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Evaluation of clay-ionene nanocomposite carriers for controlled drug delivery: Synthesis, in vitro drug release, and kinetics
Accepted Manuscript Evaluation of clay-ionene nanocomposite carriers for controlled drug delivery: Synthesis, in vitro drug release, and kinetics Hany El-Hamshary, Mohamed H. El-Newehy, Meera Mohideen, Ayman El-Faham, Abeer S. Elsherbiny PII:
S0254-0584(18)31092-7
DOI:
https://doi.org/10.1016/j.matchemphys.2018.12.054
Reference:
MAC 21217
To appear in:
Materials Chemistry and Physics
Received Date: 25 September 2018 Revised Date:
18 December 2018
Accepted Date: 20 December 2018
Please cite this article as: H. El-Hamshary, M.H. El-Newehy, M. Mohideen, A. El-Faham, A.S. Elsherbiny, Evaluation of clay-ionene nanocomposite carriers for controlled drug delivery: Synthesis, in vitro drug release, and kinetics, Materials Chemistry and Physics (2019), doi: https://doi.org/10.1016/ j.matchemphys.2018.12.054. 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.
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Evaluation of clay-ionene nanocomposite carriers for controlled drug delivery: synthesis, in vitro drug release, and kinetics
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Hany El-Hamshary*a,b, Mohamed H. El-Newehy*a,b, Meera Mohideena, Ayman El-Fahama,c, Abeer S. Elsherbinyb a
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Chemistry Department, College of Science, King Saud University, P.O. Box: 2455 Riyadh 11451, Saudi Arabia b Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt c Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria, 21321, Egypt
Hany El-Hamshary* [email protected]; [email protected] Tel: 00966508921099
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Mohamed H. El-Newehy* [email protected]
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Correspondence Author
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ABSTRACT To evaluate the impact of the different structure of quaternary ammonium salts (ionenes) as drug carrier of their corresponding organoclays, new nanocomposite clay-ionene (CI) drug carriers
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were prepared from montmorillonite (Mt) and polyquaternary ammonium salts (polyionene) and a simple bisquaternary ammonium salt. The CI drug systems were obtained by ion exchange of the sodium Mt (Na+Mt) with at least two-fold excess polyquaternary and bisquaternary
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ammonium salt compounds by ion exchange between sodium cations of the Na+Mt and the ammonium ions in the polyionene to produce CI systems with free quaternary ammonium halide
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side chains. Simple di-quaternary ammonium salts were also used to modify Mt. The structures of the prepared CI systems were characterized using Fourier transform-infrared spectroscopy (FT-IR), powder X-ray diffraction (XRD), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). As a model drug, sodium diclofenac (DS) was
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immobilized onto the CI through the remaining halide ions to provide the CI-diclofenac system (DFS). The release behavior of diclofenac from the different nanocomposites was studied at different pH values. The release behavior of the DFS showed that polyionene systems were
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slower than the simple bi-quaternary ammonium salts systems were. The kinetics of the release
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process were described using different models to explain the drug release mechanism.
KEYWORDS. Nanocomposites; Polyionene; Montmorillonite; Drug release; Sodium Diclofenac.
1.
Introduction
The therapeutic systems used to administer chemicals or drugs have received increasing consideration over the past two decades. Conventional administration of drugs is affected by
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certain restrictions including poor patient compliance associated with missed doses, adverse effects due to the fluctuation of drug levels, and difficulties in attaining steady state conditions because of incidences of typical peak-valley plasma concentration-time profiles [1]. Therefore,
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attention has been focused on methods of providing drugs continuously for prolonged periods in a controlled fashion to the site of action [2, 3]. This technique is termed controlled release and is used to describe the process of providing or delivering compounds in response to stimuli or time.
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Examples of stimulants that may be used to induce drug release include pH, enzymes, light, magnetic fields, temperature, ultrasound, and osmosis [4]. In addition to pharmaceuticals, other
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areas of application of controlled release systems currently include agriculture, food pesticides, cosmetics and personal care, and household products [5]. The benefits of controlled drug release systems over those of the conventional dosage forms are well recognized [6]. The characteristics of the systems used in the controlled delivery completely control the release behavior and the
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choice of the correct material appears crucial to certain applications [7]. The usual way to establish a controlled release system has been by combining the chemicals in a polymer matrix [4].
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Recently, clay minerals have received considerable attention as a new class of drug-delivery
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systems because of their colloidal properties, high retention, and swelling capacities [8, 9]. Other important properties include low or almost no toxicity, chemical inertness, ion exchange in the layers that allow clays to bind or host cationic drug molecules or both. In addition, they possess a high surface area with different morphologies (such as nanotubes, nanoplates and nanofibers) and adsorption capacity [10, 11]. The surface chemistry of nanoclays allows for targeted functionaliztions with organic materials so that the obtained nanocomposite can control loading and regulate release properties. The most widely used types of clay are the smectites such as
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montmorillonite (Mt) and saponite because they have a higher cation exchange capacity than that of other layered silicates used in pharmaceuticals such as kaolin, talc, and fibrous clay minerals [12-14]. The use of clay minerals in pharmaceutical formulations has been described by some
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authors [15, 16]. These minerals act as active principles or excipients. According to the curative activity for which the clay minerals are applied, they can be administered orally or topically. Oral applications include their use as gastrointestinal protectors, osmotic oral laxatives, and
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antidiarrheal. While topical applications include their use as dermatological protectors and in cosmetic products. Clay minerals used as excipients include smectites, kaolinite, talk, and
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palygorskite. They have been used as lubricants, disintegrants, inert cosmetic bases, and emulsifiers. Besides, organo-modified halloysites are among the clays which have potential for use as drug delivery carriers [17-19].
Clay minerals are layered silicates that typically exist in packed structures because of the
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favorable electrostatic attractions between the negatively charged clay sheets and positively charged counter ions [20]. Mt has a crystal structure consisted of two integrated silica tetrahedral sheets sandwiching an edge-shared octahedral sheet of either aluminum or magnesium hydroxide
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[21, 22]. The Positive counter ions are exchangeable and located in the clay interlayer. Therefore, these cations may be exchanged with other inorganic or organic cations through an
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ion-exchange reaction[23]. Organic cations include quaternary ammonium NR4 or phosphonium PR4 cations where R can be an alkyl, aryl, or polymeric group [24]. The organic cations include the polyionenes, which are polycationic compounds that contain ionic groups in the main chain. Most ion-containing polymers have quaternary nitrogen atoms in their polymeric backbone. Very few investigations have been conducted on clay-polyionene systems [25, 26]. It is worth mentioning to note that, another type of layered materials which is known as anionic clays or; the
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layered double hydroxides with a hydrotalcite-like structure has been also used as drug carriers, due to their ability to retain, by ion exchange, anionic molecule drugs [9, 27]. In this study, diclofenac sodium (DS), a non-steroidal anti-inflammatory drug, was immobilized
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onto the prepared clay-ionene (CI) system and the in vitro drug release was studied at different pH values. Moreover, the kinetics of the drug release were investigated. 2. Material and Methods
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2.1. Materials. The commercial sodium Mt (Na+Mt, Cloisite®Na) was received from
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Southern Clay Products, Gonzales, TX, USA). The cation exchange capacity (CEC) of Na+-Mt is 92.6 meq/100 g as stated by the producers and its basal spacing is 12.1 Å. Na+-Mt was used as received without any further purification. N,N-dimethyldecylamine, N,N,N′,N′tetramethylethylenediamine- (TMEDA), and methyl iodide were obtained from SigmaAldrich(Steinheim, Germany). α,αʹ-dichloro-p-xylene, and Dimethylformamide (DMF) was used
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in the state it was received from Acros Organics (Geel, Belguim). All other chemicals were used as received unless otherwise stated.
Synthesis of Ionene Materials
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2.2.
Simple diammonium salts were prepared by quaternization of a di-tert-amine with either alkyl
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halide/aryl halide or quaternization of a dihalide with either a tertiary amine or phosphine. Ionene polymers were synthesized according to the method described by Rembaum et al. [28], (Scheme1, Table S1).
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I
–
I
– +
+
N
N
CH3I N
N
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Cl
N,N,N',N'-Tetramethyl-ethane-1,2-diamine (TMEDA)
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(I-1)
Cl
Cl
α,α′-dichloro- p-xylene
+
N
Cl
Cl +
N
(I-3)
Cl
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Cl
Cl
1,2-Dichloroethane
+
N
n
+
N
n
(I-4)
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Cl
Cl
α,α′-dichloro- p-xylene
N
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N,N'-dimethyldecylamine
Cl
Cl
–
– +
N
+
N
(I-2)
Scheme 1: Synthesis of polyionene and bis-quaternary ammonium salts materials
2.2.1.
Synthesis of N,N,N,Nʹ,Nʹ,Nʹ-hexamethyl-1,2-ethanediamonium diiodide
(HMEDADI, I-1). The diammonium salt N,N,N,N’,N’,N’-hexamethyl-1,2-ethanediamonium diiodide (HMEDADI) was obtained by reacting iodomethane with TMEDA.
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2.2.2. Synthesis of benzene-1,4-diylbis (N,N-dimethyldecyl ammonium chloride, BDBDMDAC, I-2). Benzene-1,4-diylbis (N, N-dimethyldecyl ammonium chloride, BDBDMDAC, I-2) was obtained by reacting α,α′-dichloro-p-xylene with N,N-dimethyldecyl
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amine.
