Ordered Mesoporous Silica Material SBA-15: A Broad-Spectrum Formulation Platform for Poorly Soluble Drugs

Ordered Mesoporous Silica Material SBA-15: A Broad-Spectrum Formulation Platform for Poorly Soluble Drugs MICHIEL VAN SPEYBROECK,1 VALE´RY BARILLARO,1 THAO DO THI,1 RANDY MELLAERTS,2 JOHAN MARTENS,2 JAN VAN HUMBEECK,3 JAN VERMANT,4 PIETER ANNAERT,1 GUY VAN DEN MOOTER,1 PATRICK AUGUSTIJNS1 1

Laboratory for Pharmacotechnology and Biopharmacy, K.U. Leuven, Belgium

2

Centre for Surface Chemistry and Catalysis, K.U. Leuven, Belgium

3

Department of Metallurgy and Materials Sciences, K.U. Leuven, Belgium

4

Laboratory of Applied Rheology and Polymer Technology, K.U. Leuven, Belgium

Received 14 July 2008; revised 16 October 2008; accepted 23 October 2008 Published online 12 December 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21638

ABSTRACT: Encapsulating poorly soluble drugs in mesoporous silicates is an emerging strategy to improve drug dissolution. This study evaluates the applicability of the ordered mesoporous silicate SBA-15 as an excipient to enhance dissolution, for a test series of 10 poorly soluble compounds with a high degree of physicochemical diversity (carbamazepine, cinnarizine, danazol, diazepam, fenofibrate, griseofulvin, indomethacin, ketoconazole, nifedipine, and phenylbutazone). A generic solvent impregnation method was used to load all model compounds. The target drug content was 20%. The physical nature of the formulations was investigated using differential scanning calorimetry (DSC) and the pharmaceutical performance evaluated by means of in vitro dissolution. Aliquots of each formulation were stored at 258C/52% RH for 6 months, and again subjected to DSC and in vitro dissolution. The target drug content of 20% was attained in all cases. DSC data evidenced the noncrystalline state of the confined drugs. All SBA-15 formulations exhibited an enhanced dissolution as compared to their corresponding crystalline materials, and the high pharmaceutical performance of all formulations was retained during the 6 months storage period. The results of this study suggest that encapsulation in SBA-15 can be applied as a dissolution-enhancing formulation approach for a very wide variety of poorly soluble drugs. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2648–2658, 2009

Keywords: mesoporous silica SBA-15; poor solubility; adsorption; dissolution; physical characterization; physical stability

INTRODUCTION Aqueous solubility is one of the most critical physicochemical properties influencing oral bio-

Correspondence to: Patrick Augustijns 003216330301; Fax: 3216330305; E-mail: [email protected])

(Telephone:

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availability,1 as limited solubility or dissolution in the gastrointestinal tract may result in insufficient and variable absorption. The number of poorly soluble drug candidates has risen sharply over the last two decades due to evolutions in hit identification strategies2 and the discovery of new drug targets which require higher compound lipophilicity for adequate interaction.3 Enhancing the oral bioavailability of dissolution-impaired drug candidates therefore constitutes one of the

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most challenging tasks formulation scientists are faced with nowadays.4 An emerging approach to enhance dissolution is the encapsulation of hydrophobic drugs in ordered mesoporous silica materials. Adsorption onto high surface area carriers is a well known technique to enhance drug dissolution, and has already been described for silica-based excipients in the early 1970s.5,6 With the advent of the ordered mesoporous silicates,7,9 the interest for silica-based excipients is enjoying a renaissance. The term mesoporous designates porous materials that possess pores with diameters between 2 and 50 nm.8 The discovery of ordered mesoporous silicates opened up new possibilities in various areas of chemistry and material sciences,9 and since 2001, these inorganic materials are being explored as carriers for oral drug delivery.10 Their unique properties render them suitable carriers for active pharmaceutical ingredients: pore diameters that can be tuned between 2 and 30 nm, high specific surface areas (up to 1500 m2/g) creating a high potential for adsorption, large pore volumes (up to 1.5 cm3/g), and a silanolcontaining surface that can be functionalized to modify drug release. Mesoporous silicates are most frequently studied for applications within the field of controlled drug delivery, but also show great promise in the enhancement of drug dissolution.11–13 Remarkably, the number of compounds that have been used to evaluate the dissolutionenhancing effect of mesoporous silica remains rather limited. A substantial body of knowledge on the encapsulation of hydrophobic drugs in mesoporous silica has been obtained from studies that have all used the same model compound, ibuprofen.11,14–25 Although all of these studies have contributed to a better understanding of mesoporous silica-based drug delivery systems, the behavior observed for ibuprofen might not be applicable to other drugs, as ibuprofen is known to form dimers inside mesopores.15,16 Other low solubility compounds that have been formulated successfully into a mesoporous silica-based formulation include itraconazole,12,26 flurbiprofen,13 and piroxicam.27 The present study was aimed at evaluating to what extent these reported dissolution-enhancing effects were applicable to a series of compounds with a high degree of physicochemical diversity, by evaluating the release behavior and physical stability of 10 poorly soluble compounds encapsulated in the ordered mesoporous silicate SBA-15.7 Surprisingly, no prior articles DOI 10.1002/jps

