Applied Clay Science 124–125 (2016) 150–156
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Research paper
Smectite as ciprofloxacin delivery system: Intercalation and temperature-controlled release properties A. Rivera a,⁎, L. Valdés b, J. Jiménez c, I. Pérez d, A. Lam a, E. Altshuler e, L.C. de Ménorval f, J.O. Fossum g,⁎, E.L. Hansen g,1, Z. Rozynek g,2 a
Zeolites Engineering Laboratory, Institute of Materials Science and Technology (IMRE), University of Havana, Cuba Department of Basic Chemistry, Institute of Pharmacy and Food (IFAL), University of Havana, Cuba University Laboratory of Characterization of the Structure of the Substance, (LUCES), Institute of Materials Science and Technology (IMRE), University of Havana, Cuba d Department of Drugs Technology and Control, Institute of Pharmacy and Food (IFAL), University of Havana, Cuba e Group of Complex Systems and Statistical Physics, Physics Faculty, University of Havana, Cuba f Institut Charles Gerhardt Montpellier, Equipe Agregats, Interface, et Materiaux pour l'Energie (AIME), Universite Montpellier 2, France g Department of Physics, Norwegian University of Science and Technology (NTNU), Trondheim, Norway b c
a r t i c l e
i n f o
Article history: Received 15 December 2015 Received in revised form 4 February 2016 Accepted 8 February 2016 Available online xxxx Keywords: Drug Antibiotic Smectite Fluorohectorite Clay
a b s t r a c t Clays have shown to be good candidates as drug delivery carriers. In the present paper, the temperaturedependent swelling of smectites was exploited to obtain composites able to release a drug in a controlled way. More specifically, synthetic fluorohectorite-ciprofloxacin composites were prepared, in which the drug molecules were intercalated between the clay layers. The drug-release systems were characterized by X-ray diffraction (XRD), infrared spectroscopy (IR), thermal gravimetric analysis (TGA), ultraviolet spectroscopy (UV) and atomic absorption spectrometry (AAS). The results from the X-ray diffraction allowed confirming the ciprofloxacin incorporation into the interlayer space, and the results from UV spectroscopy indicated that more than 90% of the initial drug was uptaken by the clay. The thermally activated drug release from a colloidal dispersion of nanosized composite particles in both pure water and synthetic gastric juice was evaluated at temperatures from 37 °C (body temperature) to 85 °C. The studies indicated that the clay promotes the slow release of ciprofloxacin, and that the release of drug increases with both time and temperature. The profiles of drug-release from the clay fulfilled the pharmaceutical standards for these systems. As a result, a clay-based TemperatureControlled Release System (TCRS) with potential biomedical applications has been obtained. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Clays and clay minerals have been widely used for medical purposes. For example, they can be found in pharmaceutical formulations, both as inactive (excipients) and active agents (drugs) (Carretero, 2002; López-Galindo and Viseras, 2004; López-Galindo et al., 2007; USP30-NF25, 2007; Viseras et al., 2007). The therapeutic uses of these materials (López-Galindo and Viseras, 2004) are associated to their chemical and physical properties, which depend ultimately on their structure. Temperature–controlled drug release is desirable in many scenarios: for example, when the local body temperature varies during different stages of a disease, or in response to external stimuli. To date, just a ⁎ Corresponding authors. E-mail addresses:
[email protected] (A. Rivera),
[email protected] (J.O. Fossum). 1 Present address: Department of Monitoring and Research, Norwegian Radiation Protection Authority, Oslo, Norway. 2 Present address: Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61614 Poznań, Poland.
http://dx.doi.org/10.1016/j.clay.2016.02.006 0169-1317/© 2016 Elsevier B.V. All rights reserved.
