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Materials Research Bulletin 48 (2013) 1512–1517
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Facile fabrication of ibuprofen–LDH nanohybrids via a delamination/reassembling process Xiaomei Lu, Liming Meng, Haiping Li, Na Du, Renjie Zhang, Wanguo Hou * Key Laboratory for Colloid and Interface Chemistry of Education Ministry, Shandong University, Jinan 250100, PR China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 July 2012 Received in revised form 18 October 2012 Accepted 22 December 2012 Available online 31 December 2012
In this paper, a delamination/reassembling method for the facile fabrication of ibuprofen (IBU), a nonsteroidal anti-inflammatory drug, intercalated layered double hydroxide (LDH) nanohybrid was presented. In this method, LDH particles were first delaminated to well dispersed 2D nanosheets in formamide, and then the LDH nanosheets and IBU molecules coassembled into the IBU–LDH nanohybrid. The characteristics of the so-synthesized nanohybrid were the same as that of the IBU–LDH nanohybrids synthesized by the conventional methods including ion exchange, co-precipitation, reconstruction and hydrothermal methods. However, the delamination/reassembling method displayed various remarkable advantages, such as simple procedure, short reaction time, mild condition and high drug loading, compared with the conventional methods. ß 2012 Elsevier Ltd. All rights reserved.
Keywords: A. Layered compounds A. Nanostructures B. Intercalation reactions C. X-ray diffraction
1. Introduction Over the past decade, the layered double hydroxides (LDHs) have been attracting much attention in drug delivery and gene therapy for their good biocompatibility, nontoxicity, and controlled-release property [1,2]. Ibuprofen (IBU), a-methyl-4-(2methylpropyl)benzene-acetic acid, is a non-steroidal anti-inflammatory drug used for relieving of symptoms of rheumatoid arthritis and osteoarthritis [3]. A controlled-release formulation for IBU needs to be improved for the side effects and short half-life of IBU [4]. Extensive efforts have been made to synthesize IBU–LDH nanohybrids by using various methods, including ion exchange [5,6], co-precipitation [7], reconstruction [8] and hydrothermal methods [9]. However, these conventional methods have the following drawbacks: complex processes, time-consuming, low drug loading amount and high reaction temperature. Herein, we describe a delamination/reassembling process for the facile fabrication of drug–LDH nanohybrids. Firstly, LDH particles were delaminated into well dispersed 2D nanosheets, and then the nanosheets and drug molecules were coassembled into drug–LDH nanohybrids. To date, the delamination of LDHs has been widely investigated [10–14], and it was found that formamide is an excellent delaminating reagent [13]. Utilizing the re-stacking of the nanosheets provided by the exfoliation process, many core–shell materials and multilayer films were synthesized by using the
* Corresponding author. Tel.: +86 0531 88365460; fax: +86 0531 88364750. E-mail address: [email protected] (W. Hou). 0025-5408/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.materresbull.2012.12.057
layer-by-layer technique [15–18]. The delamination–restacking behaviors were also used to synthesize macromolecules, such as polyacrylamide [19] and carboxymethyl cellulose [20], intercalated LDH nanohybrids. However, to the best of our knowledge, the synthesis of drug–LDH nanohybrids by the delamination/reassembling process has not been reported. Compared with the conventional methods, the delamination/reassembling process presented in this paper exhibits excellent characteristics, such as simple procedure, short reaction time, mild condition and high drug loading. 2. Experimental 2.1. Materials Ibuprofen (95% purity) was purchased from Xi’an GuZhongGu biological technology Co., Ltd. (Xi’an, China) and used as received. Its structure is presented in Fig. 1. Other chemicals used are of analytical grade. The water used was purified with a Hitech-Kflow water purification system (China). 2.2. Synthesis and characterization of IBU–LDH nanohybrids The pristine Mg3Al-NO3 LDH sample was synthesized with a coprecipitation method [21]. The delamination of the LDH sample was performed according to the method described by Wu et al. [22]. The LDH sample (0.4 g) was dispersed in formamide (20 ml) with magnetically stirring and the dispersion was sonicated to be transparent. After resting overnight at room temperature, the delaminated LDH nanosheet dispersion was obtained.
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microanalysis of C, H, and N was obtained with a Vario EI III analyzer. The contents of Mg and Al were determined by inductively coupled plasma (ICP) atomic emission spectroscopy (Jarrel-ASH, ICAP-9000) after the samples were dissolved in a dilute acid solution. The absorbance of ibuprofen solution was measured with an HP-8453 model UV-Vis spectroscope. 2.4. In vitro drug release measurement
Fig. 1. Structure of ibuprofen molecule.
