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Effects of particle morphology, pore size and surface coating of mesoporous silica on Naproxen dissolution rate enhancement
Colloids and Surfaces B: Biointerfaces 101 (2013) 228–235
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Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb
Effects of particle morphology, pore size and surface coating of mesoporous silica on Naproxen dissolution rate enhancement Zhuo Guo a,∗ , Xiao-Meng Liu a , Lei Ma a , Jian Li b , Hong Zhang a , Yun-Peng Gao a , Yue Yuan c a b c
Department of Materials Science and Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmacetical University, Shenyang, Liaoning 110016, China
a r t i c l e
i n f o
Article history: Received 30 November 2011 Received in revised form 14 June 2012 Accepted 17 June 2012 Available online 11 July 2012 Keywords: Mesoporous silica Naproxen Dissolution
a b s t r a c t Naproxen (Nap) is a commonly used drug for antiphlogosis and analgesia, but its dissolution rate in water is quite low. In this work, the dissolution behavior of Nap after loading in mesoporous silica materials was investigated in a simulated intestinal fluid (pH = 6.8). The results indicated that the pore sizes, morphologies and surface chemical groups of the mesoporous silica were significant factors on the dissolution behavior of Nap. The physical state of encapsulated Nap was affected by the pore sizes of mesoporous silica, which influenced its dissolution rate. Amorphous Nap exhibited a higher dissolution rate than crystallized Nap, even though the larger pore size could facilitate its diffusion from the matrix. The effect of the morphology of mesoporous silicas on the dissolution of Nap can be ascribed to the length of pore channels, that the longer channel showed a longer diffusion pathway of Nap. Moreover, the release rate of Nap from functionalized mesoporous materials was effectively controlled compared with that of unmodified materials. © 2012 Elsevier B.V. All rights reserved.
1. Introduction The main disadvantage of poorly soluble drugs is their low dissolution rate in water, which will lead to low oral bioavailability. Developing strategies to overcome this hurdle and to enable oral delivery of poorly soluble drugs is now one of the greatest challenges confronting formulation scientists [1–8]. Since the discovery of ordered mesoporous silica materials in 1990s, synthesis and applications of mesoporous solids have received intensive attention due to their highly ordered structures, large pore size and well-defined surface properties [9–12]. Mesoporous materials seem ideal for encapsulation of pharmaceutical drugs, proteins and other biogenic molecules. Recently, the application of mesoporous silica as prospective vehicles for oral drug delivery has been widely studied to improve dissolution properties of poorly soluble drugs [3,5,8,13–25]. The ability of mesoporous materials to enhance the solubility and dissolution rate of the incorporated drug is due to their small pores, which can change the crystalline drug to a noncrystalline state. It has been shown that several properties of mesoporous materials can affect the loading degree and release rate of the incorporated
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (Z. Guo). 0927-7765/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.colsurfb.2012.06.026
drug, such as the surface area, pore diameter, total pore volume, pore morphology and surface chemistry. Morphology determines the extension of the interface between drug-carrying particles and body fluids, and can affect drug release kinetics [26–30]. The pore diameter is an important factor to determine the drug release rate. It was found that reducing the pore size could delay the release of drug [3,27,31–34]. Furthermore, appropriate functionalization of the inner pore walls of mesoporous materials also will potentially affect release rate by tuning the binding strength with drug molecules [14,18,21,26,35–40]. Although the delivery of different drugs using mesoporous silica materials has been investigated, the focus is mainly on the development of slow release formulations. Reports on the enhancement of dissolution of poorly aqueous soluble drugs using synthetic mesoporous silica materials are still rare [5–7,31,41]. Naproxen [(S)-6-methoxy-␣-methyl-2-naphthalenacetic acid, Nap] (Fig. 1), a nonsteroidal anti-inflammatory drug with poor solubility, is widely used to treat arthritis, post-operative pain, headache, and musculoskeletal. In the present paper, we report the application of mesoporous silica materials with different pore size, pore channel length, particle morphology and chemical moieties on the pore surface as drug delivery vehicle to evaluate the structural effect of the particles on the dissolution behavior of Nap at pH 6.8. The aim of this work was to improve the dissolution rate of poorly soluble Nap by loading in mesoporous silica materials, intending to be orally administrated.
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3-aminopropyltriethoxysilane in 25 ml toluene was added dropwise to the slurry and stirred under reflux at 100 ◦ C for 24 h. Finally the materials was filtered, washed with dry toluene, and Soxhletextracted using a mixture of 100 ml of diethyl ether and 100 ml dichloromethane for 24 h. The final solid was dried overnight in air at 90 ◦ C. The obtained samples were named as NH2 -MCM-41-A, NH2 -MCM-41-B and NH2 -SBA-15. Fig. 1. Structural formula of Naproxen.
2.4. Loading of Naproxen 2. Materials and methods 2.1. Materials Cetyltrimethylammonium bromide (C16 TAB) and dodecyltrimethylammonium bromide (C12 TAB) and tri-block copolymer poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide), pluronics P123 (EO20 -PO70 -EO20 , MW: 5800) were purchased from Aldrich (USA). TEOS was purchased from Tianjin Kermel Chemical Reagent Co., Ltd, China. Naproxen was purchased from HuBei Hezhong Biochemical Co., Ltd, China. 3Aminopropyltriethoxysilane (APTES) was purchased from Aladdin, Shanghai, China. The other reagents were analytical grade and were used as received without further purification. 2.2. Preparation of the mesoporous samples
Nap was loaded by soaking mesoporous materials into 10 ml ethanol solution of Nap (0.1000 M) under continuous magnetic stirring for 10 h at 37 ◦ C. Nap solution was covered with polyethylene film to prevent the evaporation of solvent in order to achieve maximum loading. A 1:1 (by weight) ratio of Nap to solid sample was used. Nap loaded samples were recovered by filtration, washed with ethanol until the filtrates reach to 10 ml, and left to dry for 24 h at 37 ◦ C. The filtrates were measured by an ultraviolet–visible (UV–vis) spectrophotometer to determine the drug loading amount. The dried samples were named as Nap-MCM41-A, Nap-MCM-41-B and Nap-SBA-15. The procedure of loading Nap into amine-modified mesoporous materials was similar to that used for unmodified mesoporous materials, and the dried samples were named Nap-NH2 -MCM-41-A, Nap-NH2 -MCM-41-B and Nap-NH2 -SBA-15. 2.5. Materials characterization
