branko J. and Juranić, Ivan O. and Verbić, Tatjana and Zloh, Mire and Cvijetić, Ilija",
year = "2018",
publisher = "Springer/Plenum Publishers, New York",
journal = "Structural Chemistry",
title = "Supplementary material for the article: Cvijetić, I. N.; Pešić, M. P.; Todorov, M. D.; Drakulić, B. J.; Juranić, I. O.; Verbić, T. Ž.; Zloh, M. Tautomerism of 4-Phenyl-2,4-Dioxobutanoic Acid. Insights from PH Ramping NMR Study and Quantum Chemical Calculations. Structural Chemistry 2018, 29 (2), 423–434. https://doi.org/10.1007/s11224-017-1039-3",
url = "https://hdl.handle.net/21.15107/rcub_cherry_3050"
}

Pešić, M. P., Todorov, M. D., Drakulić, B. J., Juranić, I. O., Verbić, T., Zloh, M.,& Cvijetić, I.. (2018). Supplementary material for the article: Cvijetić, I. N.; Pešić, M. P.; Todorov, M. D.; Drakulić, B. J.; Juranić, I. O.; Verbić, T. Ž.; Zloh, M. Tautomerism of 4-Phenyl-2,4-Dioxobutanoic Acid. Insights from PH Ramping NMR Study and Quantum Chemical Calculations. Structural Chemistry 2018, 29 (2), 423–434. https://doi.org/10.1007/s11224-017-1039-3. in Structural Chemistry
Springer/Plenum Publishers, New York..
https://hdl.handle.net/21.15107/rcub_cherry_3050

Pešić MP, Todorov MD, Drakulić BJ, Juranić IO, Verbić T, Zloh M, Cvijetić I. Supplementary material for the article: Cvijetić, I. N.; Pešić, M. P.; Todorov, M. D.; Drakulić, B. J.; Juranić, I. O.; Verbić, T. Ž.; Zloh, M. Tautomerism of 4-Phenyl-2,4-Dioxobutanoic Acid. Insights from PH Ramping NMR Study and Quantum Chemical Calculations. Structural Chemistry 2018, 29 (2), 423–434. https://doi.org/10.1007/s11224-017-1039-3. in Structural Chemistry. 2018;.
https://hdl.handle.net/21.15107/rcub_cherry_3050 .

Pešić, Miloš P., Todorov, Miljana D., Drakulić, Branko J., Juranić, Ivan O., Verbić, Tatjana, Zloh, Mire, Cvijetić, Ilija, "Supplementary material for the article: Cvijetić, I. N.; Pešić, M. P.; Todorov, M. D.; Drakulić, B. J.; Juranić, I. O.; Verbić, T. Ž.; Zloh, M. Tautomerism of 4-Phenyl-2,4-Dioxobutanoic Acid. Insights from PH Ramping NMR Study and Quantum Chemical Calculations. Structural Chemistry 2018, 29 (2), 423–434. https://doi.org/10.1007/s11224-017-1039-3" in Structural Chemistry (2018),
https://hdl.handle.net/21.15107/rcub_cherry_3050 .

TY  - JOUR
AU  - Cvijetić, Ilija
AU  - Pešić, Miloš P.
AU  - Todorov, Miljana D.
AU  - Drakulić, Branko J.
AU  - Juranić, Ivan O.
AU  - Verbić, Tatjana
AU  - Zloh, Mire
PY  - 2018
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2111
AB  - Aryldiketo acids (ADKs) exhibit the variety of biological activities, mainly due to large affinity toward divalent metal ions. Metal complexation ability of ADKs, as well as interactions with proteins, depend on tautomeric form present in solution. The main aim of this study was to fully explore the tautomeric preferences of 4-phenyl-2,4-dioxobutanoic acid (4PDA), as ADKs representative, in aqueous media at different pH values. 1D and 2D NMR spectroscopy in combination with quantum chemical calculations was applied in order to better understand the tautomeric preferences of 4PDA. The data in highly acidic media are especially interesting since there are no such findings in the literature due to low solubility of ADKs in molecular form. At low pH values, where 4PDA is unionized, the most abundant tautomeric form is enol with keto group closer to phenyl ring. At higher pH values, mixture of two 4PDA ionic forms coexists in solution. Their ratio calculated according to NMR data fits the values predicted using two experimentally determined pK (a) values. Based on the complexity of H-1 NMR spectrum of monoanionic 4PDA form, coexistence of two stable rotamers was assumed. In an alkaline media, 4PDA is mostly present in dianionic form. As pi-electrons of dianion are delocalized over an entire keto-enol moiety, spectral distinction between tautomers was not possible. Quantum chemical calculations were used to predict relative stability of tautomers. The predictions were in good accordance with experimental results only in case when explicit water molecule was included in calculations.
PB  - Springer/Plenum Publishers, New York
T2  - Structural Chemistry
T1  - Tautomerism of 4-phenyl-2,4-dioxobutanoic acid. Insights from pH ramping NMR study and quantum chemical calculations
VL  - 29
IS  - 2
SP  - 423
EP  - 434
DO  - 10.1007/s11224-017-1039-3
ER  - 

