Optimization of Drug loading in Modified Nano-zeolites using response surface Methodology by Box–Behnken Design

Shaghayegh Rahmani¹, Farzaaneh Zaaeri², Hamid Akbari Javar²

¹RCKA (Rezvan Chemistry Kharazmi Art) Company, Tehran, Iran

²Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences,

P.O. Box 14155–6451, Tehran 1417614411, Iran.

*Corresponding Author E-mail: akbarijo@tums.ac.ir

ABSTRACT:

Nano-zeolite NaA and cancrinite were synthesized from natural iranian clinoptilolite and Nano-zeolite sodalite was synthesized from volcanic glass perlite as silica sources. Sodium aluminate was used as aluminium source. The synthesized Nano-zeolites were characterized about structure and morphology. To improve drug loading capacity of the carrier, all the synthesized Nano-zeolites were modified with Cetyl trimethyl ammonium bromide. Response surface methodology by employing a 3-factor, 3-level Box–Behnken design was used to optimize three parameters, i.e. the type of zeolites, pH, and time for adsorption of Diclofenac sodium. Characterization methods confirmed the structure of Nano-zeolites. Drug concentrations were investigated at l_max of 275nm by Ultra Violet-Visible spectrophotometer. The Optimum conditions for drug loading were obtained pH=4, time for adsorption of 120 min and cancrinite as the best modified Nano-zeolite. In-vitro release studies were performed at optimum condition of adsorption, at simulated pH and temperature of in Vivo condition. Results show that the release of drug is increased with increasing in pH and time. Therefore, drug release will be increased when the nanoparticles move down the gastrointestinal tract from the stomach to the intestine. A desirable controlled release for drug and an operative carrier for oral drug delivery were introduced. Applying clinoptilolite and perlite as silica sources is cost-effective and available. Using response surface methodology (RSM) by employing a 3-factor, 3-level Box–Behnken design (BBD) is an effective tool for optimization of the adsorption of diclofenac sodium (DS) onto modified nanozeolites as drug carriers. Synthesized carrier can control releasing of the drug in body and enhance therapeutic efficacy of drug.

KEYWORDS: Nano-zeolite, cancrinite, Diclofenac Sodium, Drug loading, Box–Behnken design.

INTRODUCTION:

A desirable carrier for drug delivery purpose must be inactive, biocompatible, safe, efficient to achieve high drug loading, stable from random release, simple to be administrated, and easy to be prepared and sterilized. Drug delivery systems (DDSs) are designed to improve the pharmacological and therapeutic properties of drugs. The goal of many of the original controlled-release systems was to achieve a delivery profile that would yield a high blood level of the drug over a long period of time. By using traditional systems for drug delivery, the plasma level of the drug increases after each administration and decreases until the next administration¹.

Nano-carriers with optimized physicochemical and biological properties are taken up by cells more easily than larger free drug molecules as well as they protect drugs from damage and decrease side effects by delivery of drugs to target sites, therefore they can be successfully used as delivery tools for bioactive compounds².Liposomes, polymeric nanoparticles, mesoporous silica and magnetic nanoparticles have been tested as nano-carriers for drug delivery usage³.

Several toxicological studies proved that zeolites such as natural clinoptilolite are nontoxic and safe materials for use in human and veterinary medicine⁴.Zeolites are microporous crystalline aluminosilicates that contain alkaline metal ions and water molecules. They are based on a three-dimensional framework of SiO₄ and AlO₄ tetrahedral that results in an extended uniform network of channels and pores⁵. Zeolites have been widely applied in industry as catalysts, adsorbents, detergent makers, and ion exchangers based on their unique properties to absorb large amounts of molecules both in the gas and in liquid phases and act as molecular sieves ^6–
10.

