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Characterization of the Physicochemical Properties of #Cyclodextrin-Divinyl Sulfone Polymer Carrier-Bile Acid Systems Mohamed H. Mohamed, Chen Wang, Kerry M Peru, John V. Headley, and Lee D. Wilson Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00088 • Publication Date (Web): 15 Mar 2017 Downloaded from http://pubs.acs.org on March 28, 2017

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Molecular Pharmaceutics

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Characterization of the Physicochemical Properties of β-Cyclodextrin-

2

Divinyl Sulfone Polymer Carrier-Bile Acid Systems

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Mohamed H. Mohamed1; Chen Wang1, Kerry M. Peru2, John V. Headley2 and Lee D.

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Wilson*1

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1

11

Saskatchewan, S7N 5C9

12

2

13

Innovation Boulevard, Saskatoon, SK S7N 3H5, Canada

Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon,

Water Science and Technology Directorate, Environment and Climate Change Canada, 11

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*Corresponding Author: L. D. Wilson, Tel. +1-306-966-2961, Fax. +1-306-966-4730,

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Email: [email protected]

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ABSTRACT

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carriers containing β-cyclodextrin (β-CD) and divinyl sulfone (DVS). The polymer carriers

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were prepared at variable feed ratios (β-CD-DVS; 1:1, 1:2, 1:3 and 1:6) and characterized

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using spectroscopy (IR, 1H solution NMR, 13C CP-MAS solids NMR), thermogravimetric

36

analysis (TGA), scanning electron microscopy (SEM) and a dye decolorization method using

37

phenolphthalein. Uptake studies were carried out at pH 9.00 for the polymer carriers using

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single component bile acids (cholic acid; deoxycholic acid; glycodeoxycholic acid; and

39

taurodeoxycholic acid). Equilibrium uptake results were evaluated by the Langmuir isotherm

40

model where variable equilibrium parameters was related to the relative apolar character of

41

the bile acid. The goodness of fit using the Langmuir model yields a carrier/bile acid binding

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affinity ≈103 M-1 where the lipophilic inclusion sites of the polymer play a prominent role, in

43

accordance with the relative hydrophile character of the linker framework sites.

44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

Herein, we report on the systematic design and characterization of cross-linked polymer

KEYWORDS: cyclodextrin; divinyl sulfone; bile acids; adsorption; isotherm

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1. INTRODUCTION Cyclodextrins (CDs) are macrocyclic oligosaccharides containing D-glucopyranose

69

monomer units that possess unique host-guest properties due to their amphiphilic nature.1-3

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CDs remain as a subject of continued research and technological interest due to their utility

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as modular platforms for the design of advanced materials such as sensor devices4-5,

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biocatalyst supports6-7, and diverse types of polymer adsorbents8-10. The unique host-guest

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chemistry and field of application for CDs can be further extended due to the formation of

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insoluble polymer materials upon cross-linking of CDs. CD-based polymers with variable

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morphology (fibres, globules, flakes, etc.) can be obtained with unique binding properties,

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especially when the inclusion sites are accessible and steric effects are minimized.10-11

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Mohamed and coworkers have demonstrated that the inclusion site accessibility of

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polymers that contain β-CD can be estimated using absorbance changes of phenolphthalein

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(phth) as an “on-off” indicator for insoluble CD-containing polymers.12 The use of phth in its

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dianion quinoid form leads to highly stable complexes with β-CD, in agreement with the

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magnitude of the binding affinity (≈ 104 M-1). The unique host-guest chemistry of the β-

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CD/phth system has led to its use in the dye-based mapping of other polymers that contain

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CD with variable morphology such as amorphous powders to fibres and films.12-15 More

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recently, the phth decolorization method was used to distinguish between compact and

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extended polymer structures according to the accessibility of binding sites under conditions

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of dynamic adsorption.16 The ability to assess the inclusion site accessibility lends itself to

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achieving a greater understanding of the factors governing the adsorption properties of

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polymers that contain β-CD. A key parameter in the case of cross-linked CD polymers is the

