Drug loading with supercritical carbon dioxide deposition on different silica derivatives: Carvedilol study

Journal of Drug Delivery Science and Technology 53 (2019) 101213

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Drug loading with supercritical carbon dioxide deposition on different silica derivatives: Carvedilol study

T

Niyazi Özçelika, Ayşe Bayrakçeken Yurtcana,b,∗ a b

Nanoscience and Nanoengineering Department, Atatürk University, 25240, Erzurum, Turkey Chemical Engineering Department, Atatürk University, 25240, Erzurum, Turkey

A R T I C LE I N FO

A B S T R A C T

Keywords: Spherical silica MCM-41 Carvedilol Supercritical carbon dioxide Drug loading

Supercritical carbon dioxide is a promising method used to load water insouble drugs over different drug carriers. In this study, it is offered as an alternative method to load Carvedilol as a drug over different kinds of silica materials via supercritical carbon dioxide method. Two kinds of silica materials either spherical silica or MCM41 were synthesized for this purpose. The characterization of the silica materials were carried out by using SEM, BET, XRD and FT-IR. Spherical silica materials were obtained by changing the synthesis temperatures as 70, 80 and 90 °C. The diameters of the synthesized silica structures were increased with an increase in the temperature. Among the other spherical silica materials, the best homogeneity was obtained for 70 °C synthesis temperature so it is chosen as drug carrier for spherical silica. BET surface areas of spherical silica and MCM-41 were 345.9 m2/g and 1057.0 m2/g, respectively. Carvedilol, poorly water souble drug, was loaded over spherical silica and MCM-41 and subsequently characterized by XRD, BET, SEM and FT-IR. Carvedilol was loaded over these silica materials. Drug loading over these materials were achieved as 42% and 26% for spherical silica and MCM41, respectively.

1. Introduction After discovering porous silica nanoparticles, they have been studied and used in several areas from sensors, column separation to drug release [1–5]. Different kinds of silica materials including SBA-15, MCM-41 and MCM-48 were used for this purpose. These silica materials were synthesized by using different synthesis methods. SBA-15 is obtained by using amphiphilic triblock copolymer of triblock copolymer (Pluronic P-123) in high acidic medium. It has also two dimensional (2D) hexagonal structure and has sizes between micrometer and submicrometer dependent on particle shape [6]. MCM-48 is synthesized by modified Stober method at room temperature by using triblock copolymer (Pluronic P-127) [6]. Synthesis of MCM-41 is based on the reaction of tetra ethyl ortosilicate or sodium metasilicate as silica source, cetyltrimethylammonium bromide as surfactant and alkaline as catalyst. It has 2D uniform mesopores and its surface area is higher than 700 m2/g and pore diameter differs from 1.6 nm to 10 nm. Superior properties of silica nanoparticles including tunable textural properties such as pore diameter, surface area make them good candidates for drug release [6]. The larger particle diameter is the more drug amount loaded inside the pores of the particles [7,8]. There are some studies including the

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utilization of different silica nanoparticles for drug delivery. In these studies, water insouble drugs including Celecoxib and Carvedilol were used [9,10]. Surface area, pore volume and pore diameter properties of the drug carrier materials are of great interest which will affect the drug loading significantly. One of the most important parameters in drug loading is the pore diameter of the drug carrier material. In order to load drug, pore dimeter/drug molecule diameter should be bigger than 1. If this ratio is greater than 3, full of the surface area can be used and much more drug can be loaded. Apart from pore diameter, surface area and pore volume can also influence the drug loading depending on monolayers or multilayers [11]. Silica-based drug carriers for drug release were developed by various researchers. A summary of these studies are given below. Silica materials with different physical properties or silica-based composites were used in these studies. Such differences in the properties either changed the rate of drug loading or improved the effectiveness of the therapy. In addition, the drug loading rates varied depending on the solvent used in the drug loading medium. Using silica materials not only affect the drug loading but also bioavailability and biocompatibility [6,12]. Until 2001, drug release application of these materials was not investigated. Vallet-Regi et al. was the first one who studied using silica nanoparticles in drug delivery. In this research, they

Corresponding author. Atatürk University, Engineering Faculty, Department of Chemical Engineering, 25240, Erzurum, Turkey. E-mail address: [email protected] (A. Bayrakçeken Yurtcan).

https://doi.org/10.1016/j.jddst.2019.101213 Received 17 April 2019; Received in revised form 27 July 2019; Accepted 9 August 2019 Available online 10 August 2019 1773-2247/ © 2019 Elsevier B.V. All rights reserved.