2.2.3. Synthesis of poly(dimethylene, xylylene ionene, PDMXI, I-3). Poly(dimethylene,
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xylylene ionene, PDMXI, I-3 was obtained by reacting α,α′-dichloro-p-xylene with TMEDA. Synthesis of poly2,2-ionene, I-4). Poly2,2-ionene (PI, I-4) was obtained by reacting 1,2-
2.3.
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dichloroethane with TMEDA. Modification of Na+Mt- with Ionene (CI: 1-4)
The CI sample (CI-1) was prepared using a typical method (Scheme 2): Na+Mt, (2.0 g) was placed in a 100-mL Erlenmeyer flask and allowed to swell in 50 mL distilled water (H2O) under
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magnetic stirring at 40°C for 24 h. Then, aqueous ionene (I-1) solution (10 mL) in double number of moles of clay was added to the clay suspension. The contents were continuously stirred for 48 h at 40oC. The CI nanocomposite material was isolated by centrifugation at 5000
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rpm, washed thoroughly with distilled H2O until no chloride ions were observed in the filtrate using the silver nitrate (AgNO3 test), washed with ethanol, and finally with diethyl ether. The
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solid was vacuum-dried at 40°C for 24 h. The remained halide ions from excess ionene were determined using the Volhard method, [29] and the results are presented in (Table S1). Samples CI: 2-4were synthesized using the similar procedure as described for the synthesis of CI-1. The composition of CI materials and the elemental microanalysis of the synthesized CI samples is shown in Table S2.
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2.4.
Preparation of CI-Diclofenac System (CI-DFS). The CI diclofenac system (DFS)
samples were prepared as follows (Scheme 3): a suspension of CI-1 (1.0 g, 0.86 mmol Cl-/g) was placed in 25 mL H2O and stirred at 40°C for 12 h. Then, an aqueous solution of sodium
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diclofenac (DS, 0.9 mmol) was added to the suspension, and the mixture was stirred
continuously for 48 h at 40°C. The product was isolated by centrifugation at 5K rpm, and
washed thoroughly with distilled H2O, followed by ethanol and finally with diethyl ether. The
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samples were vacuum-dried at 40°C for 24 h (Table S3).
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same procedure was used to prepare the other CI-DFS samples (DFS2–4, Table S3) and the
2.5. Drug Release Study
2.5.1. Determination of Total DS Content. A sample of known mass was suspended in 3 mL buffer solution at pH 9.2 while heating at 60oC. Spectrophotometric measurement was used to
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detect the release of DS at λmax 276 nm until a fixed value was obtained. 2.5.2. In Vitro Drug Release. A fixed weight of the sample (10 mg) was suspended in 3 mL buffer solutions at pH values of 2.0, 7.4, and 9.2 at 37°C. The cumulative percentage of drug
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released was determined using spectrophotometric measurement at λmax 276 nm, using a standard calibration curve for diclofenac[30]. All the experiments were carried out in triplicate,
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and the average was calculated. The percentage amount of diclofenac released was estimated using equation:
Drug release % = Mt/Mo x 100
(1)
Where Mo and Mt represent the amount of diclofenac-loaded and released at time t, respectively.
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2.6.
Evaluation of Release Kinetics and Mechanism. To study the mechanism of diclofenac
release, the obtained release data were analyzed by fitting to different kinetic models, which
Zero order model
M = Mo + Ko t
(2)
First order model
log M = log Mo - K1 t /2.303
(3)
Higuchi Model
Mt /M∞ = KH + t1/2
(4) (5)
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Mt /M∞ = K tn
Korsmeyer-Peppas Model
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were analyzed as follows:
MO = Initial amount of drug in solution KO = Zero order rate constant t = time K1 = First order constant
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Where: Mt and M∞ = Amount of drug release or dissolved drug at time (t), and at equilibrium.
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Mt /M∞ = fraction of drug released at time t.
M∞ = amount of drug released after an infinite time KH = Higuchi rate constant
Characterization
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2.7.
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n = release exponent of Korsmeyer-Peppas power low model
2.7.1. Elemental Microanalysis. The elemental microanalysis was performed using PerkinElmer 2400 Series II CHNS/O Elemental Analyzer. Ultraviolet (UV-VIS) spectra: Measurements were recorded on a Perkin-Elmer UV/vis spectrophotometer (Lambda-35). The selected wavelengths for measuring diclofenac was 276 nm.
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2.7.2. Fourier Transform-infrared (FT-IR) Absorption Spectra. The Fourier transforminfrared (FT-IR) spectra were recorded using a Bruker, TENSOR 27 spectrophotometer, using
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the potassium bromide (KBr disc technique). 2.7.3. Nuclear Magnetic Resonance (NMR) spectra. The NMR were recorded using a JEOL JNM-PM X90 Si-NMR 400 MHz spectroscopy instrument. Experimental conditions
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2.7.4. Thermogravimetric Analysis (TGA). The thermogravimetric analysis (TGA) were carried out using the TA-Q500 System from TA Instruments at a temperature range of 30 to
kept within a 3–5 mg range.
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800oC and a scanning rate of 10ºC/min under a nitrogen atmosphere. The sample weight was
2.7.5. Scanning Electron Microscope (SEM). The surface morphology of the composites was examined using the JEOL JSM-6380 scanning electron microscope (SEM) equipped with an
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energy dispersive X-ray detector. Gold-coated compressed specimens were examined at their fracture surface for enhanced scanning electron microscopy (SEM) imaging. Experimental
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2.7.6. Transmission Electron Microscopy (TEM). The transmission electron microscopy
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(TEM) analysis was carried out using the JEOL 1011 CX (Tokyo, Japan) instrument at an accelerating voltage of 20 KV. A small amount of the polymer-clay was dispersed in 5 mL distilled water and then thoroughly sonicated using probe sonication. A copper coated grid was dipped in the solution and then completely oven-dried at 40°C. The prepared grid was loaded onto the transmission electron microscope.
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2.7.7. Powder X-Ray Diffraction (PXRD). The X-ray diffraction measurements were carried out using the Rigaku Ultima IV X-ray diffractometer operated at a Cu–Kα wavelength (λ) of 1.5418 Å, over an angular range 2θ from 3 to 40° and a scan rate of 0.5°/min. A generator setting
used to compute the crystallographic spacing.
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of 40 kV and 40 mA, and divergence slit of 2/3o were used, and Bragg's law (n λ = 2 d sin θ) was
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2.7.8. Zeta potential measurements. Zeta potential measurements were carried out using
NanoPlus zet/nano particle analyzer. A small amount of the CI-DFS nanocomposite (0.1 g) was
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dispersed in 10 mL distilled water and then thoroughly sonicated using probe sonication. The samples were allowed to settle for around 1 h and a few mLs of suspension from the top of the tube was measured. 3. RESULTS AND DISCUSSION
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The intrinsic hydrophilic nature of clay minerals renders them incompatible with a wide range of hydrophobic or nonpolar polymeric materials. Therefore, they can be made organophilic by reacting them with organic cations using ion-exchange. Organic cations that can be exchanged
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for the interlayer cations include ammonium or phosphonium ions. Exchanging the inorganic
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cations with organic cations expands the interlayer spaces, which facilitates the movement of the organic chains within these interlayers. Moreover, the surface properties become organophilic rather than hydrophilic. In the present investigation, bis-quaternary ammonium salts and polyionenes were used to both lower the surface energy of the Mt and provide a large number of active groups that could bind with the drug molecules. We compared the release behavior of the prepared quaternary ammonium compounds (ionenes) of different compositions. The ionenes were both polymeric ionenes (I-3 and I-4) and simple bis-
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quaternary ammonium salts (I-1 and I-2). Biquaternary ammonium salts such as I-1 have only terminal methyl groups while I-2 has two terminal methyl and one decyl groups. The CI was formed using an ion exchange reaction of Na+Mt with an excess amount of the prepared ionenes
+
-+
+
X A
A X
H O, 48 h, 40 oC 2 -NaX
-
O-Na+
Clay (Na+Mt-)
Ionene = I: 1-4 A= N, X = Cl- or I-
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(Scheme 1) to produce organically modified Mt-ionenes as outlined in (Scheme 2).
+
+
O- A
A X
-
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Clay-Ionene = CI: 1-4
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Scheme 2: Ion-exchange intercalation of montmorillonite with ionenes The ionenes reacted with Na+Mt by ion exchange and, therefore, the produced nanocomposites became organophilic with at least an excess pendent site capable of binding with other ionic
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substrates. Treatment of the generated CI materials (CI-1, CI-2, CI-3, and CI-4) with DS at the remaining nitrogen site provided the CI-DFS drug system (Scheme 3).
