Facile synthesis of 3D cubic mesoporous silica microspheres with a controllable pore size and their application for improved delivery of a water-insoluble drug

Journal of Colloid and Interface Science 363 (2011) 410–417

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Facile synthesis of 3D cubic mesoporous silica microspheres with a controllable pore size and their application for improved delivery of a water-insoluble drug Yanchen Hu a, Jing Wang a, Zhuangzhi Zhi b, Tongying Jiang a, Siling Wang a,⇑ a b

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, PR China Department of Physics, School of Basic Science, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, PR China

a r t i c l e

i n f o

Article history: Received 7 June 2011 Accepted 7 July 2011 Available online 4 August 2011 Keywords: 3D Cubic mesoporous SBA-16 Controllable pore size Water-insoluble drugs In vitro dissolution

a b s t r a c t A facile and simplified method was developed for the synthesis of 3D cubic mesoporous SBA-16 with both a spherical morphology and controllable pore size. The addition of CTAB during the synthesis allowed not only good control over the macroscopic morphology but also a significant reduction in the synthesis time. Notably, the pore size can simultaneously be adjusted by simply controlling the heating temperature. The pharmaceutical performance of the resulting SBA-16 for the delivery of the water-insoluble drug indomethacin (IMC), a non-steroidal anti-inflammatory agent used as a model drug, was systematically studied using nitrogen adsorption, powder X-ray diffraction, differential scanning calorimetry, infrared spectrometry and in vitro dissolution investigations. It was found that IMC could be effectively loaded into mesoporous SBA-16 via the solvent deposition method. An altered physical state and a marked improvement in the dissolution rate were observed for IMC after being loaded into SBA-16 microspheres. In particular, SBA-16 microspheres with the largest pore size (9.0 nm) and highly open and accessible pore networks exhibited the fastest drug release profile. We envisage that the improved drug delivery profiles obtained using SBA-16 as described in our work will offer an interesting option for the formulation of poorly water-soluble drugs. Ó 2011 Elsevier Inc. All rights reserved.

1. Introduction Silica-based materials, especially porous silica, have been long recognized as very promising excipients for drug delivery applications due to their simple, inexpensive, and versatile synthesis using sol–gel processes, physiologically inert and non-toxic nature [1–5]. Mesoporous silica materials refer to porous silica which exhibit pores with diameters between 2 and 50 nm (International Union of Pure and Applied Chemistry, IUPAC definition). Due to their large specific surface area and pore volume, adjustable pore diameter, easily modified surface properties and excellent biocompatibility, mesoporous silica materials have attracted immense interests for drug delivery applications over the past few years [6–10]. To date, mesoporous silica-based drug carriers with different pore characteristics (i.e. pore size, shape and connectivity) and a variety of macroscopic morphologies have been widely described in the literature, where a wide variety of molecules of pharmaceutical interest have been successfully hosted and then delivered in a controlled or immediate manner [11–14]. Among them, the most widely investigated mesoporous silica have been the 2D channellike MCM-41 and SBA-15, typically possessing a very uniform pore

⇑ Corresponding author. Fax: +86 24 23986348. E-mail address: [email protected] (S. Wang). 0021-9797/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jcis.2011.07.022

structure of unidirectional channels [15–21]. Moreover, most of the research into the use of mesoporous silica materials as drug vehicles has been devoted to sustained/controlled drug release, and little has been published on the dissolution enhancement of water-insoluble drugs [22–26]. The pore architecture, including pore size and geometry, as well as the particle size/morphology are considered to be critical factors affecting drug loading and release behaviors. For example, it has been reported that increasing the pore size of SBA-15 [22] or MCM-41 [27] can increase the drug release rate, while increasing the particle size of MCM-41 can significantly slow down the drug release rate due to extension of the diffusion path [28]. It has also been demonstrated that the highly accessible, 3D pore network of mesoporous silica TUD-1 allows the relatively unrestricted release of ibuprofen, while the long and narrow mesopore pathways of MCM-41 sterically hinder the free diffusion of ibuprofen [29]. Taking into account its unique structural characteristics, 3D cubic mesoporous silica SBA-16 appears to be an interesting candidate as a drug carrier. Firstly, it comprises 3D cubic arrangement of mesopores corresponding to the Im3m space group. Each mesopore in this body-centered cubic structure is interconnected through openings to form a multidirectional mesoporous network [30,31]. This fascinating 3D cage-type mesoporous structure is expected to facilitate the diffusion of guest molecules, being less susceptible to pore blockage and ensuring the accessibility of pores

