Complexation of daclatasvir by single isomer methylated β-cyclodextrins studied by capillary electrophoresis, NMR spectroscopy and mass spectrometry

Krait, Sulaiman; Salgado, Antonio; Peluso, Paola; Sohajda, Tamás; Benkovics, Gábor; Naumann, Lukas; Neusüß, Christian; Chankvetadze, Bezhan; Scriba, Gerhard K. E.

doi:10.1016/j.carbpol.2021.118486

Cited by 15 publications

(12 citation statements)

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“…The molecular basis of enantiorecognition processes originated by cyclodextrins (CDs) is not yet well understood despite the prominent role of this class of chiral auxiliaries in the field of the enantioselective chromatographic technologies [ 1 , 2 , 3 ]. In consideration of the quite elusive knowledge to this regard, a great deal of effort has been continuously addressed on the elucidation of the stereochemistry, dynamics, and thermodynamics of the diastereomeric complexes formed by cyclodextrins and enantiomeric substrates [ 4 ]. Such studies can be performed via spectroscopic investigations, mainly nuclear magnetic resonance (NMR) spectroscopy [ 5 , 6 , 7 , 8 ], together with computational methods [ 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Chiral Discrimination Mechanisms by Silylated-Acetylated Cyclodextrins: Superficial Interactions vs. Inclusion

Balzano

Barretta

Sicoli

et al. 2022

IJMS

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Cyclodextrin derivatives constitute a powerful class of auxiliary agents for the discrimination of apolar chiral substrates. Both host–guest inclusion phenomena and interactions with the derivatizing groups located on the surface of the macrocycle could drive the enantiodiscrimination; thus, it is important to understand the role that these processes play in the rational design of new chiral selectors. The purpose of this study is to compare via nuclear magnetic resonance (NMR) spectroscopy the efficiency of silylated-acetylated α-, β-, and γ-cyclodextrins in the chiral discrimination of 1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane (compound B) and methyl 2-chloropropionate (MCP). NMR DOSY (Diffusion Ordered SpectroscopY) experiments were conducted for the determination of the bound molar fractions and the association constants, whereas ROESY (Rotating-frame Overhauser Enhancement SpectroscopY) measurements provided information on the hosts’ conformation and on the interaction phenomena with the guests. Compound B, endowed with fluorinated moieties, is not deeply included due to attractive Si-F interactions occurring at the external surface of the cyclodextrins. Therefore, a low selectivity toward the size of cyclodextrin cavity is found. By contrast, enantiodiscrimination of MCP relies on the optimal fitting between the size of the guest and that of the cyclodextrin cavity.

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Section: Introductionmentioning

confidence: 99%

Chiral Discrimination Mechanisms by Silylated-Acetylated Cyclodextrins: Superficial Interactions vs. Inclusion

Balzano

Barretta

Sicoli

et al. 2022

IJMS

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“…644,1190 In these cases, XRD is definitely a valuable tool for absolute configuration assignment of crystallizable pure enantiomers. Alternatively, comparison of experimental and theoretical ECD spectra may also allow for assignment of absolute configuration, 680,1079 stoichiometry and structure are formed between a selector and selectand 1276,1316,1317,1326 (which complicates application of NMR spectroscopy) or when otherwise confusing peaks have to be on-line identified. 1316,1317 Earlier examples when NMR spectroscopy failed because of multiple selector−selectand complexes in solution, while MS provided a clear solution, was described in 2000.…”

Section: Nuclear Magnetic Resonancementioning

confidence: 99%

“…This is caused by the fact that the separation conditions in CE (CS in a free solution) can be best mimicked in NMR spectroscopic experiments. This is the reason why studies on noncovalent selector–selectand interaction by using the tandem combination of these two techniques have been intensely reported in the last three decades. ,,,,,− ,− NMR spectroscopy has the advantage over other spectroscopic techniques because, in theory, it can provide separate resonance signals for noncovalent diastereomeric associates of the CS with each of two enantiomers of the chiral selectand. Thus, NMR spectroscopy is applicable to racemic samples or nonracemic mixtures of enantiomers for the stereoselective determination of the stoichiometry and equilibrium binding constants of selector–selectand associates.…”

Section: Trends In Enantioselective Recognition In Separation Science...mentioning

confidence: 99%

“…Mass spectrometry with soft ionization techniques can provide useful information regarding selector–selectand association especially related to CE studies. This information is of special value when mixed complexes with various stoichiometry and structure are formed between a selector and selectand ,,, (which complicates application of NMR spectroscopy) or when otherwise confusing peaks have to be on-line identified. , Earlier examples when NMR spectroscopy failed because of multiple selector–selectand complexes in solution, while MS provided a clear solution, was described in 2000 . In the recent study by Scriba and co-authors, an unusual behavior in complex formation between the chiral drug daclatasvir (DCV) and CDs was observed.…”

