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Nortriptyline Hydrochloride Solubility-pH Profiles in a Saline Phosphate Buffer: Drug-Phosphate Complexes and Multiple pHmax Domains with a Gibbs Phase Rule “Soft” Constraints

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2022
acc-post-combined.pdf (1.035Mb)
Authors
Marković, Olivera
Patel, Nirali G.
Serajuddin, Abu T. M.
Avdeef, Alex
Verbić, Tatjana
Article (Accepted Version)
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Abstract
The solubility of a model basic drug, nortriptyline (Nor), was investigated as a function of pH in phosphate and/or a chloride-containing aqueous suspension using experimental practices recommended in the previously published “white paper” (Avdeef et al., 2016). The pH-Ramp Shake-Flask (pHRSF) method, introduced in our earlier work (Marković et al.,2019), was applied. An improved and more detailed experimentaldesign of the Nor solubility measurement allowed us to exploit thefull capacity of the pH-RSF method. Complex equilibria in theaqueous phase (cationic and anionic complex formation betweenNor and the phosphate) and solid-phase transformations (Nor freebase, 1:1 Nor hydrochloride salt, 1:1 and 1:2 Nor phosphate salts)were characterized by a detailed analysis of the solubilitymeasurements using the computer program pDISOL-X. The solid phases were characterized by thermogravimetric analysis,differential scanning calorimetry, powder X-ray diffraction, and elemental analyses. The resu...lts of the present investigation illustratethe influence of competing counterions, such as buffering agents, complexing agents, salt coformers, tonicity adjusters, and so forth,on the aqueous solubility of drugs and interconversion of salts. Careful attention given to these factors can be helpful in theformulation of drug products.

Keywords:
nortriptyline / nortriptyline hydrochloride / phosphate salts / complexes / solubility / solubility product / pH and buffer effect
Source:
Molecular Pharmaceutics, 2022, 19, 2, 710-719
Publisher:
  • American Chemical Society (ACS)
Funding / projects:
  • Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200026 (University of Belgrade, Institute of Chemistry, Technology and Metallurgy - IChTM) (RS-200026)
  • Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200168 (University of Belgrade, Faculty of Chemistry) (RS-200168)
Note:
  • This is the peer-reviewed version of the article: Marković, Olivera S., Patel, Nirali G., Serajuddin, Abu T. M., Avdeef, Alex, Verbić, Tatjana Ž., "Nortriptyline Hydrochloride Solubility-pH Profiles in a Saline Phosphate Buffer: Drug-Phosphate Complexes and Multiple pHmax Domains with a Gibbs Phase Rule “Soft” Constraints", Molecular Pharmaceutics, 19, no. 2 (2022):710-719, https://doi.org/10.1021/acs.molpharmaceut.1c00919
  • This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.molpharmaceut.1c00919
  • The published version: https://cer.ihtm.bg.ac.rs/handle/123456789/4934
  • Supporting information: https://cer.ihtm.bg.ac.rs/handle/123456789/4935
Related info:
  • Version of
    https://cer.ihtm.bg.ac.rs/handle/123456789/4934
  • Version of
    https://doi.org/10.1021/acs.molpharmaceut.1c00919
  • Referenced by
    https://cer.ihtm.bg.ac.rs/handle/123456789/4935

