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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Cyclodextrin-Mediated Enantiomeric Separation of Idelalisib: A Validated Capillary Electrophoresis and NMR Study

by
Erzsébet Várnagy
1,2,
Balázs István Urbán
3,
Mátyás Sári
3,
Balázs Volk
4,
Gyula Simig
4,
Krisztina Németh
5,
Milo Malanga
6,
Ida Fejős
1,2,* and
Szabolcs Béni
3,*
1
Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
2
Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
3
Integrative Health and Environmental Analysis Research Laboratory, Department of Analytical Chemistry, Institute of Chemistry, ELTE Eötvös Loránd University, Pázmány Péter Sétány 1/A, H-1117 Budapest, Hungary
4
Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, H-1475 Budapest, Hungary
5
Chemical Biology Research Group, Institute of Organic Chemistry, HUN-REN Research Centre for Natural Sciences, Magyar Tudósok Krt. 2, H-1117 Budapest, Hungary
6
CarboHyde Ltd., Berlini u. 47-49, H-1045 Budapest, Hungary
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(13), 6036; https://doi.org/10.3390/ijms27136036
Submission received: 6 May 2026 / Revised: 30 June 2026 / Accepted: 2 July 2026 / Published: 5 July 2026
(This article belongs to the Special Issue Cyclodextrins: Properties and Applications, 4th Edition)
Versions Notes

Abstract

Idelalisib (IDE) is a marketed chiral anticancer drug administered as the S-enantiomer, requiring sensitive monitoring of the R-enantiomer to ensure enantiomeric purity. However, no dedicated capillary electrophoresis (CE) method has been reported for trace-level quantification of R-IDE. In this study, a cyclodextrin-mediated CE method was developed for reliable detection of the R-enantiomer at the 0.1% level (LOD 2 µg/mL; LOQ 5 µg/mL). Systematic screening identified hydroxypropyl-β-cyclodextrin (HP-β-CD) with an intermediate degree of substitution (DS~6.8) as the optimal chiral selector, providing efficient enantioseparation (Rs up to 4.3). The method was validated according to ICH Q2(R2) guidelines, demonstrating suitable precision, accuracy, and robustness. Complementary NMR studies revealed hindered rotation of the 3-phenyl moiety and elucidated the molecular basis of enantioselectivity. Complexation with β-CD and HP-β-CD produced clear diastereomeric differentiation in both 1H and 19F NMR spectra, while the simplified 19F NMR profiles enabled direct enantiomer discrimination. NOESY and ROESY experiments demonstrated distinct inclusion modes, with HP-β-CD accommodating both the fluorinated aromatic ring and the 3-phenyl moiety. These interactions may account for the superior enantioseparation observed with HP-β-CD of intermediate DS. Our validated CE method addresses the distomer determination while NMR insights provide mechanistic understanding of the chiral recognition.
Keywords: selective phosphoinositide 3-kinase delta inhibitor; chiral impurity profiling; hydroxypropyl-β-cyclodextrin chiral selector; host-guest complexation; variable temperature NMR; 19F NMR; 1H-19F HOESY NMR; 2D ROESY NMR; diastereomeric splitting; design of experiments selective phosphoinositide 3-kinase delta inhibitor; chiral impurity profiling; hydroxypropyl-β-cyclodextrin chiral selector; host-guest complexation; variable temperature NMR; 19F NMR; 1H-19F HOESY NMR; 2D ROESY NMR; diastereomeric splitting; design of experiments

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MDPI and ACS Style

Várnagy, E.; Urbán, B.I.; Sári, M.; Volk, B.; Simig, G.; Németh, K.; Malanga, M.; Fejős, I.; Béni, S. Cyclodextrin-Mediated Enantiomeric Separation of Idelalisib: A Validated Capillary Electrophoresis and NMR Study. Int. J. Mol. Sci. 2026, 27, 6036. https://doi.org/10.3390/ijms27136036

AMA Style

Várnagy E, Urbán BI, Sári M, Volk B, Simig G, Németh K, Malanga M, Fejős I, Béni S. Cyclodextrin-Mediated Enantiomeric Separation of Idelalisib: A Validated Capillary Electrophoresis and NMR Study. International Journal of Molecular Sciences. 2026; 27(13):6036. https://doi.org/10.3390/ijms27136036

Chicago/Turabian Style

Várnagy, Erzsébet, Balázs István Urbán, Mátyás Sári, Balázs Volk, Gyula Simig, Krisztina Németh, Milo Malanga, Ida Fejős, and Szabolcs Béni. 2026. "Cyclodextrin-Mediated Enantiomeric Separation of Idelalisib: A Validated Capillary Electrophoresis and NMR Study" International Journal of Molecular Sciences 27, no. 13: 6036. https://doi.org/10.3390/ijms27136036

APA Style

Várnagy, E., Urbán, B. I., Sári, M., Volk, B., Simig, G., Németh, K., Malanga, M., Fejős, I., & Béni, S. (2026). Cyclodextrin-Mediated Enantiomeric Separation of Idelalisib: A Validated Capillary Electrophoresis and NMR Study. International Journal of Molecular Sciences, 27(13), 6036. https://doi.org/10.3390/ijms27136036

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