versión impresa ISSN 0327-0793
Lat. Am. appl. res. vol.40 no.3 Bahía Blanca jul. 2010
Assembly and release of diclofenac acid-pillared hydrotalcites
X. Peng†‡, K. Huang‡, S. Zhang† and J. Liu†
† Department of Chemistry and Environmental Engineering, Changsha University, Changsha 410003, China.
‡ School of Chemistry and Chemical Engineering, Central South University, Changsha 410083 China.
Abstract - A pharmaceutically active material diclofenac was intercalated into a layered double hydroxide by co-precipitation method, release studies suggest that the result diclofenac acid-pillared hydrotalcites (Dic-LDHs) have significant sustained release effect. The complex materials were characterrized using XRD, FTIR, DSC-TG, EA and ICP. The result show that the interlayer distance of the Dic-LDHs is expanded to 1.83nm and the thermal stability of material increases after the intercalation of diclofenac.
Keywords - Diclofenac Acid. Hydrotalcites. Release. Assembly.
Layered double hydroxides (LDHs), which are referred to as hydrotalcite-like compounds or as anionic clays, are an important class of ionic lamellar solids (Cavani et al., 1991). They can be described by the general formula: [M2+1-xM3+x(OH)2]x+(An-) x/n. m H2O, where M2+ and M3+ can be any divalent and trivalent metal ions (with ionic radius similar to Mg2+), x is the metal ratio M3+/(M2++M3+) and An- is the interlamellar charge-compensating anions (Bouraada et al., 2008). Their structure are made of brucite-like layers (Mg(OH)2) with partial substitution of divalent cations by trivalent cations resulting in a net positive charge balanced by interlayer anions associated with variable amounts of water (Gennequin et al., 2008). They have been widely investigated owing to their potential applications as ion exchangers, catalyst supports and so on (Carpani et al., 2004; Terry, 2004). Recently, LDHs have been investigated for storage and delivery of some drugs, such as NSAIDs (nonsteroidal anti-inflammatory drugs) widely used in rheumatism treatment.
Diclofenac (Dic) is an important analgesic and anti-inflammatory drug, widely used in the treatment of post-operative pain, rheumatoid arthritis, and chronic pain associated with cancer (Sparidans et al., 2008). Similar to other NSAIDs, Dic use is associated with rare, but serious and sometimes fatal, gastrointestinal (GI) side effects, including ulceration, and hemorrhage, so it is an ideal candidate for incorporation in a controlled release device to diminish its adverse effects after oral administration. Different approaches have been taken to decrease NSAID-induced GI toxicity (Mehta et al., 2008). For example, incorporation of NSAIDs with phospholipid has been suggested to improve GI safety of these drugs (Khazaeinia and Jamali, 2003). Another way to reduce the side effect from the treatment with NSAIDs is the concomitant use of antacids. LDHs, a commercially available antacid, shows high efficiency in the treatment of NSAIDs induced gastro duodenal lesions. Furthermore, the concomitant use is considered as an approach to improve drug solubility and decrease gastric irritation (Khan et al., 2001; Gordijo et al., 2005).
The salts of acid drugs dissociate in aqueous solution, obtaining an anionic form of the drug that can significantly interact with LDHs by anion exchange. LDHs are often used as matrices for several pharmaceuticals. Salicylate and naproxen were intercalated into the interlayer space of hydrotalcites, characterizing the solids obtained by several physicochemical techniques and studying their thermal behaviour (del Arco et al., 2004). Naproxen intercalated into LDHs was also studied by Wei et al. (2004), highlighting that the thermal stability of the intercalated naproxen is significantly enhanced compared with the pure form, which suggests that this drug-inorganic layered material may have prospective application as the basis of a novel drug delivery system. Adsorption of medical broad spectrum drugs as aspirin on LDHs appears sufficiently weak and the drug is easily removed by water, and do not modify the medical effects of the drug (Linares et al., 2004). He et al. (2004) studied several organic UV absorbents intercalated into Zn2Al LDHs: organic compounds in the interlayer space still maintain the original structure and UV absorption ability. The immobilization of the non-steroidal antiinflammatory drug ibuprofen and Cu-ibuprofen compounds on magnesium-aluminum LDHs by three routes (ion-exchange, co-precipitation, reconstruction) was studied by Gordijo et al. (2005), comparing the pharmacological potential of the materials considering the amounts of the immobilized drugs and their buffering properties. Bonina et al. (2008) studied Diclofenac-hydrotalcites used for in vitro release experiments to evaluate the percutaneous absorption of diclofenac. This sample was selected for the in vivo experiments. The result showed the diclofenac-hydrotalcite appeared to be useful for an efficient application on human skin as inhibitor of the UV-induced erythemas, also better than the usual gel samples.