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have reported on the physical stability of mesoporous silica-based formulations. This is a shortcoming in the current state of the art, as no formulation approach would be useful to the pharmaceutical industry if it fails to yield physically stable formulations. SBA-15 can readily be prepared over a wide range of uniform pore sizes, going from 5 to 30 nm.7 For pharmaceutical applications, the pore diameter usually varies between 6 and 10 nm. Typical values for the pore volume and surface area range from 0.8 to 1.2 cm3/g and 600 to 1000 m2/g, respectively. The pore network of SBA15 consists of a hexagonally ordered array of uniform two-dimensional mesopores, with a complementary system of disordered micropores (diameter < 2 nm) that are located in the mesopore wall.28 The large internal pore volume of SBA-15, combined with its highly accessible pore network, enables drug loadings that can increase up to 50% (w/w).11 In addition, due to its thick pore walls, the hydrothermal stability of SBA-15 is higher than that of the frequently used M41S materials.29 Because of its high drug loading capacity, its relatively wide pore diameter and its hydrothermal stability, SBA-15 is probably the most interesting mesoporous silicate for enhancing the dissolution of low solubility compounds.

MATERIALS AND METHODS Model Drugs Ten poorly soluble compounds were selected based upon their physicochemical profile, in order to obtain a test series with a high degree of diversity (Tab. 1). Carbamazepine and ketoconazole were purchased from PharmInnova (Waregem, Belgium); indomethacin, griseofulvin, and cinnarizine from Certa (Eigenbrakel, Belgium); nifedipine, danazol, and fenofibrate from Indis (Aartselaar, Belgium); phenylbutazone and diazepam from Fagron (Waregem, Belgium).

SBA-15 Synthesis SBA-15 was synthesized according to the procedure described by Kosuge et al.30 An aqueous HCl solution (180 g, 2 M) was added to 6 g of triblock copolymer Pluronic 123 (BTC-Benelux, La Hulpe, Belgium), and the resulting mixture was stirred until all of the Pluronic 123 had dissolved. Subsequently, 15.3 g of sodium silicate JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 8, AUGUST 2009

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Table 1. Overview of the Structural Formulas of the 10 Model Compounds, the Wavelengths Used for Quantification and the Media Used for the In Vitro Dissolution Experiments

Compound

Structural Formulaa

Wavelength Used for Quantification (nm)

Release Medium

Carbamazepine

284

Cinnarizine

254

Water þ 1% SLS

Danazol

287

SGFsp þ 0.25% SLS

Diazepam

250

Water

Fenofibrate

290

SGFsp þ 0.25% SLS

Griseofulvin

295

SGFsp þ 0.25% SLS

Indomethacin

252

SGFsp þ 0.5% SLS

Ketoconazole

230

Water þ 0.25% SLS

Nifedipine

256

SGFsp þ 0.35% SLS

Phenylbutazone

239

SGFsp þ 0.5% SLS

a

SGFsp

Structural formulas from Merck Index, 10th edition.

