Polysaccharide based superabsorbent hydrogel from Mimosa pudica: swelling–deswelling and drug release

Abstract

Herein, we have evaluated a polysaccharide, glucuronoxylan, isolated from the seeds of Mimosa pudica (MP) for its water holding capacity, pH and salt responsive swelling–deswelling behavior, and sustained drug release. The MP hydrogel (MPH) has shown a high water retention capacity. The MPH exhibited negligible swelling at pH 1.2 while high swelling was observed at pH 6.8, 7.4 and in deionized water which follows second order kinetics, whereas the MPH deswells in NaCl and KCl solutions and ethanol. The presence of interconnected macropores with an average diameter of 62.94 μm was revealed using scanning electron microscopy (SEM) of a swollen then freeze dried sample of MPH. Furthermore, the MPH was explored as a sustained release material for a tablet formulation of diclofenac sodium. The drug release mechanism from the MPH containing tablet formulation was found to be super case-II transport. The results have indicated that the MPH could be a potential candidate for sustained release formulations.

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1 Introduction

Mimosa pudica L. (Syn: chui mui, lajwanti, touch me not, sensitive plant, shy plant and sleepy plant) is a sensitive diffuse shrub of the family Mimosaceae widely distributed in Tanzania, Brazil, America, Asia, Nigeria and many Pacific islands. The plant is rich in alkaloids, sterols, terpenoids, tannins and flavonoids^1–4 and has been used to treat ulcers, piles, respiratory troubles, constipation, malaria, snake bites, depression, smallpox, dysentery, pyrexia, inflammation, etc.^5–8 MP seeds extrude a hydrogel when soaked in water. The main component of this extruded hydrogel is glucuronoxylan (GX) which is composed of D-xylose and D-glucuronic acid.^9,10

Hydrogels are water swellable polymers that retain large amounts of water depending upon the presence of hydrophilic functional groups (–OH, –COOH, –CONH₂), network flexibility, crosslinking levels and the porosity of the polymer.¹¹ Hydrogels are appropriate candidates for applications in cosmetics, agriculture, pharmaceuticals, horticulture, engineering, sustained drug release, enzyme immobilization and disposable diapers because of their bioavailability, biocompatibility, biodegradability and non-toxic nature.^12–15 These smart materials are responsive to temperature, pH, ionic strength and electric fields.^16–20 The pH sensitivity of these intelligent hydrogels makes them suitable for the controlled and sustained release of drugs.^21–23 These properties are due to the presence of the aforesaid functional groups that are present on the polymer chain.^24,25

Herein, we introduced a novel superabsorbent, superporous and smart polysaccharide, GX, isolated from MP seeds for sustained drug release. The present study was focused on the water holding capacity, swelling kinetics, pH and salt responsive properties of the MPH. We also reported on the swelling–deswelling (on–off switching) properties of the MPH against different stimuli. These attributes of the MPH had not yet been discovered. We also used simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) to evaluate the MPH as a sustained release material for diclofenac sodium formulations. We were also interested to see the morphology of the MPH, its tablet formulation and the swollen then freeze dried MPH.

2 Materials and methods

2.1 Materials

Seeds of MP were purchased from a local market. Potassium dihydrogen phosphate, n-hexane, ethanol, potassium chloride, sodium chloride and hydrochloric acid were purchased from Riedel-de-Haën, Germany. Analytical grade sodium hydroxide (Merck) was standardized with oxalic acid before further use. Deionized water was used throughout the study. SGF and SIF were prepared according to the method given in the United States Pharmacopeia (2010).²⁶ Polyvinylpyrrolidone (PVP K30), magnesium stearate, diclofenac sodium (DS) and microcrystalline cellulose were purchased from Fluka.

2.2 Methods

2.2.1 Isolation of hydrogel. Clean seeds of MP were soaked in water for 12 h and then warmed at 50 °C for 30 min. The seeds extruded a hydrogel which was separated using a cotton cloth. The extracted hydrogel was washed with n-hexane to remove lipophilic substances and then dried at 50 °C in a vacuum oven. The dried hydrogel was kept in a vacuum desiccator after being ground and passed through a 60 mesh sieve.

2.2.2 Flow-ability parameters of MPH.
2.2.2.1 Angle of repose. The angle of repose was determined using a fixed funnel method in order to study the flowability of the hydrogel.²⁷ The powdered hydrogel was allowed to fall through the fixed funnel onto graph paper. The angle of repose (θ) was determined by calculating the height (h) and radius (r) of the heap using the following eqn (1);
2.2.2.2 Bulk and tap density. The volume of the hydrogel (V_b) was recorded by placing the hydrogel (1.0 g) in a graduated cylinder. The tapped volume (V_t) was noted after tapping the graduated cylinder 100 times. Bulk density (D_b) and tap density (D_t) were calculated using eqn (2) and (3) respectively;
2.2.2.3 Hausner ratio and Carr’s index. The Hausner ratio and Carr’s index are frequently employed to study the flow properties of hydrogels.²⁷ The Hausner ratio is the ratio of tap density to bulk density given by eqn (4);whereas Carr’s index is the percentage ratio representing the arrangement of particles and is calculated using eqn (5);where D_b and D_t are the bulk and tap densities, respectively.
2.2.2.4 Moisture content. A Sartorius Thermo Control Infrared Dryer (YTC 01L, Germany) was used to determine the moisture content of the MPH. The weight of the hydrogel was recorded before and after drying at 105 °C for 1 h.

