Silica Aerogel Microparticles from Rice Husk Ash for Drug Delivery

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Silica Aerogel Microparticles from Rice Husk Ash for Drug Delivery Suresh Kumar Rajanna, Dharmendr Kumar, Madhu Vinjamur, and Mamata Mukhopadhyay Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/ie503867p • Publication Date (Web): 31 Dec 2014 Downloaded from http://pubs.acs.org on January 4, 2015

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Industrial & Engineering Chemistry Research is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Industrial & Engineering Chemistry Research

Silica Aerogel Microparticles from Rice Husk Ash for Drug Delivery Suresh Kumar Rajanna, Dharmendr Kumar, Madhu Vinjamur*, and Mamata Mukhopadhyay Department of Chemical Engineering, IIT Bombay, Powai, Mumbai – 400076, India. *Corresponding author: E-mail: [email protected]. Tel.: +91 (22) 2576 7218. Fax: +91 (22) 2572 6895 ABSTRACT The present work describes an improved process for preparation of silica aerogel microparticles (SAMs) for drug delivery from rice husk ash (RHA), an inexpensive source rich in biocompatible silica. The wet gel microparticles were produced by a sol-gel method using water-in-oil emulsion, where a mineral oil replaced vegetable oil for easy separation using less energy. Taguchi design of experiments was used to optimize the parameters controlling the sol-gel method. The wet gel particles were dried with supercritical carbon dioxide (scCO2) to obtain SAMs. They were characterized by their properties such as BET surface area, pore volume, pore diameter and morphology. The efficacy of the improved process was validated by loading a water insoluble drug, ibuprofen, and a food preservative, eugenol, in SAMs from scCO2 medium. The release kinetics of ibuprofen and eugenol from the loaded SAMs was studied. High loading and fast release kinetics confirmed that SAMs produced by the process are suitable for drug delivery. Keywords: Sol-gel, Water-in-oil emulsion, Supercritical carbon dioxide, Taguchi design

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1. Introduction

For over one decade, porous silica materials in various forms have been investigated as drug carrier materials due to their chemical inertness, biocompatibility and better physicochemical properties.1 Silica aerogels are a special kind of porous silica materials consisting of highly mesoporous nano structures. As a result of these structure, aerogels offer high specific surface area, high pore volume, high porosity and low density required for efficient drug delivery.2 Recent studies indicate that the use of aerogels for drug delivery applications is expected to grow in the future.3 Aerogels are synthesized as monoliths or small particles. Processes for synthesis of the former and the latter aerogels, in general comprise three steps: (i) preparation of wet gels by sol-gel process, (ii) solvent exchange and aging, and (iii) supercritical carbon dioxide (scCO2) drying.4,5 Here we focus on the small particles because they offer several advantages over the monoliths such as shorter drying time, larger external surface area, higher drug loading, controlled release of drugs, and energy savings as they obviate the need for crushing and recompression required for monoliths.6 The sol-gel step combined with emulsion technique produces small, gel particles in oil (continuous phase). These particles are usually separated from the oil by centrifugation or filtration. To replace water in their pores with ethanol, the separated particles are then treated with increasing concentrations of aqueous ethanol solutions and aged with pure ethanol. Finally, the ethanol is removed from the pores by drying with scCO2. Drying with scCO2 ensures that the original structure of aerogel microparticles and, therefore their surface area, is retained without collapse of the pores or shrinkage of the gel network.7 Drugs or active compounds can be loaded in aerogels via one of the three routes3,6,8: a) from drug solutions in ethanol during sol-gel and aging steps, b) from scCO2 medium during