The matrix denoted as MCM-41-A and MCM-41-B were synthesized at hydrothermal condition using C16 TAB and C12 TAB as template, respectively. For the synthesis of MCM-41-A, 3.0 g C16 TAB was dissolved in 25 ml deionized water, followed by addition of 25 ml sodium silicate solution (35–40%) under stirring. The mixture was adjusted to pH 10 by 2 M HCl solution, and then transferred to a polypropylene bottle, followed by treatment at 100 ◦ C for 72 h. The resulting white solid was recovered by filtration, washed with distilled water, dried and calcined at 550 ◦ C for 6 h in air at a heating rate of 2 ◦ C/min [9]. For the synthesis of MCM-41-B, 0.42 g of C12 TAB and 0.75 ml of 1 M sodium hydroxide solution were dissolved in 100 g of a watermethanol (3:1, w/w) solution. Then, 0.62 g of TEOS was added to the solution with vigorous stirring. After the addition of TEOS, the clear solution gradually turned opaque, resulting in a white precipitate. After 8 h stirring, the mixture was aged overnight. The white powder was then filtered out and washed with distilled water, and dried at 45 ◦ C for 72 h. The powder was calcined at 550 ◦ C for 6 h in air at a heating rate of 2 ◦ C/min [42]. SBA-15 was synthesized by using P123 as template. The procedure was as follows: 4.0 g of P123 was dissolved in 30 ml of distilled water. Then, 4 ml of 2 M HCl solution was added to the solution with vigorous stirring at 35 ◦ C. After complete dissolving of P123, 8.5 g of TEOS was added. The mixture was stirred at 35 ◦ C for 20 h and then aged at 80 ◦ C for 48 h. The white solid product was recovered by filtration, dried and calcined at 550 ◦ C for 6 h in air at a heating rate of 2 ◦ C/min [11]. As a result, the surfactant was completely removed by calcination before incorporation of Naproxen. 2.3. Modification The prepared MCM-41-A, MCM-41-B and SBA-15 were functionalized with aminopropyl groups through a postsynthesis procedure. For the chemical incorporation of organo-amine molecules, all samples were pretreated in air at 110 ◦ C for 4 h to remove any physisorbed water. Then, 3 g of the dehydrated materials were suspended in 75 ml of dry toluene and stirred at room temperature for 1 h. An excess amount of
Several instrumental techniques were used for sample characterization. Powder X-ray diffraction (XRD) data were collected on a SIEMENS D5005 diffractometer with Cu K˛ radiation at 40 KV and 30 mA. Nitrogen adsorption–desorption, Brunauer–Emmett–Teller (BET) surface area, and pore diameter were measured using a Micromeritics ASAP 2010 M sorptometer. Before measurement, all samples were degassed at 100 ◦ C for 12 h, and the measurements were carried at 77 K. Specific surface areas and pore size distributions were calculated using BET and Barrett–Joyner–Halenda (BJH) models from the adsorption branches, respectively. A Fourier transform infrared (FT-IR) spectrometer (Nicolet IS10) was used to record infrared spectra of the samples by the KBr method. The IR spectra, in absorbance mode, were obtained over the spectral region 400–4000 cm−1 . 29 Si MAS NMR experiment was performed on a Varian Infinityplus-400 spectrometer under magic-angle spinning operating at a frequency of 79.5 MHz with the following conditions: magic-angle spinning at 2.5 kHz, /2 pulse, 4.8 s, repetition time 100 s for singlepulse experiments. The samples morphologies were examined by scanning electron microscope (SEM, JSM-6360-LW, JEOL, Japan) at 5 kV. Prior to analysis, the samples were sputtered with a thin film of platinum. Transmission electron microscopy (TEM) images were recorded on JEOL 3010 with an acceleration voltage of 100 kV. Thermal analysis of the samples was carried out with a differential scanning calorimeter (DSC) instrument (Q200, TA Instruments, USA). The heating rate is 10 ◦ C/min and the nitrogen purge rate is 40 ml/min. The drug loading amounts were determined by UV–vis spectrophotometer (Uv-752, Shanghai Precision and Scientific Instrument Company, China). Thermogravimetric analysis (TGA) was performed using a TGA-50 instrument (Shimadzu, Japan) at a heating rate of 10 ◦ C/min under a nitrogen purge rate at 40 ml/min. 2.6. In vitro dissolution Before the release, Nap loaded samples equivalent to 40 mg Nap were compressed into a tablet (˚ = 10 mm) under uniaxial pressure (0.5 MPa). Dissolution studies were conducted using a USPII paddle method (50 rpm, 37 ◦ C, and 900 ml dissolution medium) with a
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Fig. 2. Small-angle XRD patterns of (A) SBA-15, (B) MCM-41-A and (C) MCM-41-B. The wide-angle XRD patterns (D) of pure Nap (a), Nap and SBA-15 physical mixture (b), Nap-SBA-15 (c), Nap-NH2 -SBA-15 (d), Nap-MCM-41-A (e); Nap-NH2 -MCM-41-A (f), Nap-MCM-41-B (g) and Nap-NH2 -MCM-41-B (h).
D-800LS dissolution tester (Tianjin University Radio Factory, China). Dissolution media was prepared by dissolving potassium dihydrogen phosphate in deionized water and the pH was adjusted by 1 M sodium hydroxide solution, to simulate intestinal fluid (pH 6.8) [1]. The samples contained 40 mg Nap were used in sink condition. Dissolution medium (5 ml) was removed from the vessel at appropriate intervals. An equal amount of fresh dissolution medium was replaced to keep the volume constant. The concentration of drug in each sample was determined by comparison with a calibration curve based on the absorption maximum (max = 332 nm). All experiments were performed in triplicate. 3. Results and discussion 3.1. XRD Small-angle XRD patterns of the mesoporous materials were shown in Fig. 2A–C. The small-angle XRD patterns of parent and amine-modified samples showed long range periodicity of the porous structure. The diffraction peaks of modified samples showed the same 2 values as those of parent silica, which indicated the fidelity of hexagonal structural arrangement during the modification. SBA-15 and MCM-41-A both showed three well-resolved XRD peaks, which can be indexed into 1 0 0, 1 1 0 and 2 0 0 reflections of the 2D hexagonal symmetry, indicating a good structural quality of these materials. These patterns can be assigned to an ordered structure of hexagonal symmetry with P6 mm space group [11,43]. The
MCM-41-B showed only one strong (1 0 0) reflection because mesoporous molecular sieve did not appear (1 1 0) and (2 0 0) diffraction peaks when prepared using short-chain surfactant C12 TAB [33]. The powder XRD patterns of mesoporous materials loaded with Nap were also exhibited in Fig. 2. The XRD patterns showed that the hexagonal mesoporous structure of samples loaded with Nap was similar to that of unloaded samples. The main XRD peaks were still observed, showing that the hexagonal mesopores of the mesoporous materials were maintained during the entrapment of drug molecules inside pores. The intensities of the reflections were diminished by the loading of Nap, similar to the behavior observed upon loading PEI into MCM-41 [44]. The diminishment of peak intensities confirmed that Nap has been loaded into the channels of mesoporous materials. Fig. 2D displayed wide-angle XRD patterns of drug-loaded samples. The diffraction pattern of pure Nap was highly crystalline in nature. Six peaks at 14.6◦ , 17.0◦ , 18.7◦ , 20.7◦ , 25.4◦ and 28.3◦ were visible and the main peak at 20.7◦ was particularly distinctive. For the physical mixture of SBA-15 and Nap, peaks at 20.7◦ were attributed to those of pure Nap. However, it can be seen that Nap loaded in MCM-41-A/or B and NH2 -MCM-41-A/or B and NH2 -SBA15 exhibited an amorphous state, as no XRD peaks were detected. It was known that the absence of characteristic peaks indicated that the Nap was in noncrystalline state [17,36,45]. But for Nap-SBA15, some small peaks for Nap nanocrystals could be observed. As expected, crystalline Nap only formed in the larger pores [46]. This observation was consistent with the result obtained by Shen et al.
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Fig. 3. FT-IR spectra of crystalline Nap (a), MCM-41-A (b), NH2 -MCM-41-A (c), NapMCM-41-A(d) and Nap-NH2 -MCM-41-A (e).
[31]. The wide-angle XRD patterns further confirmed that Nap was encapsulated inside the pore of the materials but not on the exterior surfaces. 3.2.
