Analytical aspects of achiral and cyclodextrin-mediated capillary electrophoresis of warfarin and its two main derivatives assisted by theoretical modeling

Nowak, Paweł Mateusz; Garnysz, Magdalena; Mitoraj, Mariusz P.; Sagan, Filip; Woźniakiewicz, Michał; Kościelniak, Paweł

doi:10.1016/j.chroma.2014.12.030

Cited by 25 publications

(17 citation statements)

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“…In all remaining cases, CDs exhibit stronger affinity for the protonated form of analytes which thereby is stabilized, and it is seen as the rise of p K a upon the addition of host. A similar effect was observed in the past for other analytes [1], including different coumarin derivatives [7, 8]. It can be explained by the interactions between the hydrophobic guest molecule and the non-polar interior of CD’s cavity, which are stronger for the non-ionized and more hydrophobic form of guest.…”

Section: Resultssupporting

confidence: 80%

“…It determines their solubility in aqueous environment, lipophilicity and membrane permeability, ability to ionic and hydrophobic interactions, activity and functionality in biological systems (including endo- and exo-genic compounds), and particular behaviors in analytical systems, e.g., retention on column in chromatography or migration time in electrophoresis. The idea to modify p K a using the non-covalent interactions, known as a supramolecular acidity (p K a ) tuning, is a potential way to enhance bioavailability and therapeutic activity of drugs [1–3], to modulate physicochemical properties of dyes [4, 5], to create sophisticated catalysis systems [6], and to develop more efficient analytical methods [7]. The recent studies showed that the supramolecular host-guest interactions involving the macrocyclic hosts, like cyclodextrins (CDs), calixarenes, and cucurbiturils, may induce p K a shifts in both directions and of a diverse magnitude, reaching +1.5 pH unit for CDs, +2.4 for calixarenes, and even above +5 units for cucurbiturils [1, 7, 8].…”

Section: Introductionmentioning

confidence: 99%

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Enhancing effectiveness of capillary electrophoresis as an analytical tool in the supramolecular acidity modification

et al. 2017

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A strategic modification of acidity (pK a values) by the non-covalent host-guest interactions is one of the most promising concepts in current supramolecular chemistry. This work is aimed at enhancing the effectiveness of capillary electrophoresis (CE) in determination of pK a shifts caused by such interactions and their thermal dependencies crucial in a deep thermodynamic description. We show how to (i) minimize the systematic errors related to Joule heating, (ii) minimize the influence of a voltage ramp time, (iii) speed up pK a shift identification and estimation, (iv) interpret thermal effects related to two overlapped dynamic equilibria, and (v) determine pK a shifts by an alternative spectrophotometric method (CE-DAD). The proposed solutions were implemented to examine the supramolecular pK a shifts of several coumarin derivatives, caused by a variety of structurally different cyclodextrins. It was revealed that a specific host substitution pattern determines the magnitude of apparent pK a shifts. Accordingly, heptakis(2,6-di-O-methyl)-β-cyclodextrin induces the much stronger shifts than both non-methylated-β-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin applied at the same concentration. We also show that insofar as the complexation of 4-hydroxycoumarin and its derivative (coumatetralyl) are similarly exothermic, the thermal effects accompanying the deprotonation process are remarkably different for both molecules. The pK a shift induced by complexation with calixarene was also for the first time determined by a CE method. These observations throw a new light on the background of acidity modification and confirm the applicability of CE as an analytical tool.Electronic supplementary materialThe online version of this article (doi:10.1007/s00216-017-0305-y) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Enhancing effectiveness of capillary electrophoresis as an analytical tool in the supramolecular acidity modification

et al. 2017

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“…8 To illustrate this, we have depicted these structures in Fig. 8 For WAR they occurred to be spectacularly large, around 1.50 and 1.25 pH unit for the two enantiomers, respectively, whereas for W10 they turn out to be very small, barely measurable. Stronger stabilization of the proton by the characteristic double hydrogen bonding of W10 was proposed as the reason for its higher pK a (5.95) comparing to the other hydroxywarfarins (4.97-5.16).…”