Diclofenac Sodium (DS) (Fig. 5a), a potent non-steroidal anti-inflammatory drug with pronounced analgesic properties, is used in the long-term treatment of rheumatoid arthritis and osteoarthritis¹¹. Topical formulations of DS including traditional medications such as creams, gels, transdermal products, and novel drug delivery systems of organogel and liposomal gel have been developed for local pain reduction^12,13, but oral forms of application are more common; how ever they have many limitations mostly frequent gastrointestinal adverse effects. DS has weak acidic properties and its solubility depends on the pH of the medium. It is slightly soluble in water, very slightly soluble in phosphate buffer at pH 6.8 and practically insoluble in gastric pH condition. Poor water solubility often leads to significant problems in producing formulations, bioavailability, and effective use of the drugs. Mixing and blending with hydrotropic agents such as PEG and urea, co-solvents and water soluble solutes increase the solubility of poorly water-soluble drugs in the aqueous solution which may give synergistic enhancement effect on solubility of such drugs. Co-processing with two or more excipients also provides a synergy of functionality improvement as well as masking the undesirable properties of poorly soluble drugs^14,15. Pellet formulations made by extrusion-spheronization technique provide a reduction in the dosage regimen and gastrointestinal irritation, minimize the dose dumping effect, control the drug release and increase the absorption of the active ingredient¹⁶. Modified-release dosage forms for oral administration show more effective therapeutic result than conventional or immediate-release preparations via controlling the release, and absorption of therapeutic agent from gastrointestinal tract¹⁷. Sustained release matrix tablets of DS made by natural polymers such as Xanthan gum or sodium alginate have been able to increase therapeutic efficacy, reduce frequency of administration, and improve patient compliance¹⁸. Oral sustained release formulations of DS have also decreased the effect of extensive first pass metabolism by keeping it away from being over released in systemic circulation¹⁹. Due to short biological half-life of 1–2 h and associated gastro-intestinal adverse effects such as ulceration, DS is considered as an ideal candidate for controlled drug delivery in order to achieve improved therapeutic efficacy and patient compliance²⁰.

The goal of the present study was to statistically determine the optimum condition of DS loading. Among statistical experimental designs for optimization of the process variables, response surface methodology (RSM) is used when a few significant factors are involved in optimization²¹. Among all the RSM designs, Box Behnken Design (BBD) requires fewer runs in a 3- factor experimental design^22,23. Based on the literature, there is no report on BBD optimization for loading of drugs into the synthetic Nano-zeolites as a carrier for drug delivery.

MATERIALS AND METHODS:

Natural clinoptilolite and perlite as Si sources were purchased from Afrazand company. The source of clinoptilolite and perlite was from Semnan and Meyaneh, Iran, respectively. Sodium aluminate as Al source was purchased from Prolab BDH. Diclofenac sodium was obtained from Pharma Chemie Co. Sodium dihydrogen phosphate and Cetyl trimethyl ammonium bromide (CTAB) were analytical grade, from Fluka (Munich, Germany) and disodium hydrogen phosphate from Merck (Germany).

Instruments:

X-ray diffraction (XRD) spectra were recorded by Bruker AXS D8 diffractometer with Cu Kα radiation (λ ¼ 1.5418 Å). Size distribution of Nano-zeolites was determined by scanning electron microscope (SEM). The FT-IR spectra (4000– 400cm⁻¹) of the Nano-zeolites were recorded using an FT-IR spectrometer (Tensor 27-Bruker). Ultra Violet-Visible (UV-Vis) spectrophotometer (Cambridge, UK) was used for determination of concentrations of the drug.

Synthesis of Nano-zeolites:

Nano-zeolite NaA:

A solution of clinoptilolite, sodium hydroxide and water with 1:5:50 mass ratios were mixed in a polypropylene bottle. The mixture was stirred for 1 hour at 90°C. Then, the mixture was filtered and the filtrate was used to synthesize Nano-zeolite A. Hereafter, the filtrate solution is called solution A.

To prepare the aluminum solution from sodium aluminate, sodium hydroxide, sodium aluminate and water with 1: 1.5: 7.8 mass ratios were mixed and heated to make a clear solution that called solution B. Then, solution A was added to solution B, and they were mixed together. The mixture was heated at 90°C for 2 hours in polypropylene bottle in the hydrothermal condition²⁴. The product was filtered, washed, dried and characterized by XRD, SEM and FT-IR techniques. Chemical composition of the clinoptilolite was determined by X-ray fluorescence (XRF) and it includes: 68% w/w SiO₂,10.1% Al₂O₃, 1.8% Na₂O, 1.4% K₂O, 0.9% Fe₂O₃,0.6% CaO, 17.2% L.O.I (loss on ignition).