+
O- A
A X
H2O, 48 h, 40oC -NaX
O
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Clay-Ionene (CI)
O-Na+
R
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Diclofenca sodium
O- A
A -O
R O
Clay-Ionene-Drug (DFS)
Cl
R= Cl
N H
A= N or P and X = Cl or I
Scheme 3. Preparation of clay-ionene (CI)-drug nanocomposites
3.1. Characterization: The nanocomposite drug systems were characterized by using FT-IR, XRD, TEM, and TGA. The FT-IR Spectra of DFS samples are presented in Figure 1. In DFS1 (Figure 1a), the starting material Na+Mt showed an overlapping band at 3630 and 3422 cm−1 due
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to the –OH stretching vibration, and hydrogen bonds, and for aluminum hydroxide (Al-OH) and other structural –OH groups present in the Mt. A characteristic peak of silicon dioxide (SiO2) asymmetric stretching band appeared at 1042 and 921 cm-1. Two small peaks appeared at 918
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and 550 cm-1, and they were due to Al-Al-O and Si-O-Al respectively [31, 32]. The same trend was observed for other DFS samples. The collected FT-IR spectrograms (Figure S1) showed the
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intercalation of ionene and polyionene with the clay interlayers.
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Figure 1. Fourier transform-infrared (FT-IR) spectra of diclofenac systems (DFS) 1-4 samples
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The FT-IR spectrogram of CI-1 (Figure S1) revealed a characteristic band at 3625 cm−1 for the OH group. The bands present at 2943, 1764, and 1456 cm−1 corresponded to the quaternized nitrogen (+N) group, and the band at 1073 cm−1 was related to C-N. The overlapping peak at 3022 cm−1 was related to C–H stretch of methylene units and the CH3 of R-N(CH3)2 while the band appearing at 2955 cm−1 was due to the C–H stretching of the alkyl group. The peaks at 1485 and 460 cm−1 were most probably due to the fundamental stretching and deformation vibrations of the CH3 groups of the tertiary amine salt. The FT-IR spectrum of pure diclofenac
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showed characteristic peaks for NH stretching of the secondary amine at 3385 cm-1 and the – C=O stretching of the carboxyl ion at 1575 cm-1. A band at 1557 cm-1 corresponded to the C=C ring stretching and the peak at 746 was due to the C- Cl stretching [33, 34]. The spectrum of the
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matrix attached DFS1 maintained the characteristic bands of the component of the entire
nanocomposite in which overlapping peaks appeared at 3628 and 3431 cm-1 for NH stretching, OH, and the ammonium salt, N+ R4. The peaks at 1348 cm−1 corresponded to the C-N stretching
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[35]. Group samples of DFS2, DFS3, and DFS4 showed similar spectra to those of the DFS1 group.
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The PXRD pattern of the obtained DFS nanocomposites and Na+Mt was used to characterize the intercalation of the ionene-drug with the clay. The diffraction patterns of Na+Mt and the DFS samples are illustrated in Figure 2, while the basal spacing data are shown in Table 1. The diffraction pattern of the Na+Mt (Figure 2) showed a characteristic peak at 2θ = 7.45, with a
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corresponding basal spacing (d001) of 11.86 Å, as determined by Bragg’s law (n λ = 2d sin θ), where λ is the wavelength, d is the interlayer distance of the plane of reflection, and θ is the diffraction angle. All of the modified DFS samples were shifted to lower 2θ values and is
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associated with increased basal spacing, which ranged from 1.38 to 2.54 Å as presented in Table 1. Such observed decrease in the 2θ value, and increased basal spacing is indicative of the
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effective intercalation after the cation-exchange reaction between the Na+ ions and the excess bulky quaternary ammonium ions. Such excess quaternary ammonium ions were used to fix the diclofenac by ion exchange of the remained halide ion of the ionenes with the diclofenac anions. However, the observed shoulder appeared at 2θ around 19 degree, could be attributed to the excess amount of ionene, as the polyionene and simple ionene have extra cationic sites
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exchanged with sodium cations, leading to expand the interlayer spacing while the rest of the molecules are oriented to surface of the clay, and is adsorbed on the clay surface.
d Spacing (Å) 11.83 13.90 13.21 14.30 14.37
Layer expansion --2.07 1.38 2.47 2.54
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2 theta 7.45 6.18 6.10 5.87 6.19
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Material Na+Mt DFS1 DFS2 DFS3 DFS4
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Table 1. Interlayer d-spacing and spacing shift
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Figure 2. XRD of Clay-Ionene-Drug 250
DFS-1
DFS-2
Mt Diclofenac
200
200
Intensity
DFS-1 150
Intensity
150 100
50
0 13
18
23
3
2θ
DFS-3
240
Mt Diclofenac DFS-3
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200 Intensity
160 120
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80
0 3
8
13 2θ
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40 18
23
8
13
18
23
2θ Mt
DFS-4
300.00
Diclofenac
250.00
DFS-4
200.00
Intensity
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3
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100
50
Mt Diclofenac DFS-2
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250
150.00 100.00 50.00 0.00 3
8
13
18
23
2θ
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The surface morphology of the DFS samples was examined using the SEM technique and the images of the CI-DFS1–6 and their precursor CI samples are presented in (Figure 3). The surface of CI samples (CI:1-4) looks rough and rigid with sharp edges. When these samples were
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modified with diclofenac, the surfaces did not show much difference and they were becoming slightly smoother, and edges appeared slightly less sharp. The images captured at a higher magnification (Figure S2) showed that these surfaces were homogeneous with no phase
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separation or agglomeration of the organic materials. Furthermore, the range of particle size
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domains appeared to be about < 1 µm.
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CI-2
DFS-1
DFS-2
CI-3
CI-4
DFS-3
DFS4
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Figure 3. SEM Images of CI and DFS Samples
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TEM micrographs of the prepared Mt-ionene-diclofenac were also used to further assess the physical status of the Mt-ionene and Mt-ionene diclofenac. The TEM micrographs of thin
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film samples of CI: 1-4, and DFS1–4 are illustrated in Figure 4 a and b. The TEM images enabled the additional, qualitative evaluation of the nanocomposite structural characteristics. The observed dark and bold lines are of the silicate layers due to the natural structure of the primarily
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heavier elements compared with the organic ionene materials. The images show asymmetric dispersions of silicate layers in the CI samples, and some of the particles maintained their
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original ordering while others were exfoliated. The images supported the XRD observation. The images of the DFS samples did not differ much from those of the CI, and the silicate layers were
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evident as asymmetric dispersions and exfoliated sheets.
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CI-3
CI-4
DFS-3
DFS-4
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CI-2
DFS-1
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Figure 4 Transmission electron microscopy (TEM) images of the clay-ionene diclofenac system (CI and DFS) samples
DFS-2
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The thermal behavior of Na+Mt, CI and DFS samples is presented in Figure 5. The thermograms of the simple ionenes (I:1,2) and polyionenes (I-3 and I-4) showed more than one degradation steps, where first mass loss was ranged from 30–250°C due most probably to the
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loss of water, water associated to the ionenes. The second step ranged between 90 and 380 oC, and could be attributed to the degradation of the quaternary ammonium backbones. Most of the ionene samples decomposed with trace ash residue except for sample I-4, which left
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approximately 6% residue. The slight delay of sample I-4 is probably due to the presence of the aromatic rings which resist the degradation compared with the aliphatic chains. When the ionene
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samples were reacted with Na+Mt, the thermal stability of all samples was considerably enhanced, since the clay is not volatilized upon heating. The main degradation started at approximately 200°C and was due to the degradation of the ionene quaternary ammonium residue. The overall residue left over was 73 to 82% and 76 to 86 % for the CI and DFS samples,
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respectively. In these samples, the clay acted as a greater insulator and barrier to the volatile products produced during sample decomposition [36, 37]. In addition to the higher modulus of Na+Mt, and its coefficient of thermal expansion (CTE) being lower than that of the simple or
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polymeric ionene [36, 37].
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Figure 5. Thermogravimetric analysis (TGA) thermograms for clay-ionene diclofenac (CI-DFS) samples
DFS-2
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DFS-1
DFS-3
DFS-4
3.2. In-vitro Drug Release: The principal goal of controlled drug delivery systems is to control the burst release from the formulation under study, deliver the drug to a specific location at a controlled rate and amount, and reduce the side effects of the drug. To analyze the release behavior of the nanocomposite formulation samples DFS1–4, the in-vitro release at three
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different pH values, 2.0, 7.4, and 9.2 was investigated at 37°C for 48 h. The release behavior of all the investigated systems increased with increasing pH of the medium (Figure 6). With regard to the release behavior at pH 2 (simulated gastric fluid without pepsin), the release
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of diclofenac was maximum after 2 h, where only 18% and 11% were released from DFS1, and DFS2 samples. While for samples DFS3 and DFS4, the maximum release did not exceed 5% within two hours corresponding to the average stomach transit. The general order of release from
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samples was DFS1 ˃ DFS2 ˃ DFS3 ˃ DFS4. The faster release from DFS1 and DFS2 could be due to the surface reaction of the relatively small-sized simple ionene compounds bound to Mt
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where DFS1 has two methyl pendent groups while DFS2 contains two long chains of decyl groups in addition to the dimethyl pendent groups. Whereas samples DFS3 and DFS4 which contain polymeric quaternary ammonium appear to hold the diclofenac more tightly to their multi quaternary nitrogen’s which retarded the release of diclofenac from the polymeric chains,
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Although at low pH the clay edges may be protonated (AlOOH to AlOOH2 +X-) [27] and could prevent diclofenac from release, but the nature of the polymeric structure looks to have impact on the release behavior. This release behavior also indicates the higher stability of these
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nanocomposite formulations in the acidic medium. When these samples were examined at pH 7.4 (simulating intestinal fluid without
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pancreatin), the observed released amount of diclofenac was increased compared to what was observed at pH 2.0. In the case of DFS1 and DFS2 samples, the percentage of diclofenac released from the DFS1 formulation was up to 42, 52, and 53% after approximately 5, 29, and 48 h, respectively.