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from any direction, and this has attracted increasing attention for its wide applications in a various fields [32–35]. Secondly, the inexpensive and commercially available triblock copolymer F127 is generally used as a structured directing agent to synthesize SBA16, producing a dual micro-mesoporous porosity due to the existence of a substantial amount of irregular interconnecting micropores originating from the penetration of the hydrophilic chains of F127 into the siliceous walls during synthesis [30]. Finally, SBA-16 has large pores and thick walls as well as good thermal stability, which also contributes to its wide use. All of these features make 3D cage-type SBA-16 a very promising and potential mesoporous silicate for use in drug delivery applications. Very recently, Thomas et al. [36] used mesoporous silica nanoparticles with cubic Im3m structures to incorporate three active antiepileptic agents, in which rapid release profiles were achieved within the first 3 h. However, compared with 2D channel-like mesoporous silica, research involving 3D cubic SBA-16 as a drug carrier has received relatively little attention. To our knowledge, the aforementioned study by Thomas is the only literature report that we have been able to find. Therefore, it is highly desirable to carry out a more comprehensive and systematic study to exploit the potential of 3D cage-like SBA-16 materials in terms of their pharmaceutical applications. To date SBA-16 materials have been synthesized mostly using Pluronic F127 as a template and TEOS as the silica source under acidic conditions [30,37]. However, it should be noted that the time-consuming (usually 2 or more days) and two-step synthetic procedure for SBA-16 by the conventional method would hamper its practical applications, because it is not suited to large scale production on an industrial scale. Moreover, taking into account the cage-like structure of SBA-16, it is likely that the easy transport of guest molecules into and out of the cage of SBA-16 might sometimes be restrained by the narrow windows. To overcome these disadvantages, we have proposed in our present work a simple and effective method to synthesize 3D cage-like mesoporous silica SBA-16 with both a well-defined spherical morphology and a large pore size (up to 9.0 nm) through the use of the copolymer F127 as a template and cetyltrimethylammonium bromide (CTAB) as a cotemplate. In comparison with the conventional method for synthesizing SBA-16, the addition of CTAB in this new easy method will not only help accelerate the self-assembly of F127 and silica species, thus reducing the synthesis time, but will also help regulate the shape of SBA-16, producing a spherical morphology. Furthermore, the pore diameters of the SBA-16 microspheres can simultaneously be tailored through simply controlling the synthesis temperature, which will help to extend its usefulness for applications where large pores are desired, and also permit in this study the establishment of the relationship between the pore size and

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drug delivery properties of SBA-16. For the purpose of testing the pharmaceutical performance of the resultant SBA-16, indomethacin (IMC, Fig. 1), a non-steroidal anti-inflammatory drug (NSAID) routinely used for the treatment of soft tissue inflammation, was used as a model drug and loaded into mesoporous SBA-16 via solvent deposition method. The obtained IMC/SBA-16 system was characterized by nitrogen adsorption, wide-angle X-ray diffraction, differential scanning calorimetry, infrared spectrometry and in vitro dissolution experiments. 2. Materials and methods 2.1. Materials Tetraethyl orthosilicate (TEOS) and CTAB were obtained from Tianjin Bodi Chemical Holding Co., Ltd. Non-ionic polymeric surfactant EO106–PO70–EO106 was used under the trade name Lutrol F127, or Pluronic F127, or Poloxamer 407 by BASF. Indomethacin (purity >99.0%) was kindly supplied from Shijiazhuang Pharmaceutical Group (Huasheng Pharm. Co., Ltd.). All other chemicals were of analytical/spectroscopic/HPLC grade as required and used as received. 2.2. Preparation of mesoporous silica 3D cage-like mesoporous silica SBA-16 microspheres with different pore sizes was synthesized under acidic conditions. In a typical synthesis, 1.0 g F127 and 0.12 g CTAB were dissolved under vigorous stirring into a solution of 130 ml water and 10 ml concentrated HCl, followed by the addition of 4.0 g TEOS under vigorous stirring. After 1 h stirring, the obtained gel was introduced into a Teflon cup which was inserted in an autoclave, and then put in a large oven at different temperatures (80, 120 and 150 °C, respectively) for 24 h. The solid product was filtered, washed, dried at room temperature and finally calcinated at 823 K for 5 h. For clarity, the SBA-16 samples obtained at different temperatures were denoted as S16-80, S16-120 and S16-150, respectively. 2.3. Drug loading procedure via solvent deposition method Solvent deposition method [38,39] was used to load IMC into mesoporous silica in the present work, aiming at an accurate drug loading amount of 25%. In detail, IMC was dissolved in acetone to obtain a yellow transparent solution (50 mg/ml) then an aliquot of this solution was mixed with certain amount of mesoporous silica to obtain samples with a theoretical drug–silica ratio of 25:75 (w/w). After gentle stirring for 12 h, the solvent was allowed to evaporate under reduced pressure. The samples were first dried at 35 °C in air for 24 h and subsequently placed under reduced pressure for 48 h. No organic solvent residual in drug-loaded samples were detected by thermal analysis. The actual drug loading of IMC-loaded SBA-16 samples were determined by extracting an accurately weighted amount of IMC-loaded powders with methanol and then calculating the drug content using ultraviolet (UV) spectroscopy at a wavelength of 320 nm (UV-2000, Unico, USA). 2.4. Characterization

