Photodegradation of novel oral anticoagulants under sunlight irradiation in

aqueous matrices

Montaha Yassine1ab,2, Laura Fuster1ab, Marie-Hélène Dévier1ab, Emmanuel Geneste1ab, Patrick

Pardon1ab, Axelle Grélard3, Erick Dufourc3, Mohamad Al Iskandarani2, Selim Aït-Aïssa4,

Jeanne Garric5, Hélène Budzinski1ab, Patrick Mazellier1ab, Aurélien S. Trivella1ab,*

1aUniv. Bordeaux, UMR EPOC CNRS 5805, LPTC, F-33405 Talence, France

1bCNRS, EPOC, UMR 5805, LPTC, F-33400 Talence, France

2National Council of Scientific Research (NCSR), Lebanese Atomic Energy Commission

(LAEC), Laboratory of Analysis of Organic Pollutants (LAOP), B. P. 11-8281, Riad El Solh -

1107 2260 - Beirut, Lebanon

3Institute of Chemistry and Biology of Membranes and Nano-objects, CBMN UMR 5248,

CNRS University of Bordeaux, Bordeaux National Institute of Technology, Allée Geoffroy St

Hilaire, Pessac, France

4INERIS, Unité d’écotoxicologie in vitro et in vivo (ECOT), Verneuil-en-Halatte, France

5Irstea, UR MALY, centre de Lyon-Villeurbanne, F-69616 Villeurbanne, France

*Corresponding author: Aurélien Trivella

aurelien.trivella@u-bordeaux.fr

Tel: +33 (0)553352429

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Supplementary Figure 1. UV-Vis absorption spectrum of the Isle River (Périgueux, France) recorded

after filtration on a 0.45 µm membrane.

Supplementary Figure 2. LC-UV chromatograms of dabigatran before (plain line) and after 4 hours

of Suntest irradiation (dashed line), and of the non-irradiated 4-aminobenzamidine (4-AB, dotted line).

Supplementary Figure 3. Overlaid extracted-ion chromatograms from LC-QToF analysis of

dabigatran and its photoproducts (CE = 20 eV) after 4 hour of irradiation under simulated sunlight in

purified water.

Supplementary Figure 4. Fragmentation spectra of (a) D1 and (b) 4-aminobenzamidine recorded

using a collision energy of 20 eV.

Supplementary Figure 5. Fragmentation spectra of (a) D2 and (b) D3 recorded using a collision

energy of 20 eV.

Supplementary Figure 6. LC-UV chromatograms of rivaroxaban before (plain line) and after 2 hours

(dotted line) of Suntest irradiation.

Supplementary Figure 7. Total ion current chromatograms of rivaroxaban (a) before and (b) after 2

hours of Suntest irradiation in purified water.

Supplementary Figure 8. Fragmentation spectra of (a) R and (b) R1 recorded using a collision energy

of 20 eV.

Supplementary Scheme 1. Numbering of carbon atoms of rivaroxaban (R) and of its photoisomer

(R1).

Supplementary Figure 9. 1D 1H-NMR spectra, recorded at 800 MHz, of Rivaroxaban (R) and of its

photoisomer (R1) in MeOH-d3. Only the aromatic and amide region is expanded. Schemes of

chemical structures with tabulated chemical shifts (1H and 13C) are shown in correspondence to help

reading the figure.

Supplementary Figure 10. 1D 1H-NMR spectra, recorded at 800 MHz, of Rivaroxaban (R) and of its

photoisomer (R1) in MeOH-d3. Only the aliphatic region is expanded. Schemes of chemical structures

with tabulated chemical shifts (1H and 13C) are shown in correspondence to help reading the figure.

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Supplementary Table 1. 13C and 1H chemical shifts, splitting patterns, and proton-proton coupling

constants of rivaroxaban (R) and its photoisomer (R1) recorded with a 800 MHz spectrometer.

Assignment of chemical shifts in italic are subject to caution.

Supplementary Figure 11. LC-UV chromatograms of apixaban before (plain line) and after 24 hours

of Suntest irradiation (dashed line).

Supplementary Figure 12. LC-MS chromatograms of apixaban after 24 hours of Suntest irradiation

in mineral water.

Supplementary Scheme 2. Fragmentation pattern of A1 (m/z=191) obtained using a collision energy

of 20 eV.

Supplementary Scheme 3. Fragmentation pattern of A2 (m/z=287) obtained using a collision energy

of 20 eV.

Supplementary Scheme 4. Fragmentation pattern of A3 (m/z=354) obtained using a collision energy

of 20 eV.

Supplementary Scheme 5. Fragmentation pattern of A4 (m/z=476) obtained using a collision energy

of 40 eV.

Supplementary Scheme 6. Fragmentation pattern of A5 (m/z=476) obtained using a collision energy

of 40 eV.

Supplementary Scheme 7. Fragmentation pattern of A6 (m/z=446) obtained using a collision energy

of 40 eV.

Supplementary Scheme 8. Fragmentation pattern of A7 (m/z=458) obtained using a collision energy

of 40 eV.