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drying and c) from scCO2 medium after drying . For drugs having high solubility in ethanol and low solubility is scCO2, route a is preferred9; route c is selected for drugs having high solubility in scCO22. Route b is not explored in detail and it is not clear to us when it is preferable. Alnaif and Smirnova10 produced spherical silica aerogel particles from tetramethylorthosilicate (TMOS) as a precursor. They used ethanol-in-oil emulsion technique and the mean particle size obtained is in the range of 155 µm to 1.77 mm. It was noted that the viscosity of oil controls the particle size; larger particles were produced when larger quantities of viscous vegetable oil were mixed with the sol solution. Dragosavac et al.11 developed a novel membrane emulsion technique to produce uniform silica particles in the range of 30 to 70 µm from sodium silicate solution and subsequently Cu (II) was adsorbed on them from CuSO4 solution. Hong et al.12 prepared silica aerogel granules from water glass solution and obtained dry granules between 123 and 230 µm. These were obtained by drying under ambient conditions. A few of the current sol-gel methods for producing small aerogel particles by the emulsion technique are complicated; others are energy intensive because of mixing high viscosity vegetable oil (50 cP)10 with the sol solution. Generally, larger wet gel particles are produced with high viscosity oil and accordingly it should be replaced with lower viscosity oil for generating smaller particles. In addition, the downstream steps are extensive due to difficulties in separating the oil from the produced wet gel particles. Further, cost of the production of silica aerogel is mainly due to the precursors6 and therefore, an attempt should be made to replace them with inexpensive sources of silica. Bio-based materials are more preferred in pharmaceutical industry to make new drug delivery devices.6 In this regard, rice husk (RH) is a better replacement for expensive and

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toxic precursor solutions such as TMOS and tetraethylorthosilicate (TEOS) to produce aerogels.13 RH is abundantly available natural-agricultural waste material. It is burnt to produce rice husk ash (RHA) which contains 70-98 wt% silica, which is amorphous and biocompatible14,15 and small quantities of several other elements. Accordingly RH is a good raw material for producing aerogels. There are no data available in the literature on methods to produce silica aerogel microparticles from RHA. The objective of the present work is to develop a simple process to prepare silica aerogel microparticles (SAMs) from RHA for drug delivery using water-in-mineral oil emulsion technique. A low viscosity (1.64 cP) mineral oil replaced vegetable oil used in earlier works. Taguchi design of experiments was used to obtain optimal gelation parameters for the technique. The wet gel particles were prepared at the optimized parameters and dried with scCO2 at one condition: 150 bar and 50 oC. For a commercially viable process, however, optimization of scCO2 drying parameters is important to ensure that the time of drying is minimum without sacrificing the quality of the aerogels.16 The present process is aimed at obviating the shortcomings of the earlier processes such as mechanical separation of the wet gel particles from the vegetable oil and long time for drying of the particles with scCO2. One model drug, ibuprofen, and one essential oil, eugenol, as a food preservative, are studied for their loading in SAMs and subsequent release in appropriate environment. Both of them are loaded from scCO2 phase because of their high solubility in it. 2. Experimental

2.1. Materials Rice husk was obtained from the Department of Energy Science and Engineering, IIT Bombay. Sodium hydroxide (Merck. India), hydrochloric acid (35%, Merck, India), ethanol (99% purity, Brampton, Canada), carbon dioxide of 99.99% purity (Med Gas N Equipments,

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India), odourless kerosene (SDFCL, India), Span 80 (Sigma Aldrich, India), Tween 80 (Sigma Aldrich, India), sodium dodecyl sulphate (TCI, Japan) and Millipore demineralised water were used in all experiments. 2.2. Methods 2.2.1. Sodium silicate solution from RHA RH was cleaned, washed with distilled water, dried and then burnt at 600 oC for 6 hours in an electrical muffle furnace to get grey coloured RHA. A sample of

5 g RHA was mixed

with 150 ml of 1 N NaOH solution and the mixture was refluxed for two hours. The resulting sodium silicate solution was cooled to room temperature and then filtered to remove any undigested matter. The filtrate was transferred to a beaker after which the beaker was wrapped with a ‘parafilm’ and stored in a refrigerator for further use. 2.2.2. Sol-gel-mineral oil-emulsion process for wet gel microparticles Figure 1 shows schematic diagram of one-step sol-gel process for preparation of SAMs. Sodium silicate solution was added drop wise to a mixture of mineral oil (namely kerosene) and dual surfactants (mixture of Span 80 and Tween 80, HLB value of 6.3) under constant stirring. After few minutes of agitation, gelation was started by drop-wise addition of 1 N HCl solution and the pH of the solution was adjusted to 7. Agitation was continued for an hour during which wet gel particles were produced. After agitation was stopped, the mixture of kerosene and the particles was allowed to settle down at room temperature for an hour. When the mixture separated into two layers, the top layer of kerosene was separated from the bottom layer of the wet gel microparticles by decantation. To exchange water in the pores of the particles with ethanol, the wet gel particles were then sequentially treated with increasing concentrations of ethanol/water solutions: 50% for 2 h, 75% for 2 h and twice with 100% for 12 and 24 h. The particles were finally aged with pure ethanol for 24 hours to ensure