The IBU–LDH nanohybrid was synthesized via a coassembling process between LDH nanosheets and IBU molecules. A typical synthetic procedure is shown as follows: 20 ml of the so-obtained LDH nanosheet dispersion was dropped into 20 ml of IBU ethanol solution containing 0.4 g IBU under slow magnetic stirring. After resting at 40 8C for 10 min, the dispersion was centrifuged at 6000 rpm for 5 min. The supernatant being removed, the obtained precipitate was washed two times with water and once with alcohol (3 ml each time) by a re-dispersion/centrifugation cyclic process. The precipitate, IBU–LDH nanohybrid, was dried at 60 8C in vacuum. 2.3. Characterization X-ray diffraction (XRD) patterns were recorded with a BrukerD8 Advanced diffractometer equipped with Cu Ka radiation (l = 1.54056 A˚) at 40 kV and 40 mA. Fourier-transform Infrared (FT-IR) spectra were recorded with a Bruker Vector 22 model spectrometer in air at room temperature using KBr disc technique. Morphology of the samples was observed with a JEOL-JEM-6700 scanning electron microscope (SEM) at 5.0 kV. Thermal gravimetric analyses and differential scanning calorimeters (TG–DSC) were carried out in an airflow with a NETZSCH STA 449 F3 thermal analysis system at a heating rate of 10 8C/min. Elemental
The release measurement was performed by putting 0.04 g of IBU–LDH nanohybrid sample in 400 ml of phosphate buffer solution (PBS, pH 7.4) at 37 8C under magnetic stirring. Aliquots (4 ml) of supernatant were taken at given time intervals, and meanwhile 4 ml of fresh PBS was added to the system. The supernatant withdrawn was filtered through a syringe filter with the pore of 0.45 mm in diameter, and the IBU concentrations in the supernatants were determined by measuring the absorbance at 221 nm with an HP-8453 model UV-Vis spectroscopy to obtain the release amounts (qt) of IBU from the IBU–LDH nanohybrid sample, in turn, to calculate the accumulated percent releases (Xt) of IBU from the sample. For comparison, the release profile of the physical mixture of LDH and IBU was conducted at the same condition. 3. Results and discussion 3.1. The reassembling process of LDH nanosheets with IBU After the LDH sample was dispersed in formamide, a transparent colloidal dispersion was obtained, and the Tyndall phenomenon could be observed in the dispersion (see Fig. 2). It indicates that the LDH sample was successfully delaminated to give a LDH nanosheet suspension [11]. When the LDH nanosheet suspension was dropped into IBU ethanol solution, the mixture became immediately cloudy and the Tyndall phenomenon disappeared (see Fig. 2). The disappearance of Tyndall phenomenon suggests that the addition of IBU molecules destroyed the colloidal state of LDH nanosheet suspension. In fact, a reassembling process took place to form an IBU–LDH nanohybrid. The delamination/ coassembly process can be proved by XRD examinations (see Fig. 3). Formamide, which has a very high ability to form hydrogen bonds with hydroxyl groups of the LDH host, is an effective delaminating agent for LDHs [22]. In the delaminated suspension, the carbonyl (–C5 5O) group of formamide has a strong interaction with the LDH nanosheets, whereas the amine group (–NH2) bonds weakly with NO3 [11]. After adding IBU molecules, the electrostatic interaction between the carboxyl (–COO) group of
Fig. 2. (A) Tyndall light scattering of the suspension of delaminated LDH in formamide and (B) light scattering of the suspension containing IBU and LDH.
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(Ain) of IBU was calculated to be 34.12%. It was found that the delamination/reassembling process induced the Mg/Al molar ratio to change from 2.85 to 2.23. Similar result was reported in literature [13]. In addition, it was interesting that the loading amount of IBU in the nanohybrid exceeded the maximum loading determined by the charge-balancing law between LDH layers and IBU anions. It reveals that the IBU species intercalated in the LDH gallery can exist in two forms, carboxylate anion (IBU) and carboxylic acid (IBU). This has not been reported in previous literature [3,5–9]. The possible reasons for this phenomenon are the use of organic medium (or non-alkaline medium) and the low IBU intercalation restriction in the synthetic procedure compared with the conventional methods. In order to further verify the result, the influence of the mass ratio of IBU to LDH in raw materials, RI/L, on the loading amounts and the chemical compositions of the IBU–LDH nanohybrids were examined (see Table 1). It was found that the Ain values increased with increasing RI/L, and indeed the carboxylate anion and carboxylic acid forms of IBU molecules coexisted in the gallery of LDH.
Fig. 3. XRD patterns of (A) Mg3Al-NO3 LDH, (B) delaminated LDH and (C) IBU–LDH nanohybrid.
3.3. Characterization of IBU–LDH nanohybrid 3.3.1. XRD analysis The XRD patterns of the pristine LDH, delaminated LDH and IBU–LDH nanohybrid samples are shown in Fig. 3. As can be seen, the XRD patterns of the pristine LDH sample (Fig. 3A) exhibited all characteristic diffractions of hydrotalcite (JCPDS card no. 51-1528), indicating that the pristine LDH sample was of a well-crystallized hydrotalcite-like structure. The d0 0 3 value is the interlayer distance (d-spacing) of the layered materials. It can be seen from Fig. 3A that the pristine LDH had a d-spacing of 0.86 nm, which is the same as reported in the literature for Mg-Al-NO3 LDH [22]. The XRD patterns of delaminated LDH in formamide (Fig. 3B) showed a pronounced halo in a 2u region of 20–308, which was produced by formamide [13]. It indicates the delamination of LDH was quite completed. In addition, a weak reflection at 2u = 628 (marked with *) could be observed, indicating that the 2D crystalline of the LDH layer was preserved. These results demonstrate that well-crystallized LDH crystals have been delaminated into nanosheets. After the coassembly of LDH nanosheets and IBU, the so-obtained sample showed the XRD patterns with the characteristic diffractions of hydrotalcite
