A curcumin activated carboxymethyl cellulose–montmorillonite clay nanocomposite having enhanced curcumin release in aqueous media

A curcumin activated carboxymethyl cellulose–montmorillonite clay nanocomposite having enhanced curcumin release in aqueous media

Accepted Manuscript Title: A curcumin activated carboxymethyl cellulose-montmorillonite clay nanocomposite having enhanced curcumin release in aqueous...

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Accepted Manuscript Title: A curcumin activated carboxymethyl cellulose-montmorillonite clay nanocomposite having enhanced curcumin release in aqueous media Author: Nadeesh Madusanka K.M. Nalin de Silva Gehan Amaratunga PII: DOI: Reference:

S0144-8617(15)00771-7 http://dx.doi.org/doi:10.1016/j.carbpol.2015.08.030 CARP 10233

To appear in: Received date: Revised date: Accepted date:

6-6-2015 10-8-2015 12-8-2015

Please cite this article as: Madusanka, N., Silva, K. M. N., and Amaratunga, G.,A curcumin activated carboxymethyl cellulose-montmorillonite clay nanocomposite having enhanced curcumin release in aqueous media, Carbohydrate Polymers (2015), http://dx.doi.org/10.1016/j.carbpol.2015.08.030 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

*Manuscript Click here to view linked References

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nanocomposite having enhanced curcumin release in aqueous media

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Nadeesh Madusanka1,2, K.M. Nalin de Silva1,*, Gehan Amaratunga1,2

carboxymethyl

cellulose-montmorillonite

clay

1. Sri Lanka Institute of Nanotechnology (SLINTEC), Nanotechnology and Science Park, Mahenwatta, Pitipana, Homagama, Sri Lanka.

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activated

2. Department of Engineering, University of Cambridge, Cambridge, UK. *[email protected], Tel: + 94 11 4650531, Fax: + 94 11 4741995

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Abstract

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curcumin

A novel curcumin activated carboxymethylcellulose-montmorillonite nanocomposite is

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reported. A superabsorbent biopolymer; carboxymethyl cellulose (CMC) was used as an

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emulsifier for curcuminwhich is a turmeric derived water insoluble polyphenolic compound

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with

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incorporated in the formulation as a matrix material which also plays a role in release

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kinetics. It was observed that water solubility of curcumin in the nanocomposite has

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significantly increased (60% release within 2 hours and 30 minutes in distilled water at pH

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5.4) compared to pure curcumin. The prepared curcumin activated carboxymethylcellulose-

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montmorillonite nanocomposite is suitable as a curcumin carrier having enhanced release

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and structural properties.

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Keywords: curcumin, nanocomposite, clay, carboxymethylcellulose

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Highlights

properties.

Montmorillonite

(MMT)

nanoclay

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antibacterial/anti-cancer

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A novel curcumin activated MMT-CMC nanocomposite was prepared.

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CMC was used as an emulsifier for curcumin.

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1. Introduction

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MMT nanoclay acts as a matrix material while playing a role in release kinetics. Solubility of curcumin in the nanocomposite increased in the aqueous medium.

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Curcumin [(E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-ione] is the main

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active ingredient present in herbal and dietary spice turmeric which is derived from rhizome

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of the Curcuma longa. Chemical structure of curcumin is shown in Fig.1. It has been shown

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that curcumin possesses antibacterial, antioxidant, antiinflamatory and anticancer

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properties (Srimal & Dhawan, 1973, Sharma, 1976, Ruby, Kuttan, Babu, Rajasekharan &

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Kuttan, 1995, Panchatcharam, Miriyala, Gayathri & Suguna, 2006, Aggarwal and Sung, 2009,

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Mohanty, Das & Sahoo, 2012, Feng, Zhu, Song ,Zhao & Zhai, 2013).