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level of cross-linking that relates to the synthetic feed ratio of cross-linker employed. Higher



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levels of cross-linking often lead to steric effects in the annular region of β-CD which result

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in a reduced accessibility of the inclusion sites, as outlined in a recent report.17

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Crini and coworkers have reviewed aspects of the field of such polymers related to

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cross-linked CDs, where common types of cross-linkers include epichlorohydrin,

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dialdehydes, dicarboxylic acids, and diisocyanates to name a few.11 By contrast, fewer studies

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have reported on the use of sulfone based cross-linkers.18-19 Similar to the case of

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epichlorohydrin, divinyl sulfone (DVS) is of interest since cross-linking reactions can be

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achieved in aqueous solution using facile reaction conditions. Recently, a study of the cross-

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linking of β-CD with DVS by Morales-Sanfrutos et al. suggest that inclusion binding is the

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principal mode of adsorption for low molecular weight phenols and some larger bioactive

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molecular guests.18 Similar conclusions were reported the same group in a follow-up study of

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various bile acid systems.19

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The level of interpretation from the aforementioned studies is limited, in part, by the

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ability to infer structure-property activity relationships for such polymer systems. To address

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this knowledge gap, we report on the preparation and characterization of a series of CD-

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DVS polymers along with a study of their adsorption properties using a selection of bile acid

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guests. In view of the importance of bile acids in many biological processes due to their

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unique surface active properties, a systematic study of the adsorption properties of CD-DVS

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polymers was undertaken. The relevance of such polymer carriers as drug delivery systems

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and biomedical devices is well established due to their unique host-guest chemistry, along

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with their use as responsive systems.20 We anticipate that this study will contribute to an

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improved understanding of the structure-function activity relationship of apparently simple

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polymer carriers and their potential utility as advanced materials for diverse applications.


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This includes the use of such polymer carriers as controlled-release devices to sequesterants

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for the controlled removal of chemical targets in biological systems.20-22

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2. EXPERIMENTAL SECTION 2.1 Materials β-cyclodextrin (β-CD), divinyl sulfone (DVS), phenolphthalein (phth), acetonitrile,

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ammonium hydroxide, methanol, diethyl ether, sodium hydrogen carbonate, sodium

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hydroxide, deuterated dimethyl sulfoxide (DMSO-d6), cholic acid (CA), deoxycholic acid

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(DA), glycodeoxycholic acid (GA), and taurodeoxycholic acid (TA) were used as received

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from Sigma Aldrich (Canada).

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2.2 Synthesis

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The procedure by Morales-Sanfrutos et. al18 was adapted with slight modification. 2.5

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g of β-CD was dissolved in 150 mL sodium hydrogen carbonate (0.5 M, pH 12). DVS was

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added at variable feed ratios to prepare 1:1, 1:2, 1:3 and 1:6 (CD:DVS mole ratio) polymers.

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The mixture was stirred for 24 h then the solvent was evaporated to ca. 50 mL with mild

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heating at 30oC. The addition of methanol to the concentrate resulted in precipitation the

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product, followed by filtration and washing via Soxhlet extraction with methanol for 24 h. A

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second cycle of Soxhlet extraction of the products using diethyl ether was carried out for 24

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h followed by oven-drying at 60oC. The descriptors for the polymers are denoted as CD-

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DVS-X where X is the mole ratio of DVS relative to 1 mole of β-CD.

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2.3 Characterization

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Thermogravimetry analysis (TGA). Thermal weight loss profiles of the polymer carriers

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were obtained using a TA Instruments Q50 TGA system at a heating rate of 5°C min-1 to a

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maximum temperature of 900°C using nitrogen as the carrier gas. The thermal stability of



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the respective polymer components are reported as first derivative plots of

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weight/temperature (%/°C) against temperature (°C).

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Diffuse Reflectance Infrared Fourier Transform Spectra (DRIFTS). DRIFTS results

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were obtained using a Bio-RAD FTS-40 spectrophotometer at room temperature over a

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400–4000 cm-1 spectral range in reflectance mode. Powdered polymer samples were mixed

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with pure spectroscopic grade KBr in a 1:100 wt. % ratio followed by grinding in a small

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mortar with a pestle. Multiple scans were recorded and corrected relative to a background of

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pure KBr.