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complete replacement of the water. The wet particles were dried with scCO2 to produce SAMs. Drying procedure is described in detail in Section 2.2.4.

Figure 1. Schematic diagram for preparation of SAMs. 2.2.3. Design of experiments for sol-gel/emulsion The properties of the microparticles produced by the sol-gel method using water-in-oil emulsion technique depend on the following parameters: speed of agitation, sol-to-oil ratio and surfactant concentration. These parameters affect shape, textural properties, size and size distribution of the aerogel microparticles. Therefore it is imperative to study the parametric effects and optimize them to obtain microparticles with desirable physical properties. Taguchi design of experiments has been used for this study. This design is a commonly used statistical method for process optimization. It has several advantages over one-factor-at-a-time experiments because it provides more information on parameter interactions and fewer experiments are needed to ascertain the optimal values of the parameters.17 The orthogonal design consisted of three factors (parameters) at three levels each. The fourth column in the L9 array of the Taguchi design was intentionally left blank to estimate the variance and the significance of the results. Table 1 summarizes the different levels for each parameter; these levels were chosen based on our previous work and preliminary set of experiments.13 The response data were analyzed with the Minitab 15 statistical software.

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Table 1. Taguchi orthogonal design factors (parameters) and their levels

#

Factors/Levels

1

2

3

Speed of agitation, rpm

400

800

1200

sol:oil ratio, vol/vol

1:1

1:2

1:3

Surfactant concentration, wt%#

2

5

8

based on weight of the sol solution. The mean particle size was chosen as the response factor for the Taguchi approach to

design the experiments and to optimize the process parameters. The Taguchi analysis was carried out by applying the ‘smaller the better’ signal-to-noise ratio (SN ratio), as shown in equation 1, to obtain parameters that produce small aerogel particles. Details regarding selection criteria of quality characteristic model of the Taguchi analysis can be found elsewhere.17  y2  Smaller the better SN ratio = -10log10   n where y is the response factor and

(1)

is the number of observations

2.2.4. Drying of aerogel microparticles with scCO2 Silica wet gel microparticles prepared under optimal gelation conditions were dried using scCO2 to remove ethanol from the porous network without a phase boundary. Also, traces of kerosene, if present in the wet gel particles after the ethanol-exchange steps, were removed during drying, as kerosene has high solubility in scCO2. Figure 2 shows the experimental apparatus for drying with scCO2. The wet gel particles soaked in pure ethanol (alcogels) were placed at the bottom of a 500-ml extraction vessel. It

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was ensured that the gel particles were completely immersed in ethanol to prevent any shrinkage due to evaporation of ethanol before exposure to scCO2. The extractor was heated to 50 oC; CO2 gas exiting a cylinder was liquefied in a chiller; this liquid turned into gas upon entering the vessel and filled the vessel until the pressure in it reached cylinder pressure; beyond this pressure, a high-pressure plunger pump raised the pressure in the vessel to ~150 bar. The flow rate of the CO2 at the outlet of the vessel was maintained at 2 liter per minute using a rotameter and a wet flow meter. The pressure and the temperature were maintained constant throughout the drying process using an automatic PID control system. After drying the gels, the vessel was slowly depressurized at a constant flow rate (1 liter per min) to atmospheric pressure. The dried gels were characterized by various analytical methods to ascertain their properties.

Figure 2. Apparatus for drying of wet gel particles with supercritical carbon dioxide. 2.3. Characterization 2.3.1. Particle size and size distribution The size and size distribution of silica wet gel microparticles were determined by light

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scattering method using a LS 13 320 Laser diffraction particle size analyzer (Beckman Coulter). All measurements were carried out in ethanol medium with appropriate dilution (810%) at room temperature.