In this paper, we report the intercalation of DIC (2-(2,6-dichloranilino) phenylacetic acid) into LDHs by co-precipitation method. The intercalation will be a way to prepare sustained and controlled release prepgration of diclofenac. Initial studies suggest that the medical of Dic may have application as the basis of a novel tuneable drug delivery system.
Dic was supplied by Guangzhou Baiyun Pharmaceutical Factory (Guangzhou, China). Al(NO3)3·6H2O was purchased from Tianjin Kemiou chemical reagent empolder center (Tianjin, China). Mg(NO3)2·6H2O was purchased from Guangdong Xilong chemical plant (Guangdong, China). All reactants used in this work have high purity degree and all water used was distilled.
B. Intercalation of Dic into LDHs by co-precipitation method
2.13 g (0.02mo1) of Mg(NO3)2·6H20 and 3.83 g (0.01 mo1) of Al(NO3)3·9H20 were both dissolved in 46mL of deionized water (solution A). 2.4 g NaOH and 2.719 g of diclofenac were dissolved in 80 mL of deionized water (solution B). The solution A was added dropwise under stiring and nitrogen atmosphere, to solution B with pH previously adjusted to 8 with 2 mol·L-1 NaOH solution. During the procedure, the pH value was maintained constant by continuous addition of NaOH solution. The reaction mixture was aged for 24 h at 65°C.
Powder XRD measurements were performed on a Rigaku Rint 6000 powder X-ray diffractometer, using Cu\Kα radiation at 30 mA, 40 kV. FT-IR spectra were obtained using a NICOLET AVATAR 360 FT-IR spectrophotometer by the standard KBr disk method. DSC/TG were recorded on a NETZSCH STA 449C Instruments, under a flux of 130 cm3min-1 of synthetic air, with a heating rate of 10°C/min, from room temperature to 800°C. The concentration of Dic was detected using a UV-3802 uv-vis spectrophotometer. Elemental chemical analyses for Mg, Al were carried out in a model IRIS Advantage 1000 ICP-AES spectrophtometer after dissolving the samples in nitric acid. C, H, O and N in an Elemental Analyzer from Germany in a model Elementar vario EL III.
D. Preliminary study on Dic-LDHs release in vitro.
Detection wavelength: A proper quantity Dic sodium was dissoved in phosphate buffer (pH=6.8) to obtain the concentration of 60 ug/ml solution. The maximum wavelength of the solution was 276 nm. So the detection wavelength was 276 nm.
Standard curve A proper quantity Dic sodium was dissoved in phosphate buffer (pH=7.4) to obtain the concentration of 20, 50, 60, 80 and 100 ug/ml solution. The absorbance on 276 nm was observed. The regression equation between concentration (Conc) and absorbance (Abs):
Conc = 30.9789 Abs -0.4669, r = 0.9997
The determination of drug releasing Method: Dissolution method I in the Chinese pharmacopoeia 2000 was used, with 900 ml phosphate buffer (pH=6.8) as elute phase at 100 rpm specified for 30 minutes. The investigation was performed on samples with proper quantity on 6 rotation basket. Clocking begin when samples contact with medium. 5 ml sludge solution was taken out periodly by sampler with microporous membrancemillipore filter and equivalent solute was replenished. The absorbance of sludge solutions was observed and the release percent was obtained. The Sampling time of Dic sodium and physical mixture (Dic sodium +LDHs) was 1, 3., 10, 40, 80, 90 min, while the Dic -LDHs was 0, 5, 10, 15, 20, 30, 40, 60, 80, 90 min.