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1

H NMR Spectra. 1H NMR spectra in solution were obtained with a wide-bore (89 mm)

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11.7 T Oxford superconducting magnet system equipped with 5 mm PATX1 probe

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operating at 500 MHz. The operating parameters were controlled using a SSSC 500 console

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and workstation running X-WIN NMR 3.5 (Bruker Bio Spin Corp; Billerica, MA, USA).

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Standard pulse programs included in the Top Spin 1.3 software were used for acquiring 1D

154

NMR spectra. Chemical shifts were referenced to tetramethylsilane (δ = 0.0 ppm).

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13

C Solids NMR Spectra. 13C NMR solids spectra were obtained using a Bruker AVANCE

157

III HD spectrometer operating at 125.77 MHz (1H frequency at 500.23 MHz) with a 4 mm

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DOTY CP-MAS probe. The 13C CP/TOSS (Cross-Polarization with Total Suppression of

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Spinning Sidebands) spectra were obtained with a spinning speed of 6 kHz with a 1H 90o

160

pulse of 3.5 µs, 1.0 ms contact time, and a ramp pulse on the 1H channel. Spectra were

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obtained using multiple spectral acquisition (1024 – 2048 scans) using a recycle delay of 2 s.

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All experiments were recorded using 71 kHz SPINAL-64 decoupling pulse sequence during 6 ACS Paragon Plus Environment

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acquisition. Chemical shifts were referenced to adamantane using the low field resonance

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line at 38.48 ppm.

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Scanning Electron Microscopy (SEM). The morphology of the products was studied

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using SEM (Model SU8000, HI-0867-0003) under the following instrument conditions:

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accelerating voltage (5 kV), working distance (8.7 mm), and an image magnification

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(20 000×).

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UV-vis Spectrophotometry. A Varian Cary 100 Scan UV–vis spectrophotometer was used

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to measure the absorbance (λmax = 552 nm) of phth in aqueous solution. The calculation of

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the accessibility of CD inclusion sites was reported in detail elsewhere.12, 23

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Electrospray Ionization (ESI)-High Resolution Mass Spectrometry (HRMS). Bile

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acids were quantified using negative-ion ESI-HRMS using a similar methodology adapted

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from a previous study.24

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2.4 Sorption

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The stock concentrations of bile acids were prepared in aqueous solution at pH 9.00

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using 0.1M ammonium hydroxide. 3 mL aliquots of the bile acid solutions at variable

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concentration (1-400 ppm) were incubated with constant dosage of polymer (10 mg) for 24

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h. The equilibrium uptake of the bile acid in the solid phase was estimated by Equation 1.

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qe =

(C0 − Ce ) × V m

(1)

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The uptake level of the bile acid adsorbed in the solid phase at equilibrium (qe; mmol g-1), C0

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(mmol L-1) is the initial bile acid concentration, Ce (mmol L-1) is the residual concentration of 7 ACS Paragon Plus Environment


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bile acid in solution after the adsorption process, V (L) is the volume of the bile acid

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solution and m is the weight (g) of the adsorbent. The adsorption isotherms generated using

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Equation 1 were evaluated by the Langmuir model25 (Equation 2), where KL is the Langmuir

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equilibrium constant (L.mmol-1).

qe =

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q m K L Ce 1 + K L Ce

(2)

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3. RESULTS AND DISCUSSION

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CD-DVS polymers were previously reported in an earlier study, where the

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characterization of such polymers provided limited molecular-level insight on the structure-

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function properties of such polymer carriers. Herein, the physicochemical properties of CD-

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DVS polymer carriers were characterized and their yield was variable (75-96 %). The

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influence of incremental cross-linking on the physicochemical properties of the polymers

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was assessed using adsorption studies.

