1

Jute cellulose nano-fibrils/hydroxypropylmethylcellulose nanocomposite: A 1

novel material with potential for application in packaging and transdermal drug 2

delivery system 3

4

5

Jonathan Tersur Orasugha,b

, Nayan Ranjan Sahaa, Dipak Rana

c, Gunjan Sarkar

a, Md. Masud 6

Rahaman Mollicka, Atiskumar Chattoapadhyay

d, Bhairab Chandra Mitra

e, Dibyendu Mondal*a

, 7

Swapan Kumar Ghosh*b, Dipankar Chattopadhyay*a

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9

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a Department of Polymer Science and Technology, University of Calcutta, 92 A.P.C. Road, Kolkata 11

-700 009, West Bengal, India. 12

b Department of Jute and Fiber Technology, Institute of Jute Technology, University of Calcutta, 35 13

Ballygunge Circular Road, Kolkata -700 019, West Bengal, India. 14

c Department of Chemical and Biological Engineering, Industrial Membrane Research Institute, 15

University of Ottawa, 161 Louis Pasteur St., Ottawa, ON, K1N 6N5, Canada. 16

d Secretary, Faculty Council For PG & UG Studies In Science, Jadavpur University, 188 Raja S. C. 17

Mallick Road, Kolkata, West Bengal 700032; India. 18

e Dr. M. N Dastur School of Material Science and Engineering, Indian Institute of Engineering 19

Science and Technology, Shibpur, Howrah -711103, West Bengal, India. 20

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* Corresponding author at: Tel: +91-9433379034; 23

E-mail address: dipankar.chattopadhyay@gmail.com 24

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ABSTRACT 26

Nowadays, bio-derived cellulose nano-fibrils based nanocomposites is gaining utmost interest in 27

the area of barrier films for food packaging, as reinforcing filler to make biodegradable 28

nanocomposites with different biopolymers for various applications such as transdermal drug 29

delivery, edible packaging and tissue scaffolding. Ultrasound-assisted preparation of 30

hydroxypropylmethylcellulose based nanocomposites with cellulose nano-fibrils were carried out 31

following solution mixing technique. The crystalline nature of cellulose nano-fibrils has been 32

scrutinized by X-ray diffraction study. The field emission-scanning electron micrographs of 33

cellulose nano-fibrils revealed a network of nano-fibrillar morphology. The Fourier transform 34

infrared spectroscopy results of cellulose nano-fibrils confirmed the removal of lignin and 35

hemicellulose from raw jute (Corchorus olitorius L.) fibres. The storage modulus and tensile 36

properties of hydroxypropylmethylcellulose films increased up to the addition of 1.00 wt% 37

cellulose nano-fibrils. The moisture affinity of hydrophilic hydroxypropylmethylcellulose has also 38

been reduced at 1.00 wt% cellulose nano-fibrils loading. The impact of cellulose nano-fibrils 39

loading on the cumulative percentage of drug release from prepared nanocomposites films has been 40

explored accordingly. By utilizing these versatilities of cellulose nano-fibrils, the fabricated 41

nanocomposites are expected to be highly promising in the area of packaging and transdermal drug 42

delivery system. 43

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Keywords: Jute fibres, Cellulose nano-fibrils, Hydroxypropylmethylcellulose, Nanocomposite, 47

Transdermal drug delivery 48

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3

1. Introduction 50

Cellulose nano-fibrils (CNF) with at least one of its dimensions ranging between 5-100 nm, 51

obtained from lignocellulose biomass/fibres or cellulosic biomass/fibres is of great interest in the 52

field of nanotechnology today. Some sources of CNF utilized by researchers include bacterial 53

cellulose (George et al., 2014), pineapple leaf fibres (Ananas comosus Merr.) (Cherian et al., 2010), 54

wheat straw (Triticum aestivum L.), and soy hulls (Glycine max L. Merrill.) (Silvério et al., 2014; 55

Wang and Sain 2007; Kaushik and Singh 2011), wood (Bilbao-Sáinz et al., 2011; Wang et al., 56

2014), and tunicin/tunicate (Microcosmus sulcatus (species)) (Azizi Samir et al., 2004; Favier, 57

Chanzy and Cavaille, 1995). 58

Cellulose nano-fibrils has been extracted by different approaches which range from 59

cryocrushing (Bhatnagar and Sain, 2005), high pressure homogenization (Qua et.al., 2011), acid 60

hydrolysis (Kumar et al., 2014), steam explosion (Michell, 1989), enzymic hydrolysis (Pääkkö et 61

al., 2007), grinding (Iwamoto et al., 2007), and a combination of two or more approaches including 62

cryocrushing and high pressure homogenization (Wang and Sain 2007), homogenization and 63

grinding (Iwamoto et al., 2007), refining and high pressure homogenization (Nakagaito et al., 64

2004). 65

The attention drawn to CNFs is as a result of its attractive properties which include high 66

modulus, high tensile strength, and low coefficient of thermal expansion (De Moura et al., 2011). 67

CNF has shown promising potential in several applications, such as, in oil recovery (Chen et al., 68

2011; Jin et al., 2011), pharmaceuticals (Lin and Dufresne, 2014), bio-scaffolds (Lin and Dufresne, 69

2014), foldable paper antenna (Chen et al., 2011), dye carriers (Sun et al., 2014), aerogel 70

membranes for cargo carriers (Jin et al., 2011), filtration media (Asper et al., 2015; Huang et al., 71

4

2016), dental tissue regeneration, barrier films, high strength paper boards, emulsion, dispersion, 72

biomedical (Lin and Dufresne, 2014), bioimaging (Dong and Roman, 2007), nanocomposites for 73

gas barrier films (Nair et al., 2014), novel tablet excipient (Kolakovic et al., 2011), optically 74

transparent functional materials (Koga et al., 2013; Nogi et al., 2009, 2013), and ultra flexible 75

nonvolatile memory (Nagashima et al., 2014). 76

There are three classes of nanocellulose (Lin and Dufresne, 2014) namely cellulose 77

nanocrystals (CNC) (Kumar et al., 2014; Brinchi et al., 2013) or nanocrystalline cellulose (NCC) 78

(Kumar et al., 2014) or cellulose nanowhiskers (CNWs) or cellulose nano-particles (Bilbao-Sáinz et 79

al., 2011) and cellulose nano-fibrils (CNFs) also referred to as nanofibrillated cellulose (NFC) 80