Nano-zeolite Sodalite:

For the synthesis of Nano-zeolite, 9.8g of perlite was dissolved in 100ml alkaline solution of NaOH 0.215 M (solution A). The mixture was stirred for 4 hours at 100°C, filtered and the filtrate was used to synthesize Nano-zeolite. 0.768g sodium aluminate was added to 15ml distilled water which contained 0.26 g NaOH (solution B). Then, solution A was added to solution B which was vigorously shaking. The mixture was heated at 170°C for 18 hours in stainless steel reactor. Chemical composition of perlite was determined by XRF and it includes: 79.79% w/w SiO₂, 10.66% Al₂O₃, 2.46% Na₂O, 4.67% K₂O, 0.06% MnO, 0.67% Fe₂O₃, 0.20% MgO, 0.01% P₂O₅, 0.04% SO₃, 1.34% CaO, 0.10% TiO₂, 1.31% L.O.I.

Nano-zeolite Cancrinite:

The starting material (clinoptilolite) reacts with NaOH solution 3mol/L, with a ratio (w/v) of solid to liquid 1:20. The product was heated at 160^oC for 48 hours in an 80ml high pressure/high-temperature stainless steel reactor. After hydrothermal treatment, the reactor was cooled to room temperature; synthesized products were filtered, washed with distilled water and dried at 120^oC for 6 hours. The solid products were characterized by XRD, FT-IR, and SEM.

Modification of Nano-zeolites:

Since Nano-zeolites have negative charge, they usually have low affinity to anions and, represent little adsorption of organic substances in aqueous solution. To make changes on the surface properties, modification of the surface by organic surfactants is widely used²⁵. Adsorption ability of modified Nano-zeolites was already proven for DS.

To prepare the modified zeolites, 2g of each zeolite (Nano-zeolite NaA, sodalite, and cancrinite) was added to 50mL aqueous solution of the cationic surfactant (hexadecyl trimethyl ammonium bromide) at the concentration of 10mmol/L in a polyethylene bottle. The samples were stirred for 24 h at room temperature. The suspensions were centrifuged at 10000rpm for 15 min. Finally, samples were washed with excess amounts of water until no foam was formed by shaking. The prepared modified zeolites were air-dried for 72 h²⁶.

Drug loading:

Tests determining adsorption of DS by synthesized Nano-zeolites were carried out in batch experiments at room temperature. A stock solution of the drug in the concentration of 100mg/L in 3 phosphate buffer solutions at pH 4, 5, 6 were prepared. Note that, the adsorption of the drug was favored at pH< pH_ZPC (pH at the potential of zero charges²⁷. The pH= 4 is under pH_ZPC and 6 is above pH_ZPCfor each zeolite. 200mg of each modified zeolites (Nano-zeolite NaA, sodalite, and cancrinite) were soaked with 25ml of each 3 buffer drug solution under continuous stirring at 250rpm at room temperature. According to BBD after 20, 60 and 120 min the samples were centrifuged 15 min at 10000rpm. Supernatants were examined for determination of the drug concentrations by UV-Vis spectrophotometer²⁸.

The drug concentrations in the aqueous phase were determined at 275 nm and the amount of the drug uptaken was calculated from the difference between the initial and final concentration in the aqueous supernatant after the equilibrium. The amount of drug adsorbed onto modified zeolites, q_t (mg/g) at time (t) was calculated using Equation (1):

q_t = (C₀ – C_T) V / M Eq. (1)

Where C_o (mg/L) is the initial adsorbate concentration, V(L) is the volume of the drug solution in the flask, C_T (mg/L) is the drug concentration after time t and M (g) is the mass of dry adsorbent that was used^29,
30.

This study investigates and optimizes the adsorption of diclofenac sodium (DS) onto modified Nano-zeolites as carriers of the drug, using response surface methodology by employing a 3-factor, 3-level BBD with statgraphics Centurion XVI software. Table 1 shows the three selected variables and the experimental BBD levels used in this study for adsorption of DS as a response.