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solution (>27 wt.-% SiO2, Riedel-de Hae¨n, Seelze, Germany) was diluted in 45 g of deionized water. The latter mixture was added dropwise to the acidic P123 solution under magnetic stirring, while a temperature of 358C was maintained. Stirring was continued for another 5 min before switching to quiescent synthesis conditions at 358C for 24 h. In a next step, the temperature of the mixture was increased to 908C for another 48 h. Subsequently the mixture was cooled to room temperature, vacuum filtered over a 0.47 mm membrane filter (Millipore, Brussels, Belgium), rinsed with 200 mL of deionized water (17.8 MV, Elga Ltd, Bucks, UK) and dried at 408C under reduced pressure (103 bar) in a vacuum oven (Heraeus, Hanau, Germany) for 12 h. Finally, the silica powder was calcined at 5508C for 8 h to remove the Pluronic 123 from the pores.

Nitrogen Physisorption and Calculations Nitrogen adsorption–desorption isotherms of the calcined SBA-15 powder were recorded using a Micromeritics Tristar 3000-apparatus (Norcross, GA). Measurements were performed at 1968C and all samples were pretreated at 3008C for 12 h under nitrogen flushing prior to analysis. The total surface area was calculated using the BET model31 in the relative pressure range between 0.05 and 0.2. The total pore volume was estimated using the t-plot method of Lippens and De Boer.32 The pore size distribution was derived from the adsorption branches of the nitrogen isotherms using the BJH model.33

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powder in 10 mL of an aqueous solution containing 3% of sodium lauryl sulfate (SLS, Merck Schuchardt, Hohenbrunn, Germany). These suspensions were sonicated for 30 min, and subsequently put in a rotary mixer (Snijders, Tilburg, The Netherlands) for 24 h. Preliminary tests had pointed out that a time span of 24 h was sufficient to remove the entire drug load from the SBA-15 pores. The silica was separated from the drug solutions using a PTFE-membrane filter (0.45 mm, Macherey-Nagel, Du¨ren, Germany). Quantification of the drug in solution was performed as described in Drug Quantification Section. All analyses were performed in triplicate. The mean values obtained from these experiments were used to calculate the maximum drug release in the in vitro dissolution experiments. Thermogravimetric (TG) Analysis TG analyses were performed on a TGA Q-500 apparatus (TA Instruments, Leatherhead, UK). The balance purge consisted of pure nitrogen (10 mL/min). Pure oxygen was used as the sample purge gas (90 mL/min). TG runs were recorded from 30 to 8008C at a heating rate of 108C/min. The drug content was calculated by correcting the weight loss of the SBA-15 formulations between 100 and 7508C for the weight loss of drug-free SBA-15 in the same temperature range. All experiments were performed in platinum pans (TA Instruments). Differential Scanning Calorimetry (DSC)

All model drugs were loaded onto SBA-15 according to the incipient wetness procedure18 in order to obtain a drug loading of 20%: 150 mg of SBA-15 was impregnated with 750 mL of a 50 mg/mL drug solution in methylene chloride (Fisher Scientific, Leicestershire, UK). The moist powder was homogenized with a spatula until seemingly dry, after which it was dried further at 408C under reduced pressure (103 bar) in a vacuum oven (Heraeus) for 48 h to remove any residual methylene chloride.

DSC experiments were performed on a TA Instruments Q-2000 DSC apparatus at a heating rate of 28C/min. Dry nitrogen at a flow rate of 50 mL/min was used as the purge gas through the DSC cell. All experiments were conducted in sealed aluminum pans (TA Instruments). Sample weights varied between 5 and 8 mg. The temperature scale was calibrated with benzoic acid, tin, and indium standards. The latter was used to calibrate the enthalpic response as well. All thermograms were recorded in duplicate and all data handling was performed using the Universal Analysis 2000 software package (TA Instruments).

Determination of Drug Loading

In Vitro Dissolution

The drug content of the SBA-15 formulations was determined by suspending 5 mg of drug-loaded

The pharmaceutical performance of the SBA-15 formulations was evaluated by means of in vitro