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3.1 IR Spectroscopy

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polymer product shown in Scheme 1.26 The reaction occurs via deprotonation of the CD

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hydroxyl groups in an alkaline medium, followed by reaction with the electrophile region of

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the DVS double bond.27 Figure 1 illustrates the IR spectra of pristine β-CD and the

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polymers. The IR bands between 1217-1358 cm-1 and 918-1217 cm-1 increase with increasing

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DVS content, and relate to asymmetric and symmetric stretching vibrations of S=O.18, 28-29

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The IR bands at ~1455 cm-1 and 880 cm-1 for the polymers was assigned to CH, HCH,

β-CD was cross-linked with DVS via a Michael addition reaction to yield the


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CCH, COH bending of β-CD and the C-C anomeric vibrational transitions.30 The IR bands

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for β-CD become increasingly attenuated as the level of DVS cross-linking increases.30

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Scheme 1: CD-DVS polymer formation via cross-linking with divinyl sulfone (DVS).

CD-DVS-6

CD-DVS-3 CD-DVS-2

CD-DVS-1

β-CD 5000

4000

3000

2000

1000

-1

Wavelength (cm )

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Figure 1: IR spectra of pristine β-CD and the CD-DVS polymers in the solid state.

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3.2 NMR Spectroscopy Figure 2a illustrates the 1H NMR spectra of β-CD and the CD-DVS polymers at the

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1:1 and 1:2 mole ratios. The polymer products have limited solubility in DMSO-d6 at the 1:1

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and 1:2 CD-DVS mole ratios and insufficient solubility at the 1:3 and 1:6 ratios. Integration

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of the 1H NMR spectral areas was not carried out since the dissolved fraction may not

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represent the full molecular weight distribution of the polymer on account of solubility

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consideration. NMR line broadening of the –OH signatures provide support that cross-

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linking occurs with DVS (cf. Scheme 1).9 The variable H3 and H6 NMR signature for CD-

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DVS at the 1:1 versus 1:2 mole ratio may relate to differences in cross-linking at the primary

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versus secondary –OH groups of β-CD, and the signature ~3.33 ppm relates to trace water.

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Figure 2b complements the 1H NMR results where the 13C NMR signature at ca. 60 ppm

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becomes attenuated with greater DVS content. The reduced spectral intensity relates to

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greater cross-linking at the primary –OH site, in agreement with lower cross-polarization

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efficiency from a reduced H-content of β-CD. The emergence of 13C spectral signatures at

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~55 and 66 ppm grow as the level of cross-linking increases. The emergence of these

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spectral features further support that cross-linking occurs as a result of the appearance of

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methine signatures of DVS.31 A CD-DVS-2 3.5 3.4 3.3 3.2 3.1 3.0

CD-DVS-1 3.5 3.4 3.3 3.2 3.1 3.0

OH-2, OH-3 H-1

OH-6

H-3 H-6 H-5

β-CD 6.00

236

5.75

5.50

5.25

5.00

4.75

4.50

4.25

4.00

3.75

3.50

Chemical shift (ppm)


3.25

3.00

3.5 3.4 3.3 3.2 3.1 3.0

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B C2,3,5 C1

C4

C6 CD:DVS-6 CD:DVS-3

CD:DVS-2 CD:DVS-1

β-CD

120

237 238 239 240 241 242 243

100

80

60

40

20

0

Chemical shift (ppm)

Figure 2: A) 1H NMR spectra of pristine β-CD, CD-DVS-1 and CD-DVS-2 in DMSO-d6, B) solid state 13C NMR spectra of pristine β-CD and the polymers. 3.3 TGA Results Further evidence of cross-linking between β-CD and DVS is inferred from the

244

differential thermal analysis of the TGA peak profiles (cf. Figure 3A-B). The polymers have

245

reduced thermal stability relative to pristine β-CD, where a decomposition event occurs at

246

308oC. By comparison, the thermal decomposition for the CD-DVS polymers at variable

247

composition adopts the following trend: 1:1 (280 oC) > 1:2 (248 oC) > 1:3 (237oC). The 1:6