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Figure 6. Release behavior of DFS samples at different pH’s Release at pH 2.0
% Cumulative Release
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20 15
DFS1 DFS2
10
DFS3
5 0 0.0
0.5
1.0
1.5
2.0
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Time (hours)
Release at pH 7.4
100 80 60 40 20 0 0
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% Cumulative Rlease
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DFS4
10
20
DFS1 DFS2 DFS3 DFS4
30
40
50
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Time (hours)
Release at pH 9.2 DFS-1
80
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% Cumulative Release
100
DFS-2
60
DFS-3 DFS-4
40 20 0
0
10
20
30
40
50
Time (hours)
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However, DFS2, which has a similar structure to DFS1 but a longer chain, showed only a 10% maximum release after 10 h. For samples DFS3and DFS4 with polymeric ionene in their main structure, the released amount from DFS3 and DFS4 was 40 and 25% of their
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total content after 20 h, respectively.
At pH 9.2, a slow release of diclofenac was observed from all samples. Sample DFS1 showed the highest release of 94% in approximately 20 h, whereas DFS2 was the lowest with
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approximately 20% released amount after approximately 10 h. The polyionene-containing
samples DFS3 and DFS4 showed moderate rate and release characteristics. The percentage
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amount of diclofenac released from DFS3 was 42% after 48 h, while DFS4 showed 38 and 95% after 12 and 48 h, respectively. The overall observed order of release was as follows: DFS1 ˃ DFS3 ˃ DFS4 ˃ DFS2. At high, pH the clay edges were deprotonated, and the diclofenac could be held more to the clay edges, in addition to binding to the multiple nitrogen sites.
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3.3. Modeling Release Kinetics: The release profiles at pH 7.4 were analyzed by fitting the obtained release data to different kinetic models, which were the zero order, first order, Higuchi, and Korsmeyer-Peppas models to obtain insights into the mechanism of the release [38]. The
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zero order model describes the drug delivery system, which does not decompose, the active substance is released slowly regardless of the initial concentration of the drug. While, the release
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process is directly proportional to the drug concentration embedded in the carrier as described by the first order model. In case of Higuchi’s model, the release mechanism is considered as a pure diffusion process of the drug from the carrier, without erosion or swelling in the carrier, assuming homogeneously dispersed drug in carrier. The Korsmeyer -Peppas model can be used as a decision parameter between the Higuchi and zero order models [39, 40]. The model is
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generally used to study the release kinetics from 0 to 60% of drug release data, and the release mechanism is a function of the diffusion exponent n (equation 5). The results revealed that all the release profiles showed a good fit with the four models, as
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indicated by the correlation coefficient (R2) values. The values for the key parameters of the models used are summarized in Table 2.
The present nanocomposite formulations DFS1–4 may exhibit a combination of complex release
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behaviors including diffusion, erosion, swelling, and drug dissolution controlled release [41]. The release exponent (n) values obtained from the Korsmeyer-Peppas power law model provides
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information about the release mechanism from the dosage form. A value of n = 0.43 indicates a Fickian diffusion mechanism, whereas values ranging between 0.43 and 0.85 correspond to a non-Fickian diffusion (anomalous transport) and may follow first order release kinetics [42-44]. However, for a polydisperse systems lower values of n are possible, down to 0.30 which arise
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from the breadth of particle size distribution [42]. The obtained value of the release exponent n at pH 7.4 ranged from 0.70 to 0.13. Samples DFS1 and DFS3 exhibited non-Fickian diffusion (anomalous transport) while samples DFS2 and DFS4 exhibited Fickian diffusion. At pH 9.4,
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sample DFS1 showed non-Fickian diffusion while the rest of the samples showed Fickian diffusion. Based on these results, the system clay-polyionene-diclofenac can be practically
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applied in the examined pH range.
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Table 2. Analysis of the kinetic models of the release profiles of diclofenac system (DFS) samples, at pH 7.4 and 9.2 a) Kinetic Parameters of Release Study of DFS Samples, at pH 7.4 1st order release
Higuchi model
Korsmeyer-Peppas model
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Zero order release
Mechanism of Release
Sample code
R2
K0
R2
k1
R2
kH (min
DFS1
0.941
0.149
0.963
1.18E-01
0.979
DFS2
0.929
0.014
0.926
8.06E-03
DFS3
0.926
0.095
0.963
DFS4
0.963
0.010
0.987
−0.5
R2
k (min−n)
2.957
0.971
0.894
0.978
0.239
0.989
7.88E-02
0.984
1.021
0.940
2.30E-04
0.991
0.498
0.985
n
Non-Fickian diffuson
4.709
0.13
Fickian diffuson
4.887
0.27
Fickian diffuson
0.60
Non-Fickian diffuson
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0.70
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)
4.141
b) Kinetic Parameters of Release Study of DFS Samples at pH 9.2 1st order release
Higuchi model
Sample code
R2
k0
R2
k1
R2
DFS1
0.968
0.144
0.969
1.27E-01
DFS2
0.910
0.026
0.921
8.75E-03
DFS3
0.974
0.029
0.963
7.88E-02
DFS4
0.966
0.079
0.959
6.45E-03
Korsmeyer-Peppas model
0.5
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Zero order release
Mechanism of Release
R2
k (min−n)
0.992
3.411
0.987
0.514
0.78
Non- Fickian diffusion
0.994
0.613
0.987
5.410
0.23
Fickian diffusion
0.968
0.725
0.931
11.948
0.16
Fickian diffusion
0.990
7.700
0.973
1.509
0.43
Fickian diffusion
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kH (min− )
n
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3.4. Zeta Potential Measurements In order to evaluate the possibility of using the DFS system as a suspension formulation for
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practical application, the zeta potential was measured at the three pH values studied. Zeta potential is a measure of the electrical charge of particles are that are suspended in liquid, therefore the obtained results of a drug formulation system provides information about
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the type of charge (positive or negative) on the surface of the system carrying the drug. Besides, their values signify the stability of colloidal dispersions. The zeta potential was measured at the
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three pH values studied. As shown in Table 3, the zeta potential of the CI-DFS remained negative at a basic pH may be due to deprotonation of the Mt surface. While the observed positive values at low pH could be due to protonation of the surface of an oxide with surface hydroxyl groups.
Since the zeta potential is a function of the surface charge, the observed negative values at pH
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7.4 was probably due to adsorption arising from the buffer solution. The higher values obtained at pH 7.4 and 9.2 suggest the stability of the colloidal suspension of the formulation for practical
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applications.
Table 3. Zeta potential values (mV) for diclofenac system (DFS) samples DFS1
DFS2
DFS3
DFS4
2.0
10.31
19.52
46.99
3.92
7.4
-25.94
-38.62
51.02
-86.56
9.2
-30.31
-22.81
-20.39
-28.62
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pH
4.
CONCLUSIONS
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A new drug delivery system was designed based on clay containing poly quaternary ammonium and simple bi-quaternary ammonium salts CI-DFS. The release behavior of the CI-DFS showed that polyionene systems were slower than the simple bi-quaternary ammonium salts systems
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were. The observed slow release rate of diclofenac from the polyionene-drug system could be due to attachment of diclofenac to long polymer chains, where the drug molecule should diffuse away from the entangled polymeric chains. As the pH increased from acidic (stomach pH) to
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alkaline (colon pH), the release rate was also increased. The higher zeta potential values at pH 7.4 and 9.2 suggest that this CI system would an efficient and stable colloidal suspension for
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potential use in different drug formulations. The mixing of nanoclay with polyquaternary ammonium salt (polyionene) which can be tailored to a variety of structures can greatly alter the properties of the nanoclay, so that can bind to various functional groups, ligands, drugs, fertilizers, and catalysts for various applications.
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ACKNOWLEDGEMENTS
The authors would like to extend their appreciation to the Deanship of Scientific Research at
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Supporting Information available: Procedure for the preparation of materials under study. Figures: Figure S1: Collected FTIR Spectra of DFS1-4 samples; Figure S2: SEM Images at high magnification of Clay-ionen samples CI:1,2,4,5 and DFS samples DFS1-4; Figure S3: Kinetic
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models graphs of diclofenac release
Tables: Table S1: Elemental microanalysis and yield of the prepared ionenes; Table S2:
and elemental analysis of clay-ionene-drug.
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Figure Captions
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Elemental microanalysis and yields of clay-ionene compounds; Table S3: Sample composition
Figure 1. Fourier transform-infrared (FT-IR) spectra of diclofenac systems (DFS) 1-4 samples Figure 2. PXRD of Clay-Ionene-Drug
Figure 3. SEM Images of CI and DFS Samples
Figure 4. TEM Images of CI and DFS Samples
samples
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Figure 5. Thermogravimetric analysis (TGA) thermograms for clay-ionene diclofenac (CI-DFS)
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Figure 6. Release behavior of DFS samples at different pH’s
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We have investigated montmorillonite-polyquaternary ammonium (ionene) as a model of controlled drug release system.