Journal of Drug Delivery Science and Technology 53 (2019) 101213

N. Özçelik and A. Bayrakçeken Yurtcan

widely used drug to treat hypertansion and cardiovascular disease such as angina pectoris, cardiac arrhythmias, myocardial infarction. Carvedilol has limited bioavailability, so it has to be loaded over suitable drug carriers. In the literature, Carvedilol was loaded over several carrier materials including SBA-16, MCM-41, titanium oxide, hydroxycarbonate apatite. Drug loading percentages changed depending on the corresponding carrier materials as 25%, 25%, 22.8–23.9%, and 22.5–48.7%, respectively [7]. Solubility of Carvedilol in sc-CO2 have changed with an increase in temperature and pressure. Solubility of Carvedilol was investigated in scCO2 environment in the temperature and pressure ranges of 308–338 K and 160–400 bar, respectively. The solubilities of Carvedilol was changed from 1.12 × 10−5 to 5.01 × 10−3 mol of Carvedilol/ (mole of Carvedilol + mole of CO2). All of the results showed that increase in pressure and temperature increased the solubility of Carvedilol [37]. In this study, the textural effects of the synthesized silica materials on drug loading and release for a poorly water soluble drug of Carvedilol under supercritical carbon dioxide conditions were tried to highlighted. For this purpose two different silica materials having different textural properties were synthesized. The amount of Carvedilol loading was more successful than the ones given in the literature. Silica materials and Carvedilol loaded materials were characterized by using SEM, BET, XRD, FT-IR, TGA/DSC. Drug release experiments were performed in SBF medium and investigated via UV measurements.

prepared silica nanoparticles by using different surfactants. After preparing different silica nanoparticles, they loaded Ibuprofen and examined drug release from these nanoparticles [13]. Silica and its several derivatives (rattle-type Fe3O4@SiO2 hollow mesoporous spheres, Lantanite doped MCM-41 and non order silica) were used for drug loading. In these studies, Itraconazole, Ibuprofen, Doxorubicin hydrochloride and Aspirin drug releases were studied [14–18]. Modified silica nanoparticles is also used for drug loading and release. In 2012, Wang et al. initially synthesized MCM-41, modified MCM-41 and finally loaded two different cancer drugs to improve cancer therapy [19]. Silica surfaces modified with polyelectrolytes, N[3(trimethoxysilyl) propyl]aniline and 3-aminopropyltriethoxysilane chemicals were also used for drug loading [20–23]. In 2016, Eren and co-workers synthesized SBA-15 and then modified SBA-15 with boron and (3-aminopropyl)trietoxysilane. After that, Celecoxib drug was loaded in different environments including ethanol, methanol and hexane mediums. Higher amounts of Celecoxib was loaded in hexane medium. This study showed the importance of silica surface modification and drug loading environment [24]. Silica nanoparticles can also be modified by using hydroxyapatite and gold nanoparticles. In literature, silica was covered by hydroxyapatite and gold nanoparticles for near infrared teraphy. High drug loading and phototermal therapy were achieved in this way [25,26]. Water insouble drugs account on 40% of total drugs. Some of these drugs can be summarized as Carvedilol, Celecoxib, Ezetimibe, Fenofibrate, Flurbiprofen, Glibenclamide, Ibuprofen, Indomethacin, Lovastatin, Ketoconazole etc. Solubility of these drugs are poor in water medium but various methods can increase their solubilities. Solubility improvement methods include physical modification, chemical modification and other methods [27]. Physical modifications consist of particle size reduction such as micronization or nanosuspension, altering crystal form like polymorphs or amorphous state, solid dispersion and solid solution [27]. Chemical modifications comprise of alteration of pH, salt formation, complexation and utilization of buffer. Miscellaneous method contains supercritical fluid process, usage of supportive material such as surfactant, solubilizers, cosolvency and hydrotrophy [27]. Among the other methods supercritical fluid process seems to be a promising one. The supercritical fluid is obtained when the corresponding fluid is compressed over its critical pressure and heated over its critical temperature. There are various supercritical fluids such as water, sulphur dioxide, carbon dioxide etc. One of the most widely used fluid is supercritical carbon dioxide [28] due to its low critical temperature (304.25 K) and critical pressure (7.38 MPa). In supecritical case, the fluid behaves in between a liquid and a gas. For instance, diffusion coefficient of sc-CO2 is relatively akin to gas and density of sc-CO2 is relatively akin to liquid. Sc-CO2 also thought to be inert and did not left any residue because of not using any organic solvent and it is nonflammable [28]. Sc-CO2 can be a good solvent to dissolve pharmaceutical compounds. Sc-CO2 medium is a good alternative for water insouble drugs and good outcomes were obtained for dissolving these compounds such as Ibuprofen, Fenofibrate, Nifedipene, Griseofulvin, Celecoxib and Carvedilol [27,29]. There are several studies in the literature that use nanoparticles and supercritical carbon dioxide as drug carrier and solvent system, respectively. In these studies, Ibuprofen, Fenofibrate, Asarone, Ketoprofen, and Aspirin as drugs, silica and polymeric nanoparticles as drug carriers were used. A brief summary of all these studies are given below [30–33]. lbuprofen and Fenofibrate were especially used in these studies. In one of these studies, Ibuprofen was loaded on silica microspheres with a loading of 38.6% measured by termogravimetric analysis [34]. Fenofibrate was loaded with different percentages by using sc-CO2 medium under different conditions [35]. ln addition to this, several cancer drugs such as 5-Fluorouracil and Paclitaxel were loaded on polymeric nanoparticles via sc-CO2 [36]. Carvedilol, a poorly water souble (0.583 mg/ml) drug [10], is a