few materials able to release an active principle as a function of temperature have been investigated. Recently, hydrogel-based composites have been created to release proteins (Wu et al., 2005; Kang and Song, 2008), as well as microscale polymers able to release small molecules and nanoparticles within a certain temperature range (Hyun et al., 2013). In recent years, different porous materials have been used as drug hosts (Rivera and Farías, 2005; Joshi et al., 2011). In particular, clay minerals and their modified forms have been employed in the development of new drug delivery systems (Viseras et al., 2010). Among them, montmorillonite has been the most commonly used for drug delivery applications (Park et al., 2008; Joshi et al., 2009), although kaolinite and laponite have also been investigated (Hamilton et al., 2014). Most of them have been typically used as hosts for pH-controlled release. Synthetic hectorites show a number of advantages as drug hosts, like controllable pore-size distribution, as well as purity and composition, which result in higher reproducibility. In addition, these materials have shown to be non-toxic for trans-dermal application and oral administration (Takahashi et al., 2005; Joshi et al., 2011). Their swelling transition (Hansen et al., 2012), on the other hand, suggests their
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potential as hosts of large molecules of pharmaceutical interest and their temperature–controlled release. However, few reports about the use of fluorohectorite, a commercially available synthetic smectite, as a drug-hosting material, can be found in the literature (Jung et al., 2008; Park et al., 2008; Joshi et al., 2011). From a structural point of view, in their dry form, fluorohectorite layers assemble to form stackof-card-like particles. The stacks are held together by van der Waals forces, and by electrostatic forces in the case of clays with negative layer charges. In the interlayer space of these clays, there are positive counter-ions, leading to an attractive interaction similar to a salt bridge (Franchi et al., 2003; Bosshard et al., 2004); water can be also located between lamellae (da Silva et al., 2003; Anderson et al., 2010). Ciprofloxacin (1-cyclopropyl-6-fluoro-4-oxo-7-(l-piperazinyl)1,4dihydroquinoline-3-carboxylic acid) belongs to the quinolone class of semisynthetic antibiotics and is orally administrated to patients in its hydrochloride salt form. Ciprofloxacin is a potent and broadspectrum antibiotic with high antibacterial activity against most gramnegative bacteria and gram-positive cocci (Wolfson and Hooper, 1985; Hoogkamp-Korstanje, 1997). Although the incorporation of ciprofloxacin (Cipro) into clays has been reported, the use of a temperature– dependent swelling clay as host for Cipro has not been investigated. The present work focuses on the intercalation of Cipro into the interlayer space of a Li-fluorohectorite (LiFh) to sustain the controlled release of the drug. The molecular structure of Cipro is shown in Fig. 1. The drugloaded LiFh was characterized using several experimental techniques. The in vitro drug release study from the colloidal composite dispersion was investigated in diverse media and at different temperatures. The obtained composites will be called Temperature–Controlled Release Systems (TCRS).
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2007)—were the model drugs studied; they were used as received from the Cuban pharmaceutical industry. All other chemicals used in the study were analytical grade. 2.2. Sample preparation For the interactions, 50 ml of drug solutions at 3 mg/ml (pH near 4.5) was put in contact with 0.5 g of each clay. The experiments were carried out at room temperature and at 65 °C ± 5 °C during 4 h and 24 h, in order to study the influence of temperature and time on the amount of drug captured by the clays. All these studies took place under agitation with a magnetic stirrer. By the end of the interactions, the pH of the Cipro-clay dispersions was around 8. In the case of drug adsorption in the dispersions, the drug's concentrations before and after the contact with the clays were analyzed and quantified by ultraviolet spectroscopy (UV), according to standard procedures (USP30-NF25, 2007) (the drugclay dispersions were centrifuged, and the drug contents in the supernatant was determined by UV relative to calibration curves for the pure drug solutions). The UV spectra were collected by means of a Rayleígh UV-2601 spectrophotometer in the wavelength interval 200– 400 nm (including the adsorption maxima at 276, 245 and 273 nm for the Cipro, acetaminophen and ibuprofen, respectively). Each composite LiFh-Cipro was prepared in five batches and the analysis was replicated three times for each one, in order to check repeatability. The maximum difference between the outputs and their average was of 10 mg, corresponding to a relative uncertainty of approximately 3% in the mass of incorporated drug. As demonstrated below, the UV studies showed that, among the drugs investigated, only Cipro is significantly captured by the clay, so further characterization was performed only on Cipro-clay composites.