2.3.2. Morphology and textural properties The surface morphology of dried SAMs was studied using Cryo Field Emission Gun Scanning Electron Microscopy (Cryo FEG SEM). The samples were sputtered with gold coating before the SEM analysis. The textural properties of SAMs were analyzed by BET instrument (Micromeritics, ASAP 2020). Nitrogen adsorption-desorption measurements were carried out to measure BET surface area, pore volume and pore diameter. All samples were degassed at 125 oC for 4 hour before analysis. The pore size and pore volume were calculated from the adsorption isotherm using the BJH method.

2.4. Loading of ibuprofen and eugenol Aerogels were loaded with ibuprofen and eugenol from scCO2 medium at 40 oC and 150 bar. 100 mg of the dried SAMs were wrapped in a filter paper and hung at the centre of the vessel. Weighed amounts of ibuprofen and eugenol were placed at the bottom of the vessel to avoid their physical contact with the aerogel particles. The mass of scCO2 in the 500-ml vessel was calculated based on the density of CO2 at 40 oC and 150 bar; this mass was used to calculate the mass ratio of ibuprofen or eugenol to scCO2. The vessel was heated to 40 oC and slowly pressurized to 150 bar. Once the required pressure was attained, the system was kept under static condition for 24 hours to ensure equilibrium distribution of ibuprofen or eugenol between the particles and the scCO2 medium. Then the vessel was depressurized to ambient pressure by venting out CO2 at a constant flow rate of 1 liter per minute. The drug loading of the aerogel particles was calculated as:

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Drug Loading =

mass of drug mass of drug loaded particles

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(2)

Mass measurements were accurate up to 0.1 mg. For this accuracy the error bars are small and they do not affect the conclusions on drug loading. The powder X-ray diffraction (XRD) analysis was carried out on pure ibuprofen, SAMs and ibuprofen-loaded SAMs. The powder XRD patterns were obtained on PANalytical, XPert PROMRD diffractometer using CuKa radiation.

2.5. Release kinetics of ibuprofen and eugenol A known quantity of SAMs loaded with ibuprofen was added to 200 ml of 0.1 N HCl (dissolution medium) at 37 oC taken in a beaker. 1% sodium dodecyl sulphate was added to the HCl solution to enhance the dissolution of ibuprofen. The contents of the beaker were stirred at 100 rpm with a magnetic stirrer to achieve uniform distribution of the released drug in the medium. Samples were withdrawn at pre-determined time intervals and replaced with equal volume of fresh media to ensure a constant dissolution volume. Samples withdrawn were analyzed by UV-Vis spectrophotometer (Shimadzu) for dissolved ibuprofen concentration (at 220 nm wavelength). The release kinetics was duplicated and an average value is reported here. Same procedure was followed for measuring release kinetics of pure ibuprofen. A known quantity of aerogel microparticles loaded with eugenol was accurately weighed in a filter pouch and kept in an open box not affected by ambient air flow. The mass loss of the particles at different times was considered as the quantity of eugenol released as a function of time. Same procedure was followed for measuring release kinetics of pure eugenol.

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3. Results and Discussion

3.1. Taguchi analysis for sol-gel/emulsion process Speed of agitation, sol-to-oil ratio, and surfactant concentration were considered at three levels each to study their effect on the sol-gel process. The SN ratio was calculated for A1A9 experiments (listed in Table 2) to determine the significance of each parameter on the size of aerogel particles. Figure 3 presents plots of the main effects for the SN ratio. Analysis of variance for the SN ratio was used to obtain optimal conditions of all parameters by estimating experimental conditions having minimum variability. The effect of each parameter on the response factor is discussed in detail in the following sections.