IBU and the LDH nanosheets is stronger than the hydrogen bonding interaction between the carbonyl group of formamide and the LDH nanosheets. As a result, the formamide molecules on the LDH nanosheets will be replaced by IBU molecules, resulting in the restacking of LDH layers intercalated by IBU molecules. Scheme 1 shows a possible delamination/reassembling mechanism for IBU– LDH nanohybrid. In order to verify whether the restacking process arose from the presence of IBU molecules, the same experiment was carried out with pure ethanol instead of IBU ethanol solution. No appearance change of the system was evidently observed in 48 h. 3.2. Loading of IBU on LDH The results of elemental analyses and thermogravimetric analyses showed that the chemical compositions of the pristine LDH and the IBU–LDH nanohybrid samples were [Mg0.74Al0.26(OH)2](NO3)0.20(CO32)0.030.54H2O and [Mg0.69Al0.31(OH)2](IBU)0.02(IBU)0.25(NO3)0.062.40H2O, respectively. Based on the content of C in the nanohybrid sample, the loading amount
Scheme 1. Schematic illustration of possible delamination/reassembling mechanism for IBU–LDH nanohybrid. Table 1 Chemical compositions of LDH and IBU–LDH nanohybrids obtained at different mass ratios of IBU to LDH in raw materials. RI/L
Content calculated (found)/wt% Al
Mg LDH 0.5 1.0 1.5 2.0
21.47 11.25 10.24 10.69 9.26
(21.43) (11.30) (10.30) (10.59) (9.30)
8.49 5.68 5.18 6.77 5.86
C (8.47) (5.62) (5.23) (6.74) (5.80)
0.44 21.19 26.06 30.43 40.44
N (0.47) (21.15) (25.81) (30.82) (40.45)
3.39 1.62 0.52 0.98 0.84
Ain
Chemical compositions
– 27.96 34.12 40.75 53.48
[Mg0.74Al0.26(OH)2](NO3)0.20(CO32)0.030.54H2O [Mg0.69Al0.31(OH)2](IBU)0.06(IBU)0.14(NO3)0.172.03H2O [Mg0.69Al0.31(OH)2](IBU)0.02(IBU)0.25(NO3)0.062.40H2O [Mg0.64Al0.36(OH)2](IBU)0.02(IBU)0.26(NO3)0.101.14H2O [Mg0.64Al0.36(OH)2](IBU)0.17(IBU)0.26(NO3)0.100.66H2O
H (3.74) (1.63) (0.53) (0.94) (0.87)
3.72 6.56 7.20 6.49 6.67
(3.71) (5.21) (5.60) (5.78) (6.33)
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(Fig. 3C). It reveals that a layered structure was reconstructed over a reassembling process. However, the (0 0 3) basal reflection pattern shifted to a lower angle and the d0 0 3 value increased to 2.31 nm, showing that IBU molecules were intercalated into LDH gallery. Given that the thickness of the brucite-like layer of LDH is about 0.48 nm [7], the gallery height of the IBU–LDH nanohybrid is about 1.45 nm. The length, width and thickness of IBU molecule are 1.03, 0.52 and 0.34 nm, respectively [6]. According to the size of IBU molecule and the gallery height of the nanohybrid, a possible orientation of IBU molecules in the LDH gallery is proposed, as illustrated in Scheme 1. The IBU molecules arrange as a slightly tilted bilayer with the long axis perpendicular to the brucite-like layer, where the carboxylate and carboxylic groups interact with the layer surface, as proposed by Ay et al. [6]. It needs to be noted that the IBU molecules loading on the nanohybrid may exist in two possible status: one is the intercalating form and another is the adsorbing form on the surface of LDH particle. In order to distinguish the relative amount of the above two morphologies of IBU molecules, a contrast experiment was performed using Mg3Al-CO3 LDH as adsorbent under the same conditions as the coassembling experiment. 0.4 g of Mg3Al-CO3 LDH sample was dispersed in 40 ml of the IBU formamide/ethanol (1:1 in volume ratio) solution containing 0.4 g IBU. The suspension was shaken at 200 rpm in a thermostated shaker for 1 h at 40 8C, and then centrifuged and washed two times with water and once with alcohol (3 ml each time). The IBU adsorbing amount of the so-obtained product was examined to be 3.16% which is much lower than the Ain value. Thus, it can be concluded that most of the IBU molecules loading on the IBU–LDH nanohybrid were intercalated into the gallery of LDHs. Similar result was reported in literature [8]. 3.3.2. FT-IR analysis Fig. 4 shows the FT-IR spectra of IBU, pristine LDH and IBU–LDH nanohybrid. The strong band at 1720 cm1 for pure IBU (Fig. 4A) is attributed to the stretching vibration of –COOH group [7], and it shifts to 1688 cm1 in the IBU–LDH nanohybrid (Fig. 4B), arising from the hydrogen bonding interaction of the –COOH groups with the –OH groups on the LDH layer surface. In addition, two bands at 1557 and 1395 cm1 observed from the IBU–LDH nanohybrid (Fig. 4B) are attributed to the asymmetric and symmetric stretching vibrations of the –COO group, respectively [8,23,24]. It is in accordance with the reported –COO stretching vibration
Fig. 4. FT-IR spectra of (A) free IBU, (B) IBU–LDH nanohybrid and (C) Mg3Al-NO3 LDH.
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(1584 and 1409 cm1) of IBU sodium [24]. The shift down of the two characteristic band peaks maybe arises from the hydrogen bonding and electrostatic interactions between the –COO groups and LDH layers. The above results further prove that the IBU species intercalated in the LDH gallery exist in two forms, carboxylate anion and carboxylic acid, which is in accordance with the elemental analysis results. The weak bands at about 1506 and 1462 cm1 in Fig. 4A and B are assigned to aromatic ring vibrations of IBU. Owing to the alkyl stretching vibrations of IBU [7], several typical bands can be observed at 2594, 2868, and 2918 cm1. 3.3.3. TG–DSC analysis TG–DSC curves of pure IBU, pristine LDH and IBU–LDH nanohybrid samples are shown in Fig. 5. For the pristine LDH sample (Fig. 5A), the thermal decomposition proceeded through two steps [25]: (1) the desorption of the physically adsorbed water and partial interlayer water (9.32% weight loss) between 20 and ca. 220 8C with an endothermic peak at 123.8 8C; (2) the dehydration of the brucite-like layers and the decomposition of the nitrate anions (37.12% weight loss) between 340 and 580 8C with one endothermic peak at 442.3 8C. For pure IBU (Fig. 5C), an endothermic peak at 76.7 8C in its DSC curve arose from the melting process of IBU, and the thermal complete decomposition (100% weight loss) was achieved around 240 8C with a exothermic peak at ca. 195 8C. For the IBU–LDH nanohybrid (Fig. 5B), a weight loss of 9% between 20 and 150 8C with a broad endothermic peak was related to the loss of water. The weight loss of ca. 16% between 150 and 300 8C with an exothermic peak at ca. 230 8C was mainly induced by the decomposition of the aromatic ring of IBU [26]. Two sharp exothermic peaks at about 347.5 8C and 513 8C were corresponding to the decomposition of species derived from IBU [8]. Compared with the decomposition temperature (ca. 195 8C) of pure IBU, it can be concluded that the thermal stability of the intercalated IBU is significantly enhanced [6].