(Bhatnagar and Sain 2005; Iwamoto et al., 2007) and bacterial nanocellulose (Juntaro et al., 2012; 81

Lin and Dufresne 2014). The first category is extracted by chemical method, mainly acid hydrolysis 82

(Bilbao-Sáinz et al., 2011; Kumar et al., 2014), while the second class is extracted by mechanically 83

disintegrating cellulose pulp in water (Bhatnagar and Sain, 2005; Iwamoto et al., 2007), and can be 84

isolated from different sources as stated earlier. The extraction of nanocellulose using H2SO4 has 85

been reported in some literature (Bilbao-Sáinz et al., 2011; Kumar et al., 2014; Youssef et al., 86

2015). The concentration of the acid used as reported in some literature is 63-64% (Bilbao-Sáinz et 87

al., 2011; Kumar et al., 2014; Youssef et al., 2015). It is believed that the concentration of the acid 88

used by previous researchers can be reduced and the process will be more environmentally friendly. 89

Jute is one of the most important fibres which are neglected by humans. Jute fibres possess 90

unique properties which, if utilized effectively will not only solve problems in textiles including 91

technical textiles, medical textiles, agrotextiles, but also in the fields of cosmetics, bioengineering, 92

nano-composites, automobiles, aerospace, etc. The preparation of hydroxypropylmethylcellulose 93

(HPMC) reinforced CNF from jute, which is a potential nanocomposite for advanced applications, 94

5

has not been reported earlier by anyone. Some researchers tried to synthesizing CNF from jute 95

fibres, ended up with a mixture of micro and nano-cellulose (Rahman et al., 2014; Vijay et al., 96

2011). 97

Hydroxypropylmethylcellulose is a biodegradable and biocompatible polymer. The use of 98

HPMC for advanced applications, such as in packaging, requires modifications such as 99

reinforcement with nanomaterials such as CNF, which leads to improved mechanical and moisture 100

barrier properties (Bilbao-Sáinz et al., 2010; 2011; De Moura et al., 2011; George et al., 2014). It is 101

reported that the addition of nanocellulose (NC) to HPMC led to an increase of 22% in tensile 102

strength and 55% in Young’s modulus and the NC only decreased 3–6% in transparency (Bilbao-103

Sáinz et al., 2011). 104

Ketorolac tromethamine (KT) is an anti-inflammatory and analgesic agent (Rokhade et al., 105

2006). It is a potent non-narcotic and non-opioid analgesic with cyclooxygenase inhibitory activity 106

(Estapé et al., 1990; Mroszczak et al., 1987). It is non-addictive in nature, and no respiratory side 107

effects (Saha et al., 2016), and other side effects such as nausea and vomiting are the prevalent side-108

effects in pentazocine treated patients (Estapé et al., 1990). KT has been reported to be 800 times 109

more effective than aspirin (Saha et al., 2016).This non-steroidal analgesic, which is well absorbed 110

after oral administration, has an excellent tolerance profile (Estapé et al., 1990). The administration 111

of KT is done by oral, intramuscular or intravenous routes aimed at treatment of moderate to severe 112

pain for short periods of time (biological half-life 4≥6 h). The transdermal delivery of KT would 113

help to control the therapeutic dose and also reduce the side effects in the gastrointestinal tract 114

(Saha et al., 2016). The investigation of drug loading and release of nanocomposites based on 115

biopolymer bacteria cellulose has been studied (Müller et al., 2013). The use of a 3D-network of 116

nanocellulose as a controlled drug release carrier has been reported (Huang et al., 2013). HPMC-117

6

montmorillonite based as well as other polymer nanocomposite materials have widely been studied 118

due to its superior properties (Mondal et al., 2013b). 119

Nanocomposites made from cellulose regenerated polymers reinforced with naturally 120

derived fillers such as CNF is the focal point of attraction in recent years due to its good mechanical 121

properties, low density, biodegradability, and renewability (De Moura et al., 2011). Synthetic 122

polymers derived from crude oil create the problem of accumulation of non-biodegradable waste 123

(Bilbao-Sáinz et al., 2010). The use of cellulose derived polymers for the preparation of films for 124

packaging and other advanced materials are the alternatives. The effects of incorporating different 125

filler levels (2, 4, 6, 8, and 10%) of cellulose nanocrystals from soy hulls upon the mechanical, 126

thermal, and barrier properties of methylcellulose (MC) nanocomposites have been previously 127

studied (Silvério et al., 2014). The cellulose nanocrystals from soy hulls provided a reduction in 128

water vapor permeability of up to 36.32% of the nanocomposites for 8 wt% incorporated cellulose 129

nanocrystals in the MC. A new way of processing cellulose whisker filled electrolytes with higher 130

mechanical stiffness than the one of highly cross-linked polyether networks has been also reported 131

(Azizi Samir et al., 2004). Amorphous alginate-oxidized nanocellulose with good structural and 132

mechanical strength, induced by oxidized cellulose nanocrystals having semi-interpenetrating 133

polymer network from oxidized microfibrillated cellulose, has been also reported (Lin et al., 2012). 134

At present, there is lack of report on CNF derived from jute as reinforcement filler for 135

HPMC based nanocomposites for food packaging application or for potential application as a 136

carrier for transdermal drug delivery. In this work, a simple and effective process for isolation of 137

CNF from jute lignocellulosic fibres using 48% acid which is much less than earlier reports has 138

been established, and for design/fabrication of CNF reinforced HPMC. The effect of CNF loading 139

7

on the mechanical, moisture barrier, water vapour transmission rate (WVTR), and transdermal drug 140

release properties of HPMC has also been studied. 141

142

2.0 Materials and Methods 143

2.1 Materials 144

Hydroxypropylmethylcellulose (HPMC) (50 cps) was obtained from the Central Drug 145

House (Pvt.) Ltd., New Delhi, India. Cellulose nano-fibrils were extracted from jute fibres. Caustic 146

soda (97% pure), fused calcium chloride, sulphuric acid (98%), and hydrogen peroxide (50%) 147

purchased from Merk Specialities Pvt. Ltd., Mumbai, India. Sodium sulphite was purchased from 148

Qualigens Fine Chemicals, Mumbai, India. Sodium chlorite (80% pure) was purchased from Loba 149

Chemie Laboratory Reagents & Fine Chemicals, Mumbai, India. Ketorolac tromethamine (KT) was 150

a gift sample received from Unichem Labs Ltd., Mumbai, India. 151

152

2.2 Preparation of cellulose nano-fibrils 153

Jute fibres labeled as “JF” were chopped into 2-4 mm lengths and soaked in 17.5-18% 154

