TY  - CONF
AU  - Đurđević, Mladen
AU  - Pešić, Miloš
AU  - Verbić, Tatjana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5371
AB  - Acid-base supersolubilizaton (ABS) is recently developed method to prepare highly soluble amorphous despersions of drugs practically insoluble in water.1 It was shown that haloperidol, weakly basic, antipsychotic, and very hardly solube drug, becomes supersoluble when mixed with weak acids. This is a good way to overcome the common ion effect known to lower the solubility in drug solutions when salts are formed.2 Till today, it was shown that this principle is working for several well known hardly soluble drugs,3,4 but it was not shown what are the main interactions causing the supersolubilization. This study is a part of our ongoing research on the main interactions causing ABS. We have used haloperidol as a model drug, deuteroacetic, malic and tartaric acids as model weak acids and trifluoroacetic and methanesulfonic acids as model strong acids. Solubility of haloperidol in solutions of different acid concentration was determined by shake-flask method followed by HPLC-DAD analysis. NMR spectroscopy (1H and NOESY) was used to study interactions in solutions after the equilibrium was established and solid precipitate removed by centrifugation. Our results of solubility experiments in D2O are in good accordance with previously reported results in aqueous solutions of weak acids: solubility of haloperidol in 3 M or higher concentrations of weak acids is approx. 25 to 35 times higher than solubility of haloperidol in hydrochloric acid.1 Chemical shifts of all haloperidol protons in 1H NMR spectra recorded in higher concentrations of all used acids have lower values. This trend in chemical shifts changes follows the trend of increasing haloperidol solubility in the presence of weak acids. 1H NMR spectra have also shown that in lower concentrated (0.1 M) acid solutions chemical shifts of haloperidol protons remain almost the same, independent of solution pH value. In 1.0 M solutions of weak acids chemical shifts of all haloperidol protons are similar among used acids, but different compared to chemical shifts in strong acids solutions. NOESY 2D NMR spectra have shown that some NOE correlations are changed as acids’ concentration is increased. We hope that in our future work a broad variety of available NMR techniques, accompanied with molecular modeling, will give us more pronounced insight in interactions between hardly soluble drugs and weak acids/bases that lead to supersolubilization.
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
T1  - NMR study of haloperidol in weak acid solutions
SP  - 69
EP  - 69
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5371
ER  - 

@conference{
author = "Đurđević, Mladen and Pešić, Miloš and Verbić, Tatjana",
year = "2023",
abstract = "Acid-base supersolubilizaton (ABS) is recently developed method to prepare highly soluble amorphous despersions of drugs practically insoluble in water.1 It was shown that haloperidol, weakly basic, antipsychotic, and very hardly solube drug, becomes supersoluble when mixed with weak acids. This is a good way to overcome the common ion effect known to lower the solubility in drug solutions when salts are formed.2 Till today, it was shown that this principle is working for several well known hardly soluble drugs,3,4 but it was not shown what are the main interactions causing the supersolubilization. This study is a part of our ongoing research on the main interactions causing ABS. We have used haloperidol as a model drug, deuteroacetic, malic and tartaric acids as model weak acids and trifluoroacetic and methanesulfonic acids as model strong acids. Solubility of haloperidol in solutions of different acid concentration was determined by shake-flask method followed by HPLC-DAD analysis. NMR spectroscopy (1H and NOESY) was used to study interactions in solutions after the equilibrium was established and solid precipitate removed by centrifugation. Our results of solubility experiments in D2O are in good accordance with previously reported results in aqueous solutions of weak acids: solubility of haloperidol in 3 M or higher concentrations of weak acids is approx. 25 to 35 times higher than solubility of haloperidol in hydrochloric acid.1 Chemical shifts of all haloperidol protons in 1H NMR spectra recorded in higher concentrations of all used acids have lower values. This trend in chemical shifts changes follows the trend of increasing haloperidol solubility in the presence of weak acids. 1H NMR spectra have also shown that in lower concentrated (0.1 M) acid solutions chemical shifts of haloperidol protons remain almost the same, independent of solution pH value. In 1.0 M solutions of weak acids chemical shifts of all haloperidol protons are similar among used acids, but different compared to chemical shifts in strong acids solutions. NOESY 2D NMR spectra have shown that some NOE correlations are changed as acids’ concentration is increased. We hope that in our future work a broad variety of available NMR techniques, accompanied with molecular modeling, will give us more pronounced insight in interactions between hardly soluble drugs and weak acids/bases that lead to supersolubilization.",
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",
title = "NMR study of haloperidol in weak acid solutions",
pages = "69-69",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5371"
}

Đurđević, M., Pešić, M.,& Verbić, T.. (2023). NMR study of haloperidol in weak acid solutions. 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
International Association of Physical Chemists., 69-69.
https://hdl.handle.net/21.15107/rcub_farfar_5371

Đurđević M, Pešić M, Verbić T. NMR study of haloperidol in weak acid solutions. 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;:69-69.
https://hdl.handle.net/21.15107/rcub_farfar_5371 .