Fig. 1. Molecular structure of indomethacin.

SUPRA-35 field emission scanning electron microscope (ZEISS, Germany) was used to observe the morphology of obtained mesoporous silica. Prior to analysis, samples were attached to aluminum stubs with double side adhesive carbon tape and then coated with a thin layer of gold. SA3100 surface area analyzer (Beckman coulter, USA) was used to measure the nitrogen adsorption/desorption isotherms of pure

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mesoporous silica and drug-loaded samples at the temperature of 196 °C. Before measurements, samples were out-gassed at 40 °C under vacuum for 12 h. The Brunauer–Emmett–Teller (BET) surface area was determined using experimental points at a relative pressure of P/P0 = 0.05–0.2. The pore diameter (DBJH) was calculated from the adsorption branch of isotherms using the conventional Barrett–Joyner–Halenda (BJH) method. The total pore volume (Vt) was estimated from the N2 amount adsorbed at a relative pressure of 0.9814. The physical state of IMC in mesoporous silica was examined by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and Fourier transform infrared spectroscopy (FT-IR). DSC was performed using a differential scanning calorimeter (DSC 60, Shimadzu Co., Japan). Samples were put into the aluminum pans and the thermal analysis was conducted at a rate of 10 °C/min under a nitrogen flow. PXRD was performed using a Rigaku Geigerflex powder X-ray diffractometer (Rigaku Denki, Japan) using Cu Ka radiation as the X-ray source. The measurement condition was as follows: voltage, 30 kV; current, 30 mA; step size of 0.02°; scanning speed, 4°/min. Infrared spectra of samples were recorded on a FT-IR spectrometer (Bruker, IFS 55, Switzerland) in KBr dispersion from 400 to 4000 cm 1. Samples were prepared by gently grounding the samples with KBr. 2.5. In vitro dissolution testing In vitro dissolution profiles of IMC-loaded SBA-16, including S16-80, S16-120 and S16-150, were examined and compared with crystal IMC. For comparison, the classic 2-D hexagonal mesoporous silica MCM-41 was also synthesized [40], loaded with IMC, and then submitted to dissolution testing. The experiment was conducted using USP II paddle method (KC-8D, Tianjin Guoming Medical Equipment Co. Ltd.). Powders corresponding to 25 mg IMC was added to 900 ml phosphate buffer solution (pH = 6.8) at 37 °C and the paddle speed was set at 100 rpm. At appropriate sampling time, 5 ml aliquots were taken and instantly replaced with an equal amount of fresh dissolution medium. Samples were then filtered through a 0.45 lm membrane and then determined by UV spectrophotometry (UV-2000, Unico, USA) at wavelength of 320 nm. The calibration curve was linear over a concentration range between 4 and 40 lg/ml. All experiments were performed in triplicate and the average dissolution profiles and standard deviations were supplied. 3. Results and discussion 3.1. Preparation and characterization of mesoporous SBA-16 microspheres Fig. 2 showed the SEM micrographs of SBA-16 synthesized at different hydrothermal temperatures. It was observed that both S16-80 and S16-120 samples exhibited a well-defined spherical morphology with diameters in the range of 2–6 lm, while the

