Synthesis and characterization of oral drug delivery, a pH – sensitive silver nanocomposite based on sodium alginate extracted from Sargassum asperifolium collected from Jazan coasts, KSA

The pH-sensitive nanocomposite composed of sodium alginate/ Pectin/ Tannic acid – silver SA/Pec/TA-Ag was prepared using microwave irradiation and employed as a carrier for Propranolol drug. Physico-chemical characteristics of the prepared systems using Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Field Emission Scanning Electron Microscope (FESEM), High-Resolution Transmission Electron Microscope (HRTEM), Dynamic light Scattering instrument (DLS), and Energy Dispersive X-Ray Analysis (EDX). The percentage drug release was 96% at pH 7.4 within 420 min. The drug release data was fitted into different kinetic models included zero order, First order, Higuchi and Ritger-Peppas model. The release mechanism is non-Fickian character where it controlled by diffusion and relaxation of polymer chains. It can be concluded that SA/Pec/TA-Ag nanocomposite is candidate for the oral drug carrier specific for intestinal system and has stability against gastric fluid.


Introduction
Smart hydrogels are hydrophilic polymeric three-dimensional systems that have physically or synthetically cross-inked polymer. They quickly swell and contract because of natural changes, for example, pH, temperature, magnetic or electric field because of the presence of certain functional groups along the polymeric chain [1]. Imaginative medication conveyance advances in view of insightful hydrogels have extraordinary benefit [2,3]. The pH-responsive hydrogels are considered as an appealing for the controlled release of medications because of their pH responsively moves in various locales of the body in both typical and pathological conditions [4]. 3 Biopolymers hydrogels provide great applications in pharmaceutical field due to nonpoisonous quality, high biocompatibility and biodegradability [5]. Sodium alginate (SA) is a characteristic polysaccharide of a purified carbohydrate extracted from brown seaweeds by utilizing dilute alkali [6]. It is a polyanionic natural linear copolymers of (1→4) α-Lguluronic acid (G) and (1→4) β-D-mannuronic acid (M) units it has already been widely used in a variety of biomedical applications [7]. Pectin (Pec) is natural polysaccharide found in berries, apples and other fruit. It is linear chains of α-(1-4)-linked D-galacturonic acid [8]. Tannic acid (TA) is plant polyphenol contains five pyrogallol and five catechol groups that provide multiple bonding sites with diverse interactions [9]. For this reason, it is applied on tissue engineering as a crosslinking reagent [10].
The microwave irradiation is considered a beneficial methodology for hydrogel synthesis by utilizing a mix of polymeric reactants [11]. It has high temperatures heating process for attack the solution in a short time and restricted the side reactions [12]. Nanoparticles (NP) has been extensively studied particularly noble metals because of their novel functions and exceptional properties [13]. Silver NPs are non-harmful and environmentally eco-friendly [14]. Among different noble metal NPs, silver shows extraordinary consideration due to their prevalent antibacterial properties [15]. They have high partiality toward sulfur or phosphorus containing proteins inside or outside bacterial cell layers actuating auxiliary changes, which influences bacterial cell feasibility [16,17].
Herein, the investigation of different properties of inorganic nanomaterials incorporated biopolymer hydrogels are not uncommon, however the readiness of sodium alginate/pectin/tannic acid biopolymer hydrogel consolidated with silver nanoparticle as a drug carrier is new in the literature. In this study, a pH-responsive hydrogel of SA/Pec/TA-Ag nanocomposite was synthesized using microwave irradiation to act as a drug carrier Tannic acid here has a dual impact it acts as a crosslinker and as a reducing agent for Ag ions 4 more over it rich in carboxylic acid groups. The nanocomposite was characterized by FTIR, XRD, FESEM, HRTEM and DLS and its pH-responsive swelling and controlled drug releasing properties were investigated.
It was collected from Jazan coasts, KSA. The alga was washed in distilled water, dried over night at 40-45ºC in an oven. The dry weights were gained after drying overnight at 105°C.

Extraction and Purification of sodium alginate
The samples (10 g) were suspended in 2% CaCl2 for 2 h, washed with deionized water [18]. Alginate was extracted by addition of an aqueous solution of Na2CO3 1 M and 0.5 g of EDTA and the pH of the suspension adjusted to pH 11 for 48 h. This was then filtered through muslin cloth. Sodium alginate was purified according to the method of Gomez et al., [19]. Aqueous solution of sodium alginate was directly precipitated, under stirring, by 5 addition of ethanol until reaching a proportion 1:1 in volume, respectively. Thus, the insoluble polymer was separated and then exhaustively washed with acetone by sox let for 100 h. Finally, the biopolymer was dried at room temperature under vacuum until constant mass.