NaOH solution and heated at 80-90C for about 2 h under continuous stirring. The fibre suspension 155

was filtered to collect the fibres, then washed with water several times to make neutral and dried in 156

air at 105°C for 3 h. The dried fibres were then treated with 0.70% sodium chlorite at pH 4, at 90°C 157

with stirring at intervals of 5 minutes for 2 h. The fibres were filtered and washed with water to 158

neutral and then antichlored with 2% sodium sulphite for 20 minutes. The fibres were further 159

treated with 50% H2O2 using 3-6% on the weight of fibres. The treatment was carried out for 2 h at 160

8

pH 10-11 and then the treated fibres were washed with water to neutral. After this, the fibres were 161

treated with 17.50% sodium hydroxide to remove hemicelluloses from the fibres at room 162

temperature for 1 h and then, washed repeatedly to make neutral and then dried to a constant weight 163

at 100C. The purified jute cellulose fibres were labeled as “PJF”. 164

The dried mass of PJF was then treated with 47-48% (v/v) solution of sulphuric acid 165

(H2SO4) and digested at room temperature (23-26oC) for 3 hrs under constant stirring. Thereafter, 166

the suspension was neutralized; washed with water by centrifugation, freeze-dried and labeled as 167

“CNF”. The flow chart of the entire extraction process of CNF is shown in Fig 1. 168

169

2.3 Preparation of nanocomposite films 170

2.3.1 Preparation of HPMC/CNF nanocomposite films 171

Nanocomposite films were prepared using 0.50, 0.75, 1.00, and 3.00 wt% of CNF with 172

respect to the weight of HPMC in 50 ml of distilled water and the dispersions were sonicated for 1 173

hr to obtain a uniform dispersion void of agglomerates. Then, HPMC was dissolved in 50 ml 174

distilled water and also in CNF dispersion for preparation of pure HPMC and HPMC/CNF 175

nanocomposite films. The clear solutions, void of bubbles, was cast into a glass petri dish and dried 176

in a vacuum oven for 12 h at 50°C. The dried films were removed from the petri dish and 177

characterized accordingly. The nanocomposite samples were designated as shown in Tab 1. 178

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2.3.2 Preparation of drug loaded HPMC/CNF nanocomposite films 182

In order to prepare drug loaded HPMC/CNF nanocomposite films, 0.50, 0.75, 1.00, and 3.00 183

wt% of CNF with respect to the weight of HPMC was dispersed in 50 ml of distilled water and the 184

dispersions were sonicated for 1 hr to obtain a uniform dispersion void of agglomerates. 100 mg of 185

Ketorolac tromethamine (KT) was added to all the dispersions and allowed to dissolve under 186

constant stirring for 1 hr. Then, HPMC was dissolved into all the dispersions at room temperature 187

and stirred continuously until clear dispersions were obtained. The clear dispersions void of bubbles 188

was cast into a glass petri dish and dried in the vacuum oven at 50°C for 12 h. The dried films were 189

removed from the petri dish and characterized accordingly. The five KT loaded nanocomposite 190

samples were designated as shown in Table 1. 191

192

2.4 Characterization 193

2.4.1 Fourier transform infrared (FTIR) spectroscopy 194

Fourier transform infrared spectroscopy (FT-IR) of the extracted CNF was carried out by 195

direct transmittance using KBr pellets with a Perkin Elmer spectrum two at 32 scans and with a 196

resolution of 4 cm-1 with wave number range of 400–4000 cm-1. 197

198

2.4.2. X-ray diffraction (XRD) of CNF and its nanocomposites 199

X-ray diffraction (XRD) analysis of the cellulose nano-fibrils (CNFs) and HPMC/CNF 200

nanocomposite samples were carried out by X-PERT-PRO Panalytical diffractometer using Cu Kα 201

(λ = 1.5406 Å) as the X-ray source at a generator voltage of 40 kV and current of 30 mA. The 202

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scanning rate was 2°/min. The crystallinity index of the CNFs was calculated from the equation 203

below (Daniel et al., 2015; Segal et al., 1959; Kaushik and Singh, 2011). 204

Crystallinity index = [(I020 – I18.61o)/I020] x 100 (1) 205

Where, I020 is the maximum intensity of the crystalline region (020) of CNF crystallographic 206

planes at 2θ ~ 22.73° and I18.61o is the intensity of the amorphous region of CNF at 2θ ~ 18.61° 207

(Haafiz et al., 2014). 208

209

2.4.3. Field emission-scanning electron microscopy (FE-SEM) of CNF and nanocomposites 210

About 1000 ppm of the freeze-dried CNF was dispersed in triple distilled water and 211

sonicated for 30 minutes. A drop of the dispersion was cast on a silicon slide and dried for 24 hrs. 212

The surface morphology of CNF was examined using a JEOL 6400F FE-SEM microscope. Samples 213

were sputter coated with gold to avoid build-up of electrostatic charge before it was mounted on the 214

sample holder of the FE-SEM. The accelerating voltage was set at 2 and 5 kV. The CNF 215

dimensions were determined directly from the FE-SEM analysis. The cross-sectional morphology 216

of all the prepared nanocomposites was checked using a JEOL 6400F FE-SEM microscope 217

operated with an accelerating voltage of 3 kV, at a working distance of 6-8 mm. 218

219

2.4.4 Dynamic light scattering (DLS) 220

The hydrodynamic particle size of CNF was determined using a Zetasizer Nano ZS, 221

dynamic light scattering (DLS) instrument (Malvern Instruments, Malvern UK). The concentration 222

of CNF in water (as the solvent) was 1000 ppm and the process was repeated three times. 223

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2.4.5 Mechanical properties 224

Mechanical properties of pure HPMC and its nanocomposite films were carried out using a 225

Zwick Roell (ZO10) tensile testing instrument following a previous approach (Saha et al., 2016). 226

The film samples were cut into a strip 42 mm in length and 5 mm in width and tested within an area 227

of 22 mm length by 5 mm width. The average film thickness of HN0, HN0.5, HN0.75, HN1, and 228

HN3 was measured and found to be 0.13, 0.09, 0.08, 0.09, and 0.10 mm respectively. The samples 229

were tested with a cross-head speed of 5 mm/min. Measurements were performed five times and the 230

mean value was chosen. 231

232

2.4.6 Dynamic mechanical analysis (DMA) 233

Dynamic mechanical analysis is an analytical technique employed in order to characterize 234

the dynamic mechanical behavior of viscoelastic materials (Cespi et al., 2011; Nasseri and 235