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The release behavior of the montmorillonite-ionene systems was mainly Fickian diffusion
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Stable dispersions of montmorillonite-ionene systems would be a potential for effective drug-delivery application.
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S0254-0584(18)31092-7
DOI:
https://doi.org/10.1016/j.matchemphys.2018.12.054
Reference:
MAC 21217
To appear in:
Materials Chemistry and Physics
Received Date: 25 September 2018 Revised Date:
18 December 2018
Accepted Date: 20 December 2018
Please cite this article as: H. El-Hamshary, M.H. El-Newehy, M. Mohideen, A. El-Faham, A.S. Elsherbiny, Evaluation of clay-ionene nanocomposite carriers for controlled drug delivery: Synthesis, in vitro drug release, and kinetics, Materials Chemistry and Physics (2019), doi: https://doi.org/10.1016/ j.matchemphys.2018.12.054. 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.
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Evaluation of clay-ionene nanocomposite carriers for controlled drug delivery: synthesis, in vitro drug release, and kinetics
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Hany El-Hamshary*a,b, Mohamed H. El-Newehy*a,b, Meera Mohideena, Ayman El-Fahama,c, Abeer S. Elsherbinyb a
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Chemistry Department, College of Science, King Saud University, P.O. Box: 2455 Riyadh 11451, Saudi Arabia b Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt c Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria, 21321, Egypt
Hany El-Hamshary* [email protected]; [email protected] Tel: 00966508921099
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Mohamed H. El-Newehy* [email protected]
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Correspondence Author
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ABSTRACT To evaluate the impact of the different structure of quaternary ammonium salts (ionenes) as drug carrier of their corresponding organoclays, new nanocomposite clay-ionene (CI) drug carriers
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were prepared from montmorillonite (Mt) and polyquaternary ammonium salts (polyionene) and a simple bisquaternary ammonium salt. The CI drug systems were obtained by ion exchange of the sodium Mt (Na+Mt) with at least two-fold excess polyquaternary and bisquaternary
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ammonium salt compounds by ion exchange between sodium cations of the Na+Mt and the ammonium ions in the polyionene to produce CI systems with free quaternary ammonium halide
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side chains. Simple di-quaternary ammonium salts were also used to modify Mt. The structures of the prepared CI systems were characterized using Fourier transform-infrared spectroscopy (FT-IR), powder X-ray diffraction (XRD), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). As a model drug, sodium diclofenac (DS) was
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immobilized onto the CI through the remaining halide ions to provide the CI-diclofenac system (DFS). The release behavior of diclofenac from the different nanocomposites was studied at different pH values. The release behavior of the DFS showed that polyionene systems were
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slower than the simple bi-quaternary ammonium salts systems were. The kinetics of the release
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process were described using different models to explain the drug release mechanism.
KEYWORDS. Nanocomposites; Polyionene; Montmorillonite; Drug release; Sodium Diclofenac.
1.
Introduction
The therapeutic systems used to administer chemicals or drugs have received increasing consideration over the past two decades. Conventional administration of drugs is affected by
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certain restrictions including poor patient compliance associated with missed doses, adverse effects due to the fluctuation of drug levels, and difficulties in attaining steady state conditions because of incidences of typical peak-valley plasma concentration-time profiles [1]. Therefore,
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attention has been focused on methods of providing drugs continuously for prolonged periods in a controlled fashion to the site of action [2, 3]. This technique is termed controlled release and is used to describe the process of providing or delivering compounds in response to stimuli or time.
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Examples of stimulants that may be used to induce drug release include pH, enzymes, light, magnetic fields, temperature, ultrasound, and osmosis [4]. In addition to pharmaceuticals, other
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areas of application of controlled release systems currently include agriculture, food pesticides, cosmetics and personal care, and household products [5]. The benefits of controlled drug release systems over those of the conventional dosage forms are well recognized [6]. The characteristics of the systems used in the controlled delivery completely control the release behavior and the
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choice of the correct material appears crucial to certain applications [7]. The usual way to establish a controlled release system has been by combining the chemicals in a polymer matrix [4].
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Recently, clay minerals have received considerable attention as a new class of drug-delivery
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systems because of their colloidal properties, high retention, and swelling capacities [8, 9]. Other important properties include low or almost no toxicity, chemical inertness, ion exchange in the layers that allow clays to bind or host cationic drug molecules or both. In addition, they possess a high surface area with different morphologies (such as nanotubes, nanoplates and nanofibers) and adsorption capacity [10, 11]. The surface chemistry of nanoclays allows for targeted functionaliztions with organic materials so that the obtained nanocomposite can control loading and regulate release properties. The most widely used types of clay are the smectites such as
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montmorillonite (Mt) and saponite because they have a higher cation exchange capacity than that of other layered silicates used in pharmaceuticals such as kaolin, talc, and fibrous clay minerals [12-14]. The use of clay minerals in pharmaceutical formulations has been described by some
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authors [15, 16]. These minerals act as active principles or excipients. According to the curative activity for which the clay minerals are applied, they can be administered orally or topically. Oral applications include their use as gastrointestinal protectors, osmotic oral laxatives, and
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antidiarrheal. While topical applications include their use as dermatological protectors and in cosmetic products. Clay minerals used as excipients include smectites, kaolinite, talk, and
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palygorskite. They have been used as lubricants, disintegrants, inert cosmetic bases, and emulsifiers. Besides, organo-modified halloysites are among the clays which have potential for use as drug delivery carriers [17-19].
Clay minerals are layered silicates that typically exist in packed structures because of the
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favorable electrostatic attractions between the negatively charged clay sheets and positively charged counter ions [20]. Mt has a crystal structure consisted of two integrated silica tetrahedral sheets sandwiching an edge-shared octahedral sheet of either aluminum or magnesium hydroxide
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[21, 22]. The Positive counter ions are exchangeable and located in the clay interlayer. Therefore, these cations may be exchanged with other inorganic or organic cations through an
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ion-exchange reaction[23]. Organic cations include quaternary ammonium NR4 or phosphonium PR4 cations where R can be an alkyl, aryl, or polymeric group [24]. The organic cations include the polyionenes, which are polycationic compounds that contain ionic groups in the main chain. Most ion-containing polymers have quaternary nitrogen atoms in their polymeric backbone. Very few investigations have been conducted on clay-polyionene systems [25, 26]. It is worth mentioning to note that, another type of layered materials which is known as anionic clays or; the
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layered double hydroxides with a hydrotalcite-like structure has been also used as drug carriers, due to their ability to retain, by ion exchange, anionic molecule drugs [9, 27]. In this study, diclofenac sodium (DS), a non-steroidal anti-inflammatory drug, was immobilized
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onto the prepared clay-ionene (CI) system and the in vitro drug release was studied at different pH values. Moreover, the kinetics of the drug release were investigated. 2. Material and Methods
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2.1. Materials. The commercial sodium Mt (Na+Mt, Cloisite®Na) was received from
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Southern Clay Products, Gonzales, TX, USA). The cation exchange capacity (CEC) of Na+-Mt is 92.6 meq/100 g as stated by the producers and its basal spacing is 12.1 Å. Na+-Mt was used as received without any further purification. N,N-dimethyldecylamine, N,N,N′,N′tetramethylethylenediamine- (TMEDA), and methyl iodide were obtained from SigmaAldrich(Steinheim, Germany). α,αʹ-dichloro-p-xylene, and Dimethylformamide (DMF) was used
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in the state it was received from Acros Organics (Geel, Belguim). All other chemicals were used as received unless otherwise stated.
Synthesis of Ionene Materials
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2.2.
Simple diammonium salts were prepared by quaternization of a di-tert-amine with either alkyl
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halide/aryl halide or quaternization of a dihalide with either a tertiary amine or phosphine. Ionene polymers were synthesized according to the method described by Rembaum et al. [28], (Scheme1, Table S1).
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I
–
I
– +
+
N
N
CH3I N
N
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Cl
N,N,N',N'-Tetramethyl-ethane-1,2-diamine (TMEDA)
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(I-1)
Cl
Cl
α,α′-dichloro- p-xylene
+
N
Cl
Cl +
N
(I-3)
Cl
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Cl
Cl
1,2-Dichloroethane
+
N
n
+
N
n
(I-4)
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Cl
Cl
α,α′-dichloro- p-xylene
N
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N,N'-dimethyldecylamine
Cl
Cl
–
– +
N
+
N
(I-2)
Scheme 1: Synthesis of polyionene and bis-quaternary ammonium salts materials
2.2.1.
Synthesis of N,N,N,Nʹ,Nʹ,Nʹ-hexamethyl-1,2-ethanediamonium diiodide
(HMEDADI, I-1). The diammonium salt N,N,N,N’,N’,N’-hexamethyl-1,2-ethanediamonium diiodide (HMEDADI) was obtained by reacting iodomethane with TMEDA.
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2.2.2. Synthesis of benzene-1,4-diylbis (N,N-dimethyldecyl ammonium chloride, BDBDMDAC, I-2). Benzene-1,4-diylbis (N, N-dimethyldecyl ammonium chloride, BDBDMDAC, I-2) was obtained by reacting α,α′-dichloro-p-xylene with N,N-dimethyldecyl
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amine.