Fig. 5. TG–DSC curves of (A) Mg3Al-NO3 LDH, (B) IBU–LDH nanohybrid and (C) free IBU.
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Fig. 6. SEM images of (A) LDH and (B) IBU–LDH nanohybrid.
3.3.4. Morphology analysis The SEM images of the pristine LDH and IBU–LDH nanohybrid samples are shown in Fig. 6. As can be seen, the pristine LDH particles were hexagonal platelets with sizes in the range of 50– 100 nm. In spite of that, the nanohybrid particles became aggregated and the morphology of plate shape was still visible after the intercalation of IBU. This aggregation is induced by the introduction of IBU [6]. In addition, the surface of the nanohybrid particles was very smooth, indicating an orientated arrangement and dense packing of the constituent LDH nanoplatelets by the preferential face-to-face and edge-to-edge aggregations [27]. 3.4. IBU in vitro release from IBU–LDH nanohybrid Fig. 7 shows the cumulative IBU-release profiles from the sosynthesized IBU–LDH nanohybrid and from the physical mixture of the LDH–IBU in PBS (pH 7.4) at 37 8C. As can be seen, the physical mixture released IBU quickly, and the release was completed within 60 min. The release rate of IBU from the nanohybrid was lower than that from the physical mixture. It is attributed to the restricted motion of IBU molecules arising from the steric effect of LDH and hydrogen bonds between the LDH layers and intercalated IBU molecules. In addition, it can be seen from Fig. 7B that a rapid release within the initial 60 min was followed by a slow release of remaining drug which total release amount was about 85% (w/w) and no release could be observed after 9 h. Similar results were reported in literature [7]. Furthermore, the release rate of the nanohybrid sample was relatively slower than that of the IBU–LDH samples synthesized by conventional methods [3,9,27], which
Fig. 7. Release profiles of IBU from (A) the physical mixture of LDH and IBU and (B) IBU–LDH nanohybrid at 37 8C and pH 7.4.
maybe arose from the character of the relatively oriented dense packing of the LDH nanoplatelets in the nanohybrid sample [27]. The difference of the release rate of IBU between the physical mixture and the nanohybrid can be explained by different mechanisms. The mechanism of the physical mixture is through a desorption process, whereas that of the nanohybrid is through a diffusion process or an ion-exchange between interlayer IBU and the PO43, HPO42 ions of the phosphate buffer solution. The whole release process of IBU molecules from the nanohybrid can be divided into two steps, namely, the diffusion through the LDH particle and that through the solution layer surrounding the particle. The release rate of IBU molecules should be determined by the slower step of these two processes. Bhaskar et al. [28] developed a simple procedure to establish whether the diffusion through the particle was the rate limiting step. For a particle diffusion-controlled release, Bhaskar et al. [28] obtained the following equation, 1:3 6 lnð1 X t Þ ¼ 1:59 D0:65 t 0:65 dp
(1)
where dp is the particle diameter and D is the diffusivity. It is suggested that particle diffusion control can be tested by simply testing for linearity between log(1 Xt) and t0.65. This method was applied to the experimental data, and a good linear relationship (correlation coefficient r2 = 0.9356) was obtained (see Fig. 8), indicating that the diffusion through the LDH particle was the rate limiting step.
Fig. 8. Release of IBU from the nanohybrid as a function of time0.65 at 37 8C and pH 7.4.
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the delamination/reassembling method showed various remarkable advantages, such as simple procedure, short reaction time, mild condition and high drug loading. In the viewpoint of application, formamide is not a proper delamination medium since it is a highly corrosive and toxic solvent. A special emphasis should be placed on the research of the environmentally safe delamination medium in future.
Acknowledgments This research was supported by the National Natural Science Foundation of China (No. 21173135), the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20110131130008) and the Natural Science Foundation of Shandong Province of China (ZR2010BM039).
References Fig. 9. Linear regression curve of the release data fitting with pseudo-second-order kinetic model at 37 8C and pH 7.4.