Section: Trends In Enantioselective Recognition In Separation Science...mentioning

confidence: 99%

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Recognition in the Domain of Molecular Chirality: From Noncovalent Interactions to Separation of Enantiomers

2022

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It is not a coincidence that both chirality and noncovalent interactions are ubiquitous in nature and synthetic molecular systems. Noncovalent interactivity between chiral molecules underlies enantioselective recognition as a fundamental phenomenon regulating life and human activities. Thus, noncovalent interactions represent the narrative thread of a fascinating story which goes across several disciplines of medical, chemical, physical, biological, and other natural sciences. This review has been conceived with the awareness that a modern attitude toward molecular chirality and its consequences needs to be founded on multidisciplinary approaches to disclose the molecular basis of essential enantioselective phenomena in the domain of chemical, physical, and life sciences. With the primary aim of discussing this topic in an integrated way, a comprehensive pool of rational and systematic multidisciplinary information is provided, which concerns the fundamentals of chirality, a description of noncovalent interactions, and their implications in enantioselective processes occurring in different contexts. A specific focus is devoted to enantioselection in chromatography and electromigration techniques because of their unique feature as “multistep” processes. A second motivation for writing this review is to make a clear statement about the state of the art, the tools we have at our disposal, and what is still missing to fully understand the mechanisms underlying enantioselective recognition.

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“…As well as the development of strategies and technical approaches to improve chiral separations, a considerable number of investigations have recently been carried out to better understand the intriguing mechanisms of enantiorecognition by CDs. The combination of electrophoretic data (enantioselectivity, resolution, mobility) with nuclear magnetic resonance (NMR) spectroscopy and molecular modeling have disclosed the role of the CD cavity size and substitution pattern on EMO [ 71 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]; interestingly, CE was shown to be a very sensitive technique to study the affinity patterns in CD complexes with chiral guests [ 71 , 84 ], whereas NMR and molecular modeling approaches allowed hypotheses to be advanced regarding the spatial structure of selector–analyte complexes. Recently, it was also shown by the group of Chankvetadze that inclusion complexation is not a prerequisite for CD-based enantioseparations, and that enantiodiscrimination can also be achieved through the formation of shallow, external complexes [ 92 , 93 ].…”

Section: Recent Advances In the Development Of Ce Analytical Procedur...mentioning

confidence: 99%

New Trends in the Quality Control of Enantiomeric Drugs: Quality by Design-Compliant Development of Chiral Capillary Electrophoresis Methods

et al. 2022

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Capillary electrophoresis (CE) is a potent method for analyzing chiral substances and is commonly used in the enantioseparation and chiral purity control of pharmaceuticals from different matrices. The adoption of Quality by Design (QbD) concepts in analytical method development, optimization and validation is a widespread trend observed in various analytical approaches including chiral CE. The application of Analytical QbD (AQbD) leads to the development of analytical methods based on sound science combined with risk management, and to a well understood process clarifying the influence of method parameters on the analytical output. The Design of Experiments (DoE) method employing chemometric tools is an essential part of QbD-based method development, allowing for the simultaneous evaluation of experimental parameters as well as their interaction. In 2022 the International Council for Harmonization (ICH) released two draft guidelines (ICH Q14 and ICH Q2(R2)) that are intended to encourage more robust analytical procedures. The ICH Q14 guideline intends to harmonize the scientific approaches for analytical procedures’ development, while the Q2(R2) document covers the validation principles for the use of analytical procedures including the recent applications that require multivariate statistical analyses. The aim of this review is to provide an overview of the new prospects for chiral CE method development applied for the enantiomeric purity control of pharmaceuticals using AQbD principles. The review also provides an overview of recent research (2012–2022) on the applicability of CE methods in chiral drug impurity profiling.

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Complexation of daclatasvir by single isomer methylated β-cyclodextrins studied by capillary electrophoresis, NMR spectroscopy and mass spectrometry

Cited by 15 publications

References 18 publications

Chiral Discrimination Mechanisms by Silylated-Acetylated Cyclodextrins: Superficial Interactions vs. Inclusion

Chiral Discrimination Mechanisms by Silylated-Acetylated Cyclodextrins: Superficial Interactions vs. Inclusion

Recognition in the Domain of Molecular Chirality: From Noncovalent Interactions to Separation of Enantiomers

New Trends in the Quality Control of Enantiomeric Drugs: Quality by Design-Compliant Development of Chiral Capillary Electrophoresis Methods

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