2. Experimental 2.1. Materials Carvedilol, Tetra Etyhl Orto Silicate (TEOS), ammonium hydroxide solution (NH4OH), Cetyl trimethylammonium bromide (CTAB), urea, isopropanol, cyclohexane were purchased from Sigma Aldrich. All chemical was used without any purification. 2.2. Synthesis of 2-D MCM-41 MCM-41 was synthesized according to the procedure reported by Hu et al. [9]. Shortly, 0.1 g of CTAB was dissolved in 27 ml of water and 20.5 ml of NH4OH. 1 ml of TEOS was added to the solution at 333 K when the solution became clear and mixed under these conditions for 3 h. This process led to white slurry. It was then filtered, washed with distilled water and dried at ambient temperature. Finally, the precipitate was calcined at 823 K for 4 h [10]. 2.3. Synthesis of spherical silica particles 0.6 g urea and 1 g CTAB was dissolved in 30 ml water. 4 ml of isopropanol was dispersed in 30 ml of cyclohexane and then the second solution was added to the first one. After that, 2.7 ml of TEOS was mixed under vigorous conditions for 30 min. It was then transferred to the oven kept at 343 K for 16 h in order to obtain silica particles. After this, the obtained solution was centrifuged and washed with acetone and water for several times. The precipitate was washed with 4 ml of concenrated HCI and 50 ml of ethanol for several times. Finally, the precipitate was calcined at 823 K for 6 h [38]. These spherical silica particles were named as SS70 regarding the synthesis temperature. Other synthesized silica particles were followed the same synthesis procedure except the synthesis temperature. Temperatures in other synthesis were 353 K and 363 K in which the samples were labeled as SS80 and SS90, respectively. 2.4. Drug loading with supercritical carbon dioxide Required amounts of Carvedilol and corresponding silica materials were weighted and put into a sealed custom manufactured stainless 2

Journal of Drug Delivery Science and Technology 53 (2019) 101213

N. Özçelik and A. Bayrakçeken Yurtcan

reactor having 54 ml volume in order to load Carvedilol on silica materials via supercritical carbon dioxide medium [39]. After providing the targeted temperature and pressure (343 K and 24.1 MPa) the reactor was filled with carbon dioxide and let the drug loading for 24 h time period. Reactor was then depressurized for 10 min and Carvedilol loaded silica materials were obtained. 2.5. Characterization of silica and carvedilol loaded silica materials In order to obtain information about the morphological, topographic structure of the synthesized silica materials Scanning Electron Microscope (SEM) was used (Quanta FEI 200). The surface of the samples were sputtered with gold in order to provide electrical conductivity before SEM imaging. Structural properties of silica materials including surface area and pore size distribution was evaluated by nitrogen adsorption/desorption isotherms with Micromeritics 3 Flex at 77 K. Prior to the measurements, all the samples were degassed for 16 h at 343 K. Crystal structures of the silica materials, Carvedilol and Carvedilol loaded silica materials were determined by using X-ray Diffraction instrument (Rigaku Miniflex). Functional groups of the synthesized silica materials, Carvedilol and Carvedilol loaded silica materials were examined with Fourier Transform Infrared (FTIR) Spectroscopy in between 400 and 4000 cm−1. These measurements were conducted at ambient temperature with PerkinElmer instrument. Samples were mechanically mixed with KBr and pelletized with the weight ratio of KBr:sample as 95:5. Thermal properties of the prepared samples were obtained by termogravimetric analysis (TGA) and differential scanning calorimetry (DSC) (Netzsch). TGA measurements help to provide the information about the loading of Carvedilol over silica materials. Before the measurements, all the samples were kept in desiccator to prevent moisturing. 20 mg of the powder samples put in alumina pans were used for the experiments. The instrument provides the simultaneous measurements of TGA and DSC. All measurements were conducted from ambient temperature to 700 °C under nitrogen atmosphere with a heating rate of 10 °C/min.

