The use of Zn-Ti layered double hydroxide interlayer spacing property for low-loading drug and low-dose therapy. Synthesis, characterization and release kinetics study

Accepted Manuscript The use of Zn-Ti layered double hydroxide interlayer spacing property for low-loading drug and low-dose therapy. Synthesis, characterization and release kinetics study Rima Djaballah, Abdelhadi Bentouami, Abdellah Benhamou, Bruno Boury, El Hadj Elandaloussi PII:

S0925-8388(17)34495-X

DOI:

10.1016/j.jallcom.2017.12.299

Reference:

JALCOM 44385

To appear in:

Journal of Alloys and Compounds

Received Date: 4 October 2017 Revised Date:

13 December 2017

Accepted Date: 25 December 2017

Please cite this article as: R. Djaballah, A. Bentouami, A. Benhamou, B. Boury, E.H. Elandaloussi, The use of Zn-Ti layered double hydroxide interlayer spacing property for low-loading drug and lowdose therapy. Synthesis, characterization and release kinetics study, Journal of Alloys and Compounds (2018), doi: 10.1016/j.jallcom.2017.12.299. 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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Graphical abstract

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ACCEPTED MANUSCRIPT The use of Zn-Ti layered double hydroxide interlayer spacing property for lowloading drug and low-dose therapy. Synthesis, characterization and release kinetics study Rima Djaballah1,2, Abdelhadi Bentouami*1, Abdellah Benhamou2, Bruno Boury3, El Hadj

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Elandaloussi1

Laboratoire de Valorisation des Matériaux, Faculté des Sciences et de la Technologie, Université Abdelhamid Ibn Badis - Mostaganem, BP 227, Mostaganem, Algeria

Faculté de Chimie, Université des Sciences et de la Technologie d’Oran Mohamed Boudiaf

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B.P. 1505, Oran El M’Nouer, Algeria

ICG-CMOS UMR 5253, Université Montpellier 2, Place Eugène Bataillon CC 1702, 34095

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Montpellier Cedex 05, France Tel: +213 771 906 144

[email protected] and [email protected]

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Abstract

Zn-Ti layered double hydroxide (LDH) with the shortest interlayer d-spacing (6.6-6.8 Å) was used for the first time for controlled release of the standard model drug ibuprofen. We

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show that the latter could be loaded up to ~26% (w/w) and report its kinetic release, while indicating possible uses to avoid drug overdose effects and its adaptability for low-dose drug

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therapy. Nanohybrid Ibup-Zn-Ti-LDH was characterized by PXRD,

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C NMR, TGA, SEM

and drug release was controlled in simulated intestinal medium (pH 6.8 phosphate buffer solution (PBS) at 37°C). The release kinetics showed that ~ 2/3 of the loaded drug amount was rapidly released in the first phase, followed by slow long-term release (up to 24 h) which was probably inherent to the short interlayer distance of LDH or could be attributed to the strong interaction between the drug anions and the Zn-Ti host layers due to the high charge density on the layers. The modeling kinetics for the release data indicated that the ibuprofen release process from Ibup-Zn-Ti-LDH was closely in line with the modified second-order and 1

ACCEPTED MANUSCRIPT parabolic diffusion models. These results suggest that the Ibup-Zn-Ti-LDH delivery system is controlled by the diffusion of ibuprofen ions into aqueous solutions via an exchange mechanism with phosphate anions. By comparison to LDH with higher d-spacing, the study revealed a clear effect of the short d-spacing of Zn-Ti-LDH nano-composite material.

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Keywords: Biomaterial; Ibup-Zn-Ti-LDH; Ibuprofen; Layered materials; Drug delivery system Nano- composite; Drug release. 1. Introduction

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Improvements in drug delivery systems require more efficient chemical or physical barriers in order to regulate the drug release and guarantee the desired dose [1]. They can be

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based on organic carriers, including polymers such as chitosan, [2-4] amphiphilic block copolymers, [5] copolymer micelle sequences, [6] hydrogels, [7] cellulose, [8] polysaccharides, [9] lipid micro-emulsions [10], etc.. Ibuprofen is a model molecule to check their ability, with the most recently reported being organic (with PLA, [11, 12] or bacterial

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cellulose [13]), all mineral (like hollow CaWO4 microspheres, [14] mesoporous silica [15]) or hybrid systems, such as those based on silica-gelatin composites [16] or on layered double hydroxide (LDH) LDH-polymers (with PLA [17] or chitosan [18]).