Mohammadi, 2014). The dynamic mechanical properties of the nanocomposite samples were 236

analyzed using a PerkinElmer DMA8000 by following a slightly modified approach from previous 237

literature (Cespi et al., 2011). The film sample specifications were 13 mm length and 5 mm width. 238

The tests were carried out by a temperature sweep from 40 to 200°C at a scanning rate of 5°C/min. 239

A constant frequency of 1 Hz and a preload force of 0.01 N were applied on all samples. 240

Measurements were performed in triplicate and the mean value was chosen. 241

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2.4.7 Moisture absorption (MA) 245

Moisture absorption of the HPMC and its nanocomposite films were determined at a 246

constant humidity in the chamber. A 75% constant relative humidity environment was generated in 247

a hermetic glass container with an aqueous saturated CaCl2 solution. The film samples were cut into 248

dimensions of 3 cm × 3 cm. Then the samples were dried in a vacuum oven at 60°C until constant 249

weight (Wi) was achieved. The samples were kept in the constant humidity chamber. After 24 h, the 250

film samples were weighed immediately to obtain final weight (Wf). Moisture absorption of 251

samples was calculated by the following equation. Measurements were performed in triplicate and 252

the mean value was chosen (Mondal et al., 2013b; Saha et al., 2016). 253

Moisture absorption % = [(Wf –Wi)/Wi] x 100 (2) 254

255

2.4.8 Water vapor transmission rate (WVTR) 256

Water vapor transmission/permeability rates of the CNF nanocomposite films were 257

measured according to previously reported approach (Mondal et al., 2013b). The water vapor 258

transmission rate was determined repeatedly from the weight gained by the cell after 24 h until 259

constant weight gain was reached. Water vapor transmission rate has been calculated by using the 260

following equation (Mondal et al., 2013a). 261

Q = WL/S (3) 262

Where, W is the increase in the desiccant weight per 24 h, L is the film thickness (cm), S is 263

the exposed surface area (cm2) and Q is the water vapor transmission rate (g/cm/24 h). The 264

thickness of the film was measured adopting the previous method (Sarkar et al., 2014). 265

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266

2.4.9. UV–vis spectroscopy 267

The optical clarity of all the rectangular nanocomposite samples was examined using a 268

Perkin-Elmer Lambda25 UV/Vis spectrophotometer within the wavelength range of 200 to 800 nm. 269

The auto-zero of the instrument was set in respect to an empty compartment (Saha et al., 2016). 270

Absorbance values of all the samples were converted into the transmittance values by employing 271

Lambert-Beer equation. The transmittance values were then plotted against the wavelength (Saha et 272

al., 2016). 273

274

2.4.10. Flatness and folding endurance of the transdermal patches 275

In order to measure the flatness of the samples, three samples each of HN0K, HN0.5K, 276

HN0.75K, HN1K, and HN3K were cut to 10 × 30 mm2 randomly from the transdermal films. The 277

length of each sample was then measured with the view that the variation in length being directly 278

proportional to the non-uniformity in the sample flatness is considered. The final length of each 279

sample was evaluated by calculating the percent constriction, with respect to 0% constriction 280

equivalent to 100% flatness. 281

Again, three samples, each of HN0K, HN0.5K, HN0.75K, HN1K, and HN3K were 282

repeatedly folded at the same point until the sample broke. This was carried out for the three 283

specimens of each sample and the average value was taken. The folding cycles endured by each 284

tested sample specimen without breakage was considered to be the folding endurance value of that 285

sample. 286

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287

2.4.11 In vitro drug release study 288

The in vitro release studies of HN0K, HN0.5K, HN0.75K, HN1K, and HN3K was 289

performed using a Franz diffusion cell by emulating a previous method (Sarkar et al., 2014). A 290

dialysis membrane (cellulose acetate) (LA390, width 25.27 mm, diameter 15.90 mm and capacity 291

∼1.99 ml/cm) was used to replicate the human skin to study the drug release from the drug-loaded 292

bionanocomposite films. 293

The release of KT from the prepared nanocomposite films is calculated using the power law 294

(Saha et al., 2016; Siepmann and Peppas, 2012). 295

Mt/M∞ = Ktn (4) 296

Where, Mt /M∞ is the absolute cumulative amount of drug released at time t and infinite time, 297

respectively; k is a constant incorporating structural and geometric characteristics of the device, and 298

n is the release or diffusion exponent, indicative of the mechanism of drug release. 299

300

3. Results and Discussion 301

3.1. Fourier transform infrared (FTIR) spectroscopy 302

The FTIR spectrum of JF, PJF, and CNF are depicted in Fig. 2a. From the results, it is 303

observed that the peaks at 1513 and 1633 cm-1 present in JF spectra correspond to C=C and the 304

C=O stretching vibrations of the aromatic ring of lignin in JF (He et al., 2013), disappeared in PJF 305

and CNF spectra. Again, this confirmed the complete removal of aromatic lignin. The peaks at 1705 306

15

and 1734 cm-1 in the case of JF are ascribed to the presence of the acetyl ester groups from 307

hemicellulose and also the ester linkage of carboxylic and the -OH groups present in lignin (Daniel 308

et al., 2015), whereas the former peaks disappeared in the case of the PJF and CNF. This confirms 309

the complete removal of lignin and hemicellulose from PJF and CNF. The peak at 2999 cm-1 in JF 310

corresponds to C-H stretching vibrations for the acetyl and ester linkages in lignin, hemicellulose 311

and pectin (Kumar et al., 2014). The absence of this peak in PJF and CNF also proves that lignin 312

and hemicellulose have been removed. The peak at 3458 cm-1 corresponds to O-H stretching 313

vibrations in hemicellulose (Chirayil et al., 2014). The peak at 1111 cm-1 in JF is due to the C-O-C 314

glycoside ether bond in cellulose/hemicellulose (Daniel et al., 2015), which can be seen to have a 315

reduced and is broader due to the reduction in the number of C-O-C glycoside as a result of 316

hemicelluloses removal from the PJF and CNF. The broad peaks at 3700-3100 cm-1 are due to C-H 317

and O-H groups present in cellulose (Kalita et al., 2015), and was observed to decrease and are 318

broader in PJF and CNF due to the presence of more inter hydrogen bonding between the cellulose 319

molecules. The peak at 2919 cm-1 may be due to the C-H stretching vibrations of polysaccharides 320

like cellulose, though this can be seen to be more pronounced in the spectra of PJF and CNF as a 321

result of more organized cellulose structure due to chemical treatment (Kalita et al., 2015; Tang et 322

al., 2015). The peak at 1161 cm-1 represents C-C ring stretching and 1432 cm-1 corresponds to an 323

asymmetric and symmetric -CH2 scissoring motion in cellulose II (Kumar et al., 2014), which is 324

absent in PJF and CNF. So, it is apparent that the structure of cellulose I is changed to cellulose II 325

in the reaction medium. 326

327

328

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3.2. X-ray diffraction (XRD) 329