2.2.3. Synthesis of poly(dimethylene, xylylene ionene, PDMXI, I-3). Poly(dimethylene,
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xylylene ionene, PDMXI, I-3 was obtained by reacting α,α′-dichloro-p-xylene with TMEDA. Synthesis of poly2,2-ionene, I-4). Poly2,2-ionene (PI, I-4) was obtained by reacting 1,2-
2.3.
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dichloroethane with TMEDA. Modification of Na+Mt- with Ionene (CI: 1-4)
The CI sample (CI-1) was prepared using a typical method (Scheme 2): Na+Mt, (2.0 g) was placed in a 100-mL Erlenmeyer flask and allowed to swell in 50 mL distilled water (H2O) under
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magnetic stirring at 40°C for 24 h. Then, aqueous ionene (I-1) solution (10 mL) in double number of moles of clay was added to the clay suspension. The contents were continuously stirred for 48 h at 40oC. The CI nanocomposite material was isolated by centrifugation at 5000
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rpm, washed thoroughly with distilled H2O until no chloride ions were observed in the filtrate using the silver nitrate (AgNO3 test), washed with ethanol, and finally with diethyl ether. The
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solid was vacuum-dried at 40°C for 24 h. The remained halide ions from excess ionene were determined using the Volhard method, [29] and the results are presented in (Table S1). Samples CI: 2-4were synthesized using the similar procedure as described for the synthesis of CI-1. The composition of CI materials and the elemental microanalysis of the synthesized CI samples is shown in Table S2.
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2.4.
Preparation of CI-Diclofenac System (CI-DFS). The CI diclofenac system (DFS)
samples were prepared as follows (Scheme 3): a suspension of CI-1 (1.0 g, 0.86 mmol Cl-/g) was placed in 25 mL H2O and stirred at 40°C for 12 h. Then, an aqueous solution of sodium
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diclofenac (DS, 0.9 mmol) was added to the suspension, and the mixture was stirred
continuously for 48 h at 40°C. The product was isolated by centrifugation at 5K rpm, and
washed thoroughly with distilled H2O, followed by ethanol and finally with diethyl ether. The
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samples were vacuum-dried at 40°C for 24 h (Table S3).
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same procedure was used to prepare the other CI-DFS samples (DFS2–4, Table S3) and the
2.5. Drug Release Study
2.5.1. Determination of Total DS Content. A sample of known mass was suspended in 3 mL buffer solution at pH 9.2 while heating at 60oC. Spectrophotometric measurement was used to
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detect the release of DS at λmax 276 nm until a fixed value was obtained. 2.5.2. In Vitro Drug Release. A fixed weight of the sample (10 mg) was suspended in 3 mL buffer solutions at pH values of 2.0, 7.4, and 9.2 at 37°C. The cumulative percentage of drug
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released was determined using spectrophotometric measurement at λmax 276 nm, using a standard calibration curve for diclofenac[30]. All the experiments were carried out in triplicate,
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and the average was calculated. The percentage amount of diclofenac released was estimated using equation:
Drug release % = Mt/Mo x 100
(1)
Where Mo and Mt represent the amount of diclofenac-loaded and released at time t, respectively.
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2.6.
Evaluation of Release Kinetics and Mechanism. To study the mechanism of diclofenac
release, the obtained release data were analyzed by fitting to different kinetic models, which
Zero order model
M = Mo + Ko t
(2)
First order model
log M = log Mo - K1 t /2.303
(3)
Higuchi Model
Mt /M∞ = KH + t1/2
(4) (5)
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Mt /M∞ = K tn
Korsmeyer-Peppas Model
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were analyzed as follows:
MO = Initial amount of drug in solution KO = Zero order rate constant t = time K1 = First order constant
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Where: Mt and M∞ = Amount of drug release or dissolved drug at time (t), and at equilibrium.
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Mt /M∞ = fraction of drug released at time t.
M∞ = amount of drug released after an infinite time KH = Higuchi rate constant
Characterization
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2.7.
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n = release exponent of Korsmeyer-Peppas power low model
2.7.1. Elemental Microanalysis. The elemental microanalysis was performed using PerkinElmer 2400 Series II CHNS/O Elemental Analyzer. Ultraviolet (UV-VIS) spectra: Measurements were recorded on a Perkin-Elmer UV/vis spectrophotometer (Lambda-35). The selected wavelengths for measuring diclofenac was 276 nm.
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2.7.2. Fourier Transform-infrared (FT-IR) Absorption Spectra. The Fourier transforminfrared (FT-IR) spectra were recorded using a Bruker, TENSOR 27 spectrophotometer, using
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the potassium bromide (KBr disc technique). 2.7.3. Nuclear Magnetic Resonance (NMR) spectra. The NMR were recorded using a JEOL JNM-PM X90 Si-NMR 400 MHz spectroscopy instrument. Experimental conditions
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2.7.4. Thermogravimetric Analysis (TGA). The thermogravimetric analysis (TGA) were carried out using the TA-Q500 System from TA Instruments at a temperature range of 30 to
kept within a 3–5 mg range.
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800oC and a scanning rate of 10ºC/min under a nitrogen atmosphere. The sample weight was
2.7.5. Scanning Electron Microscope (SEM). The surface morphology of the composites was examined using the JEOL JSM-6380 scanning electron microscope (SEM) equipped with an
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energy dispersive X-ray detector. Gold-coated compressed specimens were examined at their fracture surface for enhanced scanning electron microscopy (SEM) imaging. Experimental
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conditions
2.7.6. Transmission Electron Microscopy (TEM). The transmission electron microscopy
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(TEM) analysis was carried out using the JEOL 1011 CX (Tokyo, Japan) instrument at an accelerating voltage of 20 KV. A small amount of the polymer-clay was dispersed in 5 mL distilled water and then thoroughly sonicated using probe sonication. A copper coated grid was dipped in the solution and then completely oven-dried at 40°C. The prepared grid was loaded onto the transmission electron microscope.
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2.7.7. Powder X-Ray Diffraction (PXRD). The X-ray diffraction measurements were carried out using the Rigaku Ultima IV X-ray diffractometer operated at a Cu–Kα wavelength (λ) of 1.5418 Å, over an angular range 2θ from 3 to 40° and a scan rate of 0.5°/min. A generator setting
used to compute the crystallographic spacing.
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of 40 kV and 40 mA, and divergence slit of 2/3o were used, and Bragg's law (n λ = 2 d sin θ) was
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2.7.8. Zeta potential measurements. Zeta potential measurements were carried out using
NanoPlus zet/nano particle analyzer. A small amount of the CI-DFS nanocomposite (0.1 g) was
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dispersed in 10 mL distilled water and then thoroughly sonicated using probe sonication. The samples were allowed to settle for around 1 h and a few mLs of suspension from the top of the tube was measured. 3. RESULTS AND DISCUSSION
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The intrinsic hydrophilic nature of clay minerals renders them incompatible with a wide range of hydrophobic or nonpolar polymeric materials. Therefore, they can be made organophilic by reacting them with organic cations using ion-exchange. Organic cations that can be exchanged
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for the interlayer cations include ammonium or phosphonium ions. Exchanging the inorganic
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cations with organic cations expands the interlayer spaces, which facilitates the movement of the organic chains within these interlayers. Moreover, the surface properties become organophilic rather than hydrophilic. In the present investigation, bis-quaternary ammonium salts and polyionenes were used to both lower the surface energy of the Mt and provide a large number of active groups that could bind with the drug molecules. We compared the release behavior of the prepared quaternary ammonium compounds (ionenes) of different compositions. The ionenes were both polymeric ionenes (I-3 and I-4) and simple bis-
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quaternary ammonium salts (I-1 and I-2). Biquaternary ammonium salts such as I-1 have only terminal methyl groups while I-2 has two terminal methyl and one decyl groups. The CI was formed using an ion exchange reaction of Na+Mt with an excess amount of the prepared ionenes
+
-+
+
X A
A X
H O, 48 h, 40 oC 2 -NaX
-
O-Na+
Clay (Na+Mt-)
Ionene = I: 1-4 A= N, X = Cl- or I-
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(Scheme 1) to produce organically modified Mt-ionenes as outlined in (Scheme 2).
+
+
O- A
A X
-
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Clay-Ionene = CI: 1-4
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Scheme 2: Ion-exchange intercalation of montmorillonite with ionenes The ionenes reacted with Na+Mt by ion exchange and, therefore, the produced nanocomposites became organophilic with at least an excess pendent site capable of binding with other ionic
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substrates. Treatment of the generated CI materials (CI-1, CI-2, CI-3, and CI-4) with DS at the remaining nitrogen site provided the CI-DFS drug system (Scheme 3).
+
O- A
A X
H2O, 48 h, 40oC -NaX
O
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Clay-Ionene (CI)
O-Na+
R
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Diclofenca sodium
O- A
A -O
R O
Clay-Ionene-Drug (DFS)
Cl
R= Cl
N H
A= N or P and X = Cl or I
Scheme 3. Preparation of clay-ionene (CI)-drug nanocomposites
3.1. Characterization: The nanocomposite drug systems were characterized by using FT-IR, XRD, TEM, and TGA. The FT-IR Spectra of DFS samples are presented in Figure 1. In DFS1 (Figure 1a), the starting material Na+Mt showed an overlapping band at 3630 and 3422 cm−1 due
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to the –OH stretching vibration, and hydrogen bonds, and for aluminum hydroxide (Al-OH) and other structural –OH groups present in the Mt. A characteristic peak of silicon dioxide (SiO2) asymmetric stretching band appeared at 1042 and 921 cm-1. Two small peaks appeared at 918
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and 550 cm-1, and they were due to Al-Al-O and Si-O-Al respectively [31, 32]. The same trend was observed for other DFS samples. The collected FT-IR spectrograms (Figure S1) showed the
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intercalation of ionene and polyionene with the clay interlayers.