Usually, the release process of drug molecules from drug–LDH composites may be described with pseudo-first-order kinetic or pseudo-second-order kinetic equations, represented in a linear form as follows, respectively, lnðqe qt Þ ¼ ln qe k1 t
(2)
t 1 t ¼ þ qt k2 q2e qe
(3)
where qe and qt are the equilibrium release amount and the release amount at any time (t), respectively, and k1 and k2 are the rate constants of pseudo-first-order and pseudo-second-order release kinetics, respectively. With the simulating of above two kinetic models for the release kinetic data, it was found that the pseudosecond-order model was better satisfactory for describing the release kinetic process of IBU from the IBU–LDH nanohybrid. Fig. 9 shows the plot of t/qt vs. t for the IBU release. As can be seen, fair straight line was obtained, and the correlation coefficient (r2) and k2 values were 0.9929 and 1.40 h1, respectively. 4. Conclusions This work presents a delamination/reassembling method for the facile fabrication of IBU–LDH nanohybrids. The characteristics of the so-synthesized nanohybrids were the same as that of nanohybrids synthesized by conventional methods including ion exchange, co-precipitation, reconstruction and hydrothermal methods. However, compared with those conventional methods,
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Materials Research Bulletin journal homepage: www.elsevier.com/locate/matresbu
Facile fabrication of ibuprofen–LDH nanohybrids via a delamination/reassembling process Xiaomei Lu, Liming Meng, Haiping Li, Na Du, Renjie Zhang, Wanguo Hou * Key Laboratory for Colloid and Interface Chemistry of Education Ministry, Shandong University, Jinan 250100, PR China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 July 2012 Received in revised form 18 October 2012 Accepted 22 December 2012 Available online 31 December 2012
In this paper, a delamination/reassembling method for the facile fabrication of ibuprofen (IBU), a nonsteroidal anti-inflammatory drug, intercalated layered double hydroxide (LDH) nanohybrid was presented. In this method, LDH particles were first delaminated to well dispersed 2D nanosheets in formamide, and then the LDH nanosheets and IBU molecules coassembled into the IBU–LDH nanohybrid. The characteristics of the so-synthesized nanohybrid were the same as that of the IBU–LDH nanohybrids synthesized by the conventional methods including ion exchange, co-precipitation, reconstruction and hydrothermal methods. However, the delamination/reassembling method displayed various remarkable advantages, such as simple procedure, short reaction time, mild condition and high drug loading, compared with the conventional methods. ß 2012 Elsevier Ltd. All rights reserved.
Keywords: A. Layered compounds A. Nanostructures B. Intercalation reactions C. X-ray diffraction
1. Introduction Over the past decade, the layered double hydroxides (LDHs) have been attracting much attention in drug delivery and gene therapy for their good biocompatibility, nontoxicity, and controlled-release property [1,2]. Ibuprofen (IBU), a-methyl-4-(2methylpropyl)benzene-acetic acid, is a non-steroidal anti-inflammatory drug used for relieving of symptoms of rheumatoid arthritis and osteoarthritis [3]. A controlled-release formulation for IBU needs to be improved for the side effects and short half-life of IBU [4]. Extensive efforts have been made to synthesize IBU–LDH nanohybrids by using various methods, including ion exchange [5,6], co-precipitation [7], reconstruction [8] and hydrothermal methods [9]. However, these conventional methods have the following drawbacks: complex processes, time-consuming, low drug loading amount and high reaction temperature. Herein, we describe a delamination/reassembling process for the facile fabrication of drug–LDH nanohybrids. Firstly, LDH particles were delaminated into well dispersed 2D nanosheets, and then the nanosheets and drug molecules were coassembled into drug–LDH nanohybrids. To date, the delamination of LDHs has been widely investigated [10–14], and it was found that formamide is an excellent delaminating reagent [13]. Utilizing the re-stacking of the nanosheets provided by the exfoliation process, many core–shell materials and multilayer films were synthesized by using the
* Corresponding author. Tel.: +86 0531 88365460; fax: +86 0531 88364750. E-mail address: [email protected] (W. Hou). 0025-5408/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.materresbull.2012.12.057
layer-by-layer technique [15–18]. The delamination–restacking behaviors were also used to synthesize macromolecules, such as polyacrylamide [19] and carboxymethyl cellulose [20], intercalated LDH nanohybrids. However, to the best of our knowledge, the synthesis of drug–LDH nanohybrids by the delamination/reassembling process has not been reported. Compared with the conventional methods, the delamination/reassembling process presented in this paper exhibits excellent characteristics, such as simple procedure, short reaction time, mild condition and high drug loading. 2. Experimental 2.1. Materials Ibuprofen (95% purity) was purchased from Xi’an GuZhongGu biological technology Co., Ltd. (Xi’an, China) and used as received. Its structure is presented in Fig. 1. Other chemicals used are of analytical grade. The water used was purified with a Hitech-Kflow water purification system (China). 2.2. Synthesis and characterization of IBU–LDH nanohybrids The pristine Mg3Al-NO3 LDH sample was synthesized with a coprecipitation method [21]. The delamination of the LDH sample was performed according to the method described by Wu et al. [22]. The LDH sample (0.4 g) was dispersed in formamide (20 ml) with magnetically stirring and the dispersion was sonicated to be transparent. After resting overnight at room temperature, the delaminated LDH nanosheet dispersion was obtained.
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microanalysis of C, H, and N was obtained with a Vario EI III analyzer. The contents of Mg and Al were determined by inductively coupled plasma (ICP) atomic emission spectroscopy (Jarrel-ASH, ICAP-9000) after the samples were dissolved in a dilute acid solution. The absorbance of ibuprofen solution was measured with an HP-8453 model UV-Vis spectroscope. 2.4. In vitro drug release measurement
Fig. 1. Structure of ibuprofen molecule.
