Supporting Information Conventional or mechanochemically-aided intercalation of diclofenac and naproxen anions into the interlamellar space of CaFe-layered double hydroxides and their application as dermal drug delivery systems

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Supporting Information

Conventional or mechanochemically-aided intercalation of diclofenac and naproxen anions into the interlamellar space of CaFe-layered double hydroxides and their application as dermal drug delivery systems †

Márton Szabados,

^a,b

Attila Gácsi,

^b,c

Yvette Gulyás,

^b

Zoltán Kónya,

^d,e

Ákos Kukovecz,

^d

Erzsébet Csányi,

^c

István Pálinkó

^a,b

and Pál Sipos

^b,f*

aDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720 Hungary

bMaterial and Solution Structure Research Group, Institute of Chemistry, University of Szeged, Aradi vértanúk tere 1, Szeged, H-6720 Hungary

cInstitute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös utca 6, Szeged, H-6720 Hungary

dDepartment of Applied and Environmental Chemistry, University of Szeged, Rerrich B. tér 1, Szeged, H-6720 Hungary

eMTA-SZTE Reaction Kinetics and Surface Chemistry Research Group, Rerrich B. tér 1, Szeged, H-6720 Hungary

fDepartment of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, Szeged, H-6720 Hungary

Table S1

Comparative literature for drug release of Mg- and Zn-based LDH solids summarizing the applied kinetic models, n release exponents, and R² linear correlation coefficients.

Investigated

nanocomposites Intercalation method Kinetic models n R² References MgAl-LDH−naproxen Co-precipitation Korsmeyer–Peppas 0.9 0.997 Rojas et al., 2014 MgAl-LDH−naproxen Co-precipitation Korsmeyer–Peppas 0.89 0.996 Carriazo et al., 2010 MgAl-LDH−diclofenac /

Eudragit Direct anion exchange Higuchi 0.5 0.995 Ambrogi et al., 2008 MgAl-LDH−diclofenac Direct anion exchange Higuchi 0.5 0.989 Ambrogi et al., 2002 ZnAl-LDH/diclofenac /

Polycaprolactone Direct anion exchange Ritger-Peppas 0.37 0.933 Wang et al., 2019 ZnAl-LDH−diclofenac Direct anion exchange Ritger-Peppas 0.21 0.991 Joy et al., 2017 ZnAl-LDH−diclofenac Direct anion exchange Higuchi 0.5 0.986 Perioli et al., 2011

† This publication is dedicated to the memory of our mentor, friend and colleague, Prof. István Pálinkó, who passed away shortly after the submission of the current manuscript

*corresponding author

sipos@chem.u-szeged.hu (Pál Sipos)

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2

5 10 15 20 25 30 35 40 45 50 55 60



 



2 theta /

 



  

dehydroxylation-rehydration

Intensity /a.u. _{(32 nm)}





87.5% v/v ethanol 12.5% v/v water 75% v/v ethanol 25% v/v water 50% v/v ethanol 50% v/v water 25% v/v ethanol 75% v/v water

400C heat treated CaFe-LDH

 

LDH Ca₂Fe₂O₅



 (35 nm)

(18 nm)

(8 nm)

CaCO₃

Fig. S1 X-ray diffractometry patterns of diclofenac anion-intercalated LDH samples intercalated in ethanol-water mixtures of varying compositions (1:1 Fe(III):diclofenac anion molar ratio, 25°C) and the as-prepared LDH after calcination at 400°C.

5 10 15 20 25 30 35 40 45 50 55 60

2 theta /



LDH

Intensity /a.u.

75C

50C

25C (35 nm)

 



CaCO₃

Fig. S2 X-ray diffraction patterns of solids obtained at varying stirring temperature (1:1 Fe(III):diclofenac anion molar ratio, 25% v/v ethanol-water mixture).

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3

5 10 15 20 25 30 35 40 45 50 55 60

2 theta /

 



(35 nm)

(27 nm) (32 nm) 



LDH

Intensity /a.u.

1:2 Fe(III):diclofenac anion



CaCO₃

Fig. S3 X-ray diffraction patterns of the LDH composites at different Fe(III):diclofenac anion molar ratios (25% v/v ethanol-water mixture, 25°C).

