Mechanistic Investigation of Inclusion Complexes of a Sulfa Drug with

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Mechanistic investigation of inclusion complexes of a sulfa-drug with # and #-cyclodextrins Subhadeep Saha, Aditi Roy, and Mahendra Nath Roy Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.7b02619 • Publication Date (Web): 26 Sep 2017 Downloaded from http://pubs.acs.org on September 30, 2017

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Industrial & Engineering Chemistry Research

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Mechanistic investigation of inclusion complexes of a sulfa-drug with α

2

and β-cyclodextrins

3

Subhadeep Saha, Aditi Roy and Mahendra Nath Roy *

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* Department of Chemistry, University of North Bengal, Darjeeling-734013, India. Telephone: +91 353 2776381, Mobile: +91 94344 96154, Fax: +91 353 2699001, Email: [email protected] Supporting Information: Table S1-S11, Figure S1-S9 and Scheme S1 are available.

8

Abstract: Molecular encapsulation is extremely important in pharmaceutical and drug

9

delivery science. In this article, one of the most important sulfa-drugs, namely,

10

sulfacetamide sodium has been probed in solution and solid phase to encapsulate it within

11

the cavity of α and β-cyclodextrins. Various physicochemical techniques have been

12

employed to establish the outcome of the work. Isothermal titration calorimetric method

13

has been used to evaluate the stoichiometry, association constant and thermodynamic

14

parameters with high accuracy. The solid inclusion complexes have been analyzed by

15

spectroscopic technique, which ascertain the encapsulation of the investigating drug into

16

the cavity of α and β-cyclodextrins. This inclusion phenomenon of the drug is exceedingly

17

significant for its stabilization from external hazards, like oxidation, sensitization,

18

photolytic cleavage etc., for regulatory release of essential amount of drug at the targeted

19

site for a period of time proficiently and accurately and for preventing overdose when

20

applied as ophthalmic solution and ointment.

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1. Introduction

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Molecular encapsulation and release are exceptionally significant in pharmacology

23

and drug delivery science in recent years.1,2 For this purpose various host molecules, such

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as calixarenes, pillararenes, cucurbiturils, cyclodextrins, etc. have been widely used as

25

excellent receptors for drug recognition.3-6 The host-guest complexes could be applied to

26

construct stimuli-responsive supramolecular materials, where series of external stimuli,

27

such as, enzyme activation, photo sensing, temperature dependence, changes in pH/redox

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and competitive binding may be employed to operate the release of guest molecules from

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the inclusion complexes (ICs).7-10 In the last decade attention has been focused on

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molecular sensing, anti-cancer drug release, gene transfection etc. with the help of

31

mechanized nanoparticles capable of trapping and regulating the release of cargo

32

molecules by a range of external stimuli.11-14 Macrocyclic host molecules are of immense

33

importance in ICs as the cyclized and constrained conformation offer the benefit of

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molecular selectivity.15 The cyclodextrins (CDs) are exclusively interesting in this regard,

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due to their amphiphilic nature.15,16 The interest in amphiphiles comes up from their self-

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assembly in aqueous systems to form well defined structures, such as micelles, nanotubes,

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nanorods, nanosheets and vesicles, which can be applied in several grounds ranging from

38

nano-devices, drug delivery and cell imaging.17-19 In recent times cyclodextrin modified

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nanoparticles are of great attention as they appreciably improve the characteristics of the

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assemblies, such as the electronic, conductance, thermal, fluorescence and catalytic

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properties improving their potential applications as nanosensors and drug delivery

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vehicles.20,21 Various sophisticated probes have been designed for this purpose for their

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applications

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supramolecular polymers, chemosensors, transmembrane channels, molecule-based logic

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gates and other interesting host−guest systems.22-25 CDs are the cyclic oligosaccharides

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having six (α-CD), seven (β-CD) and eight (γ-CD) glucopyranose units which are bound

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together by α-(1–4) linkages making a truncated conical structure (Scheme 1), which

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allows CDs to form host–guest ICs with different sized guest molecules.26-28 The structures

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and the properties of the ICs formed by CDs are determined by their architectures, i.e.,

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interplay between the hydrophilic−hydrophobic balance and geometric packing

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constraints.27-29 The experimental conditions, such as concentration, temperature, pH, etc.