2. Experimental 2.3. Chemical and physical characterization 2.1. Starting materials The chemical composition of synthetic fluorohectorite is Mx(Mg6 − xLix)F4Si8O20, where the exchangeable cations are denoted by M. These clay particles are polydisperse with lateral dimensions of the order of μm, and they possess a net negative surface charge (x e− per unit cell), which is balanced by counter-ions localized between clay lamellar sheets. Ideally x = 1.2 (Kaviratna et al., 1996). Li-fluorohectorite (LiFh) was purchased from Corning Inc., New York, and characterized by X-ray diffraction (XRD) and atomic absorption spectrometry (AAS) using the procedures described later on. From those studies, it was concluded that the purchased material contained about 80% by mass of LiFh clay described by the nominal formula Lix(Mg6 − xLix)Si8O20F4 with x = 1.2, and about 20% of Li2O·2SiO2 impurities. Cipro in the form of ciprofloxacin hydrochloride (C17H19ClFN3O3), acetaminophen (C8H9NO2) and ibuprofen (C13H18O2)—pharmaceutical grade according to the United States Pharmacopoeia (USP30-NF25,
For atomic absorption spectrometry (AAS) measurements, 0.1 g of LiFh was digested overnight using HCl, HF and HClO4 in 100 ml of water. After that, the dissolutions were analyzed by means of standard AAS (PYE UNICAM SP9). The whole process was replicated five times. X-ray diffraction (XRD) for the different clays before and after the drug adsorption, was conducted on a Philips Xpert diffractometer, using Cu Kα radiation (λ = 1.54 Å) at room temperature, operating at a voltage of 45 kV and working current 25 mA. The experiments were done at a scan rate of 1° min−1 for a 2θ range spanned from 2 to 40°. The solid clay samples were analyzed by thermal gravimetric analysis (TGA) and infrared spectroscopy (IR) before and after interaction with the Cipro. TGA was performed on a NETZSCH STA 409 PC/PG thermal analyzer under dry air flow (50 ml/min), and a heating rate of 10 °C/min, from 20 up to 800 °C. The sensitivity of the thermobalance was ±1 μg. To perform IR analysis, the solids were dried overnight in an oven at 100 °C and 65 °C for the native clay and the clay-drug composite, respectively (the lower temperature used in the case of the composite avoids Cipro decomposition). A Nicolet AVATAR 330 Fourier-transform IR spectrometer, in the wavenumber interval 400–4000 cm−1 with a resolution of 2 cm−1, was used. The samples were prepared using the KBr pressed-disk technique, with 0.8% inclusion of the material to be analyzed. 2.4. Drug release assays
Fig. 1. Molecular structure of the ciprofloxacin drug molecule.
The studies of Cipro release from the composites were carried out for the LiFh clay. About 30 mg of the powdered composite (equivalent to 8.3 mg of Cipro determined by UV as described before) was put in contact with 50 ml of synthetic gastric juice without pepsin at 37 ± 1 °C—according to the method reported in the Pharmacopoeia for this kind of system (USP30-NF25, 2007), and 100 rpm stirring. Release studies under identical conditions but at 65 ± 5 °C were also carried out in order to evaluate the temperature dependence of the Cipro release from
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clay. No clay-drug interaction could be detected in the case of acetaminophen and ibuprofen under the conditions described above. It could be explained based on the functional groups of the drugs: in the Cipro, unlike the other two molecules, there are three amine groups, where at least one of them might easily acquire positive charge, allowing the interaction with the negatively charged clay layers. When examined by UV at 4 h and 24 h, the same amount of drug incorporation was measured (277 mg ± 10 mg of Cipro per gram of clay; equivalent to 8.3 mg of Cipro per 30 mg of composite). Thus, in the following, 4 h was the adsorption time of choice for the samples. 3.2. Samples characterization
Fig. 2. Diffraction patterns for LiFh and LiFh-Cipro composite.