S16-150 samples synthesized at the highest temperature of 150 °C exhibited an irregular spherical shape. It has to be kept in mind that, in spite of the significant progress made in the textural modifications of SBA-16, there were few literature reports available on controlling the morphology of SBA-16 [34,41–44], which may be due to the fact that SBA-16 can only be produced in a narrow window of synthesis parameters [30,35]. In most cases, irregular or agglomerated particles of SBA-16 were obtained [37]. The simple method developed in our present work, which involved the initial stirring of silica species and F127 (only 1 h) in the presence of CTAB and subsequent hydrothermal treatment (24 h) at higher temperatures, has overcome this problem and allows good control over the macroscopic morphology. It is assumed that the addition of CTAB as an additive during the synthesis, which can interact with F127 polymer to form charged complex micelles and influence the surfactant–silica assembly process, is necessary for the synthesis of SBA-16 with well-defined morphology. Poyraz et al. [45] synthesized mesoporous silica with distinct morphology using five different Pluronics with CTAB as a co-surfactant in an acidic media, and illustrated that the addition of CTAB could influence the hydrophilic–hydrophobic character of the F127, provide positive charges to the micelles and enhance the assembly of the silica species. Li et al. [46] investigated the interactions between the cationic surfactant tetradecyltrimethylammonium bromide (TTAB) and F127 and found that the cationic TTAB can be used to control and manipulate the micellar behavior of F127. In addition, it was also claimed that the macroscopic morphology of mesoporous silica was highly dependent on the local curvature energy present at the interface of the inorganic silica and the amphiphilic block copolymer species. The addition of CTAB can lower the local curvature energy and facilitate the formation of the more curved spherical morphology [47]. Previous studies have validated the potential roles of CTAB in regulating the final shape of SBA-16 and demonstrated that spherical particles could be synthesized in the presence of CTAB [34,43]. However, certain drawback associated with previous studies was either the small pore size [34] or the long synthesis time (for several days) [43]. The proposed procedure for the synthesis of SBA-16 in our study has overcome both disadvantages, permitting a significant time reduction and simultaneously producing a well-formed spherical morphology as well as enlarged pores with a tunable size. We believe that the well-defined spherical morphology is preferable and more advantageous for drug delivery applications than the use of irregular powders. Fig. 3 gave the representative N2 adsorption–desorption isotherms and pore size distribution curves of SBA-16 synthesized at different hydrothermal temperatures. In all cases, the desorption branch of the isotherm did not follow the adsorption branch, that was, adsorption–desorption hysteresis was observed. Both S1680 and S16-120 samples exhibited type-IV isotherms with a broad H2 hysteresis loop, which was characteristic of silica materials having uniform, cage-like pores with entrances (windows) much narrower than the diameter of the cage [48]. With the increase in temperature (from 80 to 120 °C), an increases in the hysteresis loop involving its height and width as well as a shift in the capillary

Fig. 2. SEM images of S16-80 (A), S16-120 (B) and S16-150 (C).

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Fig. 3. N2 adsorption–desorption isotherms and pore size distribution curves of S16-80, S16-120 and S16-150.

condensation to higher relative pressures were clearly observed, indicating a larger mesopore size of S16-120 compared with that of S16-80. On the contrary, S16-150 samples synthesized at a higher temperature of 150 °C displayed an isotherm with a H1 hysteresis loop, indicating that the entrance sizes of S16-150 samples were enlarged to a larger extent [49,50]. This trend was further confirmed by the pore size distribution of various SBA-16 samples, where SBA-16 samples synthesized at different temperatures (80, 120 and 150 °C) had pore sizes of 4.3, 6.8 and 9.0 nm, respectively. However, it was noticed that the pore size enlargement of S16-150 was accompanied by a reduced pore uniformity. A broad and bimodal pore size distribution was observed, possibly related to a decrease in mesostructured ordering at high temperatures. Based on the fact that the pore size of mesoporous silica was highly dependent on the effective volume of the hydrophobic part of the block copolymer templates, the enlargement of the pore size with the increase in temperature could be attributed to the increase in the hydrophobicity of the PEO block in the F127 polymer. For cage-like SBA-16 silica, the successful pore enlargement via this convenient approach seems significant since the narrow pore entrance from one cage to another could be a limiting factor resulting in an unfavorable mass transfer. Until now, a number of strategies, such as a change in the carbon number of surfactants [51], addition of hydrophobic organic swelling agents, such as trimethylbenzene (TMB) [52], and the increase of preparation temperatures [49,50], have been used for the enlargement of the pore size of various mesoporous silica. Taking into account the convenience and simplicity of the temperature adjustment, an attempt was therefore made in our present work to enlarge the pore size of SBA-16 through elevating the synthesis temperature. The results of the N2 sorption measurements clearly showed that it was possible to tune the textural properties of SBA-16 by this facile method, i.e., hydrothermal treatment at higher temperatures could lead to a pronounced increase in pore diameter. 3.2. Drug loading and characterization In the present work, the solvent deposition method was used to load IMC into mesoporous silica, in ordered to obtain an increased drug loading efficiency and accurate drug loading degree of 25%. This method involves the initial adsorption equilibrium followed