29 Si
MAS-NMR and FT-IR
Solid-state 29 Si MAS-NMR confirmed the presence of organofunctionalized moieties as part of the silica wall structure for all of the organically modified mesoporous silica materials (Fig. S1). Detailed positions and relative intensities of peaks were listed in Table S1. Distinct resonances could be observed for the siloxane (completely condensed Si, Q4 ; partially condensed Si, Q3 ) and organosiloxane (T3 , Si-R; and T2 , Si(OH)R) units[37]. It could be seen in Table S1 that the functionalization efficiency of SBA-15 was higher than that of MCM-41-A and MCM-41-B. The larger pore size and volume would be better explained that a significant fraction of aminopropyl groups anchored in SBA-15. MCM-41-A and MCM-41-B had the similar pore size and a quite close amount of pore volume, so they would exhibit very similar behavior in degree of functionalization. Indeed, higher amounts of organosiloxane units were detected in the mesoporous materials MCM-41-A, owing to the lower degree of condensation of the silica network (lower population of Q4 environments). Quantitative determinations of functional groups were performed by TGA (Fig. S2). The weight loss due to functional groups was 21.5%, 15.1% and 13.4% for NH2 -SBA-15, NH2 -MCM-41-A and NH2 -MCM-41-B, respectively. The 29 Si NMR measurements correlate well with the TG analysis. TGA and 29 Si NMR were clear evidence that most of the functional groups were located on the wall of pores and were accessible and useful for adsorption of drug molecules. Organic functionalization was also evidenced by FT-IR spectra. The FT-IR spectra of mesoporous materials were shown in Fig. 3. All the parent MCM-41-A/B and SBA-15 mesoporous matrix have the typical silanols absorbance in their siliceous framework in FTIR spectra, so only MCM-41-A is shown. The spectrum recorded for Nap showed numerous bands ascribed to the vibration of chemical bonds existing in the molecule (aromatic ring, carboxylic, methyl, ether groups, etc.) [47]. The FT-IR spectrum of MCM-41A was characterized by the presence of strong and broad band observed at about 1000 cm−1 , which corresponded to the asymmetric stretching vibration, as (Si O Si), of the siliceous framework. The symmetric stretch, s (Si O si), and the bending vibration,
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ı(Si O Si), of the siliceous framework were observed at 800 cm−1 and 500 cm−1 , respectively. These bands, together with the broad band at about 3400 cm−1 (stretching vibration of the physisorbed water) were observed in the spectra and were typical for MCM-41 mesoporous matrix [16]. FT-IR was known to provide surface information about materials for identification of chemical groups. Therefore, the samples modified by amine and loaded with Nap were reflected by appearance of characteristic absorbance in the IR spectra. For NH2 -MCM-41-A, a new band assigned to NH2 asymmetric bending was observed at 1559 cm−1 , and two bands at 2934 and 2847 cm−1 corresponding to the stretching (C H) vibrations were due to the methylene groups introduced during functionalization [1,39,48]. FTIR spectrum of Nap showed a carboxyl band at 1686 cm−1 , which correspond to the carboxyl group [47]. For Nap-MCM-41-A, carboxyl peaks could be observed at 1729 cm−1 , but they showed a slight shift from 1686 cm−1 , due to the hydrogen bonding to silanol groups [1]. The loading of Nap was also reflected by breathing vibrations of aromatic rings in the spectra ranging in 1600–1500 cm−1 . For NapNH2 -MCM-41-A, intense carboxylate bands at 1570 and 1371 cm−1 were detected, which indicate that proton transfer from the carboxylic acid of Nap to aminopropyl groups had taken place [37]. 3.3. N2 adsorption/desorption The nitrogen adsorption–desorption isotherms registered of parent, amino-modified and Nap loaded mesoporous materials were shown in Fig. S3. All of them can be included into type IV according to the IUPAC classification [49], which corresponds to solids with pores in 1.5–50 nm range. Due to the difference in pore sizes, MCM-41-A and MCM-41-B showed a N2 condensation step at P/P0 of 0.2–0.4, while the condensation step of SBA-15 increased to the ranges of 0.65–0.85. Both amine-functionalized and Nap loaded samples downshift the capillary condensation step to lower relative pressures, which reflected the decrease of pore sizes by amine modification and Nap encapsulation in pores. The pore size distribution, Fig. S3, showed maxima at ca. 2.78 and 2.15 nm in diameter for MCM-41-A and NH2 -MCM-41-A, respectively. After loading of Nap, the pore diameter decreased to 1.93 nm and 1.78 nm for the Nap-MCM-41-A and Nap-NH2 -MCM-41-A, respectively. The incorporation of Nap also decreased the specific surface areas and pore volumes, which indicated that the Nap was inserted inside the pores. The values for the BET specific surface area (SBET ), the total pore volume (V) and the BJH pore diameter were given in Table 1. The loading amounts of drug of all samples were shown Table 1. In the parent materials, SBA-15 exhibited the highest loading capacity of Nap. The loading amount of Nap-SBA-15 was 41.43 wt%. For Nap-MCM-41-A and Nap-MCM-41-B, they were 27.20 wt% and 21.54 wt%, respectively. Among the amino-modified materials, Nap-NH2 -SBA-15 had the largest loading, which was 39.21 wt%. Table 1 The pore characterization and drug loading amount. Sample
SBET (m2 /g)
Vpore volume (cm3 /g)
Pore size (nm)
Drug loading (wt%)
MCM-41-A NH2 -MCM-41-A Nap-NH2 -MCM-41-A Nap-MCM-41-A MCM-41-B NH2 -MCM-41-B Nap-NH2 -MCM-41-B Nap-MCM-41-B SBA-15 NH2 -SBA-15 Nap-NH2 -SBA-15 Nap-SBA-15
1176 925 524 646 1078 879 588 658 923 791 581 510
1.09 0.82 0.48 0.65 0.97 0.79 0.53 0.66 1.20 0.96 0.40 0.48
2.78 2.15 1.78 1.93 2.14 1.75 1.43 1.49 9.32 7.39 5.27 4.76
– – 25.19 27.20 – – 20.32 21.54 – – 39.21 41.43
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The highest degree of functionalization of NH2 -SBA-15 in these three functionalized materials (due to the largest pore size and volume) should lead to the largest Nap adsorption. Samples NH2 MCM-41-A and NH2 -MCM-41-B exhibited different behavior in Nap adsorption. The loading amounts of Nap-NH2 -MCM-41-A and Nap-NH2 -MCM-41-B were 25.19 wt% and 20.32 wt%, respectively. A lower density of aminopropyl groups (loading amounts/surface areas) inside the channel of NH2 -MCM-41-B could account for these results. Although NH2 -SBA-15, NH2 -MCM-41-A and NH2 -MCM-41B containing APTES in the channel had strong interaction with the drug molecule, the presence of NH2 also reduced the pore volume and pore size of the mesoporous material, resulting in the decrease of the drug loading capacity. These results suggested that the drug loading capacity of mesoporous materials was dependent on the total pore volume and pore diameter [1]. It was possible to relate the decrease of measured pore volume to the amount of adsorbed Nap in the samples [41]. For example, UV–vis analysis showed that 1.00 g Nap-MCM41-A contains 0.272 g of Nap molecules, and, consequently, 0.728 g of MCM-41-A. Taking into account that the pore volume measured for MCM-41-A was 1.09 cm3 /g, the available pore volume referred to 1.00 g of Nap-MCM-41-A was 0.728 × 1.09 = 0.79 cm3 /g of Nap-MCM-41-A. The size of Nap molecule measured by Chem. Office Ultra 8.0 2004 software is 1.172 nm × 0.501 nm × 0.366 nm. From this value, the volume of one mole Nap molecules is 129 cm3 /mol. The specific volume of Nap can be calculated as 129/MWNap = 129/230 = 0.56 cm3 /g. Therefore, the volume occupied by Nap in the Nap-MCM-41-A sample was 0.56 × 0.272 = 0.15 cm3 /g. The total pore volume was thus 0.79 − 0.15 = 0.64 cm3 /g of Nap-MCM-41-A. This value was very near to that experimentally result (0.65 cm3 /g) of Nap-MCM-41A. The result is in agreement with the adsorption of Nap molecules inside the MCM-41-A pores. 3.4. DSC The physical state of Nap entrapped in mesoporous materials was studied by DSC. As seen in Fig. 4, crystalline Nap exhibited a clear endothermic peak at 152 ◦ C, which was characteristic of the melting of the bulk phase of Nap [47]. But no signs of melting point could be observed for Nap-MCM-41-A/or B, Nap-NH2 -MCM41-A/or B and Nap-NH2 -SBA-15. This was related to finite-size effects, preventing the drug molecules from rearranging themselves in a crystal lattice, and this was in good agreement with XRD
Fig. 4. DSC thermograms of pure Nap (a), Nap-SBA-15 (b), Nap-NH2 -SBA-15 (c), Nap-MCM-41-A (d), Nap-NH2 -MCM-41-A (e), Nap-MCM-41-B (f), and Nap-NH2 MCM-41-B (g).