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Supplementary materials

Supplementary Figure 1. UV-Vis absorption spectrum of the Isle River (Périgueux, France) recorded after filtration on a 0.45 µm membrane.

Supplementary Figure 2. LC-UV chromatograms of dabigatran before (plain line) and after 4 hours of Suntest irradiation (dashed line), and of the non-irradiated 4-aminobenzamidine (4-AB, dotted line).

0 1 2 3 40,0

2,0x105

4,0x105

6,0x105

8,0x105

1,0x106

1,2x106

1,4x106

D3D

D2

Coun

ts

t (min)

D1

Supplementary Figure 3. Overlaid extracted-ion chromatograms from LC-QToF analysis of dabigatran and its photoproducts (CE = 20 eV) after 4 hour of irradiation under simulated sunlight in purified water.

4

Supplementary Figure 4. Fragmentation spectra of (a) D1 and (b) 4-aminobenzamidine recorded using a collision energy of 20 eV.

Supplementary Figure 5. Fragmentation spectra of (a) D2 and (b) D3 recorded using a collision energy of 20 eV.

Supplementary Figure 6. LC-UV chromatograms of rivaroxaban before (plain line) and after 2 hours (dotted line) of Suntest irradiation.

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Supplementary Figure 7. Total ion current chromatograms of rivaroxaban (a) before and (b) after 2 hours of Suntest irradiation in purified water.

Supplementary Figure 8. Fragmentation spectra of (a) R and (b) R1 recorded using a collision energy of 20 eV.

Supplementary Scheme 1. Numbering of carbon atoms of rivaroxaban (R) and of its photoisomer (R1).

6

Supplementary Figure 9. 1D 1H-NMR spectra, recorded at 800 MHz, of Rivaroxaban (R) and of its

photoisomer (R1) in MeOH-d3. Only the aromatic and amide region is expanded. Schemes of chemical

structures with tabulated chemical shifts (1H and 13C) are shown in correspondence to help reading the

figure.

7

Supplementary Figure 10. 1D 1H-NMR spectra, recorded at 800 MHz, of Rivaroxaban (R) and of its photoisomer (R1) in MeOH-d3. Only the aliphatic region is expanded. Schemes of chemical structures with tabulated chemical shifts (1H and 13C) are shown in correspondence to help reading the figure.

Supplementary Table 1. 13C and 1H chemical shifts, splitting patterns, and proton-proton coupling constants of rivaroxaban (R) and its photoisomer (R1) recorded with a 800 MHz spectrometer. Assignment of chemical shifts in italic are subject to caution.

R R1C atom numbe

r

13C (ppm)

1H (ppm)

Splitting

pattern

J (Hz) 13C (ppm)

1H (ppm)

Splitting

pattern

J (Hz)

1 135.16 - - - 123.31 - - -2 127.31 7.04 d 4.0 122.42 7.42 d 3.53 128.26 7.55 d 4.0 129.23 7.89 d 3.54 137.28 - - - 134.36 - - -5 162.49 - - - 164.70 - - -6 42.31 3.74 d 5.2 42.10 3.84/3.74 dd/dd 14.4/5.1;4.17 72.07 4.92 m * 72.06 4.96 m *8 48.44 4.24/3.95 dd/dd 8.9/9.2;5.9 48.46 4.26/4.00 dd/dd 8.9/9.2;6.09 155.29 - - - 155.31 - - -10 137.32 - - - 137.30 - - -

11/11’ 118.96 7.64 d 9.1 118.90 7.67 d 9.112/12’ 126.21 7.39 d 9.1 126.21 7.40 d 9.1

13 137.13 - - - 137.14 - - -14 168.11 - - - 168.11 - - -15 67.61 4.29 s - 67.61 4.29 s -16 63.63 4.05 m - 63.63 4.05 m -17 49.73 3.78 m - 49.86 3.78 m -NH - 8.93 t - - 8.75 t -

*under water signal

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Supplementary Figure 11. LC-UV chromatograms of apixaban before (plain line) and after 24 hours of Suntest irradiation (dashed line).

Supplementary Figure 12. LC-MS chromatograms of apixaban after 24 hours of Suntest irradiation in mineral water.

Supplementary Scheme 2. Fragmentation pattern of A1 (m/z=191) obtained using a collision energy of 20 eV.

Supplementary Scheme 3. Fragmentation pattern of A2 (m/z=287) obtained using a collision energy of 20 eV.

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Supplementary Scheme 4. Fragmentation pattern of A3 (m/z=354) obtained using a collision energy of 20 eV.

Supplementary Scheme 5. Fragmentation pattern of A4 (m/z=476) obtained using a collision energy of 40 eV.

Supplementary Scheme 6. Fragmentation pattern of A5 (m/z=476) obtained using a collision energy of 40 eV.

Supplementary Scheme 7. Fragmentation pattern of A6 (m/z=446) obtained using a collision energy of 40 eV.

10

Supplementary Scheme 8. Fragmentation pattern of A7 (m/z=458) obtained using a collision energy of 40 eV.

11