Table 2. Taguchi orthogonal array and response factor (mean particle size)

Exp.code

Sol:oil Speed of agitation (rpm) ratio

Surfactant concentration, wt%

Mean particle size (µm)

A1

400

1:1

2.0

123.3

A2

400

1:2

5.0

81.1

A3

400

1:3

8.0

53.8

A4

800

1:1

5.0

65.0

A5

800

1:2

8.0

44.0

A6

800

1:3

2.0

37.9

A7

1200

1:1

8.0

54.0

A8

1200

1:2

2.0

32.9

A9

1200

1:3

5.0

20.1

3.1.1. Effect of speed of agitation Figure 3a shows the main effects plot for speed of agitation. The SN ratio increased with the speed indicating that speed influences the size. This increase indicates that smaller mean size particles were produced at higher speeds of agitation. High shear at these speeds break

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big sol droplets to generate small droplets in the kerosene phase. Agitation is energy intensive; more power is required for producing small sol droplets in the emulsion at high speeds.10,18 Gelation in these droplets produced small wet gel microparticles. The mean particle size varied from 20 µm at 1200 rpm to 123 µm at 400 rpm for A1-A9 experiments (see Supplementary information). The sizes obtained in this work are significantly lower than the reported values10,19 as a mineral oil (kerosene) having much lower viscosity was used in the present work.

Figure 3. Main effects plot for SN ratios. 3.1.2. Effect of sol-to-oil ratio In general, the ratio of sol-to-oil ratio plays a major role in the preparation of microparticles. The viscosity of the continuous and the dispersed phases affect the mean particle size distribution. Figure 3b shows that the mean value of the SN ratios of sol-to-oil ratio and its levels has an influence on the particle size (response factor). Increasing oil volume, while keeping the total volume of sol-oil mixture constant, lowered the viscosity of the mixture because the mineral oil used in this work was less viscous than the sol solution. For the same speed of agitation, therefore, higher energy was delivered to sol-oil mixtures 12


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with higher oil content. Hence smaller droplets of sol were produced at higher oil contents which eventually became smaller gel particles. In earlier works,10,19 larger particles were produced at higher oil contents because the vegetable oil used was more viscous than the sol solution, whereas it was the opposite in the present work.

3.1.3. Effect of surfactant concentration Surfactant or emulsion stabilizer prevents agglomeration of particles and formation of lumps, thus stabilizing the emulsion. The type of emulsion that forms upon addition of surfactant depends on the hydrophilic-lyophilic balance (HLB) of the surfactant. HLB between 4 to 12 and a right combination of emulsifiers is necessary to achieve stable waterin-oil emulsion.20 In this work, a dual surfactant with HLB value of 6.3 was used to stabilize the emulsion by mixing Span 80 (HLB = 4.3) and Tween 80 (HLB = 14.9) in right proportions. Silica gel is highly hydrophilic due to the presence of large number of free and bound hydroxyl groups, therefore Span 80 (a more oil soluble surfactant), is alone not good enough to avoid agglomeration and to stabilize the emulsion. A more water soluble surfactant such as Tween 80 was added to stabilize the emulsion and produce discrete small wet gel particles free from agglomeration. Figure 3c reveals that the effect of surfactant concentration on the mean particle size reduction is negligible for 2 to 8 wt%. It is important, however, to use surfactant to avoid agglomeration of silica gel particles in emulsion. In the absence of surfactant, wet gel particles agglomerated and adhered to the walls of the reactor.

3.1.4. Analysis of Variance Analysis of variance (ANOVA) is a statistical method or mathematical technique to interpret experimental data. ANOVA determines the effect of each factor (parameter here) on the objective function. ANOVA helps select the most appropriate quality characteristic and

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SN ratio from among many alternatives. The various terms involved in the ANOVA Table are sum of squares, degrees of freedom, F value, p value, and percentage of significance. By performing analysis of variance on SN ratio it is possible to find the most significant factor affecting the response factor. Table 3 shows that the speed of agitation is the most dominating factor on the mean particle size of the silica aerogels followed by sol-to-oil ratio; surfactant concentration has the least effect. Figure 3d shows that the effect in the empty column due to residual error is negligible. This error is the difference between the total sum of squares and the sum of squares due to effects of individual parameters. A small residual error of 1.55% (see Table 3) indicates that the effects of all major parameters on the particle size were included in the experiments and analysis.