the clay. For both temperatures, aliquots of the solutions were collected at scheduled intervals and centrifuged. Each time, the supernatant was removed and replaced with 2 ml of synthetic gastric juice. The drug concentration in the solution as a function of time was measured by UV spectroscopy. To check the repeatability of the experiments, the assays were made in triplicate and the analysis was replicated three times for each one. The average values of the release percentage were reported, with a relative uncertainty of a 5%, corresponding to the maximum difference in release percentage between the average and the replicas. 3. Results and discussion 3.1. Drug intercalation The UV measurements demonstrated that, among the three drugs under scrutiny, only Cipro showed a significant affinity with the LiFh
The AAS assays of the LiFh showed that the unit cell chemical formulas were Lix(Mg6 − xLix)Si8O20F4, with x = 1.2 for the clay phase (80% by weight of the sample powder), and Li2O·2SiO2 for the impurities (20% by weight of the sample powder). The XRD characterization confirmed the presence of Li2O·2SiO2 impurities, as well as the fact that they were not involved in the Cipro capture, since its main reflections (Soares et al., 2003) did not show any shifts in positions after contact with the Cipro solution. Using XRD, the 001 reflection (basal reflection) from the clay stacks was studied. The diffraction patterns for LiFh and LiFh-Cipro composite can be seen in Fig. 2. In the case of the native LiFh sample, there is one layer of water intercalated between the stacks in ambient conditions (reflection marked as (a) in the figure) (Hemmen et al., 2010). The LiFh-Cipro samples under study were prepared as described above (4 h interaction at pH near 8). There were four reflections in the XRD pattern for LiFhCipro marked as b–e in Fig. 2. Reflection (b) could be associated with clay stacks in the composite that only has two layers of water intercalated (Hemmen et al., 2010). Reflection (c) could be interpreted as a fingerprint of clay stacks with Cipro intercalated (as illustrated in Fig. 1, Cipro is a much larger molecule than water and produces a much larger d-value increase). In such case, the d-value with the Cipro intercalated was 1.7 nm. Reflections (d) and (e) may correspond to different conformations of Cipro molecules in the interlayer space of fluorohectorite or
Fig. 3. Schematic representation of the atomic structure of the LiFh (a), and sketch of a possible configuration of LiFh with intercalated Cipro (b).
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Fig. 4. IR transmittance spectra for Cipro, LiFh, and LiFh-Cipro composite.
possibly water layers in addition to the drug molecule. More experiments beyond the scope of the present work are needed to reach a final conclusion on this. As has been mentioned, the interaction studies clay-drug took place at a pH around 8. In such condition, an important part of the Cipro molecules are in zwitterionic form (i.e., Cipro molecules have a positive part related with the protonated amine group and a negative part associated with the deprotonated carboxylic group). Therefore, some interaction between the positively charged amino group of the Cipro, and the clay with negative charge, is expected. A schematic representation of the atomic structure of LiFh and a sketch of a possible configuration of LiFh with intercalated Cipro is shown in Fig. 3a and Fig. 3b, respectively. IR transmittance spectra for Cipro, LiFh and the LiFh-Cipro composite are presented in Fig. 4. The characteristic O\\H and Si\\O bands of the LiFh sample were assigned in the spectrum: The main Si\\O stretching band in-plane at 997 cm−1 and the Si\\O out-of-plane bending band at 710 cm−1, as well as the Si\\O in-plane bending band at 472 cm−1 were observed. In addition it was also possible to identify the Si\\O stretching out-of-plane at 1086 cm−1 (Komadel et al., 1996). In the Cipro spectrum, the most characteristic bands are those in the interval of 1800– 1200. The band at 1707 cm−1 was ascribed to the carboxylic acid C= O stretching, that of 1624 cm−1 to the C=O stretching for ketone, and the band at 1271 cm− 1 to the coupling of the carboxylic acid C\\O
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stretching and O\\H deformation (Gu and Karthikeyan, 2005; Neugebauer et al., 2005; Trivedi and Vasudevan, 2007). The band at 1707 cm− 1 disappeared in the composite LiFh-Cipro spectrum. It is possible to explain it as follows. The natural pH of a pure Cipro solution and the natural pH of the pure clay in aqueous dispersion were measured to be 4.5 and 10, respectively. On the other hand, the pH of the Cipro-clay dispersion was around 8. This high pH value leads to de-protonation of the carboxylic group, which results in the C=O bond becoming two more or less equivalent C\\O bonds. Therefore, the band corresponding to \\COOH disappeared from the LiFh-Cipro spectrum, and was replaced by two bands at 1581 and 1390 cm−1, which may be assigned to antisymmetric (νasCOO−) and symmetric (νsCOO−) stretching