measurement. In contrast, the small melting peak of Nap can be observed at 148.2 ◦ C for Nap-SBA-15, but there was a slight shift from 152 ◦ C. The melting of crystalline Nap inside pores was observed at lower temperatures than the melting of Nap at bulk phase. The effect was due to the decrease of crystal size, which was restricted by the pore structure [50]. DSC confirmed the presence of crystalline Nap in the SBA-15 pores, and this was in good agreement with XRD measurement. But, the Nap-SBA-15 showed a significant reduction in the enthalpy of fusion, indicating the decrease of crystallinity of Nap, and also suggesting partial amorphous formation [31]. The pore sizes were found to affect the physical state and particle size of Nap. When Nap was loaded in MCM-41-A/orB, NH2 -MCM41-A/orB and NH2 -SBA-15, amorphous state of Nap was formed. In contrast, partial nanocrystals were formed when Nap was loaded in SBA-15 with larger pore size than MCM-41-A/orB and NH2 -SBA-15. The physical state of Nap played a key role in affecting the dissolution of Nap from mesoporous materials (this will be discussed in detail later). 3.5. SEM and TEM The morphology and particle size of all samples were analyzed by SEM and TEM. The morphology of SBA-15 material was similar to that of the MCM-41-A, which consisted of bundles with 20–40 m in length (Fig. 5a and c). TEM images (Fig. 5b and d) showed well-ordered hexagonal arrays of parallel one-dimensional mesopore channels in SBA-15 and MCM-41-A, which further confirmed that these materials had a P6mm hexagonal structure of one-dimensional channels. From the TEM images of these samples, the distance between the centers of the mesopores were estimated to be about 9.5 nm for SBA-15 and 2.8 nm for MCM-41-A, in nice agreement with values determined from the XRD data. The SEM image in Fig. 5e revealed that the shape of MCM-41-B was spherical with an average diameter of about 200 nm. 3.6. Effect of particle morphology, pore size and surface chemical moiety on release behavior of Nap Dissolution profiles of Nap loaded mesoporous materials were investigated in phosphate buffer dissolution medium (pH = 6.8). As shown in Fig. 6A, more than 10 wt% of Nap had been released from mesoporous carriers in the first 5 min, ten folds higher than the corresponding value from Nap crystalline powder. The amounts of release of Nap at 5, 10, and 30 min accumulated to 31.22 wt%, 65.42 wt%, and 98.66 wt% for MCM-41-B. Correspondingly, the amounts were 24.86 wt%, 57.18 wt%, and 95.14 wt% for MCM-41A, and 19.16 wt%, 41.65 wt%, and 90.41 wt% for SBA-15. This burst release effect of Nap from mesoporous materials may lead to higher adsorption rate and fast onset of analgesic effect, which was important for formulations of Nap and particularly for the treatment of post operative pain [6]. The dissolution rate of Nap was higher in Nap-MCM-41-B than in Nap-MCM-41-A and Nap-SBA-15. Since the textural properties (2D, hexagonal symmetry with P6mm space) of these mesoporous materials are so similar, the difference in pore size and particle morphology are key to explain the different release profiles of these Nap loaded mesoporous materials. The pore size for MCM-41-A and MCM-41-B were similar (about 2 nm), but MCM-41-B showed faster diffusion rate than MCM-41-A. The improvement of dissolution rate of Nap-MCM-41-B is because that MCM-41-B possessed the shorter diffusion route (20–40 m for MCM-41-A, 200 nm for MCM-41-B) which can increase its release rate. The lower dissolution rate of Nap-SBA-15 was due to the slower dissolution kinetics of partial nanocrystalline Nap (see XRD), although the large pore size in SBA-15 could facilitate the diffusion of dissolved molecules from internal pore channels to the medium.
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Fig. 5. SEM images of SBA-15 (a), MCM-41-A (c) and MCM-41-B (e); TEM images of SBA-15 (b), MCM-41-A (d) and MCM-41-B (f).
Remarkably, the dissolution rate of Nap released from all mesoporous materials was faster than the dissolution rate of pure Nap. The significant improvement of dissolution rate in all conditions was due to: (1) the high specific surface area of Nap loaded mesoporous materials; (2) amorphous or partial nanocrystals Nap in pores channels; (3) significantly reduced size of Nap in pore
channels; (4) weak hydrogen bonds between MCM-41/SBA-15 and drug molecules. The release profiles of Nap from amino-modified samples were shown in Fig. 6B. In simulated intestinal fluid, the Nap-NH2 -SBA15 exhibited 29 wt% burst release within 30 min, and about 900 min later it reached the total release, on account of the large pore size
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Fig. 6. (A) Release profiles of Nap from Nap-MCM-41-B (a), Nap-MCM-41-A (b), Nap-SBA-15 (c) and pure crystalline Nap (d) at simulated intestinal fluid (pH 6.8). (B) Release profiles of Nap from Nap-NH2 -SBA-15 (a), Nap-NH2 -MCM-41-B (b), Nap-NH2 -MCM-41-A (c) and pure crystalline Nap (d) at simulated intestinal fluid (pH 6.8) (lines n = 3, mean ± SD). Table 2 Kinetic parameters calculated for the different systems according to the KorsmeyerPeppas model. Sample
K (h−n )
n
R
Nap-MCM-41-A Nap-MCM-41-B Nap-SBA-15 Nap-NH2 -MCM-41-A Nap-NH2 -MCM-41-B Nap-NH2 -SBA-15
1.68 1.49 1.29 0.18 0.21 0.28
0.51 0.50 0.49 0.52 0.49 0.49
0.998 0.997 0.998 0.996 0.998 0.998
In addition, introduction of chemical groups on the surface of mesoporous silica will result in specific host-guest interactions with Nap, which is also important and good for controlled drug release. Acknowledgment The present work was supported by the Outstanding Young Scientist Foundation of the Liaoning Province Hi-Tech Development Project (2010114).
K: rate constant; n: release exponent; R: correlation coefficient.
Appendix A. Supplementary data making drug molecules release freely. Delivery times for Nap-NH2 MCM-41-B and Nap-NH2 -MCM-41-A were 1500 and 1800 min, respectively. Longer release route in Nap-NH2 -MCM-41-A delayed the release of Nap. Stronger interaction between Nap and functional groups on the pore walls mainly determined the release profiles, resulting in the good control ability of samples. Understanding the release process of a drug helps provide the mechanism of drug release so as to optimize the release kinetics. In order to gain information about the release mechanism we have applied the Korsmeyer-Peppas model [51], Mt M∞
= Kt n
(1)
where Mt and M∞ denote the cumulative mass of drug released at time t and at infinite time, respectively; K is the proportionality constant and n is the release index, indicative of the mechanism of drug release. When n > 0.5, non-Fickian diffusion is observed, while n = 0.5 represents the Fickian diffusion mechanism. The value of n = 1 provides case II transport mechanism in which drug release from hydrogel of slab geometry will be of zero order [8]. The kinetic data obtained for the systems were listed in Table 2. According to the Korsmeyer-Peppas model, for all the Naploaded samples, the n values approach to 0.5, which indicate that in these cases the drug release follows the Fick’s law. 4. Conclusions In conclusion, three mesoporous silicas were demonstrated to vehicle poorly aqueous soluble drug Nap. The effects of the particle morphologies, pore sizes and the surface chemical groups of mesoporous silica materials on the dissolution and release of Nap were systematically investigated. The physical state of Nap played a key role in affecting its dissolution from the solid dispersion. Nap in amorphous state exhibited a higher dissolution rate than in nanocrystalline state. The advantage of the relatively short pore channel was also a major factor to improve the dissolution.