Section: Introductionmentioning

confidence: 95%

“…[2][3][4][5][6][7][8][9][10][11][12][13][14] In these systems such issues as intrinsic exibility, molecular strain, intramolecular interactions, or specic relations with nearby solvent molecules, may be decisive factors for direction and magnitude of nal pK a shis. Some information may be however relatively easily gained by determining pK a at different temperatures.…”

Section: Introductionmentioning

confidence: 99%

Enthalpy–entropy relations in the acid–base equilibrium of warfarin and 10-hydroxywarfarin; joint experimental and theoretical studies

et al. 2015

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In this work we delineate basic thermodynamic factors that govern the acid-base equilibrium of the phenolic drug warfarin, pK a ¼ 4.99, and its metabolite 10-hydroxywarfarin, pK a ¼ 5.95. By applying experimental and theoretical approaches we have determined the enthalpic and entropic contributions to the dissociation free energy for both molecules. We have found that formation of specific intramolecular hydrogen bonds: OH/O by warfarin and OH/OH/O by 10-hydroxywarfarin, respectively, may be of a great importance for the changes in enthalpy and entropy during dissociation.The Car-Parrinello molecular dynamics have shown that these bonds are present at both temperatures T ¼ 298 K and T ¼ 378 K. We infer that an uncommon double bridge of 10-hydroxywarfarin, OH/OH/ O, imposes lower flexibility on the molecule and thereby a stronger rise of heat capacity and enthalpy upon dissociation than the single OH/O bond noted for warfarin. It has been proposed, in addition, that the entropic contributions derive from the two opposite effects related to: solvation of ionsit leads to a loss of entropy, and breaking of intramolecular bondsit causes a gain of entropy. For 10hydroxywarfarin these effects seem to be equal in magnitude, and thereby, its dissociation entropy is close to zero. Furthermore, we show that addition of a surfactant and aprotic cosolvent changes the enthalpy-entropy relations and induces the upward pK a shifts of both molecules, up to 1.5 pH unit. The changes in thermodynamics which are caused by these two additives are, however, totally different. † Electronic supplementary information (ESI) available: The calculated dissociation (deprotonation) enthalpies and entropies. The Hirshfeld atomic charges and the electrostatic potentials of WAR and W10. See

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“…. In theory, at this pH two different mechanisms may contribute to enantioseparation, the one employing different binding affinities of enantiomers for CD, and the second one, following from different p K a shifts induced by complexation with CD . Various CDs were tested as the potential chiral selectors, differing in structural features such as size, substitution type and substitution degree.…”

Section: The Values Of Validation Parameters Obtained For MC 3‐mmc Amentioning

confidence: 99%

Simultaneous enantioseparation of methcathinone and two isomeric methylmethcathinones using capillary electrophoresis assisted by 2‐hydroxyethyl‐β‐cyclodextrin

et al. 2018

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Methcathinone (ephedrone), 4-methylmethcathinone (mephedrone), and 3-methylmethcathinone (metaphedrone) are toxicologically-important cathinone derivatives used commonly as designer drugs. In this work we show the first method allowing to separate simultaneously all these molecules in a chiral medium, ensuring good resolution between all enantiomers. Eight cyclodextrins have been tested as potential chiral selectors, the best results were obtained with 2-hydroxyethyl-β-cyclodextrin, unreported so far for efficient separation of cathinones. After optimization, the method was calibrated and validated with and without the use of internal standard. The addition of standard improved an overall repeatability and precision, the use of electrophoretic mobility ratio was especially favorable (RSD < 1%). It was demonstrated that the method may be easily extended by introducing the additional cathinone-related drugs to the sample, maintaining satisfactory separation efficiency.

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Analytical aspects of achiral and cyclodextrin-mediated capillary electrophoresis of warfarin and its two main derivatives assisted by theoretical modeling

Cited by 25 publications

References 58 publications

Enhancing effectiveness of capillary electrophoresis as an analytical tool in the supramolecular acidity modification

Enhancing effectiveness of capillary electrophoresis as an analytical tool in the supramolecular acidity modification

Enthalpy–entropy relations in the acid–base equilibrium of warfarin and 10-hydroxywarfarin; joint experimental and theoretical studies

Simultaneous enantioseparation of methcathinone and two isomeric methylmethcathinones using capillary electrophoresis assisted by 2‐hydroxyethyl‐β‐cyclodextrin

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