vibrations of the \\COO– group, respectively. This was attributed to the existence of the Cipro in zwitterionic form, where the COO\\ group is deprotonated and the piperazinyl group is protonated (Turel et al., 1997; Sun et al., 2002). In addition, due to the COOH group deprotonation and loss of the carboxylic acid C=O stretching, a significant decrease in intensity of the coupled COOH modes at 1271 cm−1 was also observed. This behaviour had been reported previously in similar systems (Trivedi and Vasudevan, 2007; Qingfeng et al., 2012). A more direct interaction between Cipro and clay was detected, as follows. A variation in the wavenumber of the band assigned to the Cipro from 1624 cm− 1 to 1631 cm− 1 after the interaction with the clay was also observed. The shift of this band in the LiFh-Cipro composite, as compared to the spectrum of Cipro alone, suggests strong interactions between the structures of Cipro and the clay via the ketone group. A wide band with center near 3445 cm−1 was observed for the LiFh sample in the region from 4000 cm−1 to 2000 cm−1 (Fig. 4). It could be ascribed to the absorption bands of structural hydroxyl groups and the interlayer water, based on the fact that in the smectites, the broad absorption band of the adsorbed water near 3400 cm− 1 overlaps the structural OH–stretching band (Madejová et al., 1996). Concerning the spectrum of the LiFh-Cipro composite, two shallow bands around 3605 and 3400 cm−1 were detected, which could indicate that the absorption bands of the structural hydroxyl groups and interlayer water of the clay were modified upon Cipro intercalation. Resulting from Cipro intercalation, the water contained in the interlayer space can be replaced, in whole or in part. Then, the formation of a hydrogen bond between the amine group positively charged of the Cipro molecule and the hydroxyl groups of the clay could be expected. TG/DTG curves for Cipro, LiFh and LiFh-Cipro can be observed in Fig. 5. Four main peaks of mass loss at 154, 299, 319 and 406 °C were identified for the Cipro. The Cipro decomposition could be described as a sequence of three consecutive steps (El-Gamel et al., 2012). The first one is related to the loss of CO. The second one occurred in the range 220–370 °C and can be attributed to a loss of [C4H8N2H2 + CO] (two peaks in the DTG curve). The last one, above 370 °C, can be attributed to the removal of the residual drug as C11H8FNO. Two prominent peaks, around 100 °C and 150 °C, could be identified in the DTG curve for the clay. These peaks could be attributed to the desorption of water, in particular to the loss of mesoporous water, and to the loss of intercalated water, respectively (Rozynek et al., 2012). Peaks of mass loss in the region of 80 °C to 200 °C and approximately 350 °C were showed by the LiFh-Cipro composite. The peak around 350 °C could be assigned to the second step of the decomposition process of Cipro, which evidenced its presence in the composite. When comparing the DTG curve of the Cipro with that of the LiFh-Cipro composite, it was observed that an increase takes place in the temperature of Cipro decomposition (at 299 °C and 319 °C) after the interaction with the clay. Thus, its thermal stability was increased in the composite. The mass loss in the region 80 °C to 200 °C (last panel in Fig. 5) could be attributed to the fact that water desorbed significantly easier from the composite than from the pure clay, which could be due to increased interlayer space when Cipro is intercalated.
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Fig. 5. TG and DTG curves for Cipro, LiFh and LiFh-Cipro composite, at 10 °C/min.
3.3. In vitro Cipro release The percentage of Cipro released from the LiFh-Cipro composite as a function of time at 37 °C and 65 °C is shown in Fig. 6. The amount of Cipro released in SGJ increased as a function of time. At 37 °C and 65 °C, the composite released approximately up to 10% and 25% of the initial drug load (277 mg of Cipro per gram of clay; equivalent to 8.3 mg of Cipro per 30 mg of composite), respectively within 10 h. This demonstrated that the release dynamics of the composite is
Fig. 6. In vitro release curve of Cipro from a colloidal dispersion of the LiFh-Cipro at composite 37 °C and 65 °C in synthetic gastric juice (SGJ).
temperature–controlled, a potentially relevant feature for biomedical applications. The actual mechanism of drug capture by such clay is not understood. Three general alternative scenarios can be suggested: One possibility could be that the Cipro molecule replaces the charge-compensating cations, in which case there would nominally be about 1.2 captured Cipro molecules associated with each unit cell of the clay. Another possibility could be that the Cipro molecules do not replace the cations, but rather could be attracted to the cations. So, in this case it could be possible to nominally associate a minimum of about 1.2 Cipro molecules per unit
Fig. 7. Percent of ciprofloxacin released from the LiFh-Cipro composite at different temperatures and at a fixed time in synthetic gastric juice (SGJ).