Table 3. Analysis of variance for SN ratio Source

Degrees of Freedom Sum of Squares F

P

Percent

Speed of agitation

2

93.53

35.84 0.027

55.69

Sol to oil ratio

2

70.05

26.84 0.036

41.71

Surfactant concentration

2

1.75

00.67 0.598

01.04

Residual Error

2

2.61

---

---

01.55

Total

8

167.94

---

---

100

3.1.5. Optimal factor levels The Response Table for SN ratios (see in Supporting Information, Table S3) further confirmed that the speed of agitation is the most significant parameter affecting the mean particle size of SAMs followed by sol-to-oil ratio and surfactant concentration. To prepare SAMs from RHA by the present process, the optimum values of speed, sol-to-oil ratio and surfactant concentration were 1200 rpm, 1:3 and 5 wt%, respectively.

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3.2 Characterization of scCO2 dried SAMs The bulk density of SAMs was calculated based on their mass to volume ratio. A known volume of aerogel microparticles was weighed accurately and ratio of the weight to volume was calculated. The bulk density was found to be ~12.9 kg/m3; the pure silica density was taken as 2236 kg/m3.21 The porosity of the aerogel microparticles was calculated based on the following equation:

ρ  Porosity = 1-  b  ρ   p

(3)

Where, ρ b is the bulk density of aerogel microparticles and ρ p is the density of pure silica. The porosity mainly depends upon the size and shape of the microparticles. In general, irregular particles are more porous compared with spherical particles. The porosity of the produced SAMs calculated by equation 3 was ~99.43 %. This porosity includes voidage between the particles and internal voidage of the particles whose estimations are given below. Studies on N2 adsorption and desorption of SAMs indicated that they were highly porous and had mesoporous structures. The total pore volume was 3.0 cm3/g and the average pore diameter is 17.8 nm as recorded by the BJH adsorption method. The BET specific area was found to be 652 m2/g. which is higher than those reported by Tang and Wang15 and Yunos et al.22 They reported maximum specific surface area for silica aerogels prepared from RHA as 597.7 and 405 m2/g, respectively. Based on the pore volume found by BET, the internal mesoporosity of the particles was calculated to be 87%. The SEM images of SAMs, shown in Figure 4, indicate that they are irregular in shape and their size is in the range of tens of microns. The aerogel microparticles are opaque and porous having puff kind of structure with interconnected internal pore structures.

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Figure 4. SEM image of SAMs prepared at optimal gelation conditions 3.3. Loading of eugenol and ibuprofen from scCO2 medium The loading of eugenol and ibuprofen in SAMs was studied by varying their concentrations in scCO2 at 150 bar and 40 oC. Figure 5 shows that the equilibrium loading of eugenol rises drastically with its concentration in scCO2. The loading of ibuprofen follows a similar trend as eugenol. As high as ~0.87 (g/g) of ibuprofen loading of was achieved in this work, whereas a loading of 0.73 (g/g) was reported by Smirnova et al.23 on aerogel monoliths using scCO2 at 180 bar and 40 oC.

Figure 5. Adsorption isotherms of (■) ibuprofen and (♦) eugenol at 40°C. Drug here means ibuprofen or eugenol.

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It is to be noted that, in the present work, loading was studied at a lower scCO2 pressure of 150 bar. A higher loading of ibuprofen in this work may be attributed to precipitation of ibuprofen in the pores of the aerogel microparticles in addition to the hydrogen bonding between ibuprofen molecules and hydroxyl groups present in the aerogel microparticles.

3.3.1. X-ray diffraction analysis X-ray diffraction (XRD) analysis was carried out for pure ibuprofen, SAMs, physical mixture of aerogels and ibuprofen and ibuprofen-loaded-SAMs. Figure 6 reveals that SAMs are amorphous as no peaks for the crystalline structure were observed; pure ibuprofen exhibits highly crystalline structure with many peaks of high intensity. Physical mixture also shows sharp peaks but lower in intensity than pure ibuprofen. Ibuprofen-loaded -SAMs show even smaller peaks. These peaks indicate that ibuprofen in loaded aerogels is in crystalline form. A small quantity of ibuprofen could have precipitated on the external surface of SAMs and in the pores in crystalline form. It is expected that ibuprofen also adsorbs on aerogels in amorphous form. The fraction of crystalline and amorphous forms of ibuprofen in the loaded aerogels cannot be ascertained by the diffractograms.