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also play crucial roles exhibiting their potential applications in gene and drug delivery.30-32

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Due to their above mentioned advantages, the ICs are being widely investigated in

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materials and biomedical sciences, especially, the applications in biologically and

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pharmaceutically relevant fields have produced tremendous interest of researchers in

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recent years.33-37 The exterior of the CD cavity is highly polar due to the hydroxyl groups,

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while the interior is non-polar, making them suitable and fascinating hosts for

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supramolecular chemistry.38,39 The chemical stability of guest molecule also increases due

59

to encapsulation inside the cavity.40,41

in

the

manufacture

of

molecular

switches,


molecular

machines,

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The stabilization and regulatory release of the sulfa-drugs are of great concern in

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pharmacology.42-45 Thus to protect these drugs from external effects and for their

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regulatory release, it is crucial to investigate whether they can be encapsulated into the CD

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molecule.46,47 Sulfonamides are bacteriostatic material and their range of activity is

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analogous for all.48,49 Sulfonamides restrain bacterial synthesis of dihydrofolic acid by

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inhibiting the condensation of the pteridine with aminobenzoic acid by competitive

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inhibition of the enzyme dihydropteroate synthetase.50,51 Topically applied sulfonamides

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act against vulnerable strains of various bacterial eye pathogens, for example, Escherichia

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coli, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus, Haemophilus

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influenzae, Klebsiella species, Enterobacter species, etc.52,53 Sulfacetamide sodium (SS)

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(Scheme 1) 10% topical lotion is approved for the treatment of acne, seborrheic dermatitis,

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conjunctivitis

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microorganisms.50,52 SS has been considered in the treatment of pityriasis versicolor and

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rosacea.54 It also has anti-inflammatory property while used to treat conjunctivitis.53 It is

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found that SS may be used in the treatment of mild forms of hidradenitis suppurativa.54

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There are a number of topical products containing SS, e.g., foams, shampoos, cream, etc.50,54

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Sulfacetamide is a competitive inhibitor of bacterial para-aminobenzoic acid, which is

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necessary for bacterial synthesis of folic acid, a vital constituent for bacterial growth.50,54

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The multiplication of bacteria is thus inhibited by the action of sulfacetamide.51,54 SS can

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also be used orally to treat urinary tract infections and the oral absorption of SS is found to

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be 100%.50,55 Sulfacetamide causes slight irritation in presence of UV-A light, as it gets

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sensitized and degraded leading to toxicity when used continuously.53 Thus, stabilization

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from external hazards, i.e., oxidation, sensitization, photolytic cleavage etc.; for the

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regulatory delivery of required amount of SS at the targeted site for a period of time

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professionally and accurately and to prevent overdose, encapsulation of the drug is very

85

important.56,57

and

various

external

visual

infections

due

to

susceptible

for

86

Here, inclusion of SS has been attempted within the cavity of α and β-CD in solution

87

and solid phase both for use as ophthalmic solution and ointment. Monomolecular

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encapsulation has been explained by Job’s method, several tools have been used for the

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confirmation of inclusion. Association parameters and thermodynamics of the processes

90

have also been explained basing upon reliable ultraviolet-visible spectroscopy and 3 ACS Paragon Plus Environment


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isothermal titration calorimetric studies, while the solid ICs have been characterized by 1H

92

NMR & 2D ROESY NMR spectroscopy, HRMS and FTIR spectroscopy.

93

Hence, this novel work approaches toward the stabilization and regulatory delivery

94

of sulfacetamide sodium. Here, singly-molecular encapsulation of the drug provides the

95

drug loading ability of α and β-cyclodextrins. The association and thermodynamic

96

parameters have been evaluated by highly sophisticated methods, which help to implement

97

the proposed utilization of the encapsulated drug in the fields of applied chemistry and

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chemical engineering.

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2. Experimental

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2.1. Materials

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Sulfacetamide sodium salt monohydrate, α-cyclodextrin and β-cyclodextrin of high-

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purity grade were purchased from Sigma-Aldrich and used as received. Purity of

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sulfacetamide sodium salt monohydrate, α-cyclodextrin and β-cyclodextrin were ≥98.0%.

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2.2. Apparatus

105

UV-visible spectra were recorded by JASCO V-530 UV-Vis spectrophotometer with

106

wavelength accuracy of ±0.5 nm. Temperature of the cell was kept constant by a digital

107

thermostat.

108

The surface tension studies were accomplished by platinum ring detachment

109

technique using digital tensiometer K9, KRÜSS, Germany at the experimental temperature.

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Accuracy in the measurement was ±0.1 mNm−1. Temperature was maintained at 298.15 K

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by circulating auto-thermostat water through a double walled glass vessel holding the

112

solution.

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Specific conductivities of the studied solutions were measured by Mettler Toledo

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Seven Multi conductivity meter with uncertainty ±1.0 µS m-1. The experiments were carried

115

out in an auto-thermostat water bath keeping the temperature at 298.15 K and using HPLC

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grade water with specific conductance of 6.0 µS m-1. Calibration of the cell was done using

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a 0.01M aqueous KCl solution. 4 ACS Paragon Plus Environment

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Isothermal titration calorimetry was employed to find out the association constants

119

at 298 K using a MicroCal VP-ITC (MicroCal, Inc., Northampton, MA, USA). First, the thermal

120

equilibration was allowed at 298 K, which was followed by initial 120 s delay and the

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successive twenty five injections of SS to each CD (duration of injection was 10 s having

122

spacing of 180 s). A heat-burst curve was generated at each injection between micro cal

123

s−1 versus time in minute. The saturation curve for kcal/mol of the injectant against molar

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ratio was calculated by integration, using Origin 7.0 software to provide the heat associated

125

with the injection. The association-affinity and thermodynamic properties of the binding

126

phenomenon were found out by fitting the integrated heats of binding to the one site

127

binding model to give the association constant (KaC), stoichiometry (NC), binding enthalpy

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(ΔHoC) and the entropy (ΔSoC).