Đurđević, Mladen, Pešić, Miloš, Verbić, Tatjana, "NMR study of haloperidol in weak acid solutions" 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):69-69,
https://hdl.handle.net/21.15107/rcub_farfar_5371 .

TY  - JOUR
AU  - Verbić, Tatjana Ž.
AU  - Drakulić, Branko
AU  - Zloh, Mire
AU  - Pecelj, Jovana R.
AU  - Popović, Gordana
AU  - Juranić, Ivan O.
PY  - 2007
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/997
AB  - The protolytic equilibria of 13 4-aryl-2,4-dioxobutanoic acids (ADKs) were spectrophotometrically studied in aqueous solutions in the pH range 1-9 at 25±1 °C and an ionic strength of 0.1 mol l-1 (NaCl), with the exception of the 4-OH-derivative which was also potentiometrically studied in the pH range 7-10 at 25±1 °C and an ionic strength of 0.1 mol l-1 (NaCl). In solution, the compounds simultaneously exist in one diketo and two enolic forms; therefore, the determined acidity constants (pKa1 1.87-2.29, pKa2 6.63-8.13 and pKa3(4-OH-) 9.52) represent system macro constants. The 1H-NMR spectrum of the parent compound (4-phenyl- -2,4-dioxobutanoic acid) (25 °C, pD 5.0) proved the existence of all tautomeric forms. Using the extended Hammett relation, the determined pKa values were correlated with literature σ values. The predicted pKa values were in fair accordance with the experimentally observed ones. Molecular, monoanionic and dianionic forms of the parent compound were optimized by the semi-empirical molecular orbital PM6 method using the implicit water solvation model (COSMO). The obtained geometries were used to explain the quality of the LFER models.
AB  - Protolitičke ravnoteže 13 jedinjenja iz klase 4-aril-2,4-dioksobutanskih kiselina (ADK) spektrofotometrijski su proučavane u vodenim rastvorima u pH intervalu 1-9 pri temperaturi 25±1 °C i jonskoj jačini rastvora 0.1 mol l-1 (NaCl), sa izuzetkom 4-OH-derivata koji je proučavan i potenciometrijski u pH intervalu 7-10 pri istim uslovima. Kako ADK u vodenom rastvoru podležu keto-enolnoj tautomeriji i istovremeno postoje u diketo i dva enolna oblika, to određene kiselinske konstante (pKa1 1.87-2.29, pKa2 6.63-8.13 i pKa3(4-OH-) 9.52) predstavljaju makro konstante za dati sistem. 1H-NMR spektar osnovne supstance (4-fenil-2,4-dioksobutanska kiselina) (25 °C, pD 5.0) potvrđuje prisustvo svih tautomernih oblika. Upotrebom proširene Hametove korelacije, određene pKa vrednosti korelisane su sa literaturnim σ vrednostima. Predviđene pKa vrednosti dobro se slažu sa eksperimentalno dobijenim. Molekulski, monoanjonski i dianjonski oblici osnovne supstance su optimizovani semiempirijskom molekulsko-orbitalnom PM6 metodom sa implicitnim modelom solvatacije u vodi (COSMO). Dobijene geometrije su upotrebljene za objašnjenje kvaliteta LFER modela.
PB  - Srpsko hemijsko društvo, Beograd
T2  - Journal of the Serbian Chemical Society
T1  - An LFER study of the protolytic equilibria of 4-aryl-2,4-dioxobutanoic acids in aqueous solutions
T1  - Linearne korelacije slobodne energije (LFER) protolitičkih ravnoteža 4-aril-2,4-dioksobutanskih kiselina u vodenim rastvorima
VL  - 72
IS  - 12
SP  - 1201
EP  - 1216
DO  - 10.2298/JSC0712201V
ER  - 