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Figure 6. X-ray diffractograms of (a) pure ibuprofen, (b) physical mixing of ibuprofen and SAMs, (c) ibuprofen loaded SAMs, (d) SAMs 3.4. Release kinetics of ibuprofen and eugenol Figure 7 shows release kinetics of ibuprofen from the loaded SAMs and pure ibuprofen (crystalline) at 37 oC. In the first 30 minutes, ~80% of the former was released compared to ~14% release of the latter. A faster release of the former could be attributed to two reasons: first, it is adsorbed in amorphous form; second, the ibuprofen crystallized in the pores of SAMs as small particles with high specific surface area. It is known that the amorphous form of a material dissolves faster than the crystalline form of the same material. Also release medium penetrates into the pores of the hydrophilic SAMs disintegrating them and releasing ibuprofen quickly. The release rate slows down after the initial burst due to a drop in driving force for the release with time.

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Figure 7. Release kinetics of (■) pure ibuprofen and (♦) ibuprofen loaded SAMs. Figure 8 shows the release profiles of pure eugenol and eugenol from the loaded SAMs into ambient air for three different loadings. After a mild to medium burst of eugenol in the beginning, it was released steadily from the SAMs. Almost 100% eugenol was released over a period of 17 days. The release profiles were found to be nearly independent of initial loading of eugenol. Loaded eugenol releases faster than the pure form which could be due to high surface area of aerogels that enhances evaporation. It is to be noted that pure eugenol tends to get oxidized when exposed to air; loading in aerogels reduces this tendency. It is thus validated that the biocompatible SAMs produced from RHA by the improved process developed in this work perform better than those made from RHA by the methods reported earlier. The present method is thus suitable for drug delivery applications.

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Figure 8. Release kinetics of eugenol from loaded SAMs and pure eugenol. (•) pure eugenol, (▲) 19.8 wt%, (♦) 64.09 wt%, and (■) 89.05 wt% 4. Conclusion An improved process has been developed to prepare silica aerogel microparticles (SAMs) from rice husk ash (RHA), an inexpensive source for biocompatible silica, by water-inmineral oil emulsion method. The process is simple and uses mild operating conditions. Taguchi design of experiments was used to optimize the gelation parameters, namely, speed of agitation, sol-to-oil ratio and surfactant concentration. The optimum parameters were found to be 1200 rpm, 1:3 and 5 wt% respectively. This process produced smaller aerogel particles (mean particle size of 20 µm) with improved properties suitable for drug delivery applications. These SAMs were found to have a total porosity of 99.34%, BET specific surface area of 652 m2/g and pore volume of 3.0 cm3/g. SAMs were found to have good affinity for water insoluble drugs adsorbed from scCO2 medium. High loadings of 0.87 g ibuprofen/g of aerogel and 8.133 g eugenol/g of aerogel were obtained. Release experiments revealed that ~80 % of the adsorbed, amorphous ibuprofen was released within half an hour. Further, 100% of adsorbed eugenol was released in a sustained manner over a period of 17

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days. The performance of SAMs produced by the present process validates their suitability for drug delivery applications.

Acknowledgements The authors thank Yogesh Kadam for his help in conducting drying experiments with scCO2 drying experiments.

Supporting Information Compositional analysis of rice husk ash (Table S1), particle size and size distribution of wet gel particles (Table S2) and Response Table for SN ratios (Table S3). This material is available free of charge via Internet at http://pubs.acs.org.

References (1) Anglin, E. J.; Cheng, L.; Freeman, W. R.; Sailor, M. J. Porous Silicon in Drug Delivery Devices and Materials. Adv. Drug Deliv. Rev. 2008, 60, 1266. (2) Smirnova, I.; Mamic, J; and Arlt, W. Adsorption of Drugs on Silica Aerogels. Langmuir

2003, 1920, 8521. (3) Ulker, Z.; Erkey, C. An Emerging Platform for Drug Delivery: Aerogel Based Systems.