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2D ROESY and 1H NMR spectra were recorded in D2O at 300 MHz in Bruker Avance

130

300 MHz instrument at 298 K. The detail specifications of the 2D ROESY experiments have

131

been shown in Figure 3. Signals are cited as δ values in ppm using residual protonated

132

solvent signal as internal standard (HDO: δ 4.79 ppm). Data are presented as chemical shift.

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HRMS analyses were performed by Q-TOF high resolution instrument with positive

134

mode electro-spray ionization taking the methanol solution of the solid ICs.

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FTIR spectra were recorded in a Perkin Elmer FT-IR spectrometer according to the

136

KBr disk method. KBr disks were made in 1:100 ratios of sample and KBr. FTIR studies

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were carried out in the scanning range of 4000−400 cm−1 at room temperature.

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2.3. Procedure

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Solubilities of the two CDs and sulfacetamide sodium salt monohydrate have been

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checked in triply distilled, deionized and degassed water. All the solutions of α-CD, β-CD

141

and SS were prepared by mass using Mettler Toledo AG-285 with uncertainty ±0.1 mg at

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298.15 K. Sufficient precautions were taken to minimize the evaporation loss during mixing

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and working with these solutions.



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The two solid ICs (SS + α-CD and SS + β-CD) have been prepared in 1:1 molar ratio

145

of SS and CD. For each complex, 1.0 millimole SS and 1.0 millimole CD were dissolved in 20

146

mL water separately and stirred for 4 hours. Then the aqueous solution of SS was added

147

drop wise to the aqueous solution of CD. The mixture was then stirred for 48 hrs at 50–

148

55oC and filtered at this hot condition. It was then cooled to 5oC and kept for 12 hrs. The

149

resulting suspension was filtered to get white polycrystalline powder, which was washed

150

with ethanol and dried in air. The yield of the solid inclusion complexes were 88% and 92%

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for SS + α-CD and SS + β-CD respectively.

152

3. Result and Discussion

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3.1. Job plot: stoichiometry of the host-guest inclusion complex

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The efficient and successful method to identify the stoichiometry of the host-guest

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inclusion complex is the Job’s method, popularly known as the continuous variation

156

method.58 This technique was applied here using UV-visible spectroscopy by measuring the

157

absorbance of a set of solutions of SS with α and β-CD having their mole fractions in the

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range 0–1 (Table S1–S2, Figure S1, supporting information).59 Job plots were generated by

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plotting ΔA × R against R, where ΔA is the difference in absorbance of SS without and with

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CD and R = [SS]/([SS]+[CD]). Absorbance were calculated at λmax = 256 nm for all the

161

solutions at 298.15K. The value of R at the maxima on the curve provides the stoichiometry

162

of IC, thus, the ratio of guest and host is 1:2 if R ≈ 0.33; 1:1 if R ≈ 0.5; 2:1 if R ≈ 0.66 etc.60 In

163

the present work maxima for each of the plots were found at R ≈ 0.5, which indicate 1:1

164

stoichiometry of the host-guest inclusion complexes (Figure 1a, 1b).61

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3.2. Surface tension study: inclusion and its stoichiometric ratio

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Surface tension (γ) study provides significant evidence regarding the formation and

167

the stoichiometry of the host-guest IC.62-64 The structure of SS shows that there is a charged

168

end and also a hydrophobic portion, as a consequence SS behaves like surfactant molecule,

169

which is reflected in the lower γ value of its aqueous solution compared to pure aqueous

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media.65,66 CDs in contrast, because of having hydrophobic outer surface and hydrophilic

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rims, hardly show any change in γ while dissolved in aqueous medium for a wide range of 6 ACS Paragon Plus Environment

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concentration.67,68 In the present study γ of aqueous SS was measured with increasing

173

concentration of α and β-CD at 298.15K (Table S3, S4). In both cases there were

174

progressively rising trend of γ with increasing concentration of α and β-CD (Figure 1c, 1d),

175

may be as a result of encapsulation of the SS molecule from the surface of the solution into

176

the hydrophobic cavity of CDs forming host-guest ICs (Scheme S1).59 Both the plots also

177

demonstrate that there are single noticeable breaks in each curve (Figure 1c, 1d), which

178

not only reveal the formation of IC but also specify the 1:1 stoichiometric ratio for each of