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Figure 1Chemical structure of curcumin

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Out of the many available nanomaterials, clays particularly montmorillonite (MMT), which

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consists of stacks of alumina silicate layers which occur in nanometer scale in thickness with

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interlayer charge balancing ions, have attracted

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potential applications in the synthesis of nanocomposites based on organic/inorganic

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materials that have properties of both inorganic host and organic guest in a single system

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(Ray & Okamoto, 2003, Nguyen, Baird, 2006, Paul & Robinson, 2008). Montmorillonite

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nanoclay has been extensively used in order to improve structural properties of the active

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compound-clay nanocomposite; also in controlled/slow delivery and release applications

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(Dong & Feng, 2005, Zheng, Luan, Wang, Xi, & Yao, 2007, Meng, Zhou, Zhang & Shen,

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2009,Joshi, Kevadiya, Patel, Bajaj &Jasra,2009, Tunc & Duman, 2011).In addition, significant

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attention has recently been devoted to the use of biopolymers in preparation of

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nanocomposites due to their low toxicity, biocompatibility and biodegradability (Darder,

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Colilla& Ruiz-Hitzky, 2003, Arora & Padua, 2010, Yadollahi, Namazi, 2013, Buchtova, Lack &

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Bideau, 2014). Carboxymethyl cellulose (CMC) is a biodegradable polymer which possesses

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excellent emulsifying properties for water insoluble curcumin (Li, Sun & Wu, 2009, Ung et al.

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2010,). In addition, CMC interacts with montmorillonite clay improving the functionality of

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clay particles (Gutierrez, Echeverria, Ihl, Bifani & Mauri, 2012). Therefore CMC can be used

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as a bridging agent for water insoluble curcumin and Montmorillonite nanoclay. Over the

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last few years, clay-biopolymer nanocomposites have been reported for various applications

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(Xu, Ren& Hanna, 2006, Gutierrez et al. (2012), Mohanty et al. (2012), Malesu, Sahoo &

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Nayak, 2011, Tunc & Duman, 2010,Carli, Daitx, Guegan, Giovanela, Crespo & Mauler, 2015).

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Gutierrez

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nanocomposite films activated with murta (UgnimolinaeTurcz) leaf extract and observed

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that due to the interactions between CMC and MMT, mechanical and gas barrier properties

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considerable attention due to their

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can be significantly increased while the addition of murta leaf extract leads the composite

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having antioxidant properties. Mohanty et al., (2012) studied control release of curcumin

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from a curcumin loaded polylactic acid/MMT nanocomposite, while Malesuet al., (2011)

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prepared curcumin loaded chitosan-sodium alginate nanocomposites blended with MMT as

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a novel drug delivery system for curcumin.

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Here, we report the preparation and characterisation of a CMC-MMT nanocomposite

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activated with antibacterial/anticancer compound curcumin. Although CMC can act as an

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emulsifier for curcumin in aqueous media, in the solid state CMC-Curcumin readily absorbs

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atmospheric water and becomes sticky. In this nanocomposite solid state stability of the

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composite was achieved by incorporating MMT nanoclay while CMC which bridges MMT

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and curcumin plays an important role in curcumin solubility in aqueous medium.

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2. Experimental

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CMC (Sodium salt) was purchased from CDH Laboratory, New Delhi, India (Viscosity 1% at

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25°C, 1200-2400 cps). MMT (Sodium salt, Cloisite-Na+) was procured from Southern Clay,

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USA. Curcumin was purchased from Loba chemicals, Mumbai, India. All chemicals used were

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reagent grade and used without further purification. Distilled water was used for all

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preparations.

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2.1 Preparation of MMT-CMC nanocomposite

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CMC (5 g) was dissolved in distilled water (250 ml) at 80 °C and the resulting viscous solution

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was cooled to room temperature (25°C). Then, Na-MMT (5 g) was dispersed in distilled

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water (50 ml) under mechanical stirring for 30 minutes at 1000 rpm and the viscous CMC

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solution was gradually added into clay suspension with continued mechanical stirring for

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another 1 hour. The prepared MMT-CMC (1:1) nanocomposite was oven dried at 60 °C for 5

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hours and characterised using PXRD and FTIR.

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2.2 Preparation MMT-CMC-Curcuminnanocomposite

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CMC (0.5 g) was dissolved in distilled water (25 ml) at 80 °C and cooled to 25°C as above.

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Then, 50 mg of curcumin was dissolved in 50 ml of ethanol and gradually added into the

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CMC solution under mechanical stirring (1000 rpm for 1 hour). After that, Na-MMT (0.5 g)

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was dispersed in distilled water (50 ml) under mechanical stirring for 30 minutes at 1000

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rpm and the viscous CMC-curcumin solution was gradually added into the clay suspension

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stirred for another 1 hour. The MMT-CMC-Curcumin nanocomposite (MMT:CMC 1:1 weight

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ratio and 4.76 % curcumin) was oven dried at 60 °C for 5 hours and characterised using

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powder X-ray diffraction (PXRD), Fourier transform infra-red (FTIR), Thermo gravimetric

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analysis (TGA), scanning electron microscopy SEM and optical microscopy. Similarly,

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MMT:CMC 2:1 and 3:1 nanocomposites with 4.76 % curcumin were also prepared and

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characterised.