248

CD-DVS polymer has two thermal events at 278 and 311oC which suggests that higher DVS

249

loading above the 1:3 mole ratio results in a unique morphology with distinctive thermal

250

properties, as compared with polymers at reduced DVS loadings. A

B

90

3.5

Deriv. Weight (%/°C)

100

4.0

80

Weight (%)

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70 60 β-CD CD-DVS-1 CD-DVS-2 CD-DVS-3 CD-DVS-6

50 40 30 20

3.0 2.5 2.0 1.5 1.0 0.5

10

0.0

0 200

251

β-CD CD-DVS-1 CD-DVS-2 CD-DVS-3 CD-DVS-6

250

300

350

200

400

250

300

Temperature ( oC)

Temperature (oC)


350

400


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252 253 254 255 256 257 258 259

Figure 3: A) TGA plots (weight loss vs temperature) and B) differential thermal analysis (DTA) plots (weight loss/oC vs temperature) of TGA data for of pristine β-CD and the CDDVS polymers at variable composition.

3.3 SEM Results Figure 4 illustrates SEM images of pristine β-CD and the polymers. The surface

260

features of β-CD were found display a smooth and uniform appearance, while the cross-

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linked polymers have a rougher surface topology, except for CD-DVS-6. The CD-DVS-1

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polymer reveals the presence of linear dendrites, while the materials at higher magnification

263

indicate that the polymer surface has a rough and rod-shaped morphology. Greater cross-

264

linking seems to result in polymers with less voids, greater density, and smoother surface

265

features, as evidenced for CD-DVS-6. At reduced cross-linking, polymers such as DVS-1

266

likely adopt a linear morphology, as described elsewhere for CD-based urethane polymers (cf.

267

Scheme 3a in ref 12). At higher levels of DVS loading, the polymer is more likely to adopt a

268

branched morphology. The trend is in agreement with results for heavily cross-linked

269

polymers with greater branching, entanglement, and density. In the case of DVS-6, a unique

270

and globular morphology is observed that may relate to variable hydrophile-lipophile balance

271

(HLB) of the polymer above a certain DVS mole ratio. The incremental loss of hydroxyl

272

groups due to cross-linking favour the formation of spherical globules via polymer

273

aggregation. The tendency to minimize the interfacial energy of the resulting polymer is

274

consistent with reactions in aqueous media, especially at higher cross-link ratios.

275


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CD-DVS-1

β-CD

CD-DVS-1 x20K

CD-DVS-2

276 277 278 279 280 281 282 283 284

CD-DVS-6

CD-DVS-3

Figure 4: SEM images of pristine β-CD and CD-DVS polymers obtained at 5000× magnification except for the top right corner obtained at 20000× magnification. 3.3 β-CD accessibility As mentioned above, the role of inclusion site accessibility is a key parameter

285

governing the adsorption properties of CD-based polymers, where the details of the dye

286

decolorization method are described elsewhere.12,

287

concerning the structure-function relationship with adsorption properties of CD-based

288

polymers, the inclusion site accessibility was measured for the various CD-DVS systems.

289

The accessibility values are based on a comparative scale where decolorization of phth with

290

native β-CD implies inclusion sites with 100% accessibility. The corresponding values (%),

291

listed in parentheses for the polymer carriers, are given in descending order: DVS-1 (39.3) >

292

DVS-2 (30.0) > DVS-3 (28.1) > DVS-6 (6.58). The results show parallel agreement with

293

previous estimates for urethane-based CD polymers, where greater cross-linking results in

294

attenuated accessibility of the β-CD inclusion sites.12,

295

relative decrease in accessibility for the CD-DVS occurs over a three-fold change in linker

23

To address the knowledge gaps

23

It is interesting to note that the



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content and reveal ca. 10% variation. By contrast, a much greater change in accessibility was

297

observed for β-CD cross-linked with hexamethylene diisocyanate (HDI), where ca. 20%

298

variation occurs over a three-fold change in linker content (cf. Table 2 in Ref. 12). The

299

greater effect observed for HDI versus DVS can be partially understood on the basis of the

300

variable steric effects and the more apolar nature of HDI over DVS.