179

the ICs formed.62,63 The values of γ and corresponding concentrations of SS and CDs at each

180

break have been listed in Table 1, which also point out that at each break point the

181

concentration ratio of host and guest is about 1:1, establishing the formation of 1:1 ICs

182

between SS and CDs.59,66

183

3.3. Conductivity study: inclusion process and the stoichiometry

184

Conductivity (κ) study is an essential tool to elucidate the inclusion phenomenon in

185

solution phase.69,70 It identifies the formation as well as the stoichiometry of the ICs.65,67 In

186

the present study the conductivity of aqueous solution of SS was measured with continuous

187

addition of α and β-CD (Table S3, S4). The results are shown in Figure 1e, 1f, which show

188

gradually decreasing trend of κ, may be because of lowering of mobility of the charged SS

189

molecules due to encapsulation into the cavity of CDs.71,72 Thus, the conductivities of the

190

solutions are noticeably affected by the inclusion phenomenon (Scheme S1).67,70 At certain

191

concentrations of α and β-CD single breaks were found in each conductivity curve

192

signifying the formation of 1:1 IC (Figure 1e, 1f).59,65 The values of κ and corresponding

193

concentrations of SS and CDs at each break have been listed in Table 1, which inform that

194

the ratio of the concentrations of SS and each CD at the break point is roughly 1:1,

195

suggesting that SS-CD IC is equimolar, i.e., the host-guest ratio is 1:1 (Scheme S1).66,70

196

3.4. Ultraviolet spectroscopy: association constants and thermodynamic parameters

197

Association constants (Ka) for the inclusion phenomenon have been determined for

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the SS-CD ICs with the help of UV-visible spectroscopy.59 There should be a change in molar

199

extinction coefficient (∆ε) of the chromophore of SS when the SS molecules go from the 7 ACS Paragon Plus Environment


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200

polar aqueous environment to the apolar cavity of α or β-CD making the ICs.67,73 The

201

changes in absorbance (∆A) of SS (at λmax = 256 nm) were employed against the

202

concentration of α and β-CD at a range of temperatures to find out the association

203

constants (Ka) (Table S5, S6).65 On the basis of Benesi–Hildebrand method for 1:1 host-

204

guest complex double reciprocal plots were drawn by using the following equation (Figure

205

S2).61,74

206

∆

∆

×

+

∆

(1)

The values of Ka for the ICs have been evaluated by dividing the intercept by the

207 208

=

slope of the straight line of the double reciprocal plot (Table 2).59,65

209

Association constants (Kaφ) were also calculated for the SS-CD ICs by UV-visible

210

spectroscopy with the help of non-linear programme basing upon the changes in

211

absorbance as a result of encapsulation of the SS molecule inside into the apolar cavity of α

212

and β-CD.59,75 The following equilibrium is supposed to exist between the host and the

213

guest for 1:1 IC27,28 φ

SS + CD K IC ⇌

214

(2)

The association constant (Kaφ) for the formation of IC may be expressed as

215

φ

K =

216

(3)

217

Here, [IC], [SS]f and [CD]f represent the equilibrium concentration of IC, free SS molecule

218

and free CD respectively. According to the binding isotherm, the association constant (Kaφ)

219

for the formation of IC may be expressed as59,76,77 φ

K =

220

CD = CD

= −

( ) ( )

#$ ( )

(4) (5)

221

where,

222

Here, Ao, Aobs and A are the absorbance of SS molecule at initial state, during addition of CD

223

and final state respectively. [SS]ad and [CD]ad are the concentrations of SS and the added CD

!

( )


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224

respectively. Thus, the values of Kaφ for the ICs were estimated from the binding isotherm

225

by applying non-linear programme (Table 2).75,78

226

The thermodynamic parameters may be derived basing upon the association

227

constants found out from various isotherms by the above linear and non-linear methods

228

with the help of van’t Hoff equation (equation 6a, 6b) (Table S7-S8, Figure S3-S4).59,65,67

229

lnK = −

230

lnK = −

φ

∆'( )*

∆'(φ )*

+ +

∆( ) ∆(φ )

(6a) (6b)

231

The changes in enthalpy and entropy for the inclusion phenomenon were found

232

negative signifying the inclusion process to be exothermic and entropy restricted rather

233

than entropy driven (Table 2).59,65 It may be described basing upon the molecular

234

association that was happening while the ICs were being formed between α or β-CD and SS.

235

Due to this phenomenon, there should be a fall in entropy, which was adverse for the

236

spontaneous formation of the IC. This effect was reversed by grater negative value of

237

change in enthalpy, which makes the overall inclusion process thermodynamically

238

favourable.