Fig. 2b shows the diffraction patterns of JF, PJF, CNF, with each having diffraction peaks at 330

2θ; JF ~15.80° and ~22.27°, corresponding to the Miller indices of (1ī0), (020), for cellulose Iβ 331

convention (French, 2014). PJF ~15.80°, ~20.30°, ~22.29°, and ~34.20° corresponding to the Miller 332

indices of (1ī0), (102), (020), and (004) and CNF ~14.58°,~16.40°, 20.10o ~22.73°, and ~34.15°, 333

corresponding to the Miller indices of (1ī0), (110), (102), (020), and (004) for cellulose II (French, 334

2014; Xu et. al., 2013). The highest intensity peak at 22.27° (JF), 22.29° (PJF), and 22.70° (CNF) is 335

indicative of the crystalline structure of cellulose I (Cherian et al., 2010; Nelson et al., 1964; 336

Oudiani et al., 2011; Park et al., 2010; Xiao et al., 2016). This shows that cellulose I and cellulose II 337

are both present as a mixture in CNF as a result of caustic soda treatment and sulphuric acid 338

hydrolysis processes. Transformation of cellulose I to cellulose II occurs when natural cellulose 339

fibres are treated with alkali (mercerization) or acids (French, 2014; Oudiani et al., 2011; Xu et. al., 340

2013). The crystallinity of JF, PJF, and CNF has been found to be ~66.8%, ~81%, and ~89%. The 341

crystallinity of CNF is higher than previously reported cellulose nanocrystals from wastepaper 342

(~75.9%) (Daniel et al., 2015) and pineapple leaf fibers (~73.6%) (Cherian et al., 2010). 343

From Fig. 3, it can also be seen that the diffraction of HN0 film produced a low-intensity 344

peak at 19.86° which corresponds to the crystal plane (002) of pure HPMC. This low-intensity peak 345

at 19.86° may be due to the amorphous nature of the matrix. Hino et al. (2001) reported a similar 346

diffraction peak of HPMC, although the authors gave no reasons for the said peak. It is also 347

observed that the diffraction of the nanocomposites produced peaks at 10.12° and 19.86° 348

corresponds to the crystal plane (101) and (002), respectively. No peaks of CNF are observed in 349

case of nanocomposites, which may be due to the near perfect interactions of CNF and the matrix 350

17

(HPMC) and also may be due to the presence of a very low wt% of CNF which phenomena is 351

further supported by FESEM results. The isolated CNF from 48% H2SO4 has shown a better CI 352

value than earlier reports. 353

354

3.3. Field emission scanning electron microscopy (FESEM) of CNF 355

Fig. 2c depicts the FESEM images of CNF at low c (i) and high magnification c (ii), 356

respectively. The FESEM results showed that JF was successfully defibrillated via chemical 357

process from dimensions of 2-4 mm in length to 153-160 nm. The morphology of the CNF is a 358

network of needle-shaped fibres crossing each other in nano-dimensions. This kind of fibre like 359

morphology was also observed by other scientists (Abraham et al., 2011; Juntaro et al., 2012). The 360

fibres are almost uniform in dimension (diameter ~11.88–25 nm and length ~153–160 nm). The 361

crystal length and diameter was determined directly from the FESEM instrument by digital image 362

analysis considering about 40 crystals. The aspect ratio of CNF was found to be ~13 ± 6.40. 363

364

3.4. Dynamic light scattering (DLS) 365

The DLS result of extracted CNF is shown in Fig. 4. From the result, it is very clear that the 366

average hydrodynamic size (d. nm) of CNF is ~340 nm, while the length and diameter of CNF 367

measured using FESEM is 153-160 nm and 11.88-25 nm. The difference in size between the 368

FESEM and the DLS results is due to the fact that, DLS measures the hydrodynamic size/diameter 369

(hydrated state) of the nanomaterial (Mollick et al., 2014), which means the size of CNF, along with 370

the surrounding water/solvent used, leads to a larger hydrodynamic volume.In contrast, the FESEM 371

measures the actual dry state size of the CNF. Frone et al., (2011), synthesized cellulose nanofibres 372

18

from microcrystalline cellulose and reported that the diameter is less than 20 nm while the average 373

hydrodynamic size for the same is 989.20 nm and stated that, the larger hydrodynamic size is due to 374

quick aggregation of cellulose nanofibres in water. The size of CNC having a length of 100–400 nm 375

and a width of 15–80 nm from TEM measurement with an average particle size of 1752 nm as 376

measured by DLS has been also reported (Tang et al., 2015), and these researchers stated that the 377

higher value for the size of CNC is as a result of aggregation of CNC in water. 378

In this case, the DLS result is seen to be different from the FESEM results due to the ability 379

of CNFs to link one another through H-bonding in water, resulting to increase in the size of the 380

nanofibres. 381

382

3.5. Field emission scanning electron microscopy (FESEM) of nanocomposites 383

Fig 5 (a, b, c, d, and e), shows the cross-sectional morphology of HN0, HN0.5, HN0.75, 384

HN1, and HN3 respectively. From the results, it is apparent that uniform/isotropic distribution of 385

CNFs in the HPMC matrix occurs in HN1. CNFs are agglomerated beyond the 1 wt% concentration 386

which is very clear from Fig. 5e. Therefore, it can be concluded that HN1 is the best composition in 387

terms of dispersion morphology which may also have a positive effect on the mechanical, moisture 388

absorption (MA) and water vapour transmission rate (WVTR). 389

390

3.6. Mechanical properties 391

Fig. 6 shows the mechanical properties of HN0, HN0.5, HN0.75, HN1, and HN3. From Fig. 392

6a, it is clear that the tensile strength of HN0 increased from 41.56 MPa to 64.22 MPa, 72.45 MPa, 393