The swelling measurements
The clean, dried, weighed sample was soaked in bi-distilled water or buffer solution at room temperature for different time intervals. The sample was removed and the excess water on the surface was removed by blotting quickly with filter paper and reweighed. The swelling percent was calculated as follows: are the masses of dry and swelled sample, respectively.

In vitro Propranolol drug release studies
In vitro release studies of the drug were carried out by suspending of 100 mg of the drug loaded sample in 10 mL of the buffer-releasing medium (pH 2.1 and 7.4) at 37 o C. The amount of drug released was assayed by using spectrophotometer. All the studies were carried out in triplicate and the total uncertainly range was 2-4%.

Drug release kinetic
To contemplate the Propranolol release mechanism from SA/Pec/TA hydrogel, and SA/Pec/TA-Ag nanocomposite, different kinetic models were considered to fit the experimental data. [20,21].
Zero-order drug release kinetic model: The First order drug release kinetic model: The Higuchi Square root model: Ritger-Peppas model: Where Mt and Minf are the drug release at time t and equilibrium, respectively. k0 is zero-order release constant. k1 is first-order release constant. kH is Higuchi release constant.
k is the rate constant. n is the release exponent,

Results and Discussion
Physico    Ag, respectively [24]. The presence of these peaks confirmed the presence of Ag in the nanocomposite.  prompts improving the free spacing in the hydrogel whatever enhancing the swelling capacity.

Ag nanocomposite
It tends to be additionally seen that the swelling percent of SA/Pec/TA-Ag nanocomposite is higher than Sa/Pec/TA hydrogel. The nearness of Ag nanoparticles bring down crosslinking density in network structure and all the more free spaces that manage the opportunity for the rapid diffusion of water molecules into the matrix as well as enhanced the swelling behavior.

Propranolol drug Loading
Impact of Propranolol initial concentration on the drug stacking of SA/Pec/TA hydrogel, and SA/Pec/TA-Ag nanocomposite was learned at various pHs (1.5, 5.2, and 7.4) and results are appeared in Fig. 6. It tends to be noticed that the drug loaded amount expanded with expanding the underlying drug focus because of the free volume accessible destinations on the framework allow the diffusion of more drug molecules. It must be noticed that the -COOH groups on SA, Pec, and TA of the backbone are responsive to pH changes.
So the drug loading at pH 7.4 was higher than at pH 1.  In vitro Propranolol drug release studies 12 The cumulative percentage of Propranolol release from SA/Pec/TA hydrogel, and SA/Pec/TA-Ag nanocomposite as a function of time at 37 o C is shown in Fig. 7. It is clear that the drug release at pH 7.4 was much higher than that at pH 2.1. The drug release from SA/Pec/TA-Ag nanocomposite was 46% at pH 2.1 and was 96% at pH 7.4 within 420 min.
Drug releasing behavior relies upon the properties and behavior of matrix stacked this drug.
The release of water dissolvable drug from a system happens simply after permeation of water into the matrix which swells and dissolves the drug, trailed by diffusion of the drug [26]. In other meaning, the external medium penetrated into the matrix by the osmotic pressure as well as the drug dissolved and released into the medium.  Kinetics of releasing 13 The learning of release kinetics is fundamental for the efficient utilize of the drug carriers. With the end goal to contemplate drug release kinetic mechanism, the information obtained by in vitro release experimental data at pH 7.4 was fitted with different observational kinetic models. These models included zero order, first order, Higuchi Square root, and Ritger-Peppas models. They came about information is appeared in Fig. 8 and the examined information is abridged in Table 1. By contrasting the correlation coefficients, the R 2 of the Higuchi model is higher than the zero -order and first-order models. This implies the kinetic of Propranolol releasing from SA/Pec/TA hydrogel and SA/Pec/TA-Ag nanocomposite pursues the Higuchi Square root model.

Conclusions
A nanocomposite based on Sodium alginate /Pectin/ tannic acid incorporated with silver nanoparticles is synthesized by green method using microwave irradiation. It was found that, the presence of Ag in the nanocomposite confirmed with XRD. The surface morphology totally changed from smooth to a gruff surface by joining of Ag nanoparticles inside the polymeric structure. HRTEM examination explained that an arbitrary dispersion of Ag nanoparticles which showed up as an about circular dark of various particle size average between 21.91 -34.04 nm by DLS. The swelling studies attained that a higher swelling response of the hydrogel and the nanocomposite attributed to the high hydrophilicity of polymeric chains. pH-sensitivity was confirmed due to the presence of -COOH group and limited swelling obtained at pH 1.5 and higher swelling was done at pH 7.4. The drug release curve demonstrated that the presence of Ag nanoparticles in the network structure of the nanocomposite enhanced the drug release that was 96% at pH 7.4 within 420 min. The drug release was fitted well by Higuchi model and the mechanism found to be non-Fickian anomalous transport. It can be concluded that SA/Pec/TA-Ag nanocomposite is candidate for the oral drug carrier specific for intestinal system.