Table 1 Experimental design levels of chosen independent variables

Factor	Level
Factor	Low (−1)	Central (0)	High (1)
Type of zeolite (X₁)	Nano-zeolite Sodalite	Nano-zeolite NaA	Nano-zeolite Cancrinite
pH (X₂)	4	5	6
Time(min) (X₃)	20	60	120

In-vitro drug release:

In-vitro release studies were performed at optimum conditions adsorption which was predicted by BBD, at pH =4 for 120 min with modified Nano-zeolite cancrinite in simulated body pH and temperature conditions^31,32. Buffered solutions based on different pH in stomach (pH=1.2), intestine (pH=6.8), and blood (pH=7.4) were used as release media. The temperature was adjusted at 37 °C. For DS loading into the Nano-zeolite, 1g of modified Nano-zeolite cancrinite was soaked at pH=4 for 120 min, at room temperature, under continuous stirring in 100 ml of DS solution (100 ppm). Then, the solution was filtrated and the solid was air-dried for 24 h. After that, 200mg of DS loaded modified Nano-zeolite cancrinite as nanocarrier was immersed in 20mL of each buffered solution with magnetic stirring. Samples were taken after 2, 4 and 6 hours, subsequently centrifuged for 15 min at 10000 rpm. Supernatants were determined about concentrations of drug by UV-Vis spectrophotometer³³.

RESULTS AND DISCUSSION:

FT-IR spectra:

FT-IR spectra of the synthesized Nano-zeolites are exhibited in Figure 1A a, b and c. The original peaks are at 1250– 920cm⁻¹for internal tetrahedral, 1150–1050 cm⁻¹for pore opening vibrations, and 650–500cm⁻¹for double ring that is characteristic in the Nano-zeolites³⁴.

The XRD spectra of the synthesized Nano-zeolites are shown in Figure 1B a, b and c. According to standard spectra of zeolite framework types and the special peaks for any intended zeolite, each synthesized Nano-zeolite is equivalent with the indicated structure³⁵. Figure 1Ba shows XRD pattern of the obtained NaA Nano-zeolite. Main peaks are appeared at 2 θ degrees of 7, 10, 12, 16, 22, 24, 27, 30 and 34. Figure 1Bb shows XRD pattern of the obtained Nano-zeolite sodalite. Main peaks are appeared at 2 θ degrees of 14, 20, 22, 24, 28, 32, 35, 38 and 43. Figure 1Bc shows XRD pattern of the obtained cancrinite Nano-zeolite. Main peaks are appeared at 2 θ degrees of 14, 19, 25, 28, 33, 35, 37, 40 and 43.

The SEM results of the particles are shown in Figure 1C a, b and c. Figure 1Ca shows uniform particle morphology of Nano-zeolite NaA as well as small particle size in the range of 44-92 nm. Particles have the cubic structures of SiO₄ and AlO₄⁻tetrahedral. Figure 1C b and c shows the morphology of synthesized Nano-zeolites sodalite and cancrinite respectively. For Nano-zeolite sodalite, small particle size in the range of 30-81 nm and for Nano-zeolite cancrinite in the range of 46-95 nm is seen.

Fig. 1 Results of FTIR, XRD and SEM analyses: FT-IR spectra of Nano-zeolite NaA (Aa), Nano-zeolite sodalite (Ab) and Nano-zeolite cancrinite (Ac). XRD patterns of Nano-zeolite NaA (Ba), Nano-zeolite sodalite (Bb) and Nano-zeolite cancrinite (Bc). SEM images of Nano-zeolite NaA (Ca), Nano-zeolite sodalite (Cb) and Nano-zeolite cancrinite (Cc).

Box- Behnken design:

Response surface methodology was used in this study to determine the conditions for the adsorption of the drug onto modified zeolites as drug's carriers. The experiments were based on BBD to study the combined effects of three independent variables (initial pH of the drug solution, time and the types of modified zeolites). The design matrix of sorption variables in coded units is given in table 2 along with the predicted and the experimental values of response (q).