239

3.5. Isothermal titration calorimetry: characterization of complexation

240

Isothermal titration calorimetry (ITC) is highly sensitive and accurate analytical

241

technique for evaluation of association constant and various thermodynamic properties in

242

host–guest complexation chemistry.79 It is a competent technique for direct measurement

243

of the thermodynamic parameters than using the van't Hoff equation method.59 Upper part

244

of Figure 2a shows the data acquired from the ITC titration of SS with α-CD in water at 298

245

K, which illustrates generation of exothermic heat after each injection and the amount of

246

the released heat decreases gradually until complete complexation was achieved. Lower

247

part of Figure 2a shows the experimental data and the analyzed best fit binding curve of SS

248

with α-CD, that gives the stoichiometry (NC), association constant (KaC), standard enthalpy

249

(ΔHoC) and standard entropy (ΔSoC). The complexation of SS with β-CD in water at 298 K



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was likewise estimated by ITC as described above and shown in Figure 2b. The results of

251

calorimetric study are listed in Table 2, which are analogous with those found from the

252

investigation of UV-visible spectroscopic data, however, these are slight different from

253

those obtained by the previous spectroscopic technique studied in a range of temperature,

254

which may be due to the fact that the association constants of CD complexes decrease with

255

increase in temperature, on the basis of which the enthalpy and entropy were calculated

256

using van't Hoff method.80 But, here in ITC study, the thermodynamic parameters were

257

estimated only at 298 K, where the changes of the values of association constants are not

258

reflected. One more fact is that in spectroscopic determination, the thermodynamic

259

parameters were evaluated from association constants, which were found out basing upon

260

∆ε of SS, that was owing to the alteration in the environment around the chromophore,

261

when the SS molecules go from the polar aqueous surroundings to the hydrophobic cavity

262

of CD. Hence, the changes in enthalpy and entropy illustrated there were completely for the

263

formation of IC, not due to the solvent interactions happening in the system. But, in ITC

264

various non-covalent forces, namely, van der Waals, electrostatic, hydrophobic and H-

265

bonding play major role in the host–guest interactions, representing an overall heat

266

changes in the thermodynamic parameters.81 The binding of SS with α-CD or β-CD are

267

enthalpy favored as the entropy for the interaction is not favorable, indicating major role of

268

electrostatic and hydrophobic interactions in the complexation process.59

269

The stoichiometries (NC) of the binding additionally recommend that 1 : 1

270

complexation have taken place in the formation of complexes of SS with α-CD and β-CD

271

which is consistent with the 1 : 1 complexation realized from the Job plots.

272

3.6. 1H NMR and 2D ROESY NMR spectra analysis of solid inclusion complexes

273

Inclusion of a guest molecule into the cavity of CD results in the chemical shift of the

274

interacting protons of both the guest and CD in 1H NMR spectra, owing to their mutual

275

shielding through space.82 The spectral changes that can be observed in case of

276

encapsulation of aromatic guest molecules are the diamagnetic shielding of the interacting

277

protons of CD by the aromatic moiety of the guest.83 In the structure of CD it may be

278

observed that the H3 and H5 hydrogens are located inside the conical cavity, particularly, 10 ACS Paragon Plus Environment

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279

the H3 are placed near the wider rim while H5 are placed near the narrower rim and the

280

other H1, H2 and H4 hydrogens are located at the exterior of the CD molecule (Scheme 1).84

281

In the present work the molecular encapsulation was studied with the help of 1H NMR

282

spectra. Figure S5-S7 show the 1H NMR spectra of pure SS, α-CD and β-CD respectively,

283

where the aromatic as well as signals of H3 and H5 protons of CDs may be observed with

284

corresponding chemical shift (δ) values (Table S9). In the 1H NMR spectra of the ICs, it may

285

be noticed that the signals of interior H3 and H5 of α and β-CD as well as that of the

286

interacting aromatic protons of SS showed substantial upfield shift confirming the

287

formation of ICs (Figure S8, S9).85 It may also be observed that the chemical shift (δ) of the

288

H3 due to interaction with the aromatic guest was much higher than that of the H5 (Table

289

S9), proving the guest entered through the wider rim of α and β-CD (Scheme S1).86

290

Two-dimensional (2D) NMR spectroscopy provides conclusive evidence about the

291

spatial proximity of the interacting atoms of the host and the guest by observing the

292

intermolecular dipolar cross-correlations.87,88 Two protons which are situated within 0.4

293

nm in space may produce a Nuclear Overhauser Effect (NOE) cross-correlation in NOE

294

spectroscopy (NOESY) or rotating-frame NOE spectroscopy (ROESY).89 As the structural

295

features of α and β-CD described earlier, the inclusion phenomenon into the CD cavity may

296

be proved by the appearance of NOE cross-peaks between the H3 or H5 protons of CD and

297

the interacting protons of the guest recognizing their spatial proximity.90,91 For establishing

298

this, 2D ROESY were obtained of the ICs of SS with α and β-CD in D2O, which showed

299

significant correlation of aromatic protons of SS with the H-3 and H-5 protons of α and β-

300

CD, signifying the aromatic ring was included inside both the CD cavities (Figure 3).92 These

301

outcomes confirmed the encapsulation of the SS molecule within the cavities of α and β-CD.