III. RESULTS AND DISCUSSION
A. The crystal structure
The XRD patterns for LDHs and Dif-LDHs are shown in Fig. 1.a) and Fig. 1.b), respectively. All they are characteristic of rather well crystallized layered material with the hydrotalcite-type structure; for the Dic-containing solids the maxima due to planes (003), (006), and (009) are recorded at spacings much large than LDHs, such a swelling of the layers being due to intercalation of the Dic molecules.
The diffraction peaks due to 003 planes of LDHs shift to lower 2θ (3.82°) angle after diclofenac being intercalated into LDHs. Assuming a thickness of 0.48 nm (Cavani et al., 1991) for the LDHs layer, the basal spacing (d003) of Dic-LDHs is calculated as 2.31 nm. These values indicate that an expansion of the interlayer spacing, compared to the LDHs-CO3 (d003: 0.765 nm), may be caused by the Dic intercalation into LDHs by co-precipitation methods. The interlayer height is 1.83nm which accord with the chain length of Dic. These demonstrate a monolayer arrangement for the intercalated Dic oriented perpendicular to the LDHs layers and the carboxyl of Dic joint with LDHs layers. The intercalation of Dic anions are clearly seen in each case by virtue of the expanded interlayer space.
Fig. 1. XRD spectra of Dic-LDHs (a) and LDHs(b).
The lattice parameter of LDHs and Dif-LDHs, calculated from the positions of maxima due to reflection by planes (003) for parameter c, and (110) for parameter a, are included in Table 2. The c value of Dic-LDHs are distinctly larger than precursors.
Table 1. XRD Data of Diffraction Peaks of Dic-LDHs and Mg-Al-LDHs
Table 2. The lattice parameter of samples
From Fig. 1 (a,b), it is also clearly observed that the reflection line of diffraction peak (ambient 60.8° (110)) was not moved, which indicates the intercalation of the Dic has not changed the structure of layer but only has changed the interlayer spacing.
B. The molecular structure of Dic-LDHs
The Dic, LDHs and Dic-LDHs were further confirmed by examination of the FTIR spectra shown in Fig.2, Fig.3a) and Fig.3b), respectively. The spectra of all materials show very broad bands centered at above 3400 cm-1, relating to the v(OH) stretching vibration of hydroxyl groups of the host layers and to the interlayer and physically absorbed water molecules (Kloprogge and Frost, 1999).
Fig. 2. IR spectra of diclofenac
Fig. 3. IR spectra of Dic (a) and Dic-LDHs (b).
The characteristic peaks of CO32- disappears after intercalation, confirming that the Dic intercalated into the LDHs layers. A new band at 1549 cm-1 is due to the vas(COO-) mode, and another band at 1379 cm-1 is due to the symmetric vibration of vs (COO-). It is shown that there is an interaction between Dic and LDHs layers. The bands due to (C-C) of the aromatic ring are recorded at 1636 cm-1 and 1505 cm-1. The bands due to v(C-O) and δ(OH) modes are recorded at 1300-910 cm-1 and bands due to MgA1-0H translation modes are recorded below 600 cm-1 (Khazaeinia and Jamali, 2003). A new band at 1576 cm-1 is due to the band of v (N-H) bending vibration mode.
C. The thermal behavior
The thermal behavior of the samples before and after intercalation into the LDHs was examined by DSC-TG. The curves of LDHs and Dic-LDHs are shown in Fig. 4(a,b).
Fig.4 .DSC-TG curves for LDHs (a) and Dic-LDHs (b).
For the LDHs the TG curve (Fig.4a) shows two weight loss steps with two corresponding endothemic processes in its DSC curves which relate to the desorption of absorbed water at around 196°C, the dehydroxylation of the brucite-like layer at around 266°C.