19

84.16 MPa, and 57.87 MPa with the loading of 0.50, 0.75, 1.00, and 3.00 wt% CNF, respectively. 394

Again from Fig. 6b, it is clear that the modulus of HN0 is enhanced from 10.98 MPa to 16.80 MPa, 395

17.27 MPa, 21.20 MPa, and 14.47 MPa with the addition of 0.50, 0.75, 1.00, and 3.00 wt% CNF, 396

respectively. The increase in tensile strength and modulus up to a 1.00 wt% loading of CNF into the 397

HPMC/CNF nanocomposite is attributed to the reinforcing property of CNF into the polymer 398

matrix and the rigidity increases due to intermolecular hydrogen bonding that may have taken place 399

within the CNF and HPMC matrix. It has been reported (Bilbao-Sáinz et al., 2011) that 400

enhancement in mechanical strength of the nanocomposite was due to the high contact surface area 401

of the smaller whiskers, with the HPMC promoting the formation of hydrogen bonds between the 402

HPMC and cellulose whiskers, which might have led to a higher efficiency of the stress transfer 403

from the matrix to the fibers. Another report (Youssef et al., 2015) showed that the addition of 3, 5, 404

and 10 wt% nanocellulose (NC) of length 246 ± 64 nm and diameter of 8 ± 2 nm improved the 405

young modulus and tensile strength of carboxymethyl cellulose (CMC) films by 60%. That report 406

also stated that the improvement in mechanical properties could be attributed to the network 407

formation between the matrix and NC or the formation of hydrogen bonds between the free 408

hydroxyl groups of NC and CMC. But in the case of HN3, both tensile strength and modulus 409

decreased compared with HN1. This is due to the occurrence of an agglomerate of CNF in the 410

polymer matrix after 1.00 wt% reinforcement which is evident from the Fig. 5a-e. The percentage 411

elongation at the break of HN0, HN0.5, HN0.75, HN1, and HN3 is shown in Fig. 6c. The % 412

elongation at the break of HN0 increases with the incorporation of CNF up to 0.75 wt% and then 413

begins to decrease. The percentage elongation at break of HN0 is 43.61% which increased to 414

59.71% with loading 0.75 wt% of CNF. So, from the tensile strength, modulus and elongation break 415

20

results, it is clear that the addition of CNF is responsible for both the strengthening and toughening 416

of the HPMC matrix up to 0.75 wt% of CNF. 417

418

3.7. Dynamic mechanical analysis (DMA) 419

Dynamic mechanical analysis is used to determine the mechanical properties of polymers in 420

dynamic condition as a function of temperature. The DMA analysis results of HN0, HN0.5, 421

HN0.75, HN1, and HN3 are shown in Fig. 7a and Fig. 7b. Fig. 7a show the tan δ plots of 422

HN0, HN0.5, HN0.75, HN1, and HN3 respectively as a function of temperature. The tan δ peak of 423

HN0 is obtained at 162.4°C which is attributed to the glass transition temperature (Tg) of HPMC. 424

From the result, it is also seen that with an increase in loading wt% of CNF into the HPMC matrix, 425

the tan δ shifted to the higher temperatures. The tan δ peak value of HN0.5, HN0.75, HN1, and 426

HN3 is obtained at 163.70, 164.00, 168.58, and 166.69°C with the addition of 0.50, 0.75, 1.00, and 427

3.00 wt% CNF to the HN0 matrix. Therefore, the Tg of HN0 increased by 1.30, 1.60, 6.18, and 428

4.29°C with the loading of only 0.50, 0.75, 1.00, and 3.00 wt% CNF. This shift of glass transition 429

temperature of HN0, HN0.5, HN0.75, HN1, and HN3 is due to the reinforcing effects of CNF into 430

the polymer matrix and also strong hydrogen bonding interactions with the polymer matrix 431

(Siqueira et al., 2009). Again, from the result, it is apparent that with an increase in the wt% of the 432

CNF, the peak intensity decreases, which indicates that the HPMC/CNF composites become more 433

elastic, and also that less energy is dissipated during mechanical vibrations (Xu et al., 2013). 434

Fig. 7b shows the storage modulus (E') of HN0, HN0.5, HN0.75, HN1, and HN3. From the 435

results, it is observed that E' decreases with increasing temperature representing a reduction of the 436

material stiffness up to a characteristic temperature value (glass transition temperature) where there 437

21

is a large drop of the modulus, indicating the transition from a glassy to a rubbery state. From Fig. 438

7b, it is also clear that the storage modulus of HPMC film (HN0) increased with the addition of 439

CNF. The storage modulus was observed to have increased by 9.30, 6.20, 29.50, and 15.5% with 440

the loading of 0.50, 0.75, 1.00, and 3.00 wt% CNF at 60°C. This phenomenon indicates good 441

interfacial adhesion in the composites (Zaini et al., 2015) and here, CNF acts as a reinforcing 442

material into the nanocomposite films or as a result of efficient interactions between the filler and 443

the matrix through hydrogen bonding (Nasseri and Moohammadi, 2014). 444

445

3.8. Moisture absorption (MA) 446

The effect of nanocellulose on the moisture absorption of the HPMC matrix is shown in Fig. 447

7c. When hydrophilic polymers like HPMC are exposed in the humidity chamber, it absorbs 448

moisture through the interaction of the free –OH groups of polymer molecules with water 449

molecules. Moisture absorption value of HN0 is approximately 11.31% at constant 75% humidity. 450

A very close value of 11.33% for MA of pure HPMC (HNO) has been reported earlier (Mondal et 451

al., 2013b). Mondal et al., 2013b, also reported that the addition of 3.00% MMT to HPMC reduced 452

the MA to 8.75% which is very close to the result obtained in this work for HN3, although the 453

result for HN1 in this work has proven to be better. The addition of CNF reduced the moisture 454

absorption of HN0 from 11.31% to 9.41%, 8.75%, 7.80%, and 8.90% with the loading of 0.50, 455

0.75, 1.00 and 3.00 wt% CNF, respectively. This may be due to the interactions between CNF and 456

the hydrophilic/hydroxyl sites of the HPMC chains, which replace the HPMC–water interactions 457

that predominate in the films without inclusions (Bilbao-Sáinz et al., 2011). Therefore, the 458

interaction between the free hydroxyl groups of HPMC and the water molecules is reduced. From 459