302

Furthermore, it may be observed that the H6 protons of CDs were not influenced by the

303

inclusion processes, which suggest that the guest SS molecule was incorporated into the CD

304

cavity via the wider rim, not through the narrower rim as otherwise cross-peaks between

305

the H6 and the guest would have been observed in the ROESY spectra (Scheme S1).93

306

3.7. ESI-mass spectrometric analysis of inclusion complexes

307

The solid ICs of SS with α and β-CD were further analyzed by ESI-mass spectrometry

308

by dissolving these in methanol. The spectra have been shown in Figure 4 and the observed 11 ACS Paragon Plus Environment


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Page 12 of 31

309

peaks have been listed into Table S10 with possible ions. The peaks at m/z 1209.35 and

310

1231.33 correspond to [SS+α-CD+H]+ and [SS+α-CD+Na]+ respectively, and the peaks at m/z

311

1371.40 and 1393.38 correspond to [SS+β-CD+H]+ and [SS+β-CD+Na]+ respectively. The spectra

312

confirm that the desired ICs SS+α-CD and SS+β-CD have been formed in solid state and the

313

stoichiometric ratio of the host and guest is 1:1 (Scheme S1).94,95

314

3.8. FT-IR spectra of solid inclusion complexes

315

Inclusion phenomenon inside CD molecule may be satisfactorily illustrated by FT-IR

316

spectra.46,96 In this work IR spectra of SS, α-CD, β-CD and the ICs were obtained in solid

317

state by KBr pellet method, which show characteristic changes in IR signals of host and

318

guest confirming the formation of ICs.85,97 The spectra are shown in Figure 5 and the typical

319

signals are listed in Table S11 with the chemical bonds responsible for the corresponding

320

stretching frequencies. The binding modes of SS inside α and β-CD were described by NMR

321

studies, which may again be confirmed by the shifting of IR signals. The following changes

322

due to various interactions may be found for the SS+α-CD IC: (i) the signal of –O-H of α-CD

323

was at 3412.10 cm-1 and that of –N-H of SS was at 3433.76 cm-1, whereas the IC showed

324

signal at 3406.25 cm-1 possibly due to formation of H-bonding between them; (ii) the >C=O

325

stretching signal was at 1626.42 cm-1 for SS, which was shifted at 1633.94 cm-1 in case of IC

326

may be as a result of formation of H-bonding; (iii) S=O showed signal at 1322.43 cm-1 and

327

1132.63 cm-1 for pure SS, which changed at 1330.58 cm-1 and 1152.07 cm-1 for the IC

328

possibly owing to interaction with CD cavity; (iv) the –C-H stretching and –C-H bending of

329

α-CD were at 2930.79 cm-1 and 1406.76 cm-1 respectively and for SS out of plane C-H

330

bending were at 836.89 cm-1 and 690.32 cm-1 respectively, which shifted for the IC at

331

2933.57 cm-1, 1417.51 cm-1, 846.98 cm-1 and 685.55 cm-1 respectively may be because of

332

close proximity of –C-H of α-CD with the aromatic C-H of SS as found in 2D ROESY spectra.

333

Similarly, the following shifts in IR spectra may be found due to various interactions for the

334

SS+β-CD IC: (i) the signal of –O-H of β-CD was at 3349.84 cm-1 and that of –N-H of SS was at

335

3433.76 cm-1, whereas the IC showed signal at 3417.91 cm-1 probably due to formation of

336

H-bonding between them; (ii) the >C=O stretching signal was at 1626.42 cm-1 for SS, which

337

was shifted at 1634.83 cm-1 in case of IC possibly as a result of formation of H-bonding with


Page 13 of 31

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338

–O-H of β-CD; (iii) S=O showed signal at 1322.43 cm-1 and 1132.63 cm-1 for pure SS, which

339

changed at 1329.43 cm-1 and 1154.61 cm-1 for the IC possibly because of interaction with β-

340

CD cavity; (iv) the –C-H stretching and –C-H bending of β-CD were at 2921.52 cm-1 and

341

1412.36 cm-1 respectively and for SS out of plane C-H bending were at 836.89 cm-1 and

342

690.32 cm-1 respectively, which shifted for the IC at 2932.95 cm-1, 1416.52 cm-1, 844.09 cm-

343

1

344

C-H of SS as found from 2D ROESY spectra. In both the IR spectra of the ICs there was no

345

appearance of additional signal rejecting the possibility of any chemical reaction.93,98

346

Hence, the FT-IR study provides significant indications of formation of ICs in the solid form,

347

supporting the outcomes of the other above studies.