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Table S2

Crystal, size, heterogeneity parameters and zeta potential of pristine and organic CaFe-LDH solids (average predominant solvodynamic diameter – Zavg., polydispersity index – PDI, average zeta potential – avg.).

Samples d-value

(nm)^x a

(nm)^y Zavg. (nm) PDI avg. (mV)

CaFe−NO3-LDH 0.854 0.586 255 ± 60 0.42 −12.9 ± 1.6

co-precipitation LDH−diclofenac 2.291 0.586 1220 ± 330 0.13 −9.5 ± 1.1 direct anion exchange LDH−diclofenac 2.304 0.582 1140 ± 330 0.17 −9.3 ± 2.7 dehydroxylation-rehydration LDH−diclofenac 2.271 0.586 675 ± 185 0.35 −11.5 ± 3.4 mechanochemically-aided intercalation LDH−diclofenac 2.276 0.584 540 ± 170 0.21 −12.4 ± 1.8 co-precipitation LDH−naproxen 1.943 0.586 760 ± 180 0.46 −4.7 ± 1.5 direct anion exchange LDH−naproxen 1.935 0.586 2280 ± 605 0.22 −5.4 ± 3.4 dehydroxylation-rehydration LDH−naproxen 1.926 0.584 2770 ± 760 0.22 −2.5 ± 1.3 mechanochemically-aided intercalation LDH−naproxen 1.902 0.584 3125 ± 585 0.45 −3.9 ± 1.4

x d-value = d001 or the first reflections

y Lattice parameter a is calculated by estimation: a = 2d110

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5

1800 1600 1400 1200 1000 800 600 400 200

A

Intensity /a.u.

Raman shift /cm^1 co-precipitation

direct anion exchange dehydroxylation-rehydration

mechanochemically-aided intercalation initial CaFeNO₃^-LDH

diclofenac sodium

510

1055 715 355

1800 1600 1400 1200 1000 800 600 400 200

B

Raman shift /cm^1

510 1055

Intensity /a.u.

co-precipitation direct anion exchange dehydroxylation-rehydration mechanochemically-aided intercalation

initial CaFeNO₃^-LDH

naproxen sodium

715 355

Fig. S4 Raman spectra of the diclofenac (A) and naproxen (B) anion-intercalated LDH samples and those of the as-prepared CaFe-LDH and starting drugs.

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6

5 10 15 20 25 30 35 40 45 50 55 60

20.69

29.54

19.84

27.02

22.46

27.8

26.98

23.43

17.12

15.12

8.48

6.02

17.52

13.07

4.42

Intensity /a.u.

2 theta /

diclofenac sodium

naproxen sodium

Fig. S5 X-ray diffractograms of the naproxen and diclofenac sodium salts.

Fig. S6 Energy dispersive X-ray analysis spectrum of diclofenac anion−CaFe-LDH composite (signals of silicon and aluminium are originated from the adhesive tape/sample holder).

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Fig. S7 SEM (A) and elemental map (B and C) images from the diclofenac anion−CaFe-LDH.

A B

C

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8

100 200 300 400 500 600 700 800 900

60 65 70 75 80 85 90 95 100

Mass /%

Furnace temperature /C

Deriv. Mass /%/min

CaFe-NO₃^ LDH

-0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1

690

245 125

515

100 200 300 400 500 600 700 800 900 1000

0 20 40 60 80 100

-0.4 -0.3 -0.2 -0.1 0.0

Mass /%

620 515 diclofenac sodium

285

315 870

Deriv. Mass /%/min

100 200 300 400 500 600 700 800 900 1000

0 20 40 60 80 100

750

800

Mass /%

naproxen sodium

75

380 450

720

Deriv. Mass /%/min

-0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0.0

Fig. S8 Thermal behaviour of the pristine CaFe-LDH and sodium salts of diclofenac and naproxen.

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9 4000 3750 3500 3250 3000 2750 1750 1500 1250 1000 750

adsorbed CO₂

Wavenumber /cm^1

Absorbance /a.u.