301 302 303 304

3.4 Sorption of bile acids

305

Scheme 2). In the case of CA (cf. Figure 5A), the relative uptake decreases as the level of

306

cross-linking increases. A similar trend was observed previously, where the primary sorption

307

site for the sorbate is the β-CD inclusion site.32 The isotherm data was fit by the Langmuir

308

isotherm model, where the Qm values (cf. Table 1) are 40.1 (9.55), 30.7 (11.3), 23.2 (17.3) and

309

15.7 (13.6) µmol/g for CD-DVS-1, CD-DVS-2, CD-DVS-3 and CD-DVS-6, respectively.

310

The above values in parentheses relate to KL parameter (M-1 ×103). CD-DVS-1 (cf. Figure B)

311

was chosen as a common polymer carrier with the various types of bile acids since it revealed

312

the highest uptake. The value of Qm (µmol/g) is followed by KL (M-1 x103) in parentheses for

313

each bile acid system: CA, 40.1 (9.55); DA 50.4 (3.02); GA 44.4 (5.25); and TA 32.2 (6.18).

314

The magnitude of the Qm for a given CD-DVS polymer/bile acid system tend to vary with

315

the relative HLB of the bile acid. Greater Qm values are observed as the lipophile character

316

of the bile acid increases, in agreement with trends reported for urethane-based CD

317

polymer/ naphthenate anion complexes according to variable molecular weight.33-34 In

318

contrast to the moderate variation in accessibility (ca. 10%) of phth over a three-fold range

319

in DVS concentration, greater variability was observed for the Qm values of CA in Figure

320

5A. The effect is understood on the basis of the greater molecular size of CA (409 g/mol

Figure 5A-B illustrate the sorption isotherms of the polymer/bile acid systems (cf.


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321

and lipophilic surface area (LSA) of 293 Å2); calculated from Spartan V’14) versus phth (318

322

g/mol and LSA of 249 Å2). The trend concurs with the variable steric effects as the DVS

323

content varies. The uptake decreases ca. 45% for a three-fold increase in DVS content for

324

the polymer/CA systems, as shown in Figure 5A. A notable decrease (ca. 60%) occurs for

325

Qm for DVS-6 relative to DVS-1, in accordance with steric effects due to cross-linking.

326

Thus, there is a clear trend in uptake as the level of cross-linking increases which indicates

327

that interactions of the bile acids with the inclusion sites of β-CD are attenuated due to

328

cross-linking. Figure 5B compares the isotherms for DVS-1 with the various bile acids (CA,

329

DA, GA and TA). Based on the molecular structures in Scheme 2, variation in the uptake

330

occurs due to the lipophile character of the bile acid. Bile acids with greater apolar character

331

display greater Qm values, while hydrophilic bile acids have lower Qm values. CA and DA

332

have the highest uptake while GA and TA have lower uptake in agreement with the presence

333

of hydrophilic side chains. The results herein are corroborated by Zhu et al in their

334

independent study of β-CD-resin/bile acid systems.35 A detailed quantitative analysis was not

335

undertaken herein since the polymer/bile acid binding mode requires further structural

336

characterization and is the subject of ongoing study.

337

Based on the trends observed in the adsorption isotherms, the role of steric effects

338

of the polymer framework and hydrophobic effects related to the variable bile acid HLB

339

profile can be inferred. The isotherm results are in agreement with the key role of

340

hydrophobic effects as in the case of the formation β-CD host-guest complexes.36 While the

341

Langmuir model accounts for adsorption at homogeneous sites, the prevalence of single site

342

adsorption for the polymers relate to the β-CD inclusion sites, especially for systems with

343

moderate accessibility. In the case of urethane-based CD polymers, the linker units tend to

344

be apolar in nature which results in adsorption at multi-sites due to the role inclusion and 15 ACS Paragon Plus Environment


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345

interstitial sites, as described by a two-site Langmuir model [cf. Equation 10 in 34].37 In the

346

case of DVS polymers, the goodness-of-fit results using a single site Langmuir model supports

347

that uptake occurs at the CD inclusion sites, in agreement with the high binding affinity of

348

β-CD/bile acid complexes. The negligible contribution of the DVS linker sites may relate to

349

the dipolar nature of the sulfone groups which impart greater hydrophile character to the

350

polymer framework.35,

351

mode and affinity of these CD-DVS/bile acid systems to gain a greater understanding of the

352

structure-function relationship with the adsorption properties of these systems.