The IBU–LDH nanohybrid was synthesized via a coassembling process between LDH nanosheets and IBU molecules. A typical synthetic procedure is shown as follows: 20 ml of the so-obtained LDH nanosheet dispersion was dropped into 20 ml of IBU ethanol solution containing 0.4 g IBU under slow magnetic stirring. After resting at 40 8C for 10 min, the dispersion was centrifuged at 6000 rpm for 5 min. The supernatant being removed, the obtained precipitate was washed two times with water and once with alcohol (3 ml each time) by a re-dispersion/centrifugation cyclic process. The precipitate, IBU–LDH nanohybrid, was dried at 60 8C in vacuum. 2.3. Characterization X-ray diffraction (XRD) patterns were recorded with a BrukerD8 Advanced diffractometer equipped with Cu Ka radiation (l = 1.54056 A˚) at 40 kV and 40 mA. Fourier-transform Infrared (FT-IR) spectra were recorded with a Bruker Vector 22 model spectrometer in air at room temperature using KBr disc technique. Morphology of the samples was observed with a JEOL-JEM-6700 scanning electron microscope (SEM) at 5.0 kV. Thermal gravimetric analyses and differential scanning calorimeters (TG–DSC) were carried out in an airflow with a NETZSCH STA 449 F3 thermal analysis system at a heating rate of 10 8C/min. Elemental
The release measurement was performed by putting 0.04 g of IBU–LDH nanohybrid sample in 400 ml of phosphate buffer solution (PBS, pH 7.4) at 37 8C under magnetic stirring. Aliquots (4 ml) of supernatant were taken at given time intervals, and meanwhile 4 ml of fresh PBS was added to the system. The supernatant withdrawn was filtered through a syringe filter with the pore of 0.45 mm in diameter, and the IBU concentrations in the supernatants were determined by measuring the absorbance at 221 nm with an HP-8453 model UV-Vis spectroscopy to obtain the release amounts (qt) of IBU from the IBU–LDH nanohybrid sample, in turn, to calculate the accumulated percent releases (Xt) of IBU from the sample. For comparison, the release profile of the physical mixture of LDH and IBU was conducted at the same condition. 3. Results and discussion 3.1. The reassembling process of LDH nanosheets with IBU After the LDH sample was dispersed in formamide, a transparent colloidal dispersion was obtained, and the Tyndall phenomenon could be observed in the dispersion (see Fig. 2). It indicates that the LDH sample was successfully delaminated to give a LDH nanosheet suspension [11]. When the LDH nanosheet suspension was dropped into IBU ethanol solution, the mixture became immediately cloudy and the Tyndall phenomenon disappeared (see Fig. 2). The disappearance of Tyndall phenomenon suggests that the addition of IBU molecules destroyed the colloidal state of LDH nanosheet suspension. In fact, a reassembling process took place to form an IBU–LDH nanohybrid. The delamination/ coassembly process can be proved by XRD examinations (see Fig. 3). Formamide, which has a very high ability to form hydrogen bonds with hydroxyl groups of the LDH host, is an effective delaminating agent for LDHs [22]. In the delaminated suspension, the carbonyl (–C5 5O) group of formamide has a strong interaction with the LDH nanosheets, whereas the amine group (–NH2) bonds weakly with NO3 [11]. After adding IBU molecules, the electrostatic interaction between the carboxyl (–COO) group of
Fig. 2. (A) Tyndall light scattering of the suspension of delaminated LDH in formamide and (B) light scattering of the suspension containing IBU and LDH.
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(Ain) of IBU was calculated to be 34.12%. It was found that the delamination/reassembling process induced the Mg/Al molar ratio to change from 2.85 to 2.23. Similar result was reported in literature [13]. In addition, it was interesting that the loading amount of IBU in the nanohybrid exceeded the maximum loading determined by the charge-balancing law between LDH layers and IBU anions. It reveals that the IBU species intercalated in the LDH gallery can exist in two forms, carboxylate anion (IBU) and carboxylic acid (IBU). This has not been reported in previous literature [3,5–9]. The possible reasons for this phenomenon are the use of organic medium (or non-alkaline medium) and the low IBU intercalation restriction in the synthetic procedure compared with the conventional methods. In order to further verify the result, the influence of the mass ratio of IBU to LDH in raw materials, RI/L, on the loading amounts and the chemical compositions of the IBU–LDH nanohybrids were examined (see Table 1). It was found that the Ain values increased with increasing RI/L, and indeed the carboxylate anion and carboxylic acid forms of IBU molecules coexisted in the gallery of LDH.
Fig. 3. XRD patterns of (A) Mg3Al-NO3 LDH, (B) delaminated LDH and (C) IBU–LDH nanohybrid.
3.3. Characterization of IBU–LDH nanohybrid 3.3.1. XRD analysis The XRD patterns of the pristine LDH, delaminated LDH and IBU–LDH nanohybrid samples are shown in Fig. 3. As can be seen, the XRD patterns of the pristine LDH sample (Fig. 3A) exhibited all characteristic diffractions of hydrotalcite (JCPDS card no. 51-1528), indicating that the pristine LDH sample was of a well-crystallized hydrotalcite-like structure. The d0 0 3 value is the interlayer distance (d-spacing) of the layered materials. It can be seen from Fig. 3A that the pristine LDH had a d-spacing of 0.86 nm, which is the same as reported in the literature for Mg-Al-NO3 LDH [22]. The XRD patterns of delaminated LDH in formamide (Fig. 3B) showed a pronounced halo in a 2u region of 20–308, which was produced by formamide [13]. It indicates the delamination of LDH was quite completed. In addition, a weak reflection at 2u = 628 (marked with *) could be observed, indicating that the 2D crystalline of the LDH layer was preserved. These results demonstrate that well-crystallized LDH crystals have been delaminated into nanosheets. After the coassembly of LDH nanosheets and IBU, the so-obtained sample showed the XRD patterns with the characteristic diffractions of hydrotalcite