22

the result, it is also observed that after the addition of 1.00 wt% CNF, the moisture absorption 460

began to increase because of agglomeration as well as the increase in the number of free hydroxyl 461

groups of CNF in the nanocomposite (HN3). The reduction in moisture absorption of the 462

nanocomposite is very important in the preparation of edible packaging as also suggested in 463

previously published paper (Bilbao-Sáinz et al., 2010). 464

465

3.9. Water vapour transmission rate (WVTR) 466

The vapour transmission rate of HN0, HN0.5, HN0.75, HN1, and HN3 is shown in Fig. 7d. 467

The average film thicknesses of HN0, HN0.5, HN0.75, HN1, and HN3 were measured and found to 468

be 0.13, 0.09, 0.08, 0.09 and 0.10 mm respectively. The WVTR for HN0, HN0.5, HN0.75, HN1, 469

and HN3 was found to be 0.053, 0.044, 0.041, 0.034, and 0.039 (g/cm/24 h) respectively. From the 470

results, it is apparent that there is a reduction in WVTR of pure HPMC matrix in the 471

nanocomposites by 19.80, 28.75, 53.41, and 34.44% with CNF loading of 0.50, 0.75, 1.00, and 3.00 472

wt% respectively. This may also be due to the presence of impermeable CNF and the interactions 473

between CNF and the hydrophilic sites of the HPMC chains. This replaces the HPMC–water 474

interactions in the nanocomposites (Bilbao-Sáinzet al., 2011) and the increase in tortuosity of the 475

nanocomposite as a result of the hydrogen bridges formed between the matrix and the CNF which 476

slows the diffusion process and lowers the permeability of the composite (Youssef et al., 2015). The 477

% reduction in WVTR of HPMC with the addition of CNF has proven to be more effective than 478

that of MMT as reported in previous literature (Mondal et al., 2013b). It can be noted that the 479

reduction, as evident in Fig. 7d is progressive with the loading of CNF from 0.50% to 1.00% and 480

then an increase with 3.00 wt%. This increase in WVTR of the nanocomposite for 3.00 wt% 481

23

loading of CNF may be due to the presence of free hydroxyl groups from excess CNF and 482

agglomeration in the matrix after 1.00 wt% loading, as can be seen in Fig. 7d. This is evident in Fig. 483

5e and also supports the result from MA for HN3. WVTR of the synthesized nanocomposite does 484

not rely solely on the adsorption and desorption of water molecules but also on the diffusion of 485

water through (inside) the HPMC (Bilbao-Sáinz et al., 2011). 486

The addition of CNF to HPMC led to reduced WVTR as a result of the interaction between 487

the CNF and hydrophilic sites of HPMC and the formation of the tortuous path by the hydrogen 488

bridges formed between CNF and HPMC in the nanocomposite. The reduction in WVTR of the 489

nanocomposite is very important in the preparation of edible packaging as also suggested in 490

previous paper (Bilbao-Sáinz et al., 2010). 491

492

3.10. UV–vis spectroscopy 493

Optical transparency of the films is much important for packaging applications. The 494

comparison of the percentage light transmission against wavelengths of the nanocomposite samples 495

(Fig. 8) was studied in order to ascertain the differences in the optical transparency. The 496

transparency of HN0, HN0.5, HN0.75, HN1, and HN3 at 600 nm was found to be ~89%, ~85%, 497

~84%, ~82%, and ~78% respectively. From the result, it can be stated that the effect of CNF on the 498

percentage transmittance of HPMC within the visible range is very small. This also shows that CNF 499

is very much compatible with HPMC matrix. The percentage transmittance of the polymer matrix 500

(HPMC) and its nanocomposites is lower in the UV region 200-300 nm) which may be due to the 501

good UV resistance property of the prepared nanocomposites (Bilbao-Sáinz et. al., 2011). 502

503

24

3.11. Flatness and folding endurance of the transdermal patches 504

The flatness and folding endurance of the prepared transdermal patches are shown in Fig. 505

9a. The flatness of HN0K, HN0.5K, HN0.75K, HN1K, and HN3K is 490 ± 14.70, 482 ± 14.46, 478 506

± 14.34, 477 ± 14.31, and 449 ± 13.47 while the folding endurance for the same is 98.00 ± 2.94, 507

97.80 ± 2.93, 98.00 ± 2.94, 96.40 ± 2.89, and 96.01 ± 2.88. The folding endurance of the 508

nanocomposite is less than that of the pure HPMC due to increase in stiffness of the 509

nanocomposites with the addition of rigid CNF. 510

511

3.12. In vitro drug release 512

The release of KT from pure HPMC and HPMC/CNF nanocomposites in physiological 513

conditions (PBS pH = 7.4) is recorded so as to understand the release profile of hydrophobic 514

entities in conditions simulating the human body. The in vitro drug release results exhibited 515

prolonged release of nanocomposite films over a period of 8 hrs. From Fig. 9b, it is clear that the 516

release of KT is considerably slower and hence controlled with the addition of different 517

concentrations of CNF in HPMC based nanocomposite formulations. The trace amount of drug 518

release from these nanocomposite films at the initial stage of the in vitro drug release study could 519

probably be due to the surface adhered drug particles. The cumulative percentage of drug release 520

from prepared nanocomposites films after 8 h is 95.12, 62.31, 55.97, 36.97, and 37.15% for HN0K, 521

HN0.5K, HN0.75K, HN1K, and HN3K, respectively. The nanocomposites showed controlled and 522

sustained drug release with HN1 proving to give the best result, though very close to that of HN3K. 523

When n is <0.5, the data indicated that the drug release process of the transdermal patch 524

follows the Fickian diffusion mechanism. When n is >0.5, this also indicated that the drug release 525

25

process of the transdermal patch follows the drug diffusion mechanism based on the anomalous 526

process. The values of n calculated as per the above method are found to be 0.52, 0.59, 0.57, 0.58, 527

and 0.61 for HN0K, HN0.5K, HN0.75K, HN1K, and HN3K, respectively. It is expected that the 528

exponent n of the power law, when applied to the drug release mechanism from slab geometry thin 529

films (polymeric based) controlled delivery systems should fall within the range of 0.5 n 1.0 530

(Siepmann and Peppas, 2012). Therefore, it can be said that the controlled release mechanism of the 531

nanocomposites transport/diffusion could be an anomalous process. 532

The controlled drug release may be as a result of the trapping of the drug particles within 533

the 3D oriented structure of CNF in the composite and the blocking of the drug pathway as the drug 534

tries to leave the composite which can be seen to correlate the FESEM result for Fig. 5. This may 535

also be due to the lesser swelling property of CNF compared with HPMC (Saha et al., 2016). 536