DOI: 10.1021/acs.molpharmaceut.1c00919

ISSN: 1543-8384

PubMed: 35050628

WoS: 000746418500001

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URI
https://cer.ihtm.bg.ac.rs/handle/123456789/4936
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - JOUR
AU  - Marković, Olivera
AU  - Patel, Nirali G.
AU  - Serajuddin, Abu T. M.
AU  - Avdeef, Alex
AU  - Verbić, Tatjana
PY  - 2022
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/4936
AB  - The solubility of a model basic drug, nortriptyline (Nor), was investigated as a function of pH in phosphate and/or a chloride-containing aqueous suspension using experimental practices recommended in the previously published “white paper” (Avdeef et al., 2016). The pH-Ramp Shake-Flask (pHRSF) method, introduced in our earlier work (Marković et al.,2019), was applied. An improved and more detailed experimentaldesign of the Nor solubility measurement allowed us to exploit thefull capacity of the pH-RSF method. Complex equilibria in theaqueous phase (cationic and anionic complex formation betweenNor and the phosphate) and solid-phase transformations (Nor freebase, 1:1 Nor hydrochloride salt, 1:1 and 1:2 Nor phosphate salts)were characterized by a detailed analysis of the solubilitymeasurements using the computer program pDISOL-X. The solid phases were characterized by thermogravimetric analysis,differential scanning calorimetry, powder X-ray diffraction, and elemental analyses. The results of the present investigation illustratethe influence of competing counterions, such as buffering agents, complexing agents, salt coformers, tonicity adjusters, and so forth,on the aqueous solubility of drugs and interconversion of salts. Careful attention given to these factors can be helpful in theformulation of drug products.
PB  - American Chemical Society (ACS)
T2  - Molecular Pharmaceutics
T1  - Nortriptyline Hydrochloride Solubility-pH Profiles in a Saline Phosphate Buffer: Drug-Phosphate Complexes and Multiple pHmax Domains with a Gibbs Phase Rule “Soft” Constraints
VL  - 19
IS  - 2
SP  - 710
EP  - 719
DO  - 10.1021/acs.molpharmaceut.1c00919
ER  - 
@article{
author = "Marković, Olivera and Patel, Nirali G. and Serajuddin, Abu T. M. and Avdeef, Alex and Verbić, Tatjana",
year = "2022",
abstract = "The solubility of a model basic drug, nortriptyline (Nor), was investigated as a function of pH in phosphate and/or a chloride-containing aqueous suspension using experimental practices recommended in the previously published “white paper” (Avdeef et al., 2016). The pH-Ramp Shake-Flask (pHRSF) method, introduced in our earlier work (Marković et al.,2019), was applied. An improved and more detailed experimentaldesign of the Nor solubility measurement allowed us to exploit thefull capacity of the pH-RSF method. Complex equilibria in theaqueous phase (cationic and anionic complex formation betweenNor and the phosphate) and solid-phase transformations (Nor freebase, 1:1 Nor hydrochloride salt, 1:1 and 1:2 Nor phosphate salts)were characterized by a detailed analysis of the solubilitymeasurements using the computer program pDISOL-X. The solid phases were characterized by thermogravimetric analysis,differential scanning calorimetry, powder X-ray diffraction, and elemental analyses. The results of the present investigation illustratethe influence of competing counterions, such as buffering agents, complexing agents, salt coformers, tonicity adjusters, and so forth,on the aqueous solubility of drugs and interconversion of salts. Careful attention given to these factors can be helpful in theformulation of drug products.",
publisher = "American Chemical Society (ACS)",
journal = "Molecular Pharmaceutics",
title = "Nortriptyline Hydrochloride Solubility-pH Profiles in a Saline Phosphate Buffer: Drug-Phosphate Complexes and Multiple pHmax Domains with a Gibbs Phase Rule “Soft” Constraints",
volume = "19",
number = "2",
pages = "710-719",
doi = "10.1021/acs.molpharmaceut.1c00919"
}
Marković, O., Patel, N. G., Serajuddin, A. T. M., Avdeef, A.,& Verbić, T.. (2022). Nortriptyline Hydrochloride Solubility-pH Profiles in a Saline Phosphate Buffer: Drug-Phosphate Complexes and Multiple pHmax Domains with a Gibbs Phase Rule “Soft” Constraints. in Molecular Pharmaceutics
American Chemical Society (ACS)., 19(2), 710-719.
https://doi.org/10.1021/acs.molpharmaceut.1c00919
Marković O, Patel NG, Serajuddin ATM, Avdeef A, Verbić T. Nortriptyline Hydrochloride Solubility-pH Profiles in a Saline Phosphate Buffer: Drug-Phosphate Complexes and Multiple pHmax Domains with a Gibbs Phase Rule “Soft” Constraints. in Molecular Pharmaceutics. 2022;19(2):710-719.
doi:10.1021/acs.molpharmaceut.1c00919 .
Marković, Olivera, Patel, Nirali G., Serajuddin, Abu T. M., Avdeef, Alex, Verbić, Tatjana, "Nortriptyline Hydrochloride Solubility-pH Profiles in a Saline Phosphate Buffer: Drug-Phosphate Complexes and Multiple pHmax Domains with a Gibbs Phase Rule “Soft” Constraints" in Molecular Pharmaceutics, 19, no. 2 (2022):710-719,
https://doi.org/10.1021/acs.molpharmaceut.1c00919 . .

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