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Figure 1. Fourier transform-infrared (FT-IR) spectra of diclofenac systems (DFS) 1-4 samples
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The FT-IR spectrogram of CI-1 (Figure S1) revealed a characteristic band at 3625 cm−1 for the OH group. The bands present at 2943, 1764, and 1456 cm−1 corresponded to the quaternized nitrogen (+N) group, and the band at 1073 cm−1 was related to C-N. The overlapping peak at 3022 cm−1 was related to C–H stretch of methylene units and the CH3 of R-N(CH3)2 while the band appearing at 2955 cm−1 was due to the C–H stretching of the alkyl group. The peaks at 1485 and 460 cm−1 were most probably due to the fundamental stretching and deformation vibrations of the CH3 groups of the tertiary amine salt. The FT-IR spectrum of pure diclofenac
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showed characteristic peaks for NH stretching of the secondary amine at 3385 cm-1 and the – C=O stretching of the carboxyl ion at 1575 cm-1. A band at 1557 cm-1 corresponded to the C=C ring stretching and the peak at 746 was due to the C- Cl stretching [33, 34]. The spectrum of the
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matrix attached DFS1 maintained the characteristic bands of the component of the entire
nanocomposite in which overlapping peaks appeared at 3628 and 3431 cm-1 for NH stretching, OH, and the ammonium salt, N+ R4. The peaks at 1348 cm−1 corresponded to the C-N stretching
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[35]. Group samples of DFS2, DFS3, and DFS4 showed similar spectra to those of the DFS1 group.
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The PXRD pattern of the obtained DFS nanocomposites and Na+Mt was used to characterize the intercalation of the ionene-drug with the clay. The diffraction patterns of Na+Mt and the DFS samples are illustrated in Figure 2, while the basal spacing data are shown in Table 1. The diffraction pattern of the Na+Mt (Figure 2) showed a characteristic peak at 2θ = 7.45, with a
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corresponding basal spacing (d001) of 11.86 Å, as determined by Bragg’s law (n λ = 2d sin θ), where λ is the wavelength, d is the interlayer distance of the plane of reflection, and θ is the diffraction angle. All of the modified DFS samples were shifted to lower 2θ values and is
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associated with increased basal spacing, which ranged from 1.38 to 2.54 Å as presented in Table 1. Such observed decrease in the 2θ value, and increased basal spacing is indicative of the
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effective intercalation after the cation-exchange reaction between the Na+ ions and the excess bulky quaternary ammonium ions. Such excess quaternary ammonium ions were used to fix the diclofenac by ion exchange of the remained halide ion of the ionenes with the diclofenac anions. However, the observed shoulder appeared at 2θ around 19 degree, could be attributed to the excess amount of ionene, as the polyionene and simple ionene have extra cationic sites
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exchanged with sodium cations, leading to expand the interlayer spacing while the rest of the molecules are oriented to surface of the clay, and is adsorbed on the clay surface.
d Spacing (Å) 11.83 13.90 13.21 14.30 14.37
Layer expansion --2.07 1.38 2.47 2.54
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2 theta 7.45 6.18 6.10 5.87 6.19
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Material Na+Mt DFS1 DFS2 DFS3 DFS4
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Table 1. Interlayer d-spacing and spacing shift
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Figure 2. XRD of Clay-Ionene-Drug 250
DFS-1
DFS-2
Mt Diclofenac
200
200
Intensity
DFS-1 150
Intensity
150 100
50
0 13
18
23
3
2θ
DFS-3
240
Mt Diclofenac DFS-3
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200 Intensity
160 120
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80
0 3
8
13 2θ
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40 18
23
8
13
18
23
2θ Mt
DFS-4
300.00
Diclofenac
250.00
DFS-4
200.00
Intensity
8
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0
3
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100
50
Mt Diclofenac DFS-2
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250
150.00 100.00 50.00 0.00 3
8
13
18
23
2θ
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The surface morphology of the DFS samples was examined using the SEM technique and the images of the CI-DFS1–6 and their precursor CI samples are presented in (Figure 3). The surface of CI samples (CI:1-4) looks rough and rigid with sharp edges. When these samples were
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modified with diclofenac, the surfaces did not show much difference and they were becoming slightly smoother, and edges appeared slightly less sharp. The images captured at a higher magnification (Figure S2) showed that these surfaces were homogeneous with no phase
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separation or agglomeration of the organic materials. Furthermore, the range of particle size
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domains appeared to be about < 1 µm.
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CI-2
DFS-1
DFS-2
CI-3
CI-4
DFS-3
DFS4
AC C
EP
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C1-1
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Figure 3. SEM Images of CI and DFS Samples
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TEM micrographs of the prepared Mt-ionene-diclofenac were also used to further assess the physical status of the Mt-ionene and Mt-ionene diclofenac. The TEM micrographs of thin
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film samples of CI: 1-4, and DFS1–4 are illustrated in Figure 4 a and b. The TEM images enabled the additional, qualitative evaluation of the nanocomposite structural characteristics. The observed dark and bold lines are of the silicate layers due to the natural structure of the primarily
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heavier elements compared with the organic ionene materials. The images show asymmetric dispersions of silicate layers in the CI samples, and some of the particles maintained their
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original ordering while others were exfoliated. The images supported the XRD observation. The images of the DFS samples did not differ much from those of the CI, and the silicate layers were
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evident as asymmetric dispersions and exfoliated sheets.
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CI-3
CI-4
DFS-3
DFS-4
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CI-2
DFS-1
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EP
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C1-1
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Figure 4 Transmission electron microscopy (TEM) images of the clay-ionene diclofenac system (CI and DFS) samples
DFS-2
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The thermal behavior of Na+Mt, CI and DFS samples is presented in Figure 5. The thermograms of the simple ionenes (I:1,2) and polyionenes (I-3 and I-4) showed more than one degradation steps, where first mass loss was ranged from 30–250°C due most probably to the
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loss of water, water associated to the ionenes. The second step ranged between 90 and 380 oC, and could be attributed to the degradation of the quaternary ammonium backbones. Most of the ionene samples decomposed with trace ash residue except for sample I-4, which left
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approximately 6% residue. The slight delay of sample I-4 is probably due to the presence of the aromatic rings which resist the degradation compared with the aliphatic chains. When the ionene
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samples were reacted with Na+Mt, the thermal stability of all samples was considerably enhanced, since the clay is not volatilized upon heating. The main degradation started at approximately 200°C and was due to the degradation of the ionene quaternary ammonium residue. The overall residue left over was 73 to 82% and 76 to 86 % for the CI and DFS samples,
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respectively. In these samples, the clay acted as a greater insulator and barrier to the volatile products produced during sample decomposition [36, 37]. In addition to the higher modulus of Na+Mt, and its coefficient of thermal expansion (CTE) being lower than that of the simple or
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polymeric ionene [36, 37].
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Figure 5. Thermogravimetric analysis (TGA) thermograms for clay-ionene diclofenac (CI-DFS) samples
DFS-2
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DFS-1
DFS-3
DFS-4
3.2. In-vitro Drug Release: The principal goal of controlled drug delivery systems is to control the burst release from the formulation under study, deliver the drug to a specific location at a controlled rate and amount, and reduce the side effects of the drug. To analyze the release behavior of the nanocomposite formulation samples DFS1–4, the in-vitro release at three
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different pH values, 2.0, 7.4, and 9.2 was investigated at 37°C for 48 h. The release behavior of all the investigated systems increased with increasing pH of the medium (Figure 6). With regard to the release behavior at pH 2 (simulated gastric fluid without pepsin), the release
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of diclofenac was maximum after 2 h, where only 18% and 11% were released from DFS1, and DFS2 samples. While for samples DFS3 and DFS4, the maximum release did not exceed 5% within two hours corresponding to the average stomach transit. The general order of release from
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samples was DFS1 ˃ DFS2 ˃ DFS3 ˃ DFS4. The faster release from DFS1 and DFS2 could be due to the surface reaction of the relatively small-sized simple ionene compounds bound to Mt
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where DFS1 has two methyl pendent groups while DFS2 contains two long chains of decyl groups in addition to the dimethyl pendent groups. Whereas samples DFS3 and DFS4 which contain polymeric quaternary ammonium appear to hold the diclofenac more tightly to their multi quaternary nitrogen’s which retarded the release of diclofenac from the polymeric chains,
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Although at low pH the clay edges may be protonated (AlOOH to AlOOH2 +X-) [27] and could prevent diclofenac from release, but the nature of the polymeric structure looks to have impact on the release behavior. This release behavior also indicates the higher stability of these
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nanocomposite formulations in the acidic medium. When these samples were examined at pH 7.4 (simulating intestinal fluid without
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pancreatin), the observed released amount of diclofenac was increased compared to what was observed at pH 2.0. In the case of DFS1 and DFS2 samples, the percentage of diclofenac released from the DFS1 formulation was up to 42, 52, and 53% after approximately 5, 29, and 48 h, respectively.