353 354 355

Table 1: Qm and KL parameters obtained from the Langmuir isotherm fitting model for the uptake results of various polymer/bile acid and β-CD/bile acid systems at 295 K.

38

However, further studies are underway to establish the binding

Polymer Qm (µmol/g) KL (M-1 x103)

CD-DVS-1 40.1 9.55

CD-DVS-2 30.7 11.3

CD-DVS-3 23.2 17.3

CD-DVS-6 15.7 13.6

β-CD Qm (µmol/g) KL (M-1 x103)

CA 40.1 9.55

DA 50.4 3.02

GA 44.4 5.25

TA 32.2 6.18

356 357


Page 17 of 22

OH

H3C

O

OH

H3C

O

CH3

CH3

OH

OH H

H H

H HO

HO

OH

H

H O

OH OH CH3

N H

H

O H H HO H Na O

O O

S OH CH3

N H

H

O

H H HO

358 359

H

Scheme 2: Molecular structure of the bile acid systems.

A

B

40

30

25 20 15

25 20 15

10

10

5

5

0

0

200

CA DA GA TA

35

Qe (µ µ mol/g)

30

360 361 362 363 364 365 366 367

40

CD:DVS-1 CD:DVS-2 CD:DVS-3 CD:DVS-6

35

Qe (µ µ mol/g)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


400

600

800

Ce (µ µmol/L)

0

0

200

400

600

Ce (µ µmol/L)

Figure 5: A) Sorption isotherm of CD-DVS polymers with CA at pH 9 and 295 K and B) Sorption isotherm of CD-DVS-1 with CA, DA, GA and TA at pH 9 and 295 K. 4. CONCLUSIONS This study reports on the preparation and characterization of cross-linked polymers

368

containing β-CD with divinyl sulfone at variable composition. The polymer structure was

369

evaluated using several complementary characterization methods. The adsorption properties


800


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

370

were revealed using a dye-based decolorization method with phenolphthalein, along with a

371

systematic isotherm study of polymer/bile acid systems at alkaline conditions.

372

In general, the uptake properties of CD-DVS polymers are influenced by the level of

373

cross-linking as evidenced by the decrease in uptake as the DVS linker content of the

374

polymer increased. Trends were observed that support the role of hydrophobic effects

375

according to the greater uptake for lipophilic versus hydrophilic bile acids. This study

376

demonstrates the role of inclusion site accessibility and cross-linking on the adsorption

377

properties of CD-based polymers. Based on the relative uptake values reported herein, the

378

inclusion sites show a dominant contribution to adsorption, while the DVS linker units have

379

a secondary contribution to adsorption, in agreement with their hydrophile nature. This is in

380

stark contrast to isostructural carrier systems reported elsewhere for urethane based CD

381

polymers.31 This research contributes to the development of a new class of polymer carrier

382

systems with unique structure and morphology that stem from the presence of sulfone

383

cross-linker units that differ uniquely from urethane and glycerol based cross-linked

384

polymers containing β-CD polymer. The development of CD-based polymer carriers will

385

contribute to applications that range from controlled-release/-uptake of molecular targets

386

for advanced drug delivery, chemical separations, and biomedical devices.

387 388 389 390

ACKNOWLEDGEMENTS The authors wish to gratefully acknowledge the University of Saskatchewan and the Natural

391

Sciences and Engineering Research Council of Canada (NSERC) for supporting this

392

research (Project number: RS-346097).

393 394 395 396 18 ACS Paragon Plus Environment

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397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443


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