@article{
author = "Cvijetić, Ilija and Pešić, Miloš P. and Todorov, Miljana D. and Drakulić, Branko J. and Juranić, Ivan O. and Verbić, Tatjana and Zloh, Mire",
year = "2018",
abstract = "Aryldiketo acids (ADKs) exhibit the variety of biological activities, mainly due to large affinity toward divalent metal ions. Metal complexation ability of ADKs, as well as interactions with proteins, depend on tautomeric form present in solution. The main aim of this study was to fully explore the tautomeric preferences of 4-phenyl-2,4-dioxobutanoic acid (4PDA), as ADKs representative, in aqueous media at different pH values. 1D and 2D NMR spectroscopy in combination with quantum chemical calculations was applied in order to better understand the tautomeric preferences of 4PDA. The data in highly acidic media are especially interesting since there are no such findings in the literature due to low solubility of ADKs in molecular form. At low pH values, where 4PDA is unionized, the most abundant tautomeric form is enol with keto group closer to phenyl ring. At higher pH values, mixture of two 4PDA ionic forms coexists in solution. Their ratio calculated according to NMR data fits the values predicted using two experimentally determined pK (a) values. Based on the complexity of H-1 NMR spectrum of monoanionic 4PDA form, coexistence of two stable rotamers was assumed. In an alkaline media, 4PDA is mostly present in dianionic form. As pi-electrons of dianion are delocalized over an entire keto-enol moiety, spectral distinction between tautomers was not possible. Quantum chemical calculations were used to predict relative stability of tautomers. The predictions were in good accordance with experimental results only in case when explicit water molecule was included in calculations.",
publisher = "Springer/Plenum Publishers, New York",
journal = "Structural Chemistry",
title = "Tautomerism of 4-phenyl-2,4-dioxobutanoic acid. Insights from pH ramping NMR study and quantum chemical calculations",
volume = "29",
number = "2",
pages = "423-434",
doi = "10.1007/s11224-017-1039-3"
}

Cvijetić, I., Pešić, M. P., Todorov, M. D., Drakulić, B. J., Juranić, I. O., Verbić, T.,& Zloh, M.. (2018). Tautomerism of 4-phenyl-2,4-dioxobutanoic acid. Insights from pH ramping NMR study and quantum chemical calculations. in Structural Chemistry
Springer/Plenum Publishers, New York., 29(2), 423-434.
https://doi.org/10.1007/s11224-017-1039-3

Cvijetić I, Pešić MP, Todorov MD, Drakulić BJ, Juranić IO, Verbić T, Zloh M. Tautomerism of 4-phenyl-2,4-dioxobutanoic acid. Insights from pH ramping NMR study and quantum chemical calculations. in Structural Chemistry. 2018;29(2):423-434.
doi:10.1007/s11224-017-1039-3 .

Cvijetić, Ilija, Pešić, Miloš P., Todorov, Miljana D., Drakulić, Branko J., Juranić, Ivan O., Verbić, Tatjana, Zloh, Mire, "Tautomerism of 4-phenyl-2,4-dioxobutanoic acid. Insights from pH ramping NMR study and quantum chemical calculations" in Structural Chemistry, 29, no. 2 (2018):423-434,
https://doi.org/10.1007/s11224-017-1039-3 . .