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cell of the clay. Thirdly, and lastly, it could be possible that the drug molecules are captured by the clay surfaces, although it appears a less important mechanism in view of the relatively slow release shown in Fig. 6. In this latter scenario, there could be at least 1 Cipro molecule associated with each unit cell, since the unit cell is the in-plane repetitive unit in the clay structure. In summary, whatever is the mechanism, it can be assumed that approximately 1.1 ± 0.1 Cipro molecules could be captured per unit cell of the clay as a lower estimate for a clay fully loaded with drug molecules. The chemical formula for fluorohectorite is Mx(Mg6 − xLix)Si8O20F4, where M denotes the exchangeable cations, giving a unit cell mass of about 754 (atomic mass units) for the clay, for M = Li and x ≈ 1.2. The atomic mass of the Cipro molecule is about 368, which gives an estimate of the Cipro-to-clay mass ratio of about 368/754 (≈0.5) for a compactly packed clay sample. The clay samples under study in the present paper typically have 40% mesoporosity (Knudsen et al., 2003); thus it was possible to estimate the Cipro drug load to be approximately 0.3. The XRD and AAS characterizations suggested that about 80% of the mass of the powder samples was clay, and that the remaining 20% were impurities. The UV results showed that the Cipro mass incorporated per unit mass of sample was approximately 0.3, which translates into 0.35 of Cipro mass incorporated per unit mass of clay, assuming that 20% of the impurities do not play a role in the capture of Cipro. This suggested that an important proportion of the Cipro was captured by the clay in the powder. To understand the mechanisms involved, six standard models (Calabrese et al., 2013) applied to slow release systems were considered to describe the data. Within the error bars, the data presented in the present paper can be well fitted by the zero order model (Calabrese et al., 2013). Q t = Q e + k0t with Q e = 0 and k0 = 0.76 and 1.93 for 37 °C and 65 °C, respectively. This meant that, for both temperatures the release follows an anomalous diffusion. It implied that the composite released the same amount of drug per unit time, which is an ideal method of drug release for achieving sustained pharmacological action. The percentage of Cipro released from the composite at 6 h, as a function of temperature is displayed in Fig. 7 (here, the process was stopped at 6 h instead of the step-like aliquot collection associated to Fig. 6). A clear increase in the slope of the curve was observed as temperature increases, confirming that the release in the system was temperature–controlled. An Arrhenius thermal activation plot of the same data is shown in the inset of Fig. 7, giving an activation energy (Ea) of approximately 67 kJ mol− 1 (0.7 eV). The maximum release was observed at 85 °C, corresponding to 50% of the initial amount of Cipro. Ea can be viewed as the energy barrier a drug molecule must overcome to be released from the clay. Energies involved in physisorption are usually in the range of 5–40 kJ mol−1, while activation energies from 40 to 800 kJ mol− 1 are typical of chemisorptions (Nollet et al., 2003; Seki and Yurdakoç, 2006). Distinguishing between physical and chemical mechanisms is not always easy, in particular when the values of activation energies are near the limit between both phenomena. In the case of chemical adsorption, there is a direct chemical bond between the adsorbate and the surface; a chemically adsorbed molecule loses its identity on reaction or dissociation and cannot be recovered by desorption (Choi et al., 2001). Physical adsorption does not involve any chemical bonds: the adsorbate is held by physical forces (i.e., van der Waals and electrostatic), it usually keeps its identity and, on desorption, returns to its original form. The value of Ea calculated from Cipro desorption process was somewhat bigger than the lower limit typically used to define chemical adsorption (40 kJ mol−1). This suggested a weak chemical interaction mechanism, which was also supported by the IR spectroscopy results, where strong interactions between the Cipro structure and the clay via the ketone group may take place, as well as hydrogen bond between the amine group positively charged of the Cipro and the hydroxyl groups of the clay. In addition, the UV spectra of the Cipro solutions after the interaction of the composite with synthetic gastric juice did not reveal any chemical changes in the Cipro molecules due to their interaction with the clay. Finally, the