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Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb
Effects of particle morphology, pore size and surface coating of mesoporous silica on Naproxen dissolution rate enhancement Zhuo Guo a,∗ , Xiao-Meng Liu a , Lei Ma a , Jian Li b , Hong Zhang a , Yun-Peng Gao a , Yue Yuan c a b c
Department of Materials Science and Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmacetical University, Shenyang, Liaoning 110016, China
a r t i c l e
i n f o
Article history: Received 30 November 2011 Received in revised form 14 June 2012 Accepted 17 June 2012 Available online 11 July 2012 Keywords: Mesoporous silica Naproxen Dissolution
a b s t r a c t Naproxen (Nap) is a commonly used drug for antiphlogosis and analgesia, but its dissolution rate in water is quite low. In this work, the dissolution behavior of Nap after loading in mesoporous silica materials was investigated in a simulated intestinal fluid (pH = 6.8). The results indicated that the pore sizes, morphologies and surface chemical groups of the mesoporous silica were significant factors on the dissolution behavior of Nap. The physical state of encapsulated Nap was affected by the pore sizes of mesoporous silica, which influenced its dissolution rate. Amorphous Nap exhibited a higher dissolution rate than crystallized Nap, even though the larger pore size could facilitate its diffusion from the matrix. The effect of the morphology of mesoporous silicas on the dissolution of Nap can be ascribed to the length of pore channels, that the longer channel showed a longer diffusion pathway of Nap. Moreover, the release rate of Nap from functionalized mesoporous materials was effectively controlled compared with that of unmodified materials. © 2012 Elsevier B.V. All rights reserved.
1. Introduction The main disadvantage of poorly soluble drugs is their low dissolution rate in water, which will lead to low oral bioavailability. Developing strategies to overcome this hurdle and to enable oral delivery of poorly soluble drugs is now one of the greatest challenges confronting formulation scientists [1–8]. Since the discovery of ordered mesoporous silica materials in 1990s, synthesis and applications of mesoporous solids have received intensive attention due to their highly ordered structures, large pore size and well-defined surface properties [9–12]. Mesoporous materials seem ideal for encapsulation of pharmaceutical drugs, proteins and other biogenic molecules. Recently, the application of mesoporous silica as prospective vehicles for oral drug delivery has been widely studied to improve dissolution properties of poorly soluble drugs [3,5,8,13–25]. The ability of mesoporous materials to enhance the solubility and dissolution rate of the incorporated drug is due to their small pores, which can change the crystalline drug to a noncrystalline state. It has been shown that several properties of mesoporous materials can affect the loading degree and release rate of the incorporated
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (Z. Guo). 0927-7765/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.colsurfb.2012.06.026
drug, such as the surface area, pore diameter, total pore volume, pore morphology and surface chemistry. Morphology determines the extension of the interface between drug-carrying particles and body fluids, and can affect drug release kinetics [26–30]. The pore diameter is an important factor to determine the drug release rate. It was found that reducing the pore size could delay the release of drug [3,27,31–34]. Furthermore, appropriate functionalization of the inner pore walls of mesoporous materials also will potentially affect release rate by tuning the binding strength with drug molecules [14,18,21,26,35–40]. Although the delivery of different drugs using mesoporous silica materials has been investigated, the focus is mainly on the development of slow release formulations. Reports on the enhancement of dissolution of poorly aqueous soluble drugs using synthetic mesoporous silica materials are still rare [5–7,31,41]. Naproxen [(S)-6-methoxy-␣-methyl-2-naphthalenacetic acid, Nap] (Fig. 1), a nonsteroidal anti-inflammatory drug with poor solubility, is widely used to treat arthritis, post-operative pain, headache, and musculoskeletal. In the present paper, we report the application of mesoporous silica materials with different pore size, pore channel length, particle morphology and chemical moieties on the pore surface as drug delivery vehicle to evaluate the structural effect of the particles on the dissolution behavior of Nap at pH 6.8. The aim of this work was to improve the dissolution rate of poorly soluble Nap by loading in mesoporous silica materials, intending to be orally administrated.
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3-aminopropyltriethoxysilane in 25 ml toluene was added dropwise to the slurry and stirred under reflux at 100 ◦ C for 24 h. Finally the materials was filtered, washed with dry toluene, and Soxhletextracted using a mixture of 100 ml of diethyl ether and 100 ml dichloromethane for 24 h. The final solid was dried overnight in air at 90 ◦ C. The obtained samples were named as NH2 -MCM-41-A, NH2 -MCM-41-B and NH2 -SBA-15. Fig. 1. Structural formula of Naproxen.
2.4. Loading of Naproxen 2. Materials and methods 2.1. Materials Cetyltrimethylammonium bromide (C16 TAB) and dodecyltrimethylammonium bromide (C12 TAB) and tri-block copolymer poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide), pluronics P123 (EO20 -PO70 -EO20 , MW: 5800) were purchased from Aldrich (USA). TEOS was purchased from Tianjin Kermel Chemical Reagent Co., Ltd, China. Naproxen was purchased from HuBei Hezhong Biochemical Co., Ltd, China. 3Aminopropyltriethoxysilane (APTES) was purchased from Aladdin, Shanghai, China. The other reagents were analytical grade and were used as received without further purification. 2.2. Preparation of the mesoporous samples
Nap was loaded by soaking mesoporous materials into 10 ml ethanol solution of Nap (0.1000 M) under continuous magnetic stirring for 10 h at 37 ◦ C. Nap solution was covered with polyethylene film to prevent the evaporation of solvent in order to achieve maximum loading. A 1:1 (by weight) ratio of Nap to solid sample was used. Nap loaded samples were recovered by filtration, washed with ethanol until the filtrates reach to 10 ml, and left to dry for 24 h at 37 ◦ C. The filtrates were measured by an ultraviolet–visible (UV–vis) spectrophotometer to determine the drug loading amount. The dried samples were named as Nap-MCM41-A, Nap-MCM-41-B and Nap-SBA-15. The procedure of loading Nap into amine-modified mesoporous materials was similar to that used for unmodified mesoporous materials, and the dried samples were named Nap-NH2 -MCM-41-A, Nap-NH2 -MCM-41-B and Nap-NH2 -SBA-15. 2.5. Materials characterization