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LDHs are currently used in the pharmaceutical chemistry [19-23] and are easy to synthesize at low-cost, while having good biocompatibility, low cytotoxicity [19, 23] and

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offering high protection for intercalated drugs, while generally exhibiting no reactivity towards the drug. LDHs have thus been used in recent decades as host materials for biomolecules such as DNA, [24-27] adenosine triphosphate (ATP), [28] amino acids or enzymes, [29-32] vitamins, [33, 34] antibiotics [24, 35] and anti-inflammatories [36], not only for controlled drug release and their antacid properties, but also for their long-term preservation. Ambrogi et al. [37] intercalated ibuprofen in Mg–Al–LDH by ion exchange from the chloride form of hydrotalcite. Lu et al. [38] intercalated ibuprofen by a co-assembly

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ACCEPTED MANUSCRIPT process between ibuprofen molecules and Mg–Al–LDH sheets after delamination. Rojas et al. [39] and Gunawan and Xu [40] achieved ibuprofen intercalation into Mg-Al-LDH via coprecipitation. LDHs with the general formula [M2+1−xM3+x(OH)2(An−)x/n]·yH2O have a lamellar structure

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derived from a brucite whose properties can be adjusted through the nature of the divalent (Mg2+, Zn2+, Cu2+, etc.) and trivalent (Al3+, Cr3+, Fe3+) cations. Partial substitution of divalent cations by trivalent ones results in positively charged layers balanced with more or less

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solvated anions in the interlayer region [19, 21, 23, 41-43]. When such anions are active substances, they can be released by an ion exchange mechanism with anions of the medium.

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Mg2+, Al3+, Zn2+, Fe3+, Li+ and Cu2+ are reportedly the cations most commonly used in LDH synthesis and are known to contain intercalated biomolecules, [22] with Mg–Al–LDH being mostly used [37-39, 44-51]. It has been shown that various physico-chemical properties control the release process, including LDH-drug and drug-drug interaction modes, as reported

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by Rojas et al., [52] crystallite size, [47] pH sensitivity, [53] as well as the diffusion path length in the oriented solid matrix [35]. To the best of our knowledge, the effect of interlayer d-spacing has not been investigated despite the fact that it can have a marked impact on the

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drug packing, accessibility, loading and release. Zn-Ti LDH has been used as photocatalyst, [54-57] but to our knowledge never reported as

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an ibuprofen container. Hence, here we investigated, for the first time, the use of Zn-Ti LDH as an ibuprofen drug container and as a low-dose drug carrier. All synthesized MII/MIII LDHs have an interlayer distance of ≈7.5-9.0 Å, e.g. 7.7-8.1 Å for Mg-Al-LDH [54, 58-60] and up to 8.9 Å for Zn-Al-LDH [61, 62]. For MII/MIV-LDHs, the d-spacing can also be high, as it is for Ni-Ti-LDH (7.22-7.75 Å). Previously published findings indicate that shorter interlayer spacing is only possible with the Zn-Ti system where d-spacing of 6.6-6.8 Å, [55-57, 63, 64] results from stronger electrostatic interactions, thereby leading to slightly narrow spacing

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ACCEPTED MANUSCRIPT between sheets. This can have major effects on drug loading, solvation, diffusion, anion/LDH sheet interactions and finally on the release kinetics of intercalated biomolecules into LDH. Huang et al. [65] studied the mechanism of ibuprofen release from Mg-Al-Ibp prepared by the hydrothermal co-precipitation method. The author describes the effects of particle size,

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interlayer distance, as well as guest-guest and guest-host interactions. The 75% loaded ibuprofen release time was 560 min from Mg-Al-Ibp, with an interlayer distance (003) of 21.9 Å.