Fig. 1. SEM images of a) SS70 b) SS80 c) SS90 d) MCM-41.

Experiments were conducted by PerkinElmer UV visible spectrometer instrument. 3. Results and discussion 3.1. Synthesis and characterization of silica materials Silica materials having different physical properties were significant to determine the effect of structural parameters on drug loading, so two kinds of silica materials were synthesized. One of them was spherical silica particles which were synthesized via sol-gel method with hydrolysis in basic medium. Other type of silica was MCM-41 which was synthesized via modified Stober method. SEM images of spherical silica particles and MCM-41 are given in Fig. 1. Fig. 1 (a), (b) and (c) shows the spherical silica particles synthesized at 70, 80 and 90 °C, respectively. As can be seen from figure that all the silica particles showed spherical structure but particles synthesized at 70 °C showed more homogeneity than the others. An increase in synthesis temperature resulted in an increase in particle size and also decrease the homogeneity of the particles. SEM image of MCM-41 given in Fig. 1 (d) showed irregular shape and high diameter with heterogenous distribution. Contrary to MCM-41 having approximately 870 nm diameter, spherical silica particles showed average diameters nearly 250 nm, 300 nm and 400 nm for SS70, SS80 and SS90, respectively. Surface area, pore volume and pore diameter properties of the silica structures were calculated by using nitrogen adsorption/desorption isotherms via BET analysis. Nitrogen adsorption/desorption isotherms and also pore size distributions of the spherical silica and MCM-41 materials are given in Fig. 2. Nitrogen adsorption/desorption isotherms shown in Fig. 2 (a)–(c) fitted to Type II isotherms for spherical silica materials in terms of IUPAC. MCM-41 material showed a hysteresis in between 0.4 and 0.9 relative pressure fitted to Type IV isotherm with distinct capillary condensation steps and H1 hysteresis loops [41,42]. Furthermore, MCM-41 has also high BET surface area which is 1057 m2/g that can contribute to host more drug in pore channel or surface. MCM-41 has pore size of 2–50 nm that can be attributed to the mesoporous structure of MCM-41 [43]. Structural properties of the silica materials obtained from BET analysis are summarized in Table 2.

2.6. Drug release Before passing through the drug loading experiments fresh simulated body fluid (SBF) was prepared just before the experiments in order to prevent any coagulation related with waiting time. All the chemicals given in Table 1 were dissolved in 700 ml deionized water at 37 °C and completed to 1000 ml with deionized water. pH of the solution was maintained at 7.40 [40]. In order to detect released drug amount, silica/Carvedilol material was left into the 50 ml SBF and temperature was fixed to 310.15 K and within 30 min, 5 ml aliquot was taken from the mixture and then 5 ml of fresh SBF was added in order to keep the volume of the mixture constant. Aliquot that was taken from the mixture was passed through a 0.45 membrane filter to eliminate any particles which can come from the medium. UV–visible measurements were used to determine Carvedilol amount at 240 nm. Table 1 Chemicals used for SBF preparation. Chemical

Quantity

NaCl NaHCO3 KCl K2HPO4.3H2O MgCl2.6H2O 1M-HCl CaCl2 Na2SO4 C4H11NO3 HCl

8.035 g 0.355 g 0.225 g 0.188 g 0.311 g 39 ml 0.292 g 0.072 g 6.118 g 1–5 ml

3

Journal of Drug Delivery Science and Technology 53 (2019) 101213

N. Özçelik and A. Bayrakçeken Yurtcan

Fig. 2. Nitrogen adsorption/desorption isotherms and pore size distributions of a) SS70 b) SS80 c) SS90 d) MCM-41.