IBU and the LDH nanosheets is stronger than the hydrogen bonding interaction between the carbonyl group of formamide and the LDH nanosheets. As a result, the formamide molecules on the LDH nanosheets will be replaced by IBU molecules, resulting in the restacking of LDH layers intercalated by IBU molecules. Scheme 1 shows a possible delamination/reassembling mechanism for IBU– LDH nanohybrid. In order to verify whether the restacking process arose from the presence of IBU molecules, the same experiment was carried out with pure ethanol instead of IBU ethanol solution. No appearance change of the system was evidently observed in 48 h. 3.2. Loading of IBU on LDH The results of elemental analyses and thermogravimetric analyses showed that the chemical compositions of the pristine LDH and the IBU–LDH nanohybrid samples were [Mg0.74Al0.26(OH)2](NO3)0.20(CO32)0.030.54H2O and [Mg0.69Al0.31(OH)2](IBU)0.02(IBU)0.25(NO3)0.062.40H2O, respectively. Based on the content of C in the nanohybrid sample, the loading amount
Scheme 1. Schematic illustration of possible delamination/reassembling mechanism for IBU–LDH nanohybrid. Table 1 Chemical compositions of LDH and IBU–LDH nanohybrids obtained at different mass ratios of IBU to LDH in raw materials. RI/L
Content calculated (found)/wt% Al
Mg LDH 0.5 1.0 1.5 2.0
21.47 11.25 10.24 10.69 9.26
(21.43) (11.30) (10.30) (10.59) (9.30)
8.49 5.68 5.18 6.77 5.86
C (8.47) (5.62) (5.23) (6.74) (5.80)
0.44 21.19 26.06 30.43 40.44
N (0.47) (21.15) (25.81) (30.82) (40.45)
3.39 1.62 0.52 0.98 0.84
Ain
Chemical compositions
– 27.96 34.12 40.75 53.48
[Mg0.74Al0.26(OH)2](NO3)0.20(CO32)0.030.54H2O [Mg0.69Al0.31(OH)2](IBU)0.06(IBU)0.14(NO3)0.172.03H2O [Mg0.69Al0.31(OH)2](IBU)0.02(IBU)0.25(NO3)0.062.40H2O [Mg0.64Al0.36(OH)2](IBU)0.02(IBU)0.26(NO3)0.101.14H2O [Mg0.64Al0.36(OH)2](IBU)0.17(IBU)0.26(NO3)0.100.66H2O
H (3.74) (1.63) (0.53) (0.94) (0.87)
3.72 6.56 7.20 6.49 6.67
(3.71) (5.21) (5.60) (5.78) (6.33)
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(Fig. 3C). It reveals that a layered structure was reconstructed over a reassembling process. However, the (0 0 3) basal reflection pattern shifted to a lower angle and the d0 0 3 value increased to 2.31 nm, showing that IBU molecules were intercalated into LDH gallery. Given that the thickness of the brucite-like layer of LDH is about 0.48 nm [7], the gallery height of the IBU–LDH nanohybrid is about 1.45 nm. The length, width and thickness of IBU molecule are 1.03, 0.52 and 0.34 nm, respectively [6]. According to the size of IBU molecule and the gallery height of the nanohybrid, a possible orientation of IBU molecules in the LDH gallery is proposed, as illustrated in Scheme 1. The IBU molecules arrange as a slightly tilted bilayer with the long axis perpendicular to the brucite-like layer, where the carboxylate and carboxylic groups interact with the layer surface, as proposed by Ay et al. [6]. It needs to be noted that the IBU molecules loading on the nanohybrid may exist in two possible status: one is the intercalating form and another is the adsorbing form on the surface of LDH particle. In order to distinguish the relative amount of the above two morphologies of IBU molecules, a contrast experiment was performed using Mg3Al-CO3 LDH as adsorbent under the same conditions as the coassembling experiment. 0.4 g of Mg3Al-CO3 LDH sample was dispersed in 40 ml of the IBU formamide/ethanol (1:1 in volume ratio) solution containing 0.4 g IBU. The suspension was shaken at 200 rpm in a thermostated shaker for 1 h at 40 8C, and then centrifuged and washed two times with water and once with alcohol (3 ml each time). The IBU adsorbing amount of the so-obtained product was examined to be 3.16% which is much lower than the Ain value. Thus, it can be concluded that most of the IBU molecules loading on the IBU–LDH nanohybrid were intercalated into the gallery of LDHs. Similar result was reported in literature [8]. 3.3.2. FT-IR analysis Fig. 4 shows the FT-IR spectra of IBU, pristine LDH and IBU–LDH nanohybrid. The strong band at 1720 cm1 for pure IBU (Fig. 4A) is attributed to the stretching vibration of –COOH group [7], and it shifts to 1688 cm1 in the IBU–LDH nanohybrid (Fig. 4B), arising from the hydrogen bonding interaction of the –COOH groups with the –OH groups on the LDH layer surface. In addition, two bands at 1557 and 1395 cm1 observed from the IBU–LDH nanohybrid (Fig. 4B) are attributed to the asymmetric and symmetric stretching vibrations of the –COO group, respectively [8,23,24]. It is in accordance with the reported –COO stretching vibration
Fig. 4. FT-IR spectra of (A) free IBU, (B) IBU–LDH nanohybrid and (C) Mg3Al-NO3 LDH.
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(1584 and 1409 cm1) of IBU sodium [24]. The shift down of the two characteristic band peaks maybe arises from the hydrogen bonding and electrostatic interactions between the –COO groups and LDH layers. The above results further prove that the IBU species intercalated in the LDH gallery exist in two forms, carboxylate anion and carboxylic acid, which is in accordance with the elemental analysis results. The weak bands at about 1506 and 1462 cm1 in Fig. 4A and B are assigned to aromatic ring vibrations of IBU. Owing to the alkyl stretching vibrations of IBU [7], several typical bands can be observed at 2594, 2868, and 2918 cm1. 3.3.3. TG–DSC analysis TG–DSC curves of pure IBU, pristine LDH and IBU–LDH nanohybrid samples are shown in Fig. 5. For the pristine LDH sample (Fig. 5A), the thermal decomposition proceeded through two steps [25]: (1) the desorption of the physically adsorbed water and partial interlayer water (9.32% weight loss) between 20 and ca. 220 8C with an endothermic peak at 123.8 8C; (2) the dehydration of the brucite-like layers and the decomposition of the nitrate anions (37.12% weight loss) between 340 and 580 8C with one endothermic peak at 442.3 8C. For pure IBU (Fig. 5C), an endothermic peak at 76.7 8C in its DSC curve arose from the melting process of IBU, and the thermal complete decomposition (100% weight loss) was achieved around 240 8C with a exothermic peak at ca. 195 8C. For the IBU–LDH nanohybrid (Fig. 5B), a weight loss of 9% between 20 and 150 8C with a broad endothermic peak was related to the loss of water. The weight loss of ca. 16% between 150 and 300 8C with an exothermic peak at ca. 230 8C was mainly induced by the decomposition of the aromatic ring of IBU [26]. Two sharp exothermic peaks at about 347.5 8C and 513 8C were corresponding to the decomposition of species derived from IBU [8]. Compared with the decomposition temperature (ca. 195 8C) of pure IBU, it can be concluded that the thermal stability of the intercalated IBU is significantly enhanced [6].