Drug Loading

DOI 10.1002/jps

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dissolution experiments. Drug release from the SBA-15 formulations was compared to that of their corresponding crystalline materials and drug-SBA-15 physical mixtures. Physical mixtures containing 20% of drug were prepared by geometrical dilution using a mortar and pestle. The mixtures were gently ground for 5 min to assure adequate homogenization. All dissolution tests were carried out at ambient temperature. Twenty milliliters of release medium (see below) was added to a glass vial containing 2  0.1 mg of drug, under the form of either an SBA-15 formulation, a physical mixture or as the crystalline material. Adequate homogenization was assured by magnetic stirring (cross-shaped magnetic stirrings discs, 10 mm diameter, VWR International, Brussels, Belgium) on a 10-place magnetic stirrer (IKAMAG RO 10 power, IKA, Stanfer, Germany) at a stirring speed of 700 rpm. One milliliter samples were withdrawn with a syringe at 5, 10, 30, and 60 min, filtered over a 0.45 mm PTFE membrane filter (Macherey-Nagel) and immediately replaced with 1 mL of fresh medium. Most of the dissolution experiments were conducted in simulated gastric fluid without pepsin (SGFsp, USP 24, pH 1.2). Three compounds (ketoconazole, diazepam, and cinnarizine) exhibited a sharp increase in solubility and dissolution rate at lower pH values due to their weakly basic nature. In order to allow for better discrimination between physical mixtures and formulations, pure water was selected as the release medium for these three compounds. Although it is generally preferable to maintain sink conditions when evaluating release rates, this was not accomplished in the present study. Our goal was to illustrate the advantage in dissolution rate that formulating with SBA-15 could offer. Working under sink conditions caused several crystalline compounds/physical mixtures to dissolve very rapidly as well. Reducing the ‘‘sinkcapacity’’ of the medium allowed for better discrimination between formulations and crystalline materials/physical mixtures. The test conditions in this study could be described as ‘‘poor sink conditions.’’ This was accomplished by adding carefully selected amounts of the surfactant SLS to the release media. An overview of the release media is provided in Table 1. For all compounds, SLS was added to the medium, except for carbamazepine and diazepam (the two ‘‘highest solubility’’ compounds of the test series, 113 mg/ mL34 and 55 mg/mL35, respectively). For these JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 8, AUGUST 2009

latter two compounds, the samples withdrawn were diluted 1:4 in acetonitrile (Fisher Scientific) in order to prevent recrystallization prior to analysis. Drug Quantification All samples coming from the drug content assay and the in vitro dissolution experiments were analyzed by UV-spectrometry in a Tecan Infinite M200 microplate reader (Tecan Benelux, Mechelen, Belgium) using flat-bottomed, transparent 96-well plates (UV-star, Greiner Bio-One, Frickenhausen, Germany). The wavelengths used for quantification of the different compounds are summarized in Table 1. The standards used to construct the calibration curves were prepared in the same media used for the experiments. Sample concentrations were calculated by interpolation from the calibration curve response using a linear regression model. All calibration curves were linear over a concentration range between 2.5 and 100 mg/mL. Chemical and Physical Stability Tests The chemical stability of the drugs during the impregnation process was assessed using UVspectroscopy: a small amount of each formulation was dissolved in the same media used for the in vitro dissolution experiments, equilibrated for 1 h and filtered over a 0.45 mm PTFE membrane filter (Macherey-Nagel). The UV-spectrum of the resulting solution was compared to that of the asreceived drug. UV-spectra were recorded using a microplate reader (Tecan), between 230 and 350 nm. The physical and chemical stability of the SBA-15 formulations upon storage was evaluated by storing replicates of each formulation for 6 months in a desiccator at 258C/52% RH (saturated Mg(NO3)26H2O solution). Drug-free SBA-15 powder was stored under the same conditions. After storage, the UV-spectra, DSC thermograms and in vitro release profiles were recorded again as described above. The stored drug-free SBA-15 was again subjected to nitrogen gas adsorption.

RESULTS AND DISCUSSION The nitrogen physisorption results summarized in Table 2 illustrate that both batches of SBA-15 used throughout this study exhibited similar characteristics. The morphology of SBA-15 DOI 10.1002/jps

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Table 2. Average Pore Diameter, Total Pore Volume, and Surface Area of the Two Independently Prepared Batches of SBA-15 Used to Formulate the Model Compounds, Freshly Prepared and After 6 months of Storage at 258C/52% RH Batch 1 Freshly Prepared