TY  - CONF
AU  - Marković, Olivera S.
AU  - Pešić, Miloš P.
AU  - Verbić, Tatjana
AU  - Avdeef, Alex
PY  - 2017
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5943
AB  - Desipramine hydrochloride (DsHCl; Figure 1.) is a known 
surface-active molecule, which may form sub-micellar 
aggregates in slightly acidic solutions. If a neutral or 
slightly basic solution is prepared from DsHCl, it may 
remain supersaturated for a very long time, as aggregates 
form. Appearance of aggregates might lead to slow 
sedimentation. Furthermore, at high pH values oils might 
form that are more soluble than crystalline form; this was 
already observed for surface-active compounds [1]. There are many other druglike 
molecules with similarly challenging properties, which have not been adequately 
characterized. Thus, much attention must be paid to set up the experimental procedure 
for precise solubility determinations [2].
Although solubility data for DsHCl can be found in the literature [3], in this study 
pH-dependent solubility profile of DsHCl was studied using slightly different method: 
pH-ramp shake flask. First, the pH value of DsHCl stock solution in 0.15 M phosphate 
buffer was adjusted to 11.7 in order to minimize supersaturation effect. Then, the pH 
value in separate samples was adjusted downwards with HCl, to prepare solutions in the 
pH 1.7-11.7 region. After stirring (6 h) and sedimentation (18 h), PTFE (hydrophobic, pore 
size 0.22 µm) filters or centrifugation were used for phase separation. Concentration was 
measured using HPLC with UV/Vis detection. The computer program pDISOL-X was used 
for data processing and refinement of equilibrium constants. Different techniques were 
used for solid phase characterization.
PB  - International Association of Physical Chemists
C3  - 6th IAPC Meeting Sixth World Conference on Physico-Chemical Methods in Drug Discovery  & Third World Conference on ADMET and DMPK, Zagreb, Croatia, September 4-7, 2017
T1  - pH-Dependent  solubility profile of desipramine hydrochloride
SP  - 42
EP  - 42
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5943
ER  - 

@conference{
author = "Marković, Olivera S. and Pešić, Miloš P. and Verbić, Tatjana and Avdeef, Alex",
year = "2017",
abstract = "Desipramine hydrochloride (DsHCl; Figure 1.) is a known 
surface-active molecule, which may form sub-micellar 
aggregates in slightly acidic solutions. If a neutral or 
slightly basic solution is prepared from DsHCl, it may 
remain supersaturated for a very long time, as aggregates 
form. Appearance of aggregates might lead to slow 
sedimentation. Furthermore, at high pH values oils might 
form that are more soluble than crystalline form; this was 
already observed for surface-active compounds [1]. There are many other druglike 
molecules with similarly challenging properties, which have not been adequately 
characterized. Thus, much attention must be paid to set up the experimental procedure 
for precise solubility determinations [2].
Although solubility data for DsHCl can be found in the literature [3], in this study 
pH-dependent solubility profile of DsHCl was studied using slightly different method: 
pH-ramp shake flask. First, the pH value of DsHCl stock solution in 0.15 M phosphate 
buffer was adjusted to 11.7 in order to minimize supersaturation effect. Then, the pH 
value in separate samples was adjusted downwards with HCl, to prepare solutions in the 
pH 1.7-11.7 region. After stirring (6 h) and sedimentation (18 h), PTFE (hydrophobic, pore 
size 0.22 µm) filters or centrifugation were used for phase separation. Concentration was 
measured using HPLC with UV/Vis detection. The computer program pDISOL-X was used 
for data processing and refinement of equilibrium constants. Different techniques were 
used for solid phase characterization.",
publisher = "International Association of Physical Chemists",
journal = "6th IAPC Meeting Sixth World Conference on Physico-Chemical Methods in Drug Discovery  & Third World Conference on ADMET and DMPK, Zagreb, Croatia, September 4-7, 2017",
title = "pH-Dependent  solubility profile of desipramine hydrochloride",
pages = "42-42",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5943"
}

Marković, O. S., Pešić, M. P., Verbić, T.,& Avdeef, A.. (2017). pH-Dependent  solubility profile of desipramine hydrochloride. in 6th IAPC Meeting Sixth World Conference on Physico-Chemical Methods in Drug Discovery  & Third World Conference on ADMET and DMPK, Zagreb, Croatia, September 4-7, 2017
International Association of Physical Chemists., 42-42.
https://hdl.handle.net/21.15107/rcub_cherry_5943

Marković OS, Pešić MP, Verbić T, Avdeef A. pH-Dependent  solubility profile of desipramine hydrochloride. in 6th IAPC Meeting Sixth World Conference on Physico-Chemical Methods in Drug Discovery  & Third World Conference on ADMET and DMPK, Zagreb, Croatia, September 4-7, 2017. 2017;:42-42.
https://hdl.handle.net/21.15107/rcub_cherry_5943 .