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As shown below, we prepared and characterized a layered material with intercalated ibuprofen (Ibup-Zn-Ti-LDH) and different kinetic models were investigated to match the

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experimental data of the ibuprofen release process as closely as possible. This allowed us to investigate the effects of narrow d-spacing on the drug loading and release process. 2. Experimental 2.1. Materials

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Ibuprofen sodium salt (PubChem CID: 5338317) (analytical standard ≥ 98%) was purchased from Fluka, while the other inorganic reagents were analytical grade and used without further purification. Deionized water, from which carbon dioxide was removed by 10

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min boiling under nitrogen bubbling, was used in all preparations and washings. 2.2. Zn-Ti-LDH host preparation

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Pristine Zn-Ti-LDH (molar ratio Zn/Ti = 5.5) was synthesized by a non-conventional coprecipitation method from solutions A, B, and C as follows: Aqueous solution A was prepared by dissolving 2.25 ml (0.020 mol) of TiCl4 (PubChem CID: 24193) in 6 ml of 32% (w/w) HCl in water. Aqueous solution B was prepared by dissolving 33.58 g (0.112 mol) of Zn(NO3)2.6H2O in 30 ml of H2O. Aqueous solution C was prepared by dissolving 35.84 g (0.597 mol) of urea (PubChem CID: 1176) in 100 ml of H2O.

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ACCEPTED MANUSCRIPT Solutions A and B were mixed under stirring in a 1 L flask in which solution C was added drop wise at a flow rate of 3 ml min-1. Under a nitrogen atmosphere, the resulting mixture was heated under gentle reflux with vigorous stirring for 96 h. The obtained precipitate was separated by centrifugation and the solid was washed several times with boiling deionized

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water until the negative chloride test with AgNO3 and dried overnight at 80°C. 2.3. Ibup-Zn-Ti-LDH preparation

The ibuprofen intercalated guest, in Zn-Ti-LDH interlayers with a molar ratio of Zn/Ti set

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at 5.5, was prepared by a non-conventional co-precipitation method from solutions A, B, C and D as follows: Aqueous solution A was prepared by dissolving 2.25 ml (0.020 mol) of

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TiCl4 in 6 ml of 32% (w/w) HCl in water. Aqueous solution B was prepared by dissolving 33.58 g (0.112 mol) of Zn(NO3)2.6H2O in 30 ml of H2O. Aqueous solution C was prepared by dissolving 35.84 g (0.597 mol) of urea in 100 ml of H2O. Aqueous solution D was made by dissolving 4.12 g (0.02 mol) of ibuprofen in 280 ml of an aqueous solution of 0.01 M of

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NaOH. Solutions A and B were mixed under stirring in a 1 L flask in which a mixed C and D solution was added drop wise at a flow rate of 3 ml min-1. Under nitrogen atmosphere, the resulting mixture was heated under gentle reflux with vigorous stirring for 96 h. The obtained

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material was separated by centrifugation, washed several times with boiling deionized water until the negative chloride test with AgNO3, and dried overnight at 80°C.

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2.4. Characterization of the prepared materials Powder X-ray diffraction data were collected under monochromatic Cu Kα1 radiation (
= 1.54056 Å) at 40 kV and 30 mA using an Empyrean PANalytical diffractometer. Thermogravimetric (TG) analyses were performed with a Netzsch TGA 409 PC thermobalance at a heating rate of 20°C min-1 from 25 to 900°C. The Zn and Ti metal element analysis was conducted using inductively coupled plasma atomic emission spectrometry (ICPAES) on a Perkin Elmer Optima 8000 spectrometer. CHO elemental microanalyses were

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ACCEPTED MANUSCRIPT performed on a Thermo Finnegan Elemental Analyzer. Cross polarization magic angle spinning (CPA-MAS) 13C NMR spectra of ibuprofen, Ibup-Zn-Ti-LDH and Zn-Ti-LDH were recorded on a Bruker 300 (Digital NMR Avance) spectrometer. The morphological features of the prepared materials were monitored under a HITACHI S-

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4800 scanning electron microscope (SEM) with an excitation voltage ranging from 0.5 to 8.0 kV. Powdered samples were gently deposed on double-sided tape stuck on sample port and then Pt-metalized by sputtering under vacuum.