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Figure 6. Release behavior of DFS samples at different pH’s Release at pH 2.0
% Cumulative Release
25
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20 15
DFS1 DFS2
10
DFS3
5 0 0.0
0.5
1.0
1.5
2.0
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Time (hours)
Release at pH 7.4
100 80 60 40 20 0 0
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% Cumulative Rlease
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DFS4
10
20
DFS1 DFS2 DFS3 DFS4
30
40
50
EP
Time (hours)
Release at pH 9.2 DFS-1
80
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% Cumulative Release
100
DFS-2
60
DFS-3 DFS-4
40 20 0
0
10
20
30
40
50
Time (hours)
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However, DFS2, which has a similar structure to DFS1 but a longer chain, showed only a 10% maximum release after 10 h. For samples DFS3and DFS4 with polymeric ionene in their main structure, the released amount from DFS3 and DFS4 was 40 and 25% of their
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total content after 20 h, respectively.
At pH 9.2, a slow release of diclofenac was observed from all samples. Sample DFS1 showed the highest release of 94% in approximately 20 h, whereas DFS2 was the lowest with
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approximately 20% released amount after approximately 10 h. The polyionene-containing
samples DFS3 and DFS4 showed moderate rate and release characteristics. The percentage
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amount of diclofenac released from DFS3 was 42% after 48 h, while DFS4 showed 38 and 95% after 12 and 48 h, respectively. The overall observed order of release was as follows: DFS1 ˃ DFS3 ˃ DFS4 ˃ DFS2. At high, pH the clay edges were deprotonated, and the diclofenac could be held more to the clay edges, in addition to binding to the multiple nitrogen sites.
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3.3. Modeling Release Kinetics: The release profiles at pH 7.4 were analyzed by fitting the obtained release data to different kinetic models, which were the zero order, first order, Higuchi, and Korsmeyer-Peppas models to obtain insights into the mechanism of the release [38]. The
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zero order model describes the drug delivery system, which does not decompose, the active substance is released slowly regardless of the initial concentration of the drug. While, the release
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process is directly proportional to the drug concentration embedded in the carrier as described by the first order model. In case of Higuchi’s model, the release mechanism is considered as a pure diffusion process of the drug from the carrier, without erosion or swelling in the carrier, assuming homogeneously dispersed drug in carrier. The Korsmeyer -Peppas model can be used as a decision parameter between the Higuchi and zero order models [39, 40]. The model is
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generally used to study the release kinetics from 0 to 60% of drug release data, and the release mechanism is a function of the diffusion exponent n (equation 5). The results revealed that all the release profiles showed a good fit with the four models, as
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indicated by the correlation coefficient (R2) values. The values for the key parameters of the models used are summarized in Table 2.
The present nanocomposite formulations DFS1–4 may exhibit a combination of complex release
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behaviors including diffusion, erosion, swelling, and drug dissolution controlled release [41]. The release exponent (n) values obtained from the Korsmeyer-Peppas power law model provides
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information about the release mechanism from the dosage form. A value of n = 0.43 indicates a Fickian diffusion mechanism, whereas values ranging between 0.43 and 0.85 correspond to a non-Fickian diffusion (anomalous transport) and may follow first order release kinetics [42-44]. However, for a polydisperse systems lower values of n are possible, down to 0.30 which arise
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from the breadth of particle size distribution [42]. The obtained value of the release exponent n at pH 7.4 ranged from 0.70 to 0.13. Samples DFS1 and DFS3 exhibited non-Fickian diffusion (anomalous transport) while samples DFS2 and DFS4 exhibited Fickian diffusion. At pH 9.4,
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sample DFS1 showed non-Fickian diffusion while the rest of the samples showed Fickian diffusion. Based on these results, the system clay-polyionene-diclofenac can be practically
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applied in the examined pH range.
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Table 2. Analysis of the kinetic models of the release profiles of diclofenac system (DFS) samples, at pH 7.4 and 9.2 a) Kinetic Parameters of Release Study of DFS Samples, at pH 7.4 1st order release
Higuchi model
Korsmeyer-Peppas model
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Zero order release
Mechanism of Release
Sample code
R2
K0
R2
k1
R2
kH (min
DFS1
0.941
0.149
0.963
1.18E-01
0.979
DFS2
0.929
0.014
0.926
8.06E-03
DFS3
0.926
0.095
0.963
DFS4
0.963
0.010
0.987
−0.5
R2
k (min−n)
2.957
0.971
0.894
0.978
0.239
0.989
7.88E-02
0.984
1.021
0.940
2.30E-04
0.991
0.498
0.985
n
Non-Fickian diffuson
4.709
0.13
Fickian diffuson
4.887
0.27
Fickian diffuson
0.60
Non-Fickian diffuson
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0.70
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4.141
b) Kinetic Parameters of Release Study of DFS Samples at pH 9.2 1st order release
Higuchi model
Sample code
R2
k0
R2
k1
R2
DFS1
0.968
0.144
0.969
1.27E-01
DFS2
0.910
0.026
0.921
8.75E-03
DFS3
0.974
0.029
0.963
7.88E-02
DFS4
0.966
0.079
0.959
6.45E-03
Korsmeyer-Peppas model
0.5
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Zero order release
Mechanism of Release
R2
k (min−n)
0.992
3.411
0.987
0.514
0.78
Non- Fickian diffusion
0.994
0.613
0.987
5.410
0.23
Fickian diffusion
0.968
0.725
0.931
11.948
0.16
Fickian diffusion
0.990
7.700
0.973
1.509
0.43
Fickian diffusion
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kH (min− )
n
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3.4. Zeta Potential Measurements In order to evaluate the possibility of using the DFS system as a suspension formulation for
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practical application, the zeta potential was measured at the three pH values studied. Zeta potential is a measure of the electrical charge of particles are that are suspended in liquid, therefore the obtained results of a drug formulation system provides information about
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the type of charge (positive or negative) on the surface of the system carrying the drug. Besides, their values signify the stability of colloidal dispersions. The zeta potential was measured at the
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three pH values studied. As shown in Table 3, the zeta potential of the CI-DFS remained negative at a basic pH may be due to deprotonation of the Mt surface. While the observed positive values at low pH could be due to protonation of the surface of an oxide with surface hydroxyl groups.
Since the zeta potential is a function of the surface charge, the observed negative values at pH
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7.4 was probably due to adsorption arising from the buffer solution. The higher values obtained at pH 7.4 and 9.2 suggest the stability of the colloidal suspension of the formulation for practical
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applications.
Table 3. Zeta potential values (mV) for diclofenac system (DFS) samples DFS1
DFS2
DFS3
DFS4
2.0
10.31
19.52
46.99
3.92
7.4
-25.94
-38.62
51.02
-86.56
9.2
-30.31
-22.81
-20.39
-28.62
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pH
4.
CONCLUSIONS
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A new drug delivery system was designed based on clay containing poly quaternary ammonium and simple bi-quaternary ammonium salts CI-DFS. The release behavior of the CI-DFS showed that polyionene systems were slower than the simple bi-quaternary ammonium salts systems
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were. The observed slow release rate of diclofenac from the polyionene-drug system could be due to attachment of diclofenac to long polymer chains, where the drug molecule should diffuse away from the entangled polymeric chains. As the pH increased from acidic (stomach pH) to
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alkaline (colon pH), the release rate was also increased. The higher zeta potential values at pH 7.4 and 9.2 suggest that this CI system would an efficient and stable colloidal suspension for
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potential use in different drug formulations. The mixing of nanoclay with polyquaternary ammonium salt (polyionene) which can be tailored to a variety of structures can greatly alter the properties of the nanoclay, so that can bind to various functional groups, ligands, drugs, fertilizers, and catalysts for various applications.
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ACKNOWLEDGEMENTS
The authors would like to extend their appreciation to the Deanship of Scientific Research at
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Supporting Information available: Procedure for the preparation of materials under study. Figures: Figure S1: Collected FTIR Spectra of DFS1-4 samples; Figure S2: SEM Images at high magnification of Clay-ionen samples CI:1,2,4,5 and DFS samples DFS1-4; Figure S3: Kinetic
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models graphs of diclofenac release
Tables: Table S1: Elemental microanalysis and yield of the prepared ionenes; Table S2:
and elemental analysis of clay-ionene-drug.
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Figure Captions
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Elemental microanalysis and yields of clay-ionene compounds; Table S3: Sample composition
Figure 1. Fourier transform-infrared (FT-IR) spectra of diclofenac systems (DFS) 1-4 samples Figure 2. PXRD of Clay-Ionene-Drug
Figure 3. SEM Images of CI and DFS Samples
Figure 4. TEM Images of CI and DFS Samples
samples
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Figure 5. Thermogravimetric analysis (TGA) thermograms for clay-ionene diclofenac (CI-DFS)
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Figure 6. Release behavior of DFS samples at different pH’s
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We have investigated montmorillonite-polyquaternary ammonium (ionene) as a model of controlled drug release system.
•
The release behavior of the montmorillonite-ionene systems was mainly Fickian diffusion
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Stable dispersions of montmorillonite-ionene systems would be a potential for effective drug-delivery application.
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•