The matrix denoted as MCM-41-A and MCM-41-B were synthesized at hydrothermal condition using C16 TAB and C12 TAB as template, respectively. For the synthesis of MCM-41-A, 3.0 g C16 TAB was dissolved in 25 ml deionized water, followed by addition of 25 ml sodium silicate solution (35–40%) under stirring. The mixture was adjusted to pH 10 by 2 M HCl solution, and then transferred to a polypropylene bottle, followed by treatment at 100 ◦ C for 72 h. The resulting white solid was recovered by filtration, washed with distilled water, dried and calcined at 550 ◦ C for 6 h in air at a heating rate of 2 ◦ C/min [9]. For the synthesis of MCM-41-B, 0.42 g of C12 TAB and 0.75 ml of 1 M sodium hydroxide solution were dissolved in 100 g of a watermethanol (3:1, w/w) solution. Then, 0.62 g of TEOS was added to the solution with vigorous stirring. After the addition of TEOS, the clear solution gradually turned opaque, resulting in a white precipitate. After 8 h stirring, the mixture was aged overnight. The white powder was then filtered out and washed with distilled water, and dried at 45 ◦ C for 72 h. The powder was calcined at 550 ◦ C for 6 h in air at a heating rate of 2 ◦ C/min [42]. SBA-15 was synthesized by using P123 as template. The procedure was as follows: 4.0 g of P123 was dissolved in 30 ml of distilled water. Then, 4 ml of 2 M HCl solution was added to the solution with vigorous stirring at 35 ◦ C. After complete dissolving of P123, 8.5 g of TEOS was added. The mixture was stirred at 35 ◦ C for 20 h and then aged at 80 ◦ C for 48 h. The white solid product was recovered by filtration, dried and calcined at 550 ◦ C for 6 h in air at a heating rate of 2 ◦ C/min [11]. As a result, the surfactant was completely removed by calcination before incorporation of Naproxen. 2.3. Modification The prepared MCM-41-A, MCM-41-B and SBA-15 were functionalized with aminopropyl groups through a postsynthesis procedure. For the chemical incorporation of organo-amine molecules, all samples were pretreated in air at 110 ◦ C for 4 h to remove any physisorbed water. Then, 3 g of the dehydrated materials were suspended in 75 ml of dry toluene and stirred at room temperature for 1 h. An excess amount of
Several instrumental techniques were used for sample characterization. Powder X-ray diffraction (XRD) data were collected on a SIEMENS D5005 diffractometer with Cu K˛ radiation at 40 KV and 30 mA. Nitrogen adsorption–desorption, Brunauer–Emmett–Teller (BET) surface area, and pore diameter were measured using a Micromeritics ASAP 2010 M sorptometer. Before measurement, all samples were degassed at 100 ◦ C for 12 h, and the measurements were carried at 77 K. Specific surface areas and pore size distributions were calculated using BET and Barrett–Joyner–Halenda (BJH) models from the adsorption branches, respectively. A Fourier transform infrared (FT-IR) spectrometer (Nicolet IS10) was used to record infrared spectra of the samples by the KBr method. The IR spectra, in absorbance mode, were obtained over the spectral region 400–4000 cm−1 . 29 Si MAS NMR experiment was performed on a Varian Infinityplus-400 spectrometer under magic-angle spinning operating at a frequency of 79.5 MHz with the following conditions: magic-angle spinning at 2.5 kHz, /2 pulse, 4.8 s, repetition time 100 s for singlepulse experiments. The samples morphologies were examined by scanning electron microscope (SEM, JSM-6360-LW, JEOL, Japan) at 5 kV. Prior to analysis, the samples were sputtered with a thin film of platinum. Transmission electron microscopy (TEM) images were recorded on JEOL 3010 with an acceleration voltage of 100 kV. Thermal analysis of the samples was carried out with a differential scanning calorimeter (DSC) instrument (Q200, TA Instruments, USA). The heating rate is 10 ◦ C/min and the nitrogen purge rate is 40 ml/min. The drug loading amounts were determined by UV–vis spectrophotometer (Uv-752, Shanghai Precision and Scientific Instrument Company, China). Thermogravimetric analysis (TGA) was performed using a TGA-50 instrument (Shimadzu, Japan) at a heating rate of 10 ◦ C/min under a nitrogen purge rate at 40 ml/min. 2.6. In vitro dissolution Before the release, Nap loaded samples equivalent to 40 mg Nap were compressed into a tablet (˚ = 10 mm) under uniaxial pressure (0.5 MPa). Dissolution studies were conducted using a USPII paddle method (50 rpm, 37 ◦ C, and 900 ml dissolution medium) with a
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Fig. 2. Small-angle XRD patterns of (A) SBA-15, (B) MCM-41-A and (C) MCM-41-B. The wide-angle XRD patterns (D) of pure Nap (a), Nap and SBA-15 physical mixture (b), Nap-SBA-15 (c), Nap-NH2 -SBA-15 (d), Nap-MCM-41-A (e); Nap-NH2 -MCM-41-A (f), Nap-MCM-41-B (g) and Nap-NH2 -MCM-41-B (h).
D-800LS dissolution tester (Tianjin University Radio Factory, China). Dissolution media was prepared by dissolving potassium dihydrogen phosphate in deionized water and the pH was adjusted by 1 M sodium hydroxide solution, to simulate intestinal fluid (pH 6.8) [1]. The samples contained 40 mg Nap were used in sink condition. Dissolution medium (5 ml) was removed from the vessel at appropriate intervals. An equal amount of fresh dissolution medium was replaced to keep the volume constant. The concentration of drug in each sample was determined by comparison with a calibration curve based on the absorption maximum (max = 332 nm). All experiments were performed in triplicate. 3. Results and discussion 3.1. XRD Small-angle XRD patterns of the mesoporous materials were shown in Fig. 2A–C. The small-angle XRD patterns of parent and amine-modified samples showed long range periodicity of the porous structure. The diffraction peaks of modified samples showed the same 2 values as those of parent silica, which indicated the fidelity of hexagonal structural arrangement during the modification. SBA-15 and MCM-41-A both showed three well-resolved XRD peaks, which can be indexed into 1 0 0, 1 1 0 and 2 0 0 reflections of the 2D hexagonal symmetry, indicating a good structural quality of these materials. These patterns can be assigned to an ordered structure of hexagonal symmetry with P6 mm space group [11,43]. The
MCM-41-B showed only one strong (1 0 0) reflection because mesoporous molecular sieve did not appear (1 1 0) and (2 0 0) diffraction peaks when prepared using short-chain surfactant C12 TAB [33]. The powder XRD patterns of mesoporous materials loaded with Nap were also exhibited in Fig. 2. The XRD patterns showed that the hexagonal mesoporous structure of samples loaded with Nap was similar to that of unloaded samples. The main XRD peaks were still observed, showing that the hexagonal mesopores of the mesoporous materials were maintained during the entrapment of drug molecules inside pores. The intensities of the reflections were diminished by the loading of Nap, similar to the behavior observed upon loading PEI into MCM-41 [44]. The diminishment of peak intensities confirmed that Nap has been loaded into the channels of mesoporous materials. Fig. 2D displayed wide-angle XRD patterns of drug-loaded samples. The diffraction pattern of pure Nap was highly crystalline in nature. Six peaks at 14.6◦ , 17.0◦ , 18.7◦ , 20.7◦ , 25.4◦ and 28.3◦ were visible and the main peak at 20.7◦ was particularly distinctive. For the physical mixture of SBA-15 and Nap, peaks at 20.7◦ were attributed to those of pure Nap. However, it can be seen that Nap loaded in MCM-41-A/or B and NH2 -MCM-41-A/or B and NH2 -SBA15 exhibited an amorphous state, as no XRD peaks were detected. It was known that the absence of characteristic peaks indicated that the Nap was in noncrystalline state [17,36,45]. But for Nap-SBA15, some small peaks for Nap nanocrystals could be observed. As expected, crystalline Nap only formed in the larger pores [46]. This observation was consistent with the result obtained by Shen et al.
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Fig. 3. FT-IR spectra of crystalline Nap (a), MCM-41-A (b), NH2 -MCM-41-A (c), NapMCM-41-A(d) and Nap-NH2 -MCM-41-A (e).
[31]. The wide-angle XRD patterns further confirmed that Nap was encapsulated inside the pore of the materials but not on the exterior surfaces. 3.2.