Fig. 5. TG–DSC curves of (A) Mg3Al-NO3 LDH, (B) IBU–LDH nanohybrid and (C) free IBU.
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Fig. 6. SEM images of (A) LDH and (B) IBU–LDH nanohybrid.
3.3.4. Morphology analysis The SEM images of the pristine LDH and IBU–LDH nanohybrid samples are shown in Fig. 6. As can be seen, the pristine LDH particles were hexagonal platelets with sizes in the range of 50– 100 nm. In spite of that, the nanohybrid particles became aggregated and the morphology of plate shape was still visible after the intercalation of IBU. This aggregation is induced by the introduction of IBU [6]. In addition, the surface of the nanohybrid particles was very smooth, indicating an orientated arrangement and dense packing of the constituent LDH nanoplatelets by the preferential face-to-face and edge-to-edge aggregations [27]. 3.4. IBU in vitro release from IBU–LDH nanohybrid Fig. 7 shows the cumulative IBU-release profiles from the sosynthesized IBU–LDH nanohybrid and from the physical mixture of the LDH–IBU in PBS (pH 7.4) at 37 8C. As can be seen, the physical mixture released IBU quickly, and the release was completed within 60 min. The release rate of IBU from the nanohybrid was lower than that from the physical mixture. It is attributed to the restricted motion of IBU molecules arising from the steric effect of LDH and hydrogen bonds between the LDH layers and intercalated IBU molecules. In addition, it can be seen from Fig. 7B that a rapid release within the initial 60 min was followed by a slow release of remaining drug which total release amount was about 85% (w/w) and no release could be observed after 9 h. Similar results were reported in literature [7]. Furthermore, the release rate of the nanohybrid sample was relatively slower than that of the IBU–LDH samples synthesized by conventional methods [3,9,27], which
Fig. 7. Release profiles of IBU from (A) the physical mixture of LDH and IBU and (B) IBU–LDH nanohybrid at 37 8C and pH 7.4.
maybe arose from the character of the relatively oriented dense packing of the LDH nanoplatelets in the nanohybrid sample [27]. The difference of the release rate of IBU between the physical mixture and the nanohybrid can be explained by different mechanisms. The mechanism of the physical mixture is through a desorption process, whereas that of the nanohybrid is through a diffusion process or an ion-exchange between interlayer IBU and the PO43, HPO42 ions of the phosphate buffer solution. The whole release process of IBU molecules from the nanohybrid can be divided into two steps, namely, the diffusion through the LDH particle and that through the solution layer surrounding the particle. The release rate of IBU molecules should be determined by the slower step of these two processes. Bhaskar et al. [28] developed a simple procedure to establish whether the diffusion through the particle was the rate limiting step. For a particle diffusion-controlled release, Bhaskar et al. [28] obtained the following equation, 1:3 6 lnð1 X t Þ ¼ 1:59 D0:65 t 0:65 dp
(1)
where dp is the particle diameter and D is the diffusivity. It is suggested that particle diffusion control can be tested by simply testing for linearity between log(1 Xt) and t0.65. This method was applied to the experimental data, and a good linear relationship (correlation coefficient r2 = 0.9356) was obtained (see Fig. 8), indicating that the diffusion through the LDH particle was the rate limiting step.
Fig. 8. Release of IBU from the nanohybrid as a function of time0.65 at 37 8C and pH 7.4.
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the delamination/reassembling method showed various remarkable advantages, such as simple procedure, short reaction time, mild condition and high drug loading. In the viewpoint of application, formamide is not a proper delamination medium since it is a highly corrosive and toxic solvent. A special emphasis should be placed on the research of the environmentally safe delamination medium in future.
Acknowledgments This research was supported by the National Natural Science Foundation of China (No. 21173135), the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20110131130008) and the Natural Science Foundation of Shandong Province of China (ZR2010BM039).
References Fig. 9. Linear regression curve of the release data fitting with pseudo-second-order kinetic model at 37 8C and pH 7.4.
Usually, the release process of drug molecules from drug–LDH composites may be described with pseudo-first-order kinetic or pseudo-second-order kinetic equations, represented in a linear form as follows, respectively, lnðqe qt Þ ¼ ln qe k1 t
(2)
t 1 t ¼ þ qt k2 q2e qe
(3)
where qe and qt are the equilibrium release amount and the release amount at any time (t), respectively, and k1 and k2 are the rate constants of pseudo-first-order and pseudo-second-order release kinetics, respectively. With the simulating of above two kinetic models for the release kinetic data, it was found that the pseudosecond-order model was better satisfactory for describing the release kinetic process of IBU from the IBU–LDH nanohybrid. Fig. 9 shows the plot of t/qt vs. t for the IBU release. As can be seen, fair straight line was obtained, and the correlation coefficient (r2) and k2 values were 0.9929 and 1.40 h1, respectively. 4. Conclusions This work presents a delamination/reassembling method for the facile fabrication of IBU–LDH nanohybrids. The characteristics of the so-synthesized nanohybrids were the same as that of nanohybrids synthesized by conventional methods including ion exchange, co-precipitation, reconstruction and hydrothermal methods. However, compared with those conventional methods,
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