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2.3 Release of curcumin

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A calibration curve for curcumin was obtained for known concentration solutions in ethanol:

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water (2:3) mixture at room temperature. The amount of curcumin was analysed using a

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UV/Vis spectrophotometer (Shimadzu UV 3600 UV spectrophotometer) at the λmax value of

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430 nm. A pelletised MMT-CMC (3:1)-Curcumin composite (50 mg) was placed in a 100 ml of

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distilled water beaker (pH-5.4) at room temperature and 3ml aliquot was used each time for

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released curcumin content at a fixed time interval. The aliquot taken out was treated with 2

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ml of ethanol maintaining the ratio of ethanol : wateras 2:3 prior to UV analysis.

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3. Characterisation

PXRD patterns of all synthesized samples were recorded using a Bruker D8 Focus X-ray

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powder diffractometer using Cu Kα radiation (λ= 0.154 nm) over a 2θ range of 3-65°with a

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step size of 0.02° and a step time of 1 s. The particle size and the morphology of the

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synthesized samples were studied using a HITACHI SU6600 scanning electron microscope.

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The ground samples were mounted on adhesive carbon tape attached to a SEM metal stub

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and samples were coated with a thin layer of Au prior to observation. Optical images were

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obtained using an Olympus BX 51 microscope. The nature of chemical bonding of the

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synthesized samples was determined using a Bruker Vertex80 Fourier transform infra-red

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spectrometer in the range from 600 to 4000 cm-1 using the attenuated total reflectance

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technique.

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thermogravimetric analysis, TA Instruments SDTQ600. The samples (10-15 mg) were heated

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from ambient temperature to 1000 °C (ramp 10 °C/min) in a nitrogen environment (100

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cm3/min N2 flow rate).

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The thermal behavior of the synthesized samples was studied using

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4. Results and Discussion 4.1 Characterisation of MMT-CMC-Curcumin nanocomposites

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4.1.1 PXRD Characterisation

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PXRD traces for MMT, MMT-CMC and MMT-CMC-Curcumin nanocomposites are shown in

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Fig. 2. An interlayer spacing of 12.18 Å is seen for Na-MMT oven dried at 60 oC as calculated

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according to the Bragg’s law, referring to the first basal reflection (001) of the PXRD pattern.

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The introduction of CMC, increases the interlayer spacing of the parent Na-MMT to 13.55 Å.

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The hydrophilic nature of the interlayer space and surface active sites of MMT allow CMC to

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bind through strong H-bonding thus leading to an expansion in the interlayer distance.

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However, with the addition of CMC-Curcumin dispersion into MMT the interlayer spacing of

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the parent Na-MMT increased to 12.90 Å which is less than that of the MMT-CMC system

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(13.55 Å). This could be an indication of the interaction of curcumin molecules with MMT

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intercalated CMC.

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Figure 2 PXRD patterns of (a) parent MMT oven dried at 60 °C(b) MMT-CMC (1:1 by weight) (c) MMT-CMC(1:1)-4.76% Curcumin (d) MMT-CMC(2:1)-4.76% Curcumin(e)MMT-CMC(3:1)-4.76% Curcumin nanocomposites

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4.1.2 FTIR characterisation

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FTIR spectrum of curcumin, CMC, parent MMT, MMT-CMC (1:1) composite and MMT-CMC

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(1:1) 4.76% Curcumin nanocomposite are shown in Fig. 3. 154

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Figure 3FTIR spectrum of (a) Curcumin (b) CMC (c) parent MMT oven dried at 60 oC(d) MMT-CMC (1:1) composite (b) MMT-CMC (1:1) 4.76% Curcumin nanocomposite Curcumin shows a broad absorption band at 3350cm−1due to phenolic stretching vibration.