After Storage

Freshly Prepared

After Storage

7.6 635.5 0.81 0.10

7.5 557.8 0.76 0.07

8.3 663.5 0.83 0.12

8.4 628.5 0.82 0.09

Average pore diameter (nm) Surface area (m2/g) Total pore volume (cm3/g) Micropore volume (cm3/g)

synthesized under the conditions described in SBA-15 Synthesis Section has been documented in earlier work from our group.26 Briefly, SBA-15 consists of single particles with sizes ranging from 0.2 to 1 mm, which cluster together to form larger aggregates of about 50 mm. The UV-spectra of the aqueous solutions obtained after suspending the freshly prepared SBA-15 formulations were perfectly similar to those of the as-received drugs, indicating that the impregnation process did not affect the drugs’ chemical stability (data not shown). As seen in Table 3, the target drug loading of 20% was attained in all cases. The drug contents determined as described in Determination of Drug Loading Section were corroborated by TG data. In addition, TG results indicated that the drug-free SBA-15 powder lost 4.1  0.9% of its weight in the region below 1008C, whereas none of the formulations lost more than 1.6%. Since the weight loss below 1008C originates from the evaporation of physically adsorbed water, TG data reflect a lower water content for the formulations as compared to the drug-free SBA-15 powder. In the formulations, the pores are filled with hydrophobic drug molecules, which reduces the pore volume and Table 3. Drug Contents of the SBA-15 Formulations, as Determined Via Extraction (n ¼ 3) and TG (n ¼ 1) Drug Content (%) Compound

Extraction

TG

Carbamazepine Cinnarizine Danazol Diazepam Fenofibrate Griseofulvin Indomethacin Ketoconazole Nifedipine Phenylbutazone

22.9  0.2 20.3  0.5 19.7  0.1 20.9  0.1 21.1  0.4 20.0  0.3 18.4  0.5 20.4  0.1 20.0  0.5 20.2  0.5

22.5 20.7 20.9 21.7 21.5 19.7 18.6 20.4 20.7 19.8

DOI 10.1002/jps

Batch 2

thus the amount of water that can condensate in the SBA-15 capillaries. The in vitro release results in Figure 1 demonstrate that, for all model compounds, drug release from SBA-15 was faster that the dissolution of their respective crystalline counterparts. The release profiles show great similarity among all SBA-15 formulations. All formulations, except danazol, released 80% of drug within the first 5 min of the experiment. This rapid release results from the fast dissolution of the confined material, followed by a quick diffusion into the bulk medium. Drug release was not slower for the larger molecules of the test series, indicating that the pore diameter of SBA-15 is sufficiently wide as to allow for a relatively unhindered diffusion of all test compounds. The release profiles of the drugSBA-15 physical mixtures resembled those of the crystalline drugs very well. Only in the case of carbamazepine, indomethacin, and nifedipine, dissolution was faster for the physical mixtures, reflecting a dissolution-enhancing interaction with SBA-15 induced by simple physical blending. It also appears from Figure 1 that the release profiles of the stored formulations overlap with those recorded 6 months earlier, evidencing the physical stability of the formulations. Only danazol exhibited a significantly lowered drug release after 6 months of storage, which is related to its chemical degradation during storage (see below). The enhanced dissolution of the model compounds when formulated with SBA-15 originates from a suppression of crystallization of the adsorbed drug fraction, as seen in the DSC results. Figure 2 depicts the DSC thermograms for indomethacin, in its crystalline form and formulated with SBA-15. Comparable images were obtained for all other model compounds. In none of the thermograms signs, of melting could be detected, neither at the bulk melting point, nor at depressed temperatures. The absence of melting endotherms reflects the noncrystalline state of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 8, AUGUST 2009

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Figure 1. In vitro dissolution profiles of all model compounds. The depicted results are mean values (n ¼ 3). Standard deviations are depicted but are often masked by symbols. All SBA-15 formulations exhibited a clear enhancement of dissolution as compared to their crystalline counterparts. Physical blending with SBA-15 resulted in an accelerated dissolution for carbamazepine, indomethacin, and nifedipine. The dissolution profiles of the stored SBA-15 formulations overlap with those recorded 6 months earlier (except for danazol, see text), evidencing the physical stability of the formulations. [Color figure can be seen in the online version of this article, available on the website, www.interscience. wiley.com.]