348

4. Conclusion

and 684.45 cm-1 respectively may be due to closeness of –C-H of β-CD with the aromatic

349

Host-guest inclusion phenomenon is accomplished through molecular recognition of

350

the guest by the host molecule. There also must be dimensional suitability between the two

351

species. One of the driving forces for the formation of IC was the release of the water

352

molecules from the hydrophobic cavity of CD to the bulk of water thereby increasing the

353

entropy of the system. The ICs were stabilized by both hydrophobic and H-bonding

354

interactions. Here, formations of 1:1 ICs were established and the ICs were characterized

355

by various techniques in aqueous medium as well as in solid state. The ICs stabilize SS from

356

chemical modification, photo sensitization and act as regulatory releaser at the targeted

357

site for a specified period of time reducing the overdose. Thus, the present study conveys a

358

new approach over the already known versatile use of SS by applying α and β-CD in bio-

359

medical sciences and pharmaceutical industries.

360

Acknowledgement

361

All authors are highly thankful to the SAP, Dept. of Chemistry, UNB under University

362

Grants Commission and RUSA under MHRD, Govt. of India for monetary assistance to

363

facilitate the research work.

364

Disclosure of interest: The authors report no conflicts of interest.



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Novel Approach in Determining Inclusion Mechanisms: Thermodynamics and Kinetics of the

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Host-Guest Interactions for α-Cyclodextrin Complexes. J. Am. Chem. Soc. 2000, 122, 592-602.

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with Natural Cyclodextrins: Spectroscopy, Calorimetry and NMR Studies. RSC Adv. 2015, 5,

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(81) Giglio, V.; Sgarlata, C.; Vecchio, G. Novel Amino-Cyclodextrin Cross-Linked Oligomer as

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Efficient Carrier for Anionic Drugs: a Spectroscopic and Nanocalorimetric Investigation. RSC

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Characterization of Inclusion Complexes of Naringenin with β-Cyclodextrin or its Derivative.

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Investigation of Inclusion Complex of Epothilone A with Cyclodextrins. Carbohydrate Polymers

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Supramolecular Nanovalves for pH-Triggered Release of p-Coumaric Acid. Chem. Commun.

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Capillary Electrophoretic and Nuclear Magnetic Resonance Studies on the Opposite Affinity

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Pattern of Propranolol Enantiomers towards Various Cyclodextrins. J. Sep. Sci. 2010, 33,

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Complexes of Acridine with β- and (2,6-di-O-methyl)-β-Cyclodextrin by Use of Solubility

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Cyclodextrin. An Aqueous 1H NMR Study. J. Chem. Soc. Perkin Trans. 2 2002, 999–1004.

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639

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640

2016, 147, 344-353.

641 642

Scheme and figures:

643 644 645

Scheme 1. Molecular structures of (a) sulfacetamide sodium salt and (b) cyclodextrin molecule with interior and exterior protons (n = 6, 7 for α-CD and β-CD respectively). 22 ACS Paragon Plus Environment

0.50

0.40

0.40

0.30

0.30

ΔA * R

0.50

0.20

0.20

0.10

0.10

0.00 0.00

0.25

0.50 R

0.75

0.00 0.00

1.00

0.75

1.00

72

Surface tension (mN m-1)

Surface tension (mN m-1)

70

70

68

68

66

66

64

64

62

62

60

60 0

1

2

3

4

5

6

0

7

1

2

α-CD (mM) (c)

647

3

4

5

6

7

5

6

7

β-CD (mM) (d) 1.0

Conductivity (mS m-1)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0

649 650 651 652 653

0.50 R

(b)

72

648

0.25

(a)

646

Conductivity (mS m-1)

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


ΔA * R

Page 23 of 31

1

2

3

4

5

6

7

0.9 0.8 0.7 0.6 0.5 0.4 0

1

α-CD (mM) (e)

2

3

4

β-CD (mM) (f)

Figure 1. Job plots of (a) SS-α-CD system and (b) SS-β-CD system at λmax = 256 nm at 298.15 K. R = [SS]/([SS] + [CD]), ΔA = absorbance difference of SS without and with CD. Variation of surface tension of aqueous SS with increasing concentration of (c) α-CD and (d) β-CD solution respectively at 298.15 K. Variation of conductivity of aqueous SS with increasing concentration of (e) α-CD and (f) β-CD solution respectively at 298.15 K. 23 ACS Paragon Plus Environment


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Page 24 of 31

654 655 656 657 658 659 660 661

(a)

(b)

Figure 2. ITC isotherms for the interaction of (a) SS with α-cyclodextrin and (b) SS with βcyclodextrin at 298 K. For each titration, cyclodextrin concentration in sample cell was 50 μM and SS concentration in syringe was 500 μM. The upper panels represent the raw heats of association obtained upon titration of SS to α and β-cyclodextrin. The lower panels are the association isotherm fitted to the raw data using one site model.


