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 .