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2.5. Ibuprofen release study

Ibuprofen release from Ibup-Zn-Ti-LDH was studied using simulated intestinal fluid

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without enzymes (0.05 mol L-1 PBS, pH = 6.8 ± 0.1) according to the United States Pharmacopoeia (USP) guidelines. Ibup-Zn-Ti-LDH (0.500 g) was dispersed in 500 mL of PBS at pH 6.8. The suspension was shacked at a constant rate of 100 rpm at a temperature of 37 ± 1°C. A 5 mL aliquot was withdrawn at given time intervals and replaced with the same

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volume of fresh PBS medium solution maintained at 37 ± 1°C. After centrifugation at 4000 rpm for 15 min, the ibuprofen concentration in the supernatant was determined after dilution at 221.5 nm under a UV-visible spectrophotometer HACH DR/4000 using the predetermined

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calibration curve. The release tests were repeated three times to obtain the average results. 3. Results and Discussion

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3.1. Synthesis and characterization of prepared materials An original co-precipitation method was used to enhance the layer formation. Urea was thus used as reactant to promote slow LDH precipitation at a urea/(Zn2+ + Ti4+) molar ratio of 4.5. This system allowed better precipitation regulation by controlling pH variations during controlled urea decomposition into cyanate, giving rise to carbonate and ammonia. [66, 67] This method was fully compatible with the presence of ibuprofen, which could be positioned as compensating anions in the lamellar structure.

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ACCEPTED MANUSCRIPT Fig. 1 shows the PXRD patterns obtained for ibuprofen (Fig. 1 (a)); Zn-Ti-LDH (Fig. 1 (b)) and Ibup-Zn-Ti-LDH (Fig. 1 (c)), i.e. typical of lamellar materials. As shown in the ibuprofen X-ray pattern, no peaks were observed at position 2θ below 10°. Moreover, no crystalized ibuprofen peaks were observed in the Ibup-Zn-Ti-LDH X-ray pattern. Zn-Ti-LDH

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exhibited a strong reflection peak on the basal plane (003) at 2θ = 12.94°, and other peaks with low intensities on the other planes (006), (009), (012), (015), (018), (110) and (113), corresponding to 2θ values of 24.05°, 30.91°, 35.87°, 38.64°, 47.27°, 57.86° and 59.58°,

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respectively, in agreement with previous data [39, 55, 57]. Moreover, from the 003 reflection peak at 2θ = 12.94°, the basal interlayer distance d003 of Zn-Ti-LDH was calculated to be 6.83

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Ǻ, i.e. which was slightly higher than the values reported by Chen et al.[55] (d003 = 6.76 Ǻ) and Shao et al. [57] (d003 = 6.60 Ǻ) for Zn-Ti-LDH. In Ibup-Zn-Ti-LDH, the 00l peaks shifted to lower 2θ values, but with lower intensity (Fig. 1 (c), inset), suggesting that a few ibuprofen molecules were intercalated between LDH sheets. However, the presence of two 003

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reflection peaks at 2θ = 5.29° and 10.59°, corresponding to d003 spacing values of 16.71 Ǻ and 8.34 Ǻ, respectively, indicated the coexistence of disordered sheets. Hence, not all LDH sheets were intercalated and the interlayer distance thus increased from 6.83 Ǻ (for Zn-Ti-

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LDH) to 16.71 Ǻ (for Ibup-Zn-Ti-LDH).

Considering the thickness of the brucite-like sheet (4.8 Ǻ), the interlayer d-spacing value

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owed to the presence of the ibuprofen anion could therefore be estimated at 11.91 Ǻ in IbupZn-Ti-LDH. This suggests that the ibuprofen anions were not arranged along and flat against the brucite-like layers, but rather were tilted towards the sheets (Fig. 2). Given the length of the ibuprofen molecule (10.05 Ǻ, as calculated with Chem3D software), a ≈ 90° tilt angle could be assumed, which also suggests that an additional water molecule was present (1.86 Ǻ), so the calculation becomes 10.05 + 1.86 + 4.8 = 16.71 Ǻ, in agreement with the experimental value.