Table 2. Correlation between the experimental (observed) and the predicted responses

Run	X₁	X₂	X₃	q^a exp	q^apre
1	0	-1	-1	20.015	20.220
2	1	0	1	24.985	25.060
3	-1	1	0	17.215	16.939
4	0	-1	1	23.950	23.590
5	0	0	0	20.625	20.625
6	0	0	0	20.625	20.625
7	0	0	0	20.625	20.625
8	-1	-1	0	17.625	17.494
9	-1	0	-1	16.400	16.325
10	1	1	0	21.800	21.930
11	1	-1	0	23.750	24.075
12	1	0	-1	21.100	21.218
13	0	1	-1	18.950	19.300
14	0	1	1	22.075	21.869
15	-1	0	1	17.950	18.413

q^aexp = experimental (observed) responses.

q^apre = predicted responses.

Analyzing the measured responses with the mentioned software, the fit summary of the output indicates that the quadratic model is statistically significant for the present adsorbate-adsorbent system. The correlation between the experimental (observed) and the predicted responses are presented in Figure 2. The data points of this plot lie reasonably close to a straight line and the good correlation between the experimental (observed) and predicted (by the model) values confirms the quality of this model.

Fig. 2 Scatter diagram of predicted response versus experimental (observed) response for DS adsorption onto modified Nano-zeolites

Also, the statistical significance of the ratio of mean square variation due to regression and mean square residual error were tested using the analysis of variance (ANOVA) ³⁶. According to the analysis of variance (table 3), the F values indicate that the variation in the response can be clarified by the regression. The associated P-value is used to estimate whether F is large enough to indicate the statistical significance or not. If P-value is lower than 0.05, it indicates that the model is statistically significant ³⁷.

Table 3 Analysis of variance (ANOVA) table of BBD

Source of variation	Sum of square	Df ^a	Mean square	F-ratio^b	P-value^c
X₁: type of zeolite	66.384	1	66.384	334.95	0.0000
X₂: pH	3.51125	1	3.51125	17.72	0.0084
X₃: time	17.6864	1	17.6864	89.24	0.0002
X₁X₁	2.12217	1	2.12217	10.71	0.0221
X₁X₂	0.5929	1	0.5929	2.99	0.1443
X₁X₃	0.752556	1	0.752556	3.80	0.1089
X₂X₂	0.196386	1	0.196386	0.99	0.3652
X₂X₃	0.164025	1	0.164025	0.83	0.4047
X₃X₃	0.567013	1	0.567013	2.86	0.1515
Lack of fit^d	2.40483	1	0.469311	1.18	0.2983
Residual	26.8192	13	2.06301
Pure error	24.4144	12	2.03453
Total (Corr)	03.2032	14	-
R²= 0.9893 Standard error= 0.445187

^a Degrees of freedom.

^b Test for comparing model variance with residual (error) variance.

^c Probability of seeing the observed F-value if the null hypothesis is true.

^dThe variation of the data around the fitted model.

By fitting multiple regression analysis on the design matrix according table 3, the following second-order polynomial equation (2) in coded form was created:

q=20.625+2.880X₁-0.662X₂+1.486X₃-0.758X₁²Eq. (2)

As seen in Equation 2, X₁ and X₃have positive and X₂ has negative effect. By increasing the time of mixing and level type of zeolite, the response was increased, but by the increase in pH, the response was decreased.

Figure 3 a, b and c shows the 3D response surfaces of the relationship between pH, time and the types of modified Nano-zeolites, and their effect on the response (adsorption of DS). Figure 3a shows that at a lower level of pH, the adsorption of DS was increased with an increase in the level of types of Nano-zeolites. Figure 3b indicates that at a higher level of types of Nano-zeolites, response, was increased with an increase in time and with a decrease in the level of pH, the adsorption of DS, was increased, with an increase in time (Fig. 3c).

Fig. 3 The effect of independent variables for DS adsorption (response, q) onto modified Nano-zeolites: type of zeolite and pH (a), type of zeolite and time (b), pH and time (c)

Table 3 shows that the linear and quadratic effects of variables were significant (P-value is lower than 0.05). It means that there was a linear relationship between the main effects of initial pH of drug, time, and the types of modified zeolites, and the quadratic relationship with these factors, while there was no significant interaction and lack-of-fit (P-value more than 0.05). The non-significant lack-of fit (more than 0.05) was good for data fitness and showed that the model is trusty for the present study. Therefore, the analysis shows that the form of the model chosen to explain the relationship between the factors and the response was correct³⁸.