CaFe-LDH  diclofenac 400C diclofenac sodium 400C CaFe-LDH  diclofenac 350C

diclofenac sodium 350C CaFe-LDH  diclofenac 300C

diclofenac sodium 300C CaFe-LDH  diclofenac 250C

diclofenac sodium 250C CaFe-LDH  diclofenac 200C CaFe-LDH  diclofenac initial

diclofenac sodium initial

disappearing OH network and CH, CO, CC vibrations in LDHs

4000 3750 3500 3250 3000 2750 1500 1250 1000 750

disappearing OH network and CH, CO, CC vibrations in LDHs

CaFe-LDH  naproxen 350C

CaFe-LDH  naproxen 200C CaFe-LDH  naproxen initial

naproxen sodium initial naproxen sodium 350C

naproxen sodium 300C

naproxen sodium 250C CaFe-LDH  naproxen 400C

naproxen sodium 400C

Absorbance /a.u.

Wavenumber /cm^1adsorbed CO₂

Fig. S9 Infrared spectra of diclofenac, naproxen sodium salts and drug-intercalated (by the dehydroxylation-rehydration technique) LDH solids after heat treatments at various temperatures.

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10

100 1000

0 5 10 15 20 25

Diameter (nm)

intercalated diclofenac anion

CaFe-NO₃^-LDH co-precipitation direct anion exchange dehydroxylation-rehydration mechanochemically-aided intercalation

Number (%)

1150 1060 620 260 510

1000 10000

0 5 10 15 20 25

5000

Number (%)

Diameter (nm)

co-precipitation direct anion exchange

dehydroxylation-rehydration mechanochemically-aided intercalation 710

3240

2700 2200 intercalated

naproxen anion

Fig. S10 The number-weighed size distribution patterns of the as-prepared (nitrate-containing), the diclofenac and the naproxen anion-intercalated CaFe-LDH particles (the numbers show the predominant solvodynamic diameters).

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0 100 200 300 400 500 600 700 800 900 1000

1 5 10 25 50 75 100 200 400 600 800 0.1%

0.4% 0.1%

0.9% 1.5%

1.8%

6.2%

20.7%

47.9%

20.1%

co-precipitation naproxenLDH

Area /mm²

Number of particles

0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000

1 5 10 25 50 75 100 200 400 600 800 0.04%

0.02%

1.1% 0.4%

2.4% 0.9%

7.7%

28.8%

43.4%

15.4%

direct anion exchange naproxenLDH

Area /mm²

Number of particles

0 100 200 300 400 500 600 700 800 900 1000

1 5 10 25 50 75 100 200 400 600 800 0.2% 0%

2.6% 1.4%

1.2% 1.5%

4.9%

14.9%

47.4%

26.0%

dehydroxylation-rehydration naproxenLDH

Area /mm²

Number of particles

0 100 200 300 400 500 600 700 800 900 1000

1 5 10 25 50 75 100 200 400 600 800 0.5% 0.2%

2% 1.1%

2.1% 1.5%

9.7%

24.1%

43.9%

14.5%

mechanochemically-aided intercalation naproxenLDH

Area /mm²

Number of particles

Fig. S11 Particle size distribution histograms of the naproxen anion-intercalated CaFe-LDH solids dispersed in hydrogels.

Ambrogi, V., Fardella, G., Grandolini, G., Perioli, L., Tiralti, M.C., 2002. Intercalation compounds of hydrotalcite-like anionic clays with anti-inflammatory agents, II: Uptake of diclofenac for a controlled release formulation. AAPS PharmSciTech. 3, 26.

https://doi.org/10.1208/pt030326

Ambrogi, V., Perioli, L., Ricci, M., Pulcini, L., Nocchetti, M., Giovagnoli, S., Rossi, C., 2008.

Eudragit and hydrotalcite-like anionic clay composite system for diclofenac colonic

delivery. Micropor. Mesopor. Mat. 115, 405–415.

https://doi.org/10.1016/j.micromeso.2008.02.014

Carriazo, D., del Arco, M., Martín, C., Ramos, C., Rives, V., 2010. Influence of the inorganic matrix nature on the sustained release of naproxen. Micropor. Mesopor. Mat. 130, 229–238.

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Joy, M., Iyengar, S.J., Chakraborty, J., Ghosh, S., 2017. Layered double hydroxide using hydrothermal treatment: morphology evolution, intercalation and release kinetics of diclofenac sodium. Front. Mater. Sci. 11, 395–408. https://doi.org/10.1007/s11706-017- 0400-1

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https://doi.org/10.1016/j.clay.2010.06.028

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