After the intercalation of Dic into the LDH host, the thermal decomposition characteristics of the resulting product are significantly different from those of the precursors. The DSC-TG curves of Dic-LDHs are shown in Fig.4b). The TG curve of Dic-LDHs shows three weight losses. For the first one, 8.51% of weight, is attributed to the elimination of surface adsorbed water at 92°C, the second weight loss attributed to the elimination of interlayer water and dehydroxylation at 242°C. The third one, 34.25% of weight, due to the combustion of the Dic molecule is observed in the temperature region 400-540°C.
Comparing the DSC curve of LDHs with Dic-LDHs, one can see a significant change on the thermal behavior of the materials after intercalation. In the case of the Dic-LDHs, the combustion temperature of the intercalated Dic is higher than that region of Dic (170-300°C). It indicates that Dic is intercalated into the LDHs and the thermal stability of intercalated LDHs is increased.
Based on IR spectra and DSC-TG curves, it is possible to indicate the existence of an interattraction induced by supramolecular interaction between the host LDHs layers and the guest Dic molecules after the intercalation of Dic.
D. Element chemical analyses
The results from elemental chemical analysis (metals) are included in Table 3. The contents of Dic in Dic-LDHs is 33.14% and 37.3%. Nitrate ions are also co-intercalated within the gallery spaces to balance the charges.
Table 3 Chemical compositions (wt%) and structural formulae of samples (The theoretical values in the brackets)
E. Supramolecular structure model of Dic-LDHs
The height of gallery in Dic-LDHs is 1.83 nm once the thickness of LDH layers (0.48 nm) has been measured. The molecular model of Dic was constructed and fully optimized by the semi-empirical PM3 molecular orbital method. According to the calculations, the interlayer height is 1.83nm which accord with the chain length of Dic. These demonstrate a monolayer arrangement for the intercalated Dic oriented perpendicular to the LDHs layers and the carboxyl of Dic joint with LDHs layers. According to the XRD data and literature information, we propose the supramolecular structure of Dic-LDHs depicted in Fig. 5, a perpendicular bilayer with carboxylate groups pointing toward the LDHs layers. The supramolecular force is attributed to two main interactions, hydrogen bond and stack function of Π-Π bond. On one hand, carboxylate groups can form hydrogen bonds with -OH. On the other hand, the two planes associated with aromatic ring of Dic molecules are parallel to each other and the orbits of bonds overlapped partly, forming two big off-region Π bonds. Since the energy of two big Π bonds is much lower than that of Π bonds of one molecule with two aromatic rings, the structure of Dic-LDHs is more stable.
Fig. 5 Sketch of Dic-LDHs
F. The release of Dic-LDHs
The release curves of Dic-LDHs, physical mixture and Dic dissoved in phosphate buffer (pH=6.8) are shown in Fig. 6. B, D, F. The release curves of physical mixture and Dic are coincide with each other. The release of physical mixture and Dic cannot be controlled. They release completely within 3 minutes so they have not sustained release effect. The Dic-LDHs release 89% of its weight in 20 minutes, and release completely in 90 minutes. So the Dic-LDHs possesses significant sustained release effect. The release mechanism of Dic-LDHs in buffer may be the phosphate ions substituted Dic anions. The exchange speed was high in the beginning stage and then low gradually.
Fig. 6. Release profiles for Dic-LDHs(B), physical mixture(D) and diclofenac(F).
In this work, an new medical release Dic-LDHs has been prepared by co-precipitation method, and it have an obvious sustained-release effect. The interlayer height is 1.83nm and a monolayer arrangement for the intercalated Dic oriented perpendicular to the LDHs layers and the carboxyl of Dic joint with LDHs layers. The thermal stability of intercalated LDHs is increased when the Dic is intercalated into LDHs layers.
This work was supported by the Natural Science Foundation of China (50872014).
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Received: May 29, 2009
Accepted: July 24, 2009
Recommended by Subject Editor: Ricardo Gómez