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slow release of Cipro in time suggested either a weak chemical interaction or a strong physical interaction. New experiments and computational simulations are on course in order to shed light on the precise mechanisms involved in the incorporation and release of Cipro hydrochloride into/from clay fluorhectorite. Computational studies—using classic Molecular Dynamics and periodic quantum calculations—are being performed in order to corroborate our IR results suggesting cipro-clay interactions via the ketone group, and to evaluate if other functional groups of the Cipro interact with the clay, as well as the possibility of hydrogen bonding. Studies of Cipro capture by different exchanged forms, Na-fluorohectorite (NaFh) and Cufluorohectorite (CuFh), are also in progress in order know the influence of the cation. Preliminary results indicate that NaFh is able to incorporate Cipro, while CuFh incorporates a very moderate amount of the drug. It is worth noticing that related studies have been carried out by other groups for different clays with diverse model drugs (Mohanambe and Vasudevan, 2005; Park et al., 2008; de Sousa Rodrigues et al., 2013). 4. Conclusions The ability of the clay Li-fluorohectorite to incorporate the antibiotic ciprofloxacin, up to 277 mg per gram of material, has been shown. The incorporation was demonstrated to take place in the clay interlayer space. In vitro release studies on the LiFh-Cipro composite showed that the clay promotes the slow release of ciprofloxacin, and that the percentage of drug released increases both with time and with temperature. The profiles of drug release from the composite in the gastric environment fulfilled the pharmaceutical standards for these systems. While the drug release behaviour of the composite has been studied in this paper within a temperature range from the normal human body to approximately 85 °C, it is possible to visualize future specific potential biomedical applications, such as the increased release of drug in the human stomach during an episode of fever. However, such application would demand, first of all, the modification of the fluorohectorite clay in order to decrease its swallowing temperature. Acknowledgments A. R. thanks The Academy of Sciences for the Developing World (TWAS) for the research grants no. 00-360 RG/CHE/LA and no. 07-016 RG/CHE/LA. A. R. and L. Ch. M. thank the technical support from Pôle de Recherche et d'Enseignement Supérieur Sud de France (PRES). J. O. F., E. L. H. and Z. R. acknowledge support from the Research Council of Norway. E. A. and J. O. F. thank the Centre for Advanced Study at the Norwegian Academy of Science and Letters (CAS) under the project Complex Matter Science 2011-12. E.A. and A. R. recognize support by a TOTALESPCI ParisTech Chair, and by PMMH/ESPCI. Z. R. acknowledges financial support from the National Science Centre through FUGA4 programme (DEC-2015/16/S/ST3/00470). Laboratorios MEDSOL are thanked for providing the pharmaceutical grade raw materials. The authors acknowledge the insightful comments of ACS associate editor J. T. Kloprogge. References Anderson, R.L., Ratcliffe, I., Greenwell, H.C., Williams, P.A., Cliffe, S., Coveney, P.V., 2010. Clay swelling – a challenge in the oilfield. Earth-Sci. Rev. 98, 201–216. Bosshard, H.R., Marti, D.N., Jelesarov, I., 2004. Protein stabilization by salt bridges: concepts, experimental approaches and clarification of some misunderstandings. J. Mol. Recognit. 17, 1–16. Calabrese, I., Cavallaro, G., Scialabba, C., Licciardi, M., Merlic, M., Sciascia, L., Liria, M., Turco Liveri, M.L., 2013. Pharmaceutical nanotechnology montmorillonite nanodevices for the colon metronidazole delivery. Int. J. Pharm. 457, 224–236. Carretero, M.I., 2002. Clay minerals and their beneficial effects upon human health. Appl. Clay Sci. 21, 155–163. Choi, J.-G., Do, D.D., Do, H.D., 2001. Surface diffusion of adsorbed molecules in Porous Media: monolayer, multilayer, and capillary condensation regimes. Ind. Eng. Chem. Res. 40, 4005–4031. El-Gamel, N.E.A., Hawash, M.F., Fahmey, M.A., 2012. Structure characterization and spectroscopic investigation of ciprofloxacin drug. J. Therm. Anal. Calorim. 108, 253–262.
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