HPMC is reported to have high swellability which makes it release drugs at a faster rate when it 537

comes in contact with water or biological fluid, resulting in the lattice and consequently, relaxation 538

of polymer chains, and then release the incorporated drug into the system (Siepmann and Peppas, 539

2012). It is reported that the best cumulative percentage of controlled drug release from 540

methylcellulose/pectin/montmorillonite nanocomposite films after 4 h was 51.92% (Saha et al., 541

2016), but with the addition of CNF to HPMC, the best cumulative percentage of controlled 542

(reduced) drug release was ~30 ± 2%. This showed that CNF has a fantastic control of drug release 543

rate in CNF based nanocomposite. 544

545

4. Conclusion 546

CNF having a crystallinity index of ~89.50% and a fibrillar network of nanofibres with a 547

diameter of 11-25 nm and length of 153-160 nm has been successfully isolated. The FTIR result of 548

26

CNF confirmed the removal of lignin and hemicellulose. The prepared CNF-polymer 549

nanocomposites have shown improved mechanical properties and reduced MA and WVTR which 550

correlates the FESEM results of the nanocomposites. The in vitro drug release data revealed that the 551

cumulative drug release percentage is decreased with the increase of CNF concentration in the 552

nanocomposites with HN1K as the best formulation. The prepared HPMC/CNF nanocomposites 553

can be used for food packaging and transdermal drug delivery applications. 554

555

Acknowledgements 556

Jonathan Tersur Orasugh appreciates the Centre for Research in Nanoscience and 557

Nanotechnology (CRNN), Department of Polymer Science and Technology, and Department of 558

Jute and Fibre Technology, Institute of Jute Technology, University of Calcutta for giving him the 559

chance to continue his research work. Nayan Ranjan Saha likes to thank the University Grant 560

Commission (UGC), Govt. of India, for his fellowship. Gunjan Sarkar likes to thank the University 561

Grant Commission, Govt. of India, for his fellowship under Rajiv Gandhi National Fellowship 562

(RGNF) scheme. 563

564

27

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757

32

Table caption 758

Table 1 Composition of nanocomposite samples 759

760

33

Figure captions 761

762

Fig. 1. Flowchart showing the extraction of cellulose nano-fibrils (CNFs) from jute fibres (JF). 763

Fig. 2. (a) Fourier transform infrared (FTIR) spectra, (b) X-ray diffraction patterns of jute fibres 764

(JF), pretreated jute fibres (PJF) & cellulose nano-fibrils (CNF) and (c) Field emission-scanning 765

electron microscopy (FE-SEM) micrographs of (i&ii) cellulose nano-fibrils (CNF) at low (X 50 766

000) and high magnification (X 77 000). 767

Fig. 3. X-ray diffraction patterns of HN0, HN0.5, HN0.75, HN1, and HN3 768

Fig. 4. Hydrodynamic size of cellulose nano-fibrils (CNF). 769

Fig. 5. The cross-sectional morphology (same magnification “X 70, 000”) of (a) HN0, (b) HN0.5, 770

(c) HN0.75, (d) HN1 and (e) HN3 films. 771

Fig. 6. (a) Tensile strength, (b) Tensile modulus and (c) Elongation at break of pure 772

hydroxypropylmethylcellulose (HPMC) and nanocomposites. 773

Fig. 7. (a) Tan δ, (b) Storage modulus, (c) moisture absorption (MA) and (d) water vapour 774

transmission rate (WVTR) of pure hydroxypropylmethylcellulose (HPMC) and nanocomposites. 775

Fig. 8. The % transmittance of pure hydroxypropylmethylcellulose (HPMC) and nanocomposites. 776

Fig. 9. (a) Folding endurance and flatness (b) In-vitro drug release study from pure 777

hydroxypropylmethylcellulose (HPMC) and its nanocomposites. 778

779

34

Table 1 Composition of nanocomposite samples 780

Sample HPMC*

(%)

CNF**

(wt%)

KT***

(%)

HN0 100 0.00 -

HN0.5 100 0.50 -

HN0.75 100 0.75 -

HN1 100 1.00 -

HN3 100 3.00 -

HN0K 100 0.00 5

HN0.5K 100 0.50 5

HN0.75K 100 0.75 5

HN1K 100 1.00 5

HN3K 100 3.00 5

781

*HPMC: Hydroxypropylmethylcellulose 782

**CNF: Cellulose nano-fibrils 783

***KT: Ketorolac tromethamine 784

35

785

Fig. 1. Flowchart showing the extraction of cellulose nano-fibrils (CNFs) from jute fibres (JF). 786

787

36

788

789

Fig. 2. (a) Fourier transform infrared (FTIR) spectra, (b) X-ray diffraction patterns of jute fibres 790

(JF), pretreated jute fibres (PJF) & cellulose nano-fibrils (CNF) and (c) Field emission-scanning 791

electron microscopy (FE-SEM) micrographs of (i&ii) cellulose nano-fibrils (CNF) at low (X 50 792

000) and high magnification (X 77 000). 793

794

37

795

796

Fig. 3. X-ray diffraction patterns of HN0, HN0.5, HN0.75, HN1, and HN3 797

798

38

799

800

801

Fig. 4. Hydrodynamic size of cellulose nano-fibrils (CNF). 802

803

804

39

805

806

Fig. 5. The cross-sectional morphology (same magnification “X 70, 000”) of (a) HN0, (b) 807

HN0.5, (c) HN0.75, (d) HN1 and (e) HN3 films. 808

40

809

810

Fig. 6. (a) Tensile strength, (b) Tensile modulus and (c) Elongation at break of pure 811

hydroxypropylmethylcellulose (HPMC) and nanocomposites. 812

813

41

814

815

Fig. 7. (a) Tan δ, (b) Storage modulus, (c) moisture absorption (MA) and (d) water vapour 816

transmission rate (WVTR) of pure hydroxypropylmethylcellulose (HPMC) and 817

nanocomposites. 818

819

42

820

821

Fig. 8. The % transmittance of pure hydroxypropylmethylcellulose (HPMC) and 822

nanocomposites. 823

824

825

43

826

827

Fig. 9. (a) Folding endurance and flatness (b) In-vitro drug release study from pure 828

hydroxypropylmethylcellulose (HPMC) and its nanocomposites. 829

830 831