4

Journal of Drug Delivery Science and Technology 53 (2019) 101213

N. Özçelik and A. Bayrakçeken Yurtcan

asymmetric stretching vibration of siloxane (SiOSi), respectively, which corresponds to the movement of bridging oxygen atom to Si–Si lines in opposite direction to their Si neighbors [45]. FTIR results for Carvedilol showed the characteristic peaks as follows; 3346 cm−1 (N–H, stretching), 2996 cm−1 (C–H, strethcing, Sp2), 2925 cm−1 (C–H, stretching, Sp3), 1599 cm−1 (N–H bending) and 1106 cm−1 (C–O, strethcing) [46,47].

Table 2 Structural properties of silica materials obtained by nitrogen adsorption/desorption isotherms. Material

Multiple point BET surface area (m2/g)

BJH Pore volume(cm3/ g)

DR micro pore volume (cm3/ g)

BJH Pore diameter (nm)

SS70 SS80 SS90 MCM-41

345.9 341.4 281.6 1057.0

0.377 0.328 0.298 1.092

0.133 0.132 0.112 0.393

3.40 3.35 3.83 2.75

3.2. Characterization of Carvedilol loaded silica materials XRD patterns of Carvedilol loaded SS70 and MCM-41 silica materials are given in Fig. 4 (a). Although, Carvedilol showed crystalline structure no peaks related to the crystal structure were observed after drug loading. In the literature, similar trends were observed for the drugs like Carbamazepine and Indomethacin loaded on the silica particles which can be attributed to the geometric confinement or space confinement of the Carvedilol into the pores of silica particles [48–50]. FTIR spectra are shown in Fig. 4 (b) and (c) for SS70/Carvedilol and MCM-41/Carvedilol. Bands located at around 804 cm−1 and 1085 cm−1 confirm the existence of silica. Bands located nearly in between 1500 cm−1 and 2000 cm−1 indicate the existence of Carvedilol inside the pores of silica materials. In addition to these results, there is no obvious chemical interaction between Carvedilol and silica particles. Spherical silica having the highest BET surface area which was synthesized at 70 °C was selected for drug loading experiments. TGA is a common method that is used to quantify the total amount of drug loading on the particles. TGA results of plain silica materials and also Carvedilol loaded silica materials are given in Fig. 5. Carvedilol loading over the silica materials were determined by comparing the TGAs of the

As seen from Table 2, synthesis temperature significantly affect the structural properties of the spherical silica materials. BET surface areas, pore volumes and also micropore volumes of the spherical silica particles decreased with an increase in the synthesis temperature which can be attributed to the collapse of the pores. MCM-41 has the highest surface area and the lowest pore diameter when compared to the spherical silica particles. The crystal structures of Carvedilol, spherical silica particles as well as MCM-41 were also investigated by XRD analysis (Fig. 3 (a)). XRD patterns showed that all silica materials either spherical or MCM-41 are in amorphous state but Carvedilol showed a crystalline form with the indicative peaks mostly located in between 5 and 30° [44]. FT-IR analysis was also conducted to determine the functional groups on the synthesized silica materials which were then compared with Carvedilol as given in Fig. 3 (b) and (c). FTIR results for spherical silica and MCM-41 materials clearly showed the functional groups related with silica structure with the bands located at 804 cm−1 and 1085 cm−1 which represent the asymmetric vibration band of SiOH and

Fig. 3. a) XRD patterns of SS70, SS80, SS90, MCM-41 and Carvedilol, FT-IR spectra of b) SS70, SS80 and SS90 c) MCM-41 and Carvedilol. 5

Journal of Drug Delivery Science and Technology 53 (2019) 101213

N. Özçelik and A. Bayrakçeken Yurtcan

Fig. 4. a) XRD patterns of Carvedilol, SS70/Carvedilol and MCM-41/Carvedilol, FT-IR spectra of b) SS70/Carvedilol c) MCM-41/Carvedilol.

plain and drug loaded materials. TGA curves of the un-loaded silica materials either spherical silica or MCM-41 showed almost horizontal trend after 5% weight loss. This small weight loss could be due to the physically adsorbed water. As shown in Fig. 5, decomposition range of Carvedilol is between 300 °C and 700 °C. After examing all the TGA curves, the percentages of drug loadings were determined nearly as 42 and 26% for spherical silica and MCM-41 materials, respectively. It was recognized that sc-CO2 deposition method is a promising alternative for Carvedilol loading on silica materials when these results were compared with the solvent impregnation method. Although, MCM-41 showed higher BET surface area, micropore volume to total pore volume of two silica particles were similar. The difference in the Carvedilol loading on spherical silica or MCM-41 at the same conditions can be attributed to the change in the pore diameter with respect to