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ACCEPTED MANUSCRIPT This was much smaller than the values reported by authors who had inserted ibuprofen in various M(II)/M(III) LDHs other than a Zn/Ti pair. Khan et al. [48] obtained d-spacing of 22.3 Ǻ with ibuprofen intercalated in Li-Al-LDH, while Lu et al. [38] reported that the interlayer spacing was 23.1 Ǻ once ibuprofen was located between Mg-Al-LDH sheets. This new

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situation could cause moderate to slow release kinetics owed to the more limited diffusion processes and nano-confinement.

The solid-state 13C MAS NMR spectra of Zn-Ti-LDH, Ibup-Zn-Ti-LDH and ibuprofen are

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shown in Fig. 3. This characterization confirmed the presence of ibuprofen.

All signals of the different ibuprofen carbon atoms appeared in the 13C spectrum of Ibup-

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Zn-Ti-LDH. However, the signal obtained at 164.6 ppm in the spectrum could be attributed to interlayer carbonate anions found in both Zn-Ti-LDH and Ibup-Zn-Ti-LDH. This corroborated the presence of two layered phases, as suggested by the PXRD analysis, i.e. one with carbonate and the other with ibuprofen.

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Table 1 summarizes the ibuprofen chemical shift values from the Ibup-Zn-Ti-LDH spectrum in comparison to those of pure ibuprofen and Zn-Ti-LDH. Nanoplate morphology was observed by SEM (Fig. 4) for both materials, i.e. typical of

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layered double hydroxide materials. Intercalation of ibuprofen between Zn-Ti-LDH sheets had a slight influence on the nanoplate morphology. Indeed, the nanoplates appeared to be

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smoother than those observed in the case of Zn-Ti-LDH (Fig. 4 (A-D)). In addition, this intercalation resulted in a slight change in the Ibup-Zn-Ti-LDH nanoplate morphology (Fig. 4 (E-H)) since they were stacked on top of each other with dimensions greater than those of Zn-Ti-LDH. No ibuprofen crystallization on the surface of LDH sheets was observed which have been suggested on PXRD discussion part. Thermogravimetric (TG) and differential thermal analysis (DTA) curves of Zn-Ti-LDH and Ibup-Zn-Ti-LDH performed in an air environment are shown in Fig. 5.

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ACCEPTED MANUSCRIPT For Ibup-Zn-Ti-LDH (Fig. 5 (a)), the TG curve exhibited four decomposition steps: (i) up to 190-200°C first elimination of carbonates and water from deshydroxylation (ca. 190 250°C), (ii) second elimination between 250 and 350°C, (iii) ibuprofen decomposition (≈350 460°C) and (iv) from 460 to 900°C, about 0.9% was lost due to final deshydroxylation and

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metal oxide formation.

Thermal elimination of ibuprofen from Ibup-Zn-Ti-LDH thus occurred in two steps or more, in contrast to the thermal decomposition of pure ibuprofen (Fig. 5 (c)). We noted that

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part of the carbonates degraded at lower temperature for Ibup-Zn-Ti-LDH (Fig. 5 (a)) compared to Zn-Ti-LDH (Fig. 5 (b)). This raises the question on the nature of the second

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weight loss that we could attribute to either the decomposition of another part of the carbonates (as for Zn-Ti-LDH) or loss of ibuprofen vapor.

From the (TG) and (DT) analysis, ICP-AES and CHO elemental analysis, the composition and general formula of Zn-Ti-LDH and Ibup-Zn-Ti-LDH were determined, as presented in

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Table 2. The Zn/Ti molar ratio determined from the analysis results was slightly less than that of the starting solutions in the case of Zn-Ti-LDH. However, for Ibup-Zn-Ti-LDH, this molar ratio was slightly greater than that of the starting solutions. Importantly, based on the

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composition given in Table 2, the amount of ibuprofen contained in LDH was estimated at 25.53% (w/w). This was less than found in other LDHs, especially Mg-Al-LDH (36% [38] to