by solvent evaporation, which has been proved to be an effective approach for the preparation of solid dispersions of poorly soluble drugs [38,39]. Acetone was selected here as the loading solvent due to its volatility and the fact that IMC was readily soluble in the solvent. For all IMC-loaded SBA-16 samples, the target drug loading of 25% was attained from the results of UV analysis, implying that there was no loss of drug content during the loading process. The successful drug loading characteristics of various forms of mesoporous silica were then confirmed by the results of N2 adsorption measurements. Fig. 4 displayed the N2 adsorption–desorption isotherms of mesoporous silica before (Fig. 4A) and after (Fig. 4B) loading with IMC. As can be seen, the drug loading process significantly altered the porosity of the samples due to the incorporation of IMC into the pores. The nitrogen sorption isotherms showed a noticeable decrease in the total volume of adsorbed nitrogen compared with that of pure silica, indicating a substantial mesopore filling. Despite these changes, the shape of the isotherm remained unchanged after IMC introduction, indicating the preservation of the mesoporous texture. The textural parameters, such as the BET surface area, total pore volume and BJH average pore diameter for various SBA-16 samples before and after drug loading were summarized in Table 1. The clear reduction in the BET specific surface area, pore size and pore volume of SBA-16 was further evidence of the effective loading of IMC inside the mesopores. However, pore size enlargement was observed for S16-120 after IMC introduction, probably attributed to the total filling of the smaller mesopores and the remaining of small amounts of free volume for larger mesopores [13,29]. To further prove the effective inclusion of IMC into the mesopores and also to examine the possible interactions between IMC and mesoporous silica, the FT-IR spectra of pure IMC, S16-80 and IMC-loaded S16-80 samples, together with the corresponding physical mixtures, were presented in Fig. 5. Since the spectrum of silica was similar, only S16-80 was used and taken as an example. As can be seen, pure IMC showed its characteristic peaks at 1714 and 1690 cm 1 (assigned to the carbonyl group of the acid and amide, respectively). For the spectrum of the physical mixture, peaks associated with both SBA-16 and IMC were present, indicating no occurrence of interactions between IMC and SBA-16. However, the spectrum of the IMC-loaded SBA-16 system showed a marked decrease of carbonyl stretching peaks and a slight shift

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Fig. 4. N2 adsorption–desorption isotherms of S16-80, S16-120 and S16-150 before (A) and after (B) drug loading.

Table 1 Detailed textural parameters of samples by N2 adsorption measurements. Sample

SBET (m2/g)

Vt (cm3/g)

WBJH (nm)

S16-80 S16-80-I S16-120 S16-120-I S16-150 S16-150-I

540 235 724 279 413 239

0.34 0.18 0.73 0.38 1.03 0.49

4.3 3.9 6.8 10.7 9.0 <4 nm

SBET: BET surface area. Vt: total pore volume calculated as the amount of nitrogen adsorbed at the relative pressure of 0.98. WBJH: average pore diameter was calculated by using BJH model. S16-X-I: IMC-loaded S16-X samples.

molecules [53–55]. This type of interaction between the silica matrix and drugs has previously been shown to be essential for achieving a high drug loading [1,11].