J. of Controlled Release 2014. 1770, 51. (4) Dorcheh, S.; Abbasi, M. H. Silica Aerogel; Synthesis, Properties and Characterization. J.

Mater. Process. Technol. 2008, 199, 10. (5) Fricke, J.; Tillotson, T. Aerogels: Production, Characterization, and Applications. Thin

Solid Films 1997, 2971–2, 212. (6) García-González, C. A.; Alnaief, M; Smirnova, I. Polysaccharide-based Aerogels— Promising Biodegradable Carriers for Drug Delivery Systems. Carbohydr. Polym. 2011, 864, 1425. 21



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(7) Bisson, A.; Rigacci, A.; Lecomte, D.; Rodier, E.; Achard, P. Drying of Silica Gels to Obtain Aerogel: Phenomenology and Basic Techniques. Drying Technol. 2003, 21, 593. (8) Comin, L. M.; Temelli, F.; Saldaña, M. D. A. Barley β-glucan aerogels as a Carrier for Flax Oil via Supercritical CO2. J. Food Eng. 2012, 1114, 625. (9) Mehling, T.; Smirnova, I.; Guenther, U.; Neubert, R. H. H. Polysaccharide-based Aerogels as Dug Carriers. J. Non-Cryst. Solids 2009, 35550–51, 2472. (10) Alnaief, M.; Smirnova, I. In Situ Production of Spherical Aerogel Microparticles. J.

Supercrit. Fluids 2011, 553, 1118. (11) Dragosavac, M.; Vladisavljević, G.; Holdich, R.; Stillwell, M. Novel Membrane Emulsification Method of Producing Highly Uniform Silica Particles Using Inexpensive Silica Sources. Prog. Colloid Polym. Sci. 2012, 139, 7. (12) Hong, S. K.; Yoon, M. Y.; Hwang, H. J. Fabrication of Spherical Silica Aerogel Granules from Water Glass by Ambient Pressure Drying. J. Am. Ceram. Soc. 2011, 94, 3198. (13) Kumar, R. S.; Vinjamur, M.; Mukhopadhyay, M. A Simple Process to Prepare Silica Aerogel Microparticles from Rice Husk Ash. Int. J. Chem. Eng.Appl. 2013, 4, 321. (14) Alshatwi, A.A.; Athinarayanan, J.; Periasamy, V.S. Biocompatibility Assessment of Rice Husk-derived Biogenic Silica Nanoparticles for Biomedical Applications. Mater. Sci.

Eng., C 2015, 470, 8. (15) Tang, Q.; Wang, T. Preparation of Silica Aerogel from Rice Hull Ash by Supercritical Carbon Dioxide Drying. J. Supercrit. Fluids 2005, 35, 91. (16) García-González, C. A.; Camino-Rey, M. C.; Alnaief, M.; Zetzl, C.; Smirnova, I. Supercritical Drying of Aerogels Using CO2: Effect of Extraction Time on The End Material Textural Properties. J. Supercrit. Fluids 2012, 660, 297.

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List of Figures Figure Number

Figure captions

Figure 1.

Schematic diagram for preparation of SAMs

Figure 2.

Apparatus for drying of wet gel particles with supercritical carbon dioxide.

Figure 3.

Main effects plot for SN ratios

Figure 4.

SEM image of SAMs prepared at optimal gelation conditions

Figure 5.

Adsorption isotherms of (■) ibuprofen and (♦) eugenol at 40°C. Drug here means ibuprofen or eugenol

Figure 6.

X-ray diffractograms of (a) pure crystalline ibuprofen, (b) physical mixing of ibuprofen and SAMs, (c) ibuprofen loaded SAMs, (d) SAMs

Figure 7.

Release kinetics of (■) pure ibuprofen and (♦) ibuprofen loaded SAMs

Figure 8.

Release kinetics of eugenol from loaded SAMs and pure eugenol. (•) pure eugenol, (▲) 19.8 wt%, (♦) 64.09 wt%, and (■) 89.05 wt%

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Silica Aerogel Microparticles from Rice Husk Ash for Drug Delivery

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