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54% (w/w) [39]) but it could be sufficient in low-dose therapy. 3.2. In vitro ibuprofen release from Ibup-Zn-Ti-LDH Ibuprofen release was achieved in simulated intestinal fluid without enzymes (0.05 mol L-1 PBS, pH = 6.8 ±0.1). The profile of ibuprofen release from Ibup-Zn-Ti-LDH is shown in Fig. 6 and is based on the anionic exchange with phosphate anions from aqueous solution achieved in two steps. A burst was observed in the first step (20 min) and was ascribed to the presence of an ibuprofen anion on the external surface of LDH particles. For medical applications, this

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ACCEPTED MANUSCRIPT could be easily eliminated by pre-conditioning. More interestingly, in a second step, ≈40% of the ibuprofen was released over a very long period of up to 24 h. This second phase was the key step of the release process and was certainly related to the short distance between the LDH sheets. The two phases played an important role in the therapeutic treatment by the rapid

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release of 2/3 of the total dose followed by the slow release of the remaining drug over a long period.

This should be compared to ibuprofen release with other LDH systems: Ambrogi et al. [37]

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reported 60% release after 20 min and 100% after 100 min for Mg-Al-Ibup LDH, whereas for Lu et al. [38] it took 9 h for Mg-Al LDH to release ibuprofen. The slower release that we

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observed for Ibup-Zn-Ti-LDH was probably inherent to the short interlayer distance of LDH or could be attributed to the strong interaction between the drug anions and the Zn-Ti host layers due to the high charge density on the layers compared to that of Mg-Al. The drug diffusion rate out of LDH was not only controlled by the rigidity of the sheets

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and the diffusion path length but also by the spacing between the LDH sheets. This spacing was governed by the nature of the metals involved in the LDH synthesis. Indeed, divalent metals such as Mg, Ca, Zn, Ni, Fe(II), and trivalent ones such as Al, Fe(III), produce LDHs

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with an interlayer distance greater than 7.7 Å [42, 44, 45, 59], with the exception of the association between Zn and Ti [57, 68, 69], which gives d-spacing of less than 7 Å. Perioli et

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al. [70] reported that the reduction in the distance to reach the external part of crystals in nanosized particles in comparison to larger sized particles was the only aspect which influenced the drug release rate. This means that for a rapid release of anionic drugs intercalated between LDH sheets, it is preferable that LDH be prepared from the divalent and trivalent metals mentioned above. However, for slow release, it is advisable to choose Zn and Ti as metals for drug carrier LDH synthesis.

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ACCEPTED MANUSCRIPT 3.3. Modeling ibuprofen kinetics release Several types of drug release kinetics models have been proposed for LDHs to predict release profiles and understand the mechanisms involved. Among these models, four are often applied for these materials: the modified Freundlich model (Eq. (1)), the parabolic diffusion

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model (Eq. (2)), the Elovich model (Eq. (3)), and the Bhaskar model (Eq. (4)) [71-73]

Various studies have reported that the solute adsorption kinetics of materials such as layered double hydroxides involve solution to solid mass transfers. Drug delivery from the

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material to the solution, which in most cases is driven by ion exchange, is also considered as involving mass transfer from the solid phase to the solution. For these considerations, the

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adsorption kinetics laws can be applied over existing ones to the release process. Accordingly, the modified second-order model (Eq. (5)) [74] was also tested in the LDH drug release kinetics. 

(1 −  ) = ( ) +  ()    



=   . + 



1- = () + 





=



! 

+

(1)

(2) (3) (4) (5)

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Log 1 −   = −  .

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Mt is the amount of ibuprofen released at time t in buffer solution, Mi is the initial amount intercalated on LDH, k is the rate constant, and finally a, b are the constants. The experimental data plots according to the five models are presented in Fig. 7. Linear correlation coefficient R2 values were all greater than 0.82. However, very good correlations were obtained between the experimental data and the modified second-order and parabolic diffusion models, with R2 values of 0.9988 and 0.9680, respectively. These results suggest that the ibuprofen release process from Ibup-Zn-Ti-LDH was closely in line with the modified 11

ACCEPTED MANUSCRIPT second-order and parabolic diffusion models. Both models explain that the delivery system is controlled by a diffusion process via intra-particle diffusion or surface diffusion. Yang et al. [73] reported that a parabolic equation has been used to describe diffusion controlled phenomena in clays. The Ibup-Zn-Ti-LDH delivery system was controlled by ibuprofen ion