29 Si
MAS-NMR and FT-IR
Solid-state 29 Si MAS-NMR confirmed the presence of organofunctionalized moieties as part of the silica wall structure for all of the organically modified mesoporous silica materials (Fig. S1). Detailed positions and relative intensities of peaks were listed in Table S1. Distinct resonances could be observed for the siloxane (completely condensed Si, Q4 ; partially condensed Si, Q3 ) and organosiloxane (T3 , Si-R; and T2 , Si(OH)R) units[37]. It could be seen in Table S1 that the functionalization efficiency of SBA-15 was higher than that of MCM-41-A and MCM-41-B. The larger pore size and volume would be better explained that a significant fraction of aminopropyl groups anchored in SBA-15. MCM-41-A and MCM-41-B had the similar pore size and a quite close amount of pore volume, so they would exhibit very similar behavior in degree of functionalization. Indeed, higher amounts of organosiloxane units were detected in the mesoporous materials MCM-41-A, owing to the lower degree of condensation of the silica network (lower population of Q4 environments). Quantitative determinations of functional groups were performed by TGA (Fig. S2). The weight loss due to functional groups was 21.5%, 15.1% and 13.4% for NH2 -SBA-15, NH2 -MCM-41-A and NH2 -MCM-41-B, respectively. The 29 Si NMR measurements correlate well with the TG analysis. TGA and 29 Si NMR were clear evidence that most of the functional groups were located on the wall of pores and were accessible and useful for adsorption of drug molecules. Organic functionalization was also evidenced by FT-IR spectra. The FT-IR spectra of mesoporous materials were shown in Fig. 3. All the parent MCM-41-A/B and SBA-15 mesoporous matrix have the typical silanols absorbance in their siliceous framework in FTIR spectra, so only MCM-41-A is shown. The spectrum recorded for Nap showed numerous bands ascribed to the vibration of chemical bonds existing in the molecule (aromatic ring, carboxylic, methyl, ether groups, etc.) [47]. The FT-IR spectrum of MCM-41A was characterized by the presence of strong and broad band observed at about 1000 cm−1 , which corresponded to the asymmetric stretching vibration, as (Si O Si), of the siliceous framework. The symmetric stretch, s (Si O si), and the bending vibration,
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ı(Si O Si), of the siliceous framework were observed at 800 cm−1 and 500 cm−1 , respectively. These bands, together with the broad band at about 3400 cm−1 (stretching vibration of the physisorbed water) were observed in the spectra and were typical for MCM-41 mesoporous matrix [16]. FT-IR was known to provide surface information about materials for identification of chemical groups. Therefore, the samples modified by amine and loaded with Nap were reflected by appearance of characteristic absorbance in the IR spectra. For NH2 -MCM-41-A, a new band assigned to NH2 asymmetric bending was observed at 1559 cm−1 , and two bands at 2934 and 2847 cm−1 corresponding to the stretching (C H) vibrations were due to the methylene groups introduced during functionalization [1,39,48]. FTIR spectrum of Nap showed a carboxyl band at 1686 cm−1 , which correspond to the carboxyl group [47]. For Nap-MCM-41-A, carboxyl peaks could be observed at 1729 cm−1 , but they showed a slight shift from 1686 cm−1 , due to the hydrogen bonding to silanol groups [1]. The loading of Nap was also reflected by breathing vibrations of aromatic rings in the spectra ranging in 1600–1500 cm−1 . For NapNH2 -MCM-41-A, intense carboxylate bands at 1570 and 1371 cm−1 were detected, which indicate that proton transfer from the carboxylic acid of Nap to aminopropyl groups had taken place [37]. 3.3. N2 adsorption/desorption The nitrogen adsorption–desorption isotherms registered of parent, amino-modified and Nap loaded mesoporous materials were shown in Fig. S3. All of them can be included into type IV according to the IUPAC classification [49], which corresponds to solids with pores in 1.5–50 nm range. Due to the difference in pore sizes, MCM-41-A and MCM-41-B showed a N2 condensation step at P/P0 of 0.2–0.4, while the condensation step of SBA-15 increased to the ranges of 0.65–0.85. Both amine-functionalized and Nap loaded samples downshift the capillary condensation step to lower relative pressures, which reflected the decrease of pore sizes by amine modification and Nap encapsulation in pores. The pore size distribution, Fig. S3, showed maxima at ca. 2.78 and 2.15 nm in diameter for MCM-41-A and NH2 -MCM-41-A, respectively. After loading of Nap, the pore diameter decreased to 1.93 nm and 1.78 nm for the Nap-MCM-41-A and Nap-NH2 -MCM-41-A, respectively. The incorporation of Nap also decreased the specific surface areas and pore volumes, which indicated that the Nap was inserted inside the pores. The values for the BET specific surface area (SBET ), the total pore volume (V) and the BJH pore diameter were given in Table 1. The loading amounts of drug of all samples were shown Table 1. In the parent materials, SBA-15 exhibited the highest loading capacity of Nap. The loading amount of Nap-SBA-15 was 41.43 wt%. For Nap-MCM-41-A and Nap-MCM-41-B, they were 27.20 wt% and 21.54 wt%, respectively. Among the amino-modified materials, Nap-NH2 -SBA-15 had the largest loading, which was 39.21 wt%. Table 1 The pore characterization and drug loading amount. Sample
SBET (m2 /g)
Vpore volume (cm3 /g)
Pore size (nm)
Drug loading (wt%)
MCM-41-A NH2 -MCM-41-A Nap-NH2 -MCM-41-A Nap-MCM-41-A MCM-41-B NH2 -MCM-41-B Nap-NH2 -MCM-41-B Nap-MCM-41-B SBA-15 NH2 -SBA-15 Nap-NH2 -SBA-15 Nap-SBA-15
1176 925 524 646 1078 879 588 658 923 791 581 510
1.09 0.82 0.48 0.65 0.97 0.79 0.53 0.66 1.20 0.96 0.40 0.48
2.78 2.15 1.78 1.93 2.14 1.75 1.43 1.49 9.32 7.39 5.27 4.76
– – 25.19 27.20 – – 20.32 21.54 – – 39.21 41.43
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The highest degree of functionalization of NH2 -SBA-15 in these three functionalized materials (due to the largest pore size and volume) should lead to the largest Nap adsorption. Samples NH2 MCM-41-A and NH2 -MCM-41-B exhibited different behavior in Nap adsorption. The loading amounts of Nap-NH2 -MCM-41-A and Nap-NH2 -MCM-41-B were 25.19 wt% and 20.32 wt%, respectively. A lower density of aminopropyl groups (loading amounts/surface areas) inside the channel of NH2 -MCM-41-B could account for these results. Although NH2 -SBA-15, NH2 -MCM-41-A and NH2 -MCM-41B containing APTES in the channel had strong interaction with the drug molecule, the presence of NH2 also reduced the pore volume and pore size of the mesoporous material, resulting in the decrease of the drug loading capacity. These results suggested that the drug loading capacity of mesoporous materials was dependent on the total pore volume and pore diameter [1]. It was possible to relate the decrease of measured pore volume to the amount of adsorbed Nap in the samples [41]. For example, UV–vis analysis showed that 1.00 g Nap-MCM41-A contains 0.272 g of Nap molecules, and, consequently, 0.728 g of MCM-41-A. Taking into account that the pore volume measured for MCM-41-A was 1.09 cm3 /g, the available pore volume referred to 1.00 g of Nap-MCM-41-A was 0.728 × 1.09 = 0.79 cm3 /g of Nap-MCM-41-A. The size of Nap molecule measured by Chem. Office Ultra 8.0 2004 software is 1.172 nm × 0.501 nm × 0.366 nm. From this value, the volume of one mole Nap molecules is 129 cm3 /mol. The specific volume of Nap can be calculated as 129/MWNap = 129/230 = 0.56 cm3 /g. Therefore, the volume occupied by Nap in the Nap-MCM-41-A sample was 0.56 × 0.272 = 0.15 cm3 /g. The total pore volume was thus 0.79 − 0.15 = 0.64 cm3 /g of Nap-MCM-41-A. This value was very near to that experimentally result (0.65 cm3 /g) of Nap-MCM-41A. The result is in agreement with the adsorption of Nap molecules inside the MCM-41-A pores. 3.4. DSC The physical state of Nap entrapped in mesoporous materials was studied by DSC. As seen in Fig. 4, crystalline Nap exhibited a clear endothermic peak at 152 ◦ C, which was characteristic of the melting of the bulk phase of Nap [47]. But no signs of melting point could be observed for Nap-MCM-41-A/or B, Nap-NH2 -MCM41-A/or B and Nap-NH2 -SBA-15. This was related to finite-size effects, preventing the drug molecules from rearranging themselves in a crystal lattice, and this was in good agreement with XRD
Fig. 4. DSC thermograms of pure Nap (a), Nap-SBA-15 (b), Nap-NH2 -SBA-15 (c), Nap-MCM-41-A (d), Nap-NH2 -MCM-41-A (e), Nap-MCM-41-B (f), and Nap-NH2 MCM-41-B (g).