Table 3 Carvedilol loadings on different silica materials. Material

Method

SBET

Pore Volume

Avarage Pore Diameter

Drug loading (%)

Reference

SBA-16 MCM-41 SS70 MCM-41

Sol-gel Sol-gel Sol-gel Sol-gel

540.5 996.2 345.9 1057

0.344 0.704 0.377 1.092

4.3 3.9 3.40 2.75

25.00 25.00 42.00 26.00

[10] [10] This work This work

different silica materials. In literature, Carvedilol was loaded on several materials and textural properties of these materials and drug loading percentages are represented in Table 3. It can be said that sc-CO2 can load Carvedilol over silica materials more efficiently especially for

Fig. 5. TGA curves of a) SS70/Carvedilol b) MCM-41/Carvedilol. 6

Journal of Drug Delivery Science and Technology 53 (2019) 101213

N. Özçelik and A. Bayrakçeken Yurtcan

Fig. 6. DSC plots of Carvedilol and a) SS70 and SS70/Carvedilol b) MCM-41 and MCM-41/Carvedilol. Fig. 7. Carvedilol release from a) SS70/Carvedilol b) MCM-41/Carvedilol.

spherical silica structures. This result also showed that the structure of the silica is very important during the drug loading. DSC measurements are taken in order to recognize the interaction between Carvedilol and silica materials. After examining Fig. 6, it was seen that Carvedilol gave a sharp endothermic peak at nearly 125 °C corresponding to its melting point which confirms the crystalline nature of it which was confirmed by XRD result. However, silica materials did not reveal any peak related with the crystalline form. Carvedilol loaded silica materials were also showed a similar trend as silica materials with non-crystalline nature. This behavior can be attributed to the geometric confinement of Carvedilol into the pores of silica particles as confirmed by XRD result. Drug release experiments were performed in SBF medium at pH = 7. Carvedilol release amounts with respect to time are given in Fig. 7. Drug release can be affected by both surface area and pore arrangement. As surface area increases, drug release rate can increase but this trend have a limit until the linearization of release rate. In addition, pore arrangement is crucial factor for drug release [51]. On the other hand, drug release can be depended upon pore size, pore geometry and connection between the pores [11,52,53]. Similar trend was also obtained for foam like mesoporous silica and SBA-15 structures. In addition, fast drug release could be due to the expanding of pore size of the carrier. Under these explanations, fast drug release from the structures synthesized in our study can be based on the similar effects [10]. Released drug amount from MCM-41 composite was nearly 35% within 1 h indicating a burst release which can be due to the loading of

Carvedilol on the surface of MCM-41. Silica has hydrophilic nature, silica materials can be wetted, this water can surround the drug molecule and this may help better dissolution of Carvedilol. Contrary to MCM-41, SS70 showed a lower drug release depending on the change in structural properties. 4. Conlusions In summary, sc-CO2 was used as an efficient drug loading medium for poorly water soluble Carvedilol drug. Different silica structures either spherical or MCM-41 were synthesized and used as drug carriers. Spherical silica synthesis is achieved by changing the temperature of the reaction environment which caused different textural properties such as particle diameter, BET surface area, pore volume and avarage pore diameter. High surface area MCM-41 was also synthesized. Carvedilol was then successfully loaded on these silica materials via scCO2 under 343 K and 24.1 MPa. It was realized that pore diameter is an important parameter as well as BET surface area. The drug loading percentages of SS70 and MCM-41 materials were compared and SS70 material having higher average pore diameter and smaller BET surface area showed higher drug loading than MCM-41 having smaller average pore diameter and higher BET surface area. Our results showed that Carvedilol loading can be controlled by changing the structural properties of the silica materials and using sc-CO2 as drug loading environment. 7

Journal of Drug Delivery Science and Technology 53 (2019) 101213

N. Özçelik and A. Bayrakçeken Yurtcan

Conflicts of interest [24]

The authors declare no conflicts of interest associated with this publication.

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Acknowledgments [26]

The authors gratefully acknowledged the financial support from the Scientific and Technological Research Council of Turkey (TÜBİTAK) through grant number 214Z272.

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Appendix A. Supplementary data [29]

Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jddst.2019.101213.

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