Page 25 of 31

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


662 663

(a)



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

Page 26 of 31

664 665

(b)

666 667 668

Figure 3. (a) 2D ROESY spectra of solid inclusion complex of SS and α-CD in D2O (correlation signals are marked by red circles). (b) 2D ROESY spectra of solid inclusion complex of SS and β-CD in D2O (correlation signals are marked by red circles).


Page 27 of 31

1209.35

100000

1231.33

Counts

80000

237.03

60000

973.32 995.31

259.01

40000 20000 0

0

400

800

1200

1600

m/z (a)

669 100000

1371.40

80000

Counts

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


1393.38

1135.38 237.03

60000

1157.36 259.01

40000 20000 0

0

670 671 672 673

400

800

1200

1600

m/z (b)

Figure 4. ESI mass spectra of (a) SS-α-CD inclusion complex and (b) SS-β-CD inclusion complex.

674



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

Page 28 of 31

1874.65

(a)

4000

690.32

1086.51 1322.43 1626.42 1598.20 1132.63

3433.76

675

836.89

1375.35

3100

2200

1300

400

2076.19 952.36

(b) 3412.10

676

4000

1406.76 1636.80 1154.39

2930.79 3100

2200

1030.39

1300

2066.61

400

1157.57

(c) 938.53

3349.84

1637.44

2921.52 677

4000

3100

1033.51

1412.36

2200

1300

400

1080.79

(d)

1417.51

2933.57

846.98

951.71

685.55

1594.92

3406.25

1330.58

1633.94

1152.07

1031.75

678

4000

3100

2200

1300

400

948.07

(e) 3417.91

1080.79

1416.52

2932.95

1593.38

1634.83

1329.43

844.09

1031.10

684.45

1154.61

4000

679 680

3100

2200 cm-1

1300

Figure 5. FTIR spectra of (a) SS, (b) α-CD, (c) β-CD, (d) SS-α-CD IC, (e) SS-β-CD IC. 28 ACS Paragon Plus Environment

400

Page 29 of 31

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


681

Tables:

682 683

Table 1. Values of surface tension (γ) and conductivity (κ) at the break point with corresponding concentrations of SS and CD at 298.15 K a Conc of SS

Conc of CD

γa

/mM

/mM

/mN·m-1

α-CD

4.94

5.06

70.6

β-CD

4.85

5.15

70.9

Conc of SS

Conc of CD

κa

/mM

/mM

/mS·m-1

α-CD

4.74

5.26

0.495

β-CD

4.79

5.21

0.494

684

685 686

Standard uncertainties (u): temperature: u(T) = ±0.01 K, surface tension: u(γ) = ±0.1 mN∙m−1, conductivity: u(κ) = ±0.001 mS·m-1. a

687 688 689 690 691 692 693 694 695 696 697 698 699 700 29 ACS Paragon Plus Environment


705 706 707

1.94

293.15

1.65

1.71

298.15

1.44

1.49

303.15

1.26

308.15

1.12

1.14

313.15

0.98

1.01

a Standard b Mean

-4.95

-19.50

1.30

NC /Sites

1.88

0.98±0.0113

288.15

0.99±0.0111

0.97

ΔSoC /J mol-1K-1

0.94

-2.99

313.15

-3.19

1.09

ΔHoC /kJ mol-1

1.06

-19.98±1.47

308.15

1.23

-20.38±1.12

1.20

KaC × 10-3 /M-1

303.15

1.424±0.131

1.40

1.515±0.142

1.37

ΔSoφ /J mol-1K-1b

298.15

-3.84

1.60

-5.52

1.56

ΔHoφ /kJ mol-1b

293.15

-19.11

1.83

-19.74

Kaφ×10-3 /M-1b

ΔSo /J mol-1K-1b

1.77

-3.95

Ka×10-3 /M-1b

288.15

-19.07

Temp /Ka

ΔHo /kJ mol-1b

Table 2. Association constants obtained by Benesi–Hildebrand method (Ka), association constants obtained by non-linear programme (Kaφ), association constant obtained by isothermal titration calorimetric study (KaC), corresponding thermodynamic parameters and stoichiometry (NC) of SS-CD inclusion complexes

α-cyclodextrin

701 702 703 704

β-cyclodextrin

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

Page 30 of 31

uncertainties in temperature u are: u(T) = ±0.01 K. φ

φ

errors in Ka = ±0.02×10-3 M-1; ΔHo = ±0.01 kJ mol-1; ΔSo = ±0.01 J mol-1K-1; Ka = ±0.01×10-3 M-1; ΔHo =

±0.01 kJ mol-1; ΔSoφ = ±0.01 J mol-1K-1.

708 709 710 711 712 713 30 ACS Paragon Plus Environment

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714


Table of Contents

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Mechanistic Investigation of Inclusion Complexes of a Sulfa Drug with

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