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Additionally, sharp peaks at 1508cm−1and 1423cm−1are due to stretching vibration of C=C

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of benzene rings and olefinic bending vibrations of C–H bound to the benzene rings of

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curcumin. The peak at 820 cm-1relates to the stretching vibrations of C-O groups present in

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curcumin (Mai et al., 2012).CMC shows a band at 2908 cm−1due to C–H stretching of the –

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CH2 groups and the band due to ring stretching of –COO- appears at 1600 cm−1. In addition,

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the bands in the region 1350–1450 cm−1 are due to symmetrical deformations of CH2 and

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COH groups. The bands due to –CH2OH stretching mode and CH2 vibrations appear at 1070

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and 1020 cm−1, respectively (Ismail, Bono, Valintinus, Nilus & Chng 2010). MMT shows a

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characteristics absorption band at 3400 cm-1 due to the O-H stretching of adsorbed water

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and the shoulder at 3625 cm-1mainly due to structural OH groups present in the MMT.

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Peaks at 995 cm-1 and 1125 cm-1are responsible for Si-O stretching vibrations of MMT layers

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(Meng et al., 2009). In the FTIR spectrum of MMT-CMC, CH2OH stretching mode and CH2

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vibrations of CMC and Si-O stretching vibrations of MMT have overlapped. The band around

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1350 cm-1 which is responsible for COH symmetrical deformations has broadened compared

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to parent CMC.

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encapsulated with MMT nano layers displayed peaks due to CMC, Curcumin and Na-MMT

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confirming the presence of the CMC-Curcumin within the Na-MMT. Peak broadening at

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3600 cm-1 of the parent clay suggests an H-bonding environment within the nanoclay

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interlayer spacing while the shift in –COO- bond of CMC from 1600 cm-1 to 1585 cm-1

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accounts for the interactions of CMC with curcumin and MMT nanoclay. Other than the

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encapsulated CMC-Curcumin there is a possibility of CMC-Curcumin binding with the surface

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of the nanoclay particles which supplies almost a similar environment as the interlayer

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space of the nanoclay.

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As seen from Figure 3 (e), the FTIR spectra of the CMC-Curcumin

4.1.3 Thermal analysis

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TGA trace for MMT-CMC -Curcumin nanocomposites are shown in Fig. 4.

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Figure 4 (a) TGA (b) Differential Thermal Analysis (DTA) profiles for MMT-CMC -Curcumin nanocomposites

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Two major weight losses were observed for Na-MMT 10 % weight loss up to 180 °C is due to

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dehydration; and 20 % weight loss of the total weight around 650 °C is due to collapsing of

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the clay layers. In addition, MMT-CMC (1:1) showed three main weight losses where 5 % up

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to 200 °C due to dehydration, 25 % around 350 °C due to decomposition of CMC, 8 % around

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450 °C due to the further decomposition CMC residues and 3 % around 650 0C due to

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collapsing of the clay layers (Supplementary Information S2). Four major weight losses were

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observed for MMT-CMC-curcumin nanocomposites. For MMT-CMC (1:1)-Curcumin, 14 % up

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to 200 °C due to dehydration, 17 % around 350 °C due to decomposition of CMC, 11 %

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around 450 °C due to decomposition of curcumin and CMC residues and 1 % around 650 0C

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due to collapsing of the clay layers. A similar trend was observed for MMT-CMC (2:1)-

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Curcumin and MMT-CMC (3:1)-Curcumin nanocomposites as shown in Fig.4.Furthermore, it

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was observed that decomposition temperature of CMC has increases with increasing of the

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MMT nanoclay content in the nanocomposite (It has been noted in the figure around 250°C

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with an arrow).Thermal decomposition of CMC of the nanocomposite is the 1 st

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decomposition event followed by removal of adsorbed water and T initial of MMT-CMC (1:1),

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(2:1) and (3:1) –Curcumin are 238 °C 243 °C and 246 °C respectively. Similarly Tmaxvalues for

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MMT-CMC (1:1), (2:1) and (3:1) –Curcumin are 296 °C 299 °C and 303 °C respectively.

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However, decomposition of curcumin is not clearly distinguishable as CMC residues further

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decompose around the same temperature. In general, thermal stability of the

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nanocomposite has increased with higher MMT clay loading.

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4.1.4 Electron microscopy

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As seen from Fig. 5 in the SEM image of the MMT-CMC-Curcumin nanocomposite displayed

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typical plate like morphology. The plate like appearance of MMT is maintained even after

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encapsulation of CMC-Curcumin. In addition, no agglomerations of curcumin or CMC are

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seen with MMT confirming the successful synthesis of a homogeneous nanocomposite.