The optimized parameters for DS sorption obtained from the statistical software are listed in table 4. Also, confirmatory in-vitro release studies were performed at the optimum condition which was predicted by BBD and the results were shown as actual experimental values in table 4. The results in the case of expected and confirmatory experiments were in good agreement with each other at the optimum condition and the values of q (responses) were observed to have an error of 2.38%.

Table 4 Optimum and confirmative values of the process parameters for maximum efficiency

Process parameters	Optimized parameter (predicted value)	Confirmation experiments (actual value)
q: amount of drug (mg/g)	26.539	25.908
X₁: type of zeolite	nanocancrinite	nanocancrinite
X₂: pH	4	4
X₃: time (min)	120	120

The result shows that with a decrease in the level of pH, the adsorption of DS increased. The possible mechanisms of the DS sorption can be explained on the basis of the zero point charge of the adsorbent (in this study pH_ZPC~ 5). Adsorption of cations is favored at pH > pH_ZPC, while the adsorption of anions is favored at pH<pH_ZPC. At a pH above the zero point charge, the Nano-zeolite cancrinite surface became negatively charged, which repelled the negatively charged DS (anionic drug). The maximum adsorption at pH=4 may be due to the development of a positive charge at the surface of Nano-zeolite cancrinite which helps the anionic drug to be adsorbed on the sorbent ³⁹. To clarify the possible mechanisms of the DS sorption by Nano-zeolite cancrinite we have taken into consideration the physico-chemical properties with the chemical structure of the adsorbate molecule as well as the nature of the porous structure ⁴⁰. The primary porous structure of cancrinite has been well-studied, and primary pores of two types were sized as 5.9 ˚A × 5.9 ˚ A ⁴¹. In our study, the size of DS molecules was modeled by ISIS/Draw software. The diameter and thickness of DS molecules were sized as 5.9 ˚A × 5.9 ˚A × 3.7 A˚. Therefore, DS molecule diffusion into the primary porous structure of the cancrinite seems to be possible.

Drug release studies:

In order to investigate the potential of using prepared Nano-zeolites as drug carriers, their release behavior was evaluated in three different buffered solutions with pH=1.2, 6.8 and 7.4 at 37 °C. In-vitro release profiles were shown in Figure 4. Results express that the release of drug is increased with increasing the pH value. Hence, the release is increased by moving of nanoparticles from the stomach to the intestine.

Fig. 4 Diclofenac release profiles for drug loaded modified Nano-zeolite cancrinite in different pH values (1.2, 6.8 and 7.4) at 37 °C

According to Figure 5b, in acidic condition (stomach), the balance is actuated towards the form of protonated DS that is the insoluble form of this drug, therefore in acidic solution the amount of DS is reduced.

Fig. 5 Structural formula of diclofenac sodium (a) and schematic diagram for dissociation of DS in aqueous solution (b)

The following figure shows schematic steps of the synthesis of nano-zeolite carrier and loading of Diclofenac sodium by adsorption mechanism.

CONCLUSION:

Our study displayed that clinoptilolite is a suitable Si source for preparing of Nano-zeolite NaA and cancrinite while perlite is a suitable and cost-effective source of Si for preparing of Nano-zeolite sodalite. Synthesis methods are fast and easy. Adsorption of Diclofenac sodium on the surface of modified Nano-zeolites was successful. This study optimized the adsorption of DS onto modified zeolites as carriers for the drug, using response surface methodology by employing a 3-factor, 3-level of BBD. Preparation of nanoparticles was performed at optimum conditions at pH of 4 for 120 min with modified Nano-zeolite cancrinite in simulated pH and temperature of in Vivo condition. The study on the zeolites that was done, demonstrated that Nano-zeolites can be used effectively as a carrier in drug delivery applications. This carrier can reduce toxicity and improve the therapeutic effect of the drug as well as control release of drug in the body.

ACKNOWLEDGMENT:

This study was supported by a grant from RCKA (Rezvan Chemistry Kharazmi Art) Company.

CONFLICT OF INTEREST:

Shaghayegh Rahmani has financial interest related to this study.

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Received on 12.11.2019 Modified on 23.11.2019

Asian J. Pharm. Res. 2020; 10(2):55-61.

DOI: 10.5958/2231-5691.2020.00011.8