3.3. Solid state characterization For practical applications, the existing state of the drug substance in a drug delivery system is an important factor and a necessary consideration. In order to assess the physical state of IMC in mesoporous silica, both PXRD and DSC measurements were performed, which were also expected to provide indirect evidence for the effective entrapment of IMC into mesoporous SBA-16. Fig. 6 showed the PXRD patterns of IMC before and after incorporation into mesoporous SBA-16. The diffractogram of pure IMC showed intense and typical diffraction reflections, suggesting the crystalline characteristics of IMC. After incorporation into mesoporous silica, however, no X-ray diffraction peak assigned to the crystalline form could be detected, suggesting the non-crystalline state of IMC in mesoporous SBA-16. It was supposed that the

Fig. 5. FT-IR spectrum for pure IMC (A), S16-80 (B), the physical mixtures of IMC and S16-80 (C), and IMC-loaded S16-80 (D).

to lower wavenumbers (1705 cm 1 and 1679 cm 1 corresponding to the acid and amide groups, respectively). This suggested that the acid and amide functional groups in the IMC molecules were involved in hydrogen bonding with the silanol groups of the silica surface, which provided active sites for interaction with drug

Fig. 6. Wide-angle XRD patterns for crystalline IMC powders and IMC-loaded mesoporous SBA-16 samples.

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Fig. 7. DSC thermograms for pure IMC powder and IMC-loaded mesoporous SBA-16 samples.

crystallization of IMC was greatly hindered and suppressed when constrained into the mesopores of SBA-16 with a size of only a few molecular diameters. Further confirmation of the crystal state of IMC was performed by DSC measurement (Fig. 7). The pure IMC thermogram showed a strong endothermic peak at 161 °C, which reflected the melting of the bulk phase of IMC. However, the thermograms of IMC-loaded mesoporous silica did not exhibit any bulk phase transitions or the glass transition of IMC. It was assumed that the limited nanospace of mesoporous silica prevented the crystallization of drugs inside the mesopores due to the space confinement, and so giving rise to the disordered non-crystalline form [25]. Furthermore, the hydrogen bonds formed between the silica matrix and IMC might also be responsible for the observed amorphization of IMC [56]. 3.4. In vitro dissolution Fig. 8 depicted the dissolution profiles of IMC from pure crystalline IMC and IMC-loaded mesoporous silica. The in vitro dissolution study was performed in PBS (pH = 6.8) and all samples were in the powder form. It can be seen from Fig. 8 that the dissolution

Fig. 8. In vitro dissolution profiles for crystalline IMC and IMC-loaded mesoporous SBA-16 samples.

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rate of IMC from all mesoporous silica samples was drastically enhanced in compared with that of pure IMC crystals within the first 60 min. For untreated original crystalline IMC, only 64% of IMC was dissolved within 1 h. However, all mesoporous silica samples, regardless of the pore size and silica type, exhibited a significant dissolution-enhancing effect on IMC, with 72%, 75%, 81% and 90% of IMC being dissolved within 60 min for MCM-41, S16-80, S16120 and S16-150, respectively. One possible reason for the improved dissolution of IMC from mesoporous silica may be that the mesoporous silica matrix changed the solid state of IMC compounds from the crystalline state to the non-crystalline form, which was known to dramatically increase the apparent solubility and dissolution rate of poorly water-soluble drugs due to its higher energy state [57]. In addition, other factors, such as the increased surface area available for dissolution after being confined in mesoporous silica and the hydrophilic surface of the silica matrix [58], were also believed to contribute to the improved dissolution of IMC. Comparing the dissolution of IMC from SBA-16 samples with different pore diameters, it was found that the IMC dissolution behavior was markedly affected by the pore diameter of SBA-16. Enlarging the pore size of SBA-16 from 4.3 to 9.0 nm significantly improved the IMC dissolution rate, with 90% of IMC being dissolved for S16-150 samples having the largest pores (9.0 nm). The possible explanation for the different dissolution profiles may origin from the different pore architectures of SBA-16 samples synthesized at different temperatures. For S16-80 samples synthesized at low temperatures, the relatively small cages and tight windows between the cages may hinder the rapid and easy diffusion of IMC molecules into the dissolution media, thereby delaying the dissolution of IMC. However, the relatively larger pores of S16150 synthesized at higher temperatures and the resultant highly open and accessible surface areas are more resistant to pore blocking and able to reduce the chance of restricting drug diffusions in the multidirectional pore system, thus allowing a faster dissolution of dissolved IMC molecules (Fig. 9). This significant dissolutionenhancing effect provided by mesoporous SBA-16, especially S16150 samples with the largest pores and highly open pore systems, will be particularly beneficial for the improved delivery of poorly soluble drugs belonging to the BCS-II class for which the oral bioavailability is limited by the low solubility. Further comparison of the release profiles of IMC from MCM-41 (see Figs. S1 and S2 for SEM and N2 sorption characterization of MCM-41) and S16-80 which had similar pore sizes (3.9 and 4.3 nm, respectively) showed that there was no significant difference in release behavior between these two samples. Regarding the pore architecture, MCM-41 features hexagonal pores in a 2D array with long channels (P6mm plane group), while SBA-16 possesses a 3D cubic arrangement of spherical mesopores (Im3m group). It seems therefore plausible to expect that the 3D structure of SBA-16 will provide more favorable drug release kinetics, while MCM-41 might exhibit sterical hindrance caused by the long pore channels. However, in our present study only minor differences in the release profiles of IMC were observed between S16-80 and MCM-41, with slightly faster release rate for S16-80 samples than MCM-41 (72% and 75% of IMC for MCM-41 and S16-80, respectively). Aside from the above-mentioned narrow windows of S16-80 preventing the facile diffusion of IMC molecules, another possible reason may be the different particle size of MCM-41 and S16-80, resulting in a different time needed for the drug molecules to diffuse from the inner pores into the outer media [28]. It’s known that drug release from mesoporous silica matrix is presumed to be a mainly diffusion-controlled process [11,28]. As soon as the release medium penetrates into mesopores, the drug molecules will dissolve in the fluid and then diffuse from the inner pores into the outer dissolution medium. Despite the long and