@article{
author = "Verbić, Tatjana Ž. and Drakulić, Branko and Zloh, Mire and Pecelj, Jovana R. and Popović, Gordana and Juranić, Ivan O.",
year = "2007",
abstract = "The protolytic equilibria of 13 4-aryl-2,4-dioxobutanoic acids (ADKs) were spectrophotometrically studied in aqueous solutions in the pH range 1-9 at 25±1 °C and an ionic strength of 0.1 mol l-1 (NaCl), with the exception of the 4-OH-derivative which was also potentiometrically studied in the pH range 7-10 at 25±1 °C and an ionic strength of 0.1 mol l-1 (NaCl). In solution, the compounds simultaneously exist in one diketo and two enolic forms; therefore, the determined acidity constants (pKa1 1.87-2.29, pKa2 6.63-8.13 and pKa3(4-OH-) 9.52) represent system macro constants. The 1H-NMR spectrum of the parent compound (4-phenyl- -2,4-dioxobutanoic acid) (25 °C, pD 5.0) proved the existence of all tautomeric forms. Using the extended Hammett relation, the determined pKa values were correlated with literature σ values. The predicted pKa values were in fair accordance with the experimentally observed ones. Molecular, monoanionic and dianionic forms of the parent compound were optimized by the semi-empirical molecular orbital PM6 method using the implicit water solvation model (COSMO). The obtained geometries were used to explain the quality of the LFER models., Protolitičke ravnoteže 13 jedinjenja iz klase 4-aril-2,4-dioksobutanskih kiselina (ADK) spektrofotometrijski su proučavane u vodenim rastvorima u pH intervalu 1-9 pri temperaturi 25±1 °C i jonskoj jačini rastvora 0.1 mol l-1 (NaCl), sa izuzetkom 4-OH-derivata koji je proučavan i potenciometrijski u pH intervalu 7-10 pri istim uslovima. Kako ADK u vodenom rastvoru podležu keto-enolnoj tautomeriji i istovremeno postoje u diketo i dva enolna oblika, to određene kiselinske konstante (pKa1 1.87-2.29, pKa2 6.63-8.13 i pKa3(4-OH-) 9.52) predstavljaju makro konstante za dati sistem. 1H-NMR spektar osnovne supstance (4-fenil-2,4-dioksobutanska kiselina) (25 °C, pD 5.0) potvrđuje prisustvo svih tautomernih oblika. Upotrebom proširene Hametove korelacije, određene pKa vrednosti korelisane su sa literaturnim σ vrednostima. Predviđene pKa vrednosti dobro se slažu sa eksperimentalno dobijenim. Molekulski, monoanjonski i dianjonski oblici osnovne supstance su optimizovani semiempirijskom molekulsko-orbitalnom PM6 metodom sa implicitnim modelom solvatacije u vodi (COSMO). Dobijene geometrije su upotrebljene za objašnjenje kvaliteta LFER modela.",
publisher = "Srpsko hemijsko društvo, Beograd",
journal = "Journal of the Serbian Chemical Society",
title = "An LFER study of the protolytic equilibria of 4-aryl-2,4-dioxobutanoic acids in aqueous solutions, Linearne korelacije slobodne energije (LFER) protolitičkih ravnoteža 4-aril-2,4-dioksobutanskih kiselina u vodenim rastvorima",
volume = "72",
number = "12",
pages = "1201-1216",
doi = "10.2298/JSC0712201V"
}

Verbić, T. Ž., Drakulić, B., Zloh, M., Pecelj, J. R., Popović, G.,& Juranić, I. O.. (2007). An LFER study of the protolytic equilibria of 4-aryl-2,4-dioxobutanoic acids in aqueous solutions. in Journal of the Serbian Chemical Society
Srpsko hemijsko društvo, Beograd., 72(12), 1201-1216.
https://doi.org/10.2298/JSC0712201V

Verbić TŽ, Drakulić B, Zloh M, Pecelj JR, Popović G, Juranić IO. An LFER study of the protolytic equilibria of 4-aryl-2,4-dioxobutanoic acids in aqueous solutions. in Journal of the Serbian Chemical Society. 2007;72(12):1201-1216.
doi:10.2298/JSC0712201V .

Verbić, Tatjana Ž., Drakulić, Branko, Zloh, Mire, Pecelj, Jovana R., Popović, Gordana, Juranić, Ivan O., "An LFER study of the protolytic equilibria of 4-aryl-2,4-dioxobutanoic acids in aqueous solutions" in Journal of the Serbian Chemical Society, 72, no. 12 (2007):1201-1216,
https://doi.org/10.2298/JSC0712201V . .