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Figure 5 SEM images for MMT-CMC [1:1 (a),2:1 (b) and 3:1(c)] 4.76% Curcumin nanocomposites 4.1.5 Optical microscopy

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Optical microscopy images of parent CCM, MMT and MMT-CMC (1:1, 2:1 and 3:1) 4.76%

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Curcumin nanocomposites are shown in Fig. 6 below. It confirms the formation of CMC and

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Curcumin encapsulated MMT by yellow coloured clay particles with Curcumin and CMC.

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Furthermore, it can be clearly seen that clay particles are coated with curcumin

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impregnated CMC polymer. Therefore in this composite, clay phase could be the continuous

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phase, especially for composites with higher clay loading as the clay phase become more

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dominant compared to the polymer phase. However, polymer chains can make a network

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with encapsulated clay particles in the composite.

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Figure 6 Optical microscopy images of (a) CMC (b) MMT and MMT-CMC [1:1 (c), 2:1 (d) and 3:1(e)] 4.76% Curcumin nanocomposites

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4.2 Invitro curcumin release

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The release behaviour of curcumin from the nanocomposite in distilled water (pH 5.4) at 25

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°

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different MMT loading (MMT:CMC 1:1, 2:1 and 3:1), MMT-CMC (3:1)- 4.76% Curcumin was

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selected for the release study which contains highest clay loading. It was observed that

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MMT-CMC- 4.76% Curcumin nanocomposites with low clay loading tend to absorb

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atmospheric water resulting a sticky material as CMC is a super absorbent polymer.

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However, MMT-CMC (3:1)- 4.76% Curcumin nanocomposite with the highest clay loading

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with lower CMC content was stable in the presence of atmospheric water and it was

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selected for the release study.

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C is shown in Fig 7. Out of all three MMT-CMC- 4.76% Curcumin nanocomposites with

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NC after 30 min

NC after 60 min

NC after 90 min

NC after 150 min

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Nanocomposite (NC)

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purecurcumin

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Figure 7Curcumin release profile for MMT-CMC (3:1) 4.76% Curcumin nanocomposites in distilled water(pH 5.4) at 25 °C

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The aqueous solubility of curcumin is very low and particularly low at acidic and neutral pH

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and relatively higher in basic conditions. However, it was observed that over 60% of

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curcumin has been released within 2 hours and 30 minutes. There was no solubility

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observed for pure curcumin and in effect remained insoluble in the aqueous medium. More

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importantly there is a significant improvement of curcumin release rate under acidic pH

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compared to previously reported clay based curcumin composites (Mohanty, Biswal &

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Nayak, 2015). This results show that carboxymethyl cellulose biopolymer can play a major

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role in enhancing the solubility of curcumin via its emulsifying properties. MMT clay in the

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composite improves the textural properties while contributing to the release kinetics of

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curcumin. Schematic representation of the MMT-CMC-Curcumin nanocomposite is shown in

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Fig 8. Dried films of carboxymethylcellulose-curcumin without clay absorb moisture from

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the atmosphere and become sticky within a short period of time.

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Figure 8A schematic representation of MMT-CMC-Curcumin nanocomposite

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5. Conclusions

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A clay and bio polymer based curcumin activated nanocomposite has been successfully

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formulated. FTIR data, TGA and expansion of interlayer spacing of MMT confirm the

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interaction of curcumin and CMC with MMT. The plate like appearance of MMT is

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maintained even after encapsulation of CMC-Curcumin. The release of curcumin from the

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nanocomposite in distilled water (pH 5.4) at 25 °C is over 60% within 2 hours and 30

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minutes. The curcumin activated carboxymethylcellulose-montmoriilonite nanocomposite is

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an effective curcumin carrier with enhanced solid state properties. It also has commercial

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potential given that three components are nontoxic and pharmaceutically accepted and

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economical. The solid composite material is stable under ambient conditions and can be

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easily pellatised to form tablets.

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Nanocomposite (NC)

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Supplementary data

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Figure S1 PXRD patterns of Curcumin, CMC and MMT nanoclay

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Figure S2 TGA curves of MMT nanoclay and MMT: CMC (1:1) nanocomposite

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