measurement. In contrast, the small melting peak of Nap can be observed at 148.2 ◦ C for Nap-SBA-15, but there was a slight shift from 152 ◦ C. The melting of crystalline Nap inside pores was observed at lower temperatures than the melting of Nap at bulk phase. The effect was due to the decrease of crystal size, which was restricted by the pore structure [50]. DSC confirmed the presence of crystalline Nap in the SBA-15 pores, and this was in good agreement with XRD measurement. But, the Nap-SBA-15 showed a significant reduction in the enthalpy of fusion, indicating the decrease of crystallinity of Nap, and also suggesting partial amorphous formation [31]. The pore sizes were found to affect the physical state and particle size of Nap. When Nap was loaded in MCM-41-A/orB, NH2 -MCM41-A/orB and NH2 -SBA-15, amorphous state of Nap was formed. In contrast, partial nanocrystals were formed when Nap was loaded in SBA-15 with larger pore size than MCM-41-A/orB and NH2 -SBA-15. The physical state of Nap played a key role in affecting the dissolution of Nap from mesoporous materials (this will be discussed in detail later). 3.5. SEM and TEM The morphology and particle size of all samples were analyzed by SEM and TEM. The morphology of SBA-15 material was similar to that of the MCM-41-A, which consisted of bundles with 20–40 m in length (Fig. 5a and c). TEM images (Fig. 5b and d) showed well-ordered hexagonal arrays of parallel one-dimensional mesopore channels in SBA-15 and MCM-41-A, which further confirmed that these materials had a P6mm hexagonal structure of one-dimensional channels. From the TEM images of these samples, the distance between the centers of the mesopores were estimated to be about 9.5 nm for SBA-15 and 2.8 nm for MCM-41-A, in nice agreement with values determined from the XRD data. The SEM image in Fig. 5e revealed that the shape of MCM-41-B was spherical with an average diameter of about 200 nm. 3.6. Effect of particle morphology, pore size and surface chemical moiety on release behavior of Nap Dissolution profiles of Nap loaded mesoporous materials were investigated in phosphate buffer dissolution medium (pH = 6.8). As shown in Fig. 6A, more than 10 wt% of Nap had been released from mesoporous carriers in the first 5 min, ten folds higher than the corresponding value from Nap crystalline powder. The amounts of release of Nap at 5, 10, and 30 min accumulated to 31.22 wt%, 65.42 wt%, and 98.66 wt% for MCM-41-B. Correspondingly, the amounts were 24.86 wt%, 57.18 wt%, and 95.14 wt% for MCM-41A, and 19.16 wt%, 41.65 wt%, and 90.41 wt% for SBA-15. This burst release effect of Nap from mesoporous materials may lead to higher adsorption rate and fast onset of analgesic effect, which was important for formulations of Nap and particularly for the treatment of post operative pain [6]. The dissolution rate of Nap was higher in Nap-MCM-41-B than in Nap-MCM-41-A and Nap-SBA-15. Since the textural properties (2D, hexagonal symmetry with P6mm space) of these mesoporous materials are so similar, the difference in pore size and particle morphology are key to explain the different release profiles of these Nap loaded mesoporous materials. The pore size for MCM-41-A and MCM-41-B were similar (about 2 nm), but MCM-41-B showed faster diffusion rate than MCM-41-A. The improvement of dissolution rate of Nap-MCM-41-B is because that MCM-41-B possessed the shorter diffusion route (20–40 m for MCM-41-A, 200 nm for MCM-41-B) which can increase its release rate. The lower dissolution rate of Nap-SBA-15 was due to the slower dissolution kinetics of partial nanocrystalline Nap (see XRD), although the large pore size in SBA-15 could facilitate the diffusion of dissolved molecules from internal pore channels to the medium.
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Fig. 5. SEM images of SBA-15 (a), MCM-41-A (c) and MCM-41-B (e); TEM images of SBA-15 (b), MCM-41-A (d) and MCM-41-B (f).
Remarkably, the dissolution rate of Nap released from all mesoporous materials was faster than the dissolution rate of pure Nap. The significant improvement of dissolution rate in all conditions was due to: (1) the high specific surface area of Nap loaded mesoporous materials; (2) amorphous or partial nanocrystals Nap in pores channels; (3) significantly reduced size of Nap in pore
channels; (4) weak hydrogen bonds between MCM-41/SBA-15 and drug molecules. The release profiles of Nap from amino-modified samples were shown in Fig. 6B. In simulated intestinal fluid, the Nap-NH2 -SBA15 exhibited 29 wt% burst release within 30 min, and about 900 min later it reached the total release, on account of the large pore size
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Fig. 6. (A) Release profiles of Nap from Nap-MCM-41-B (a), Nap-MCM-41-A (b), Nap-SBA-15 (c) and pure crystalline Nap (d) at simulated intestinal fluid (pH 6.8). (B) Release profiles of Nap from Nap-NH2 -SBA-15 (a), Nap-NH2 -MCM-41-B (b), Nap-NH2 -MCM-41-A (c) and pure crystalline Nap (d) at simulated intestinal fluid (pH 6.8) (lines n = 3, mean ± SD). Table 2 Kinetic parameters calculated for the different systems according to the KorsmeyerPeppas model. Sample
K (h−n )
n
R
Nap-MCM-41-A Nap-MCM-41-B Nap-SBA-15 Nap-NH2 -MCM-41-A Nap-NH2 -MCM-41-B Nap-NH2 -SBA-15
1.68 1.49 1.29 0.18 0.21 0.28
0.51 0.50 0.49 0.52 0.49 0.49
0.998 0.997 0.998 0.996 0.998 0.998
In addition, introduction of chemical groups on the surface of mesoporous silica will result in specific host-guest interactions with Nap, which is also important and good for controlled drug release. Acknowledgment The present work was supported by the Outstanding Young Scientist Foundation of the Liaoning Province Hi-Tech Development Project (2010114).
K: rate constant; n: release exponent; R: correlation coefficient.
Appendix A. Supplementary data making drug molecules release freely. Delivery times for Nap-NH2 MCM-41-B and Nap-NH2 -MCM-41-A were 1500 and 1800 min, respectively. Longer release route in Nap-NH2 -MCM-41-A delayed the release of Nap. Stronger interaction between Nap and functional groups on the pore walls mainly determined the release profiles, resulting in the good control ability of samples. Understanding the release process of a drug helps provide the mechanism of drug release so as to optimize the release kinetics. In order to gain information about the release mechanism we have applied the Korsmeyer-Peppas model [51], Mt M∞
= Kt n
(1)
where Mt and M∞ denote the cumulative mass of drug released at time t and at infinite time, respectively; K is the proportionality constant and n is the release index, indicative of the mechanism of drug release. When n > 0.5, non-Fickian diffusion is observed, while n = 0.5 represents the Fickian diffusion mechanism. The value of n = 1 provides case II transport mechanism in which drug release from hydrogel of slab geometry will be of zero order [8]. The kinetic data obtained for the systems were listed in Table 2. According to the Korsmeyer-Peppas model, for all the Naploaded samples, the n values approach to 0.5, which indicate that in these cases the drug release follows the Fick’s law. 4. Conclusions In conclusion, three mesoporous silicas were demonstrated to vehicle poorly aqueous soluble drug Nap. The effects of the particle morphologies, pore sizes and the surface chemical groups of mesoporous silica materials on the dissolution and release of Nap were systematically investigated. The physical state of Nap played a key role in affecting its dissolution from the solid dispersion. Nap in amorphous state exhibited a higher dissolution rate than in nanocrystalline state. The advantage of the relatively short pore channel was also a major factor to improve the dissolution.
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