the confined drug molecules. Although the exact physical nature of drugs confined to mesopores is not yet fully understood, it is clear that the thermodynamic properties of molecules confined to porous solids alter significantly when compared to those of the bulk phase. Several studies have indicated that, below a critical pore diameter, crystallization of the entrapped molecules is suppressed. This has been demonstrated for JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 8, AUGUST 2009

several small organic molecules such as benzene,36 cyclohexane,36 and methanol.37 The number of studies addressing the phase transformations of low molecular weight drugs confined to mesopores remains very limited. A recent study reported on the behavior of ibuprofen encapsulated in MCM-41.15 Using solid-state NMR, the authors demonstrated that, at low temperature, ibuprofen recrystallized in MCM-41 with a pore DOI 10.1002/jps

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Figure 2. DSC thermograms of indomethacin (IND) in its crystalline form (left Y-axis), formulated with SBA-15 (IND–SBA-15) (right Y-axis) and formulated with SBA-15 after 6 months of storage (IND–SBA15_stored) (right Y-axis). The melting of crystalline IND is clearly visible at 1608C. The SBA-15 formulations did not show any sign of bulk melting, neither immediately after preparation, nor after 6 months of storage. Furthermore, no melting peaks were observed at depressed temperatures, indicating that IND is confined to the pores in a noncrystalline state. The baseline curvature in IND–SBA-15 and IND–SBA-15_stored originates from the evaporation of physically adsorbed water.

size of 11.6 nm, whereas it existed in a glassy state if the pore size was decreased to 3.5 nm. When confined to the narrow pores, the drug molecules are prevented from arranging themselves into a crystal lattice. At ambient temperature, the confined ibuprofen behaved as a liquid in both the MCM-41 with high and low pore diameter. Confinement effects have also been the subject of a great number of theoretical studies. Radhakrishnan et al.38 reported on a molecular simulation study that involved the crystallization behavior of small organic molecules in cylindrical pores. For pore diameters smaller than 12 times the diameter of the confined molecule, the authors found the low temperature phase to be completely amorphous. It is well known that the high free energy associated with noncondensed states can result in major advantages in dissolution rate,39 and the high pharmaceutical performance of the SBA-15 formulations as compared to the crystalline compounds can be attributed to a complete loss of crystallinity of the confined drug molecules. Since the compounds of the test series differ substantially in terms of chemical structure, one can assume that the drug-silica interactions differ accordingly. Based upon the comparable appeaDOI 10.1002/jps

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rance of the release profiles among all model compounds, we hypothesize that interactions between hydrophobic drug molecules and the silanol groups covering the silica surface are not a major factor influencing drug release. The ratelimiting step for drug release will rather be the time needed for diffusion out of the internal pore network, which in turn is a function of the silica particle size22 and the pore diameter.12,14,40 Note that the short experiment time (1 h) and the low solubility of SBA-15 in water29 and acidic media such as SGFsp41 rule out the effect of matrix erosion on drug release. For three model compounds (carbamazepine, indomethacin, and nifedipine), physical blending with SBA-15 resulted in a considerable dissolution-enhancing effect. It has been reported that physically mixing hydrophobic drugs with mesoporous silicates can already induce a high degree of interaction.13,42 Looking at Figure 3, it appears that the DSC thermogram of the carbamazepine–SBA-15 physical mixture resembles that of the SBA-15 formulation very well. Surprisingly, no glass transition of carbamazepine could be detected in the physical mixture, although amorphous carbamazepine, obtained by quench-cooling the melt in liquid nitrogen, exhibited a clear glass transition at 598C. Under the experimental conditions used to investigate the formulations, quantities of 0.25 mg amorphous carbamazepine could still readily be detected. The absence of a glass transition in the physical mixture therefore suggests that the carbamazepine molecules

Figure 3. DSC thermograms of carbamazepine (CBZ) in its crystalline form; as a physical mixture with SBA-15 (CBZ–SBA-15_phys mix) and as an SBA-15 formulation (CBZ–SBA-15). The absence of bulk melting in CBZ–SBA-15_phys mix reflects a strong interaction with the silica surface induced by simple physical blending. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 8, AUGUST 2009