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diffusion into aqueous solutions via an exchange mechanism with phosphates anions. 4. Conclusion

The present study revealed for the first time the excellent properties of Zn-Ti-LDH,

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different from the properties of previously used Mg-Al LDH. Thanks to the very short interlayer space in Zn-Ti-LDH, the amount of ibuprofen intercalated into LDH (≈ 26

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%) was suitable for small-dose therapy and the release process was extended to up to 24 h. The latter was adequately described by both parabolic diffusion and modified second-order models, indicating that the release process is controlled by surface diffusion or intra-particle diffusion (interlayer space). Finally, the results of this study

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demonstrated that the LDH interlayer distance could be considered as a key parameter and tailored to the drug targeted for release and appeared to be the most suitable for ibuprofen and others anionic drugs LDH prepared from zinc and titanium.

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Acknowledgements

The authors are grateful for the assistance provided by Dr. Bernard Fraisse for material

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characterization by DRX in the Laboratory for Aggregates, Interfaces and Materials for Energy (AIME) of the Charles Gerhardt Institute for Molecular Chemistry (ICGM), UMR 5253, Montpellier 2 University (France).

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pharmaceutically active compounds from a layered double hydroxide, Chem. Commun., (2001) 2342-2343.

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Biochem., 34 (1999) 451-465.

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ACCEPTED MANUSCRIPT Figures Captions Figure 1: PXRD patterns of (a) ibuprofen, (b) Zn–Ti-LDH and (c) Ibup-Zn-Ti-LDH. Figure 2: Schematic representation of the LDH structure (a) before and (b) after ibuprofen intercalation.

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Figure 3: MAS 13C NMR spectra of ibuprofen, Ibup-Zn-Ti-LDH and Zn-Ti-LDH.

Figure 4: SEM images of Zn–Ti-LDH (A-D) and of Ibup-Zn-Ti-LDH (E–H) LDH.

Figure 5: TGA-DTA curves of (a) Zn-Ti-LDH, (b) Ibup-Zn-Ti-LDH and (c) pure

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ibuprofen.

Figure 6: In vitro ibuprofen release from Ibup-Zn-Ti-LDH in pH 6.8 PBS at 37°C.

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Figure 7: Plots of ibuprofen release kinetics from Ibup-Zn-Ti-LDH according to the five

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ACCEPTED MANUSCRIPT Table 1 Assignment of 13C solid-sate spectra for samples

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Chemical shift (ppm) Ibup-Zn-Ti-LDH Zn-Ti-LDH 183.9 46.1 139.3 129.1 30.6 22.8 164.2

164.6 169.1

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1 2 and 9 3 and 8 4, 5, 6 and 7 10 11 and 12 13 CO32-C-O-N

Ibuprofen 184.1 45.3 139.3 129.3 30.9 23.4 17.3

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Material

% Zn 47.13 36.94

% Ti 6.34 4.85

%C 3.65 17.44

%H 1.29 3.35

Chemical formula Zn0.84Ti0.16(OH)2CO3)0.16.0.47 H2O Zn0.85Ti0.15(OH)2(Ibup)0.169(CO3)0.075.0.298 H2O

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Zn-Ti-LDH Ibup-Zn-Ti-LDH

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Table 2 Chemical Compositions of the prepared materials

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ACCEPTED MANUSCRIPT Figure 1 (a)

70000 60000

40000

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cps

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006

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cps

20000

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Figure 2

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H3C

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Ibuprofen

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Figure 5

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y = - 0.0921 + 0.7120 2 R = 0.9067

0.05

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Modified Freundlich Model

-1.0

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y = -0.7685x + 2.1856 R² = 0.8258

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Ln(t) 1.8 Bhaskar Model

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ACCEPTED MANUSCRIPT Highlights
The Synthesis of a new hybrid layered material Ibu-Zn-Ti LDH is described
The shorter d-spacing is the special one for LDH prepared only by Zn and Ti
The hybrid material is based on short d-spacing as parameter for low drug loading

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This property also leads to low prolonged drug release

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The kind of this LDH is an efficiency host for anionic drug for low-dose therapy