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Fig. 9. Schematical illustration for the pore structures of the SBA-16 microspheres synthesized at different heating temperatures.

tight channels of MCM-41, the relatively small particle size significantly reduced the pathway IMC had to take to escape from the inner pores, thus contributing to the fast drug release profiles. The large particle size of S16-80 microspheres, however, can be a limiting factor for the facile diffusion of drug molecules. It should also be noted that, in spite of the larger particle size of S16-80 microspheres than MCM-41, the release rate of IMC from S16-80 microsphere was slightly faster than that from MCM-41, which can mainly be ascribed to the 3D cubic structures of S16-80 microspheres.

Acknowledgments

4. Conclusion

Appendix A. Supplementary material

In the first part of this study, we have reported a modified synthetic approach for 3D cubic mesoporous silica SBA-16 having both a spherical morphology and a tunable pore size. It was found that the addition of CTAB during the synthesis could, on one hand, control the macroscopic morphology of SBA-16 and, on the other hand, induce the rapid formation of F127 micelles which significantly reduced the synthesis time for SBA-16. Meanwhile, the pore size of SBA-16 could be conveniently tailored by simply controlling the heating temperature, with an enlarged pore diameter up to 9.0 nm. In the second part, the potential of the produced SBA-16 microspheres as matrices for efficient loading and then the improved delivery of the poorly water-soluble drug IMC was validated. The combination of N2 sorption, FT-IR, DSC and PXRD measurements proved the successful inclusion and confirmed the non-crystalline state of IMC after loading into mesoporous silica using the solvent deposition method. In particular, synthetic SBA-16 significantly improved the dissolution rate of IMC in comparison with raw IMC crystals. Moreover, a close correlation between the dissolution rate of IMC and the pore size of SBA-16 was observed. The larger the pore size, the faster was the drug release rate. The improved delivery of IMC may origin from the non-crystalline state of IMC and the increased surface areas available for dissolution after being confined to mesopores as well as the 3D accessible pore networks provided by SBA-16. Due to the simple synthetic procedure, well-defined spherical morphology, convenient pore size adjustment through simply controlling the heating temperature and, in particular, the 3D interconnected pore networks which provide favorable mass transfer kinetics, the SBA-16 microspheres in the present study are considered to be excellent candidates as matrices for the delivery of poorly water-soluble drugs, as well as for the immobilization of biomolecules or catalysis.

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jcis.2011.07.022.

This work was financially supported by National Basic Research Program of China (973 Program) (No. 2009CB930300), National Natural Science Foundation of China (No. 81072605), Major national platform for innovative pharmaceuticals (2009ZX09301012), Key Laboratory of Drug Preparation Design & Evaluation of Liaoning Provincial Education Department, and Shenyang Special Fund for Exploration of Intellectual Resources. In particular, we thank Dr. David for languages correction.

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