Marković, Olivera S., Pešić, Miloš P., Verbić, Tatjana, Avdeef, Alex, "pH-Dependent  solubility profile of desipramine hydrochloride" in 6th IAPC Meeting Sixth World Conference on Physico-Chemical Methods in Drug Discovery  & Third World Conference on ADMET and DMPK, Zagreb, Croatia, September 4-7, 2017 (2017):42-42,
https://hdl.handle.net/21.15107/rcub_cherry_5943 .

TY  - CONF
AU  - Marković, Olivera S.
AU  - Stojkov, Dragana D.
AU  - Ranković, Petar M.
AU  - Pešić, Miloš P.
AU  - Cvijetić, Ilija 
AU  - Verbić, Tatjana
PY  - 2016
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5944
AB  - Određivanje rastvorljivosti je važno u svim fazama razvoja leka. Dobijeni podaci se koriste 
za nalaženje potencijalnih lekova-kandidata, biofarmaceutsku klasifikciju i optimizaciju 
formulacije leka. Na merenje rastvorljivosti utiču različiti faktori: vreme mešanja, vreme 
sedimentacije, sastav pufera, temperatura, višak čvrste faze i tehnika odvajanja faza.[1] Cilj 
ovog rada je ispitivanje uticaja vrste membrane filtera u procesu odvajanja faza pri 
određivanju rastvorljivosti „shake-flask“ metodom. Izabrani su polietar-sulfon (hidrofobni) 
i poliviniliden-fluorid (hidrofilni) filteri. Koncentracija je merena pomoću UV/Vis 
spektrofotometrije. Kao model supstance korišćeni su karvedilol (baza) i ibuprofen 
(kiselina). Minijaturizovanom „shake-flask“ metodom i optimizovanom metodom 
potenciometrijske titracije određene su i logP vrednosti. Pokazano je da rezultat 
određivanja rastvorljivosti može zavisiti od vrste membrane filtera koji se koristi za 
odvajanje filtrata nakon uspostavljanja ravnoteže u rastvoru tokom rastvaranja. Jačina 
uticaja zavisi od lipofilnosti i pKa vrednosti ispitavanog molekula kao i od pH vrednosti 
rastvora u kom se izvodi određivanje.
AB  - Solubility determination is important in both early and development phase of drug 
research. This data is used to screen out drug-like candidates, biopharmaceutical 
classification and formulation optimization. Solubility measurements are influenced by 
several experimental factors: stirring and sedimentation time, composition of the aqueous 
buffer, temperature, amount of solid excess and the technique of phase-separation.1
The 
aim of the present study was to examine the influence of the filter type during phase 
separation on solubility determination. Polyether sulfone (hydrophobic) and 
polyvinylidene fluoride (hydrophilic) filters were chosen. The concentration was measured 
by UV/Vis spectrophotometry. Carvedilol (base) and ibuprofen (acid) are used as a model 
compounds. LogP values were determined by miniaturized shake-flask method and by 
optimized potentiometric titration. It is shown that solubility data can be influenced by 
membrane filter type which is used for filtration, after the equilibrium is established during 
dissolution. Magnitude of this influence depends of lipophilicity and pKa value of molecule 
and a solution pH value
PB  - Beograd : Srpsko hemijsko društvo
C3  - 53. Savetovanje Srpskog hemijskog društva, Kragujevac, 10. i 11. jun 2016
T1  - Uticaj vrste filtera na kvalitet određivanja rastvorljivosti  “shake-flask” metodom
T1  - The effect of the filter type on the quality of “shake flask” solubility determinations
SP  - 17
EP  - 17
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5944
ER  - 