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are being adsorbed monomolecularly onto the silica surface upon physical mixing. The mechanism underpinning this odd behavior of carbamazepine is currently being investigated. One possible explanation for the slightly faster drug release from the physical mixture as compared to the formulation is the difference in preparative process. During the solvent-based impregnation process, capillary forces favor drug adsorption into the internal pore network, whereas adsorption onto the carrier’s external surface is predominant upon simple physical mixing. The faster drug release from the physical mixture can then be explained in terms of the localization of the adsorbed drug fraction: drug molecules residing on the external surface (physical mixture) will be immediately displaced upon contact with water, whereas internally deposited molecules (formulation) need time to diffuse out of the pores. The predominant mechanism of interaction is most probably hydrogen bonding between the carbamazepine amide function and the SBA-15 silanol groups. This type of interaction has recently been described for a physical mixture of carbamazepine and the mesoporous silicate MCM-41.43 The enhanced dissolution rate of the indomethacin– SBA-15 physical mixture as compared to its crystalline form most likely originates from the formation of hydrogen bonds between the SBA-15 silanol groups and the indomethacin carboxyl function. This interaction mechanism has been reported earlier for indomethacin and colloidal fumed silica.44 Nifedipine has also been reported to benefit from adsorption onto high surface area silica-based carriers.45 DSC results (Fig. 2) evidenced that no crystallization had occurred during storage. This physical stability was clearly reflected in the in vitro release results, in that the high pharmaceutical performance observed immediately after preparation was fully retained after 6 months of storage (Fig. 1). Due to the earlier mentioned confinement effect, recrystallization of the entrapped molecules is suppressed. Nitrogen adsorption experiments performed on the drug-free SBA-15-powder indicated that the average pore diameter remained unaffected upon storage, although a slight decrease of microporosity and surface area had occurred. This is in agreement with literature data.29 Although water, taken up during storage, affects the porosity of drug-free SBA-15, its effect on the drug-loaded carrier is reduced, since hydrophobic drug molecules cover the silica surface. The physical stability of the formulations can JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 8, AUGUST 2009

therefore be explained in terms of the stability of the carrier: knowing that the average pore diameter remained constant during the 6 months storage period, the ability of SBA-15 to retain the entrapped drug molecules in a noncrystalline state was retained accordingly. The only compound exhibiting a major decrease in performance after storage was danazol. Although the DSC thermogram of the stored formulation did not show any signs of recrystallization (data not shown), its UV-spectrum had altered considerably. The peak absorbance at 287 nm was still present, but had decreased, while a shoulder appeared at 240 nm, suggesting chemical degradation of danazol during storage (data not shown). Note that danazol also stood out negatively from the other compounds when comparing the release profiles recorded immediately after preparation, in that the maximum drug release for danazol reached only 80%, whereas all other compounds released more than 95% of drug at the end of the experiment. This suggests that danazol degradation might already have occurred in the time interval between preparation and the release experiment.

CONCLUSIONS Using a generic solvent impregnation method, 10 physicochemically diverse model compounds were successfully loaded onto SBA-15. In all cases, the adsorbed drug fraction was found to be noncrystalline, as evidenced by DSC results. This loss of crystallinity resulted in a significant improvement in dissolution rate as compared to the crystalline drugs. No drug crystallization was observed after 6 months of storage at 258C/52% RH, and the pharmaceutical performance of the SBA-15 formulations was retained accordingly. The comparable results, observed for a test series of poorly soluble compounds with a high degree of physicochemical diversity, suggest that encapsulation in SBA-15 can be applied as a dissolutionenhancing formulation approach for a very wide variety of poorly soluble drugs. This shows great promise for the future, as every dissolutionenhancing formulation approach used nowadays is known to depend on the active compound’s physicochemical profile. The solid dispersion technology has widely been investigated, but drug-carrier miscibility is a prerequisite for successful formulation.46,47 In addition, metastability sets a limit on commercial breakthroughs. DOI 10.1002/jps

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Particle size reduction (micronization/nanonization) is a commonly used technique to enhance dissolution, but comes short for extremely low solubility compounds. Complexation with cyclodextrins enjoys the highest commercial success rate, but, as for the solid dispersions, drug-carrier compatibility is a prerequisite.48,49 The potential of SBA-15 to yield physically stable, dissolutionenhancing formulations, irrespective of a drug’s physicochemical profile, therefore seems very promising. In addition, considering the relatively low cost of the SBA-15 synthesis and the simplicity of the drug loading process, it is clear that encapsulation in SBA-15 constitutes a potentially great expansion of the formulation scientist’s toolbox to overcome dissolution-limited bioavailability.

ACKNOWLEDGMENTS Financial support for this study was provided by a K.U. Leuven Industrial Research Fund (IOF). MVS acknowledges the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen) for a PhD grant.

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