Estimating the hydrophobicity extent of molecular fragments using reversed-phase liquid chromatography
© 2023 The Authors. Journal of Separation Science published by Wiley-VCH GmbH..
A fast HPLC method was developed to study the hydrophobicity extent of pharmaceutically relevant molecular fragments. By this strategy, the reduced amount of sample available for physico-chemical evaluations in early-phase drug discovery programs does not represent a limiting factor. The sixteen acid fragments investigated were previously synthesized also determining potentiometrically their experimental log D values. For four fragments it was not possible to determine such property since their values were outside of the instrumental working range (2 < pKa < 12). An RP-HPLC method was therefore optimized. For each scrutinized method, some derived chromatographic indices were calculated, and Pearson's correlation coefficient (r) allowed to select the so-called "φ0 index" as the best correlating with the log D. The w s p H ${}_w^spH$ was fixed at 3.5 and a modification of some variables [organic modifier (methanol vs. ACN), stationary phase (octyl vs. octadecyl), presence/absence of the additives n-octanol, n-butylamine, and n-octylamine], allowed to select the best correlation conditions, producing a r = 0.94 (p < 0.001). Importantly, the φ0 index enabled the estimation of log D values for four fragments which were unattainable by potentiometric titration. Moreover, a series of molecular descriptors were calculated to identify the chemical characteristics of the fragments explaining the obtained φ0 . The number of hydrogen bond donors and the index of cohesive interaction correlated with the experimental data.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:46 |
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| Enthalten in: |
Journal of separation science - 46(2023), 18 vom: 12. Sept., Seite e2300346 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Carotti, Andrea [VerfasserIn] |
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| Links: |
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| Themen: |
Chromatographic hydrophobicity indices |
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| Anmerkungen: |
Date Revised 25.09.2023 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1002/jssc.202300346 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359398014 |
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| 520 | |a © 2023 The Authors. Journal of Separation Science published by Wiley-VCH GmbH. | ||
| 520 | |a A fast HPLC method was developed to study the hydrophobicity extent of pharmaceutically relevant molecular fragments. By this strategy, the reduced amount of sample available for physico-chemical evaluations in early-phase drug discovery programs does not represent a limiting factor. The sixteen acid fragments investigated were previously synthesized also determining potentiometrically their experimental log D values. For four fragments it was not possible to determine such property since their values were outside of the instrumental working range (2 < pKa < 12). An RP-HPLC method was therefore optimized. For each scrutinized method, some derived chromatographic indices were calculated, and Pearson's correlation coefficient (r) allowed to select the so-called "φ0 index" as the best correlating with the log D. The w s p H ${}_w^spH$ was fixed at 3.5 and a modification of some variables [organic modifier (methanol vs. ACN), stationary phase (octyl vs. octadecyl), presence/absence of the additives n-octanol, n-butylamine, and n-octylamine], allowed to select the best correlation conditions, producing a r = 0.94 (p < 0.001). Importantly, the φ0 index enabled the estimation of log D values for four fragments which were unattainable by potentiometric titration. Moreover, a series of molecular descriptors were calculated to identify the chemical characteristics of the fragments explaining the obtained φ0 . The number of hydrogen bond donors and the index of cohesive interaction correlated with the experimental data | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a chromatographic hydrophobicity indices | |
| 650 | 4 | |a linear correlation | |
| 650 | 4 | |a log D | |
| 650 | 4 | |a molecular descriptors | |
| 650 | 4 | |a reversed-phase chromatography | |
| 700 | 1 | |a Varfaj, Ina |e verfasserin |4 aut | |
| 700 | 1 | |a Pruscini, Ilaria |e verfasserin |4 aut | |
| 700 | 1 | |a Abualzulof, Ghaid W A |e verfasserin |4 aut | |
| 700 | 1 | |a Mercolini, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Bianconi, Elisa |e verfasserin |4 aut | |
| 700 | 1 | |a Macchiarulo, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Camaioni, Emidio |e verfasserin |4 aut | |
| 700 | 1 | |a Sardella, Roccaldo |e verfasserin |4 aut | |
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