@conference{
author = "Marković, Olivera S. and Stojkov, Dragana D. and Ranković, Petar M. and Pešić, Miloš P. and Cvijetić, Ilija  and Verbić, Tatjana",
year = "2016",
abstract = "Određivanje rastvorljivosti je važno u svim fazama razvoja leka. Dobijeni podaci se koriste 
za nalaženje potencijalnih lekova-kandidata, biofarmaceutsku klasifikciju i optimizaciju 
formulacije leka. Na merenje rastvorljivosti utiču različiti faktori: vreme mešanja, vreme 
sedimentacije, sastav pufera, temperatura, višak čvrste faze i tehnika odvajanja faza.[1] Cilj 
ovog rada je ispitivanje uticaja vrste membrane filtera u procesu odvajanja faza pri 
određivanju rastvorljivosti „shake-flask“ metodom. Izabrani su polietar-sulfon (hidrofobni) 
i poliviniliden-fluorid (hidrofilni) filteri. Koncentracija je merena pomoću UV/Vis 
spektrofotometrije. Kao model supstance korišćeni su karvedilol (baza) i ibuprofen 
(kiselina). Minijaturizovanom „shake-flask“ metodom i optimizovanom metodom 
potenciometrijske titracije određene su i logP vrednosti. Pokazano je da rezultat 
određivanja rastvorljivosti može zavisiti od vrste membrane filtera koji se koristi za 
odvajanje filtrata nakon uspostavljanja ravnoteže u rastvoru tokom rastvaranja. Jačina 
uticaja zavisi od lipofilnosti i pKa vrednosti ispitavanog molekula kao i od pH vrednosti 
rastvora u kom se izvodi određivanje., Solubility determination is important in both early and development phase of drug 
research. This data is used to screen out drug-like candidates, biopharmaceutical 
classification and formulation optimization. Solubility measurements are influenced by 
several experimental factors: stirring and sedimentation time, composition of the aqueous 
buffer, temperature, amount of solid excess and the technique of phase-separation.1
The 
aim of the present study was to examine the influence of the filter type during phase 
separation on solubility determination. Polyether sulfone (hydrophobic) and 
polyvinylidene fluoride (hydrophilic) filters were chosen. The concentration was measured 
by UV/Vis spectrophotometry. Carvedilol (base) and ibuprofen (acid) are used as a model 
compounds. LogP values were determined by miniaturized shake-flask method and by 
optimized potentiometric titration. It is shown that solubility data can be influenced by 
membrane filter type which is used for filtration, after the equilibrium is established during 
dissolution. Magnitude of this influence depends of lipophilicity and pKa value of molecule 
and a solution pH value",
publisher = "Beograd : Srpsko hemijsko društvo",
journal = "53. Savetovanje Srpskog hemijskog društva, Kragujevac, 10. i 11. jun 2016",
title = "Uticaj vrste filtera na kvalitet određivanja rastvorljivosti  “shake-flask” metodom, The effect of the filter type on the quality of “shake flask” solubility determinations",
pages = "17-17",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5944"
}

Marković, O. S., Stojkov, D. D., Ranković, P. M., Pešić, M. P., Cvijetić, I.,& Verbić, T.. (2016). Uticaj vrste filtera na kvalitet određivanja rastvorljivosti  “shake-flask” metodom. in 53. Savetovanje Srpskog hemijskog društva, Kragujevac, 10. i 11. jun 2016
Beograd : Srpsko hemijsko društvo., 17-17.
https://hdl.handle.net/21.15107/rcub_cherry_5944

Marković OS, Stojkov DD, Ranković PM, Pešić MP, Cvijetić I, Verbić T. Uticaj vrste filtera na kvalitet određivanja rastvorljivosti  “shake-flask” metodom. in 53. Savetovanje Srpskog hemijskog društva, Kragujevac, 10. i 11. jun 2016. 2016;:17-17.
https://hdl.handle.net/21.15107/rcub_cherry_5944 .

Marković, Olivera S., Stojkov, Dragana D., Ranković, Petar M., Pešić, Miloš P., Cvijetić, Ilija , Verbić, Tatjana, "Uticaj vrste filtera na kvalitet određivanja rastvorljivosti  “shake-flask” metodom" in 53. Savetovanje Srpskog hemijskog društva, Kragujevac, 10. i 11. jun 2016 (2016):17-17,
https://hdl.handle.net/21.15107/rcub_cherry_5944 .