2.2.3 Centrifuge retention capacity. The water retention capacity or centrifuge retention capacity was assessed by centrifuging a freshly prepared solution of the hydrogel (1% w/w) in deionized water at 4500 rpm for 30 min at room temperature. The supernatant was decanted and the weight of the wet sediment paste was noted. This wet sediment paste was completely dried at 70 °C and the weight of the dried mass was noted. The water retention capacity is the ratio of wet sediment mass to dried mass.^28,29

2.2.4 Swelling capacity. The tapped volume of the powdered hydrogel (1.0 g) was measured by placing it in a graduated cylinder and tapping it 100 times. Then the hydrogel was mixed with deionized water thoroughly and the volume was adjusted to 100 cm³. The sediment volume of the swollen hydrogel was observed after letting it stand for 24 h and the swelling capacity (v/v) was calculated as a ratio of the swollen to tapped volume.

2.2.5 Dynamic and equilibrium swelling. To measure the pH dependent swelling, the MPH (0.5 g) was packed in cellophane bags and soaked in hydrochloric acid buffer (pH 1.2), phosphate buffers (pH 6.8 and 7.4) and deionized water for 24 h. The pH values were calibrated precisely using a pH meter (JENWAY 3510, UK). The weight of the swollen hydrogel was noted after regular intervals for 24 h and the swelling capacity (g g⁻¹) in each case was calculated as;where W_t is the weight of the swollen hydrogel with the wet cellophane bag, W₀ is the weight of the dry hydrogel and W_c is the weight of the wet cellophane bag.

The normalized degree of swelling, Q_t, is the ratio of media (buffers of pH 1.2, 6.8, 7.4 and deionized water) penetrated into the gel to the initial weight of the hydrogel at time t and can be calculated using eqn (8).

where W_s is the weight of the swollen hydrogel at time t, W_d is the weight of the dried hydrogel at time t = 0 and W_t is the weight of water penetrated into the hydrogel at time t.

The normalized equilibrium degree of swelling (Q_e) is the ratio of media penetrated into the hydrogel at t_∞ to the weight of the dried hydrogel at t = 0. It can be determined using eqn (9);

where W_∞ is the weight of the swollen hydrogel at time t_∞ when the swelling remains constant, W_d is the weight of the dried hydrogel at t = 0 and W_e is the amount of water absorbed by the hydrogel at t_∞.

2.2.6 Swelling kinetics. The normalized degree of swelling (Q_t) and the normalized equilibrium degree of the swelling (Q_e) values can be used to find the kinetic order of swelling.³⁰ For second order kinetics, eqn (10) was used.³¹

The plot between on the y-axis and t on the x-axis should be a linear line with a slope of and an intercept of .

2.2.7 Swelling in salt solutions. The swelling behavior of the MPH was recorded by soaking cellophane bags containing the hydrogel in 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5 and 2.0 M solutions of NaCl and KCl at 25 °C and the equilibrium swelling was recorded after 24 h using eqn (7).

2.2.8 Swelling–deswelling behavior in response to external stimuli. A gravimetric method was employed to monitor the swelling and deswelling of the MPH. The hydrogel was allowed to swell in deionized water for 1 h and was then immersed in pure ethanol to measure its weight as a function of a deswelling time of 1 h.

In another experiment, the swelling–deswelling behaviour was studied using buffer solutions (pH 7.4 and 1.2). The hydrogel was kept in pH 7.4 buffer for 1 h to determine its swelling and then allowed to deswell for 1 h in buffer solution (pH 1.2). Similarly, swelling–deswelling was studied in water and aqueous NaCl solution (0.9%). These on–off experiments were performed four times. All experiments were repeated three times and the mean values were reported.

2.2.9 Scanning electron microscopy (SEM). The surface morphology and internal structure of the MPH were analyzed using a scanning electron microscope (FEI Nova, NanoSEM 450) operating at 10 kV, equipped with a low energy Everhart–Thornley detector (ETD) using secondary electrons. For this purpose, the dried hydrogel (0.1 g) was mixed with deionized water (2 mL) using a mixer mill and then sonicated (30 min) to remove air bubbles. The swollen MPH was frozen at −20 °C and then freeze-dried. Afterwards, transverse and vertical cross-sections of the hydrogel were obtained using a sharp blade to reveal its porous nature. The obtained cross-sections were mounted on an aluminum stub with silver paint and further coated with gold using a sputter coater (Denton, Desk V HP) operating at 40 mA for 30 s under vacuum and analyzed using SEM. SEM analysis was also recorded for the air dried MPH and the surface of the tablets.

2.2.10 Preparation of tablets. The wet granulation method was employed to prepare tablets of DS. For this purpose, MPH, DS and microcrystalline cellulose were passed through a 40-mesh sieve, thoroughly homogenized using a pestle and mortar, and granulated with a solution of polyvinylpyrrolidone (PVP K30) in isopropyl alcohol. The resultant wet mass was passed through a 20-mesh sieve after drying at 40 °C and then lubricated with magnesium stearate. A rotary tablet press fitted with an 11 mm punch was used to prepare the tablet (350 ± 5 mg). The manufactured tablets were studied for their hardness, thickness and friability which were found to be in the range of 6–7 kg cm⁻², 4.15–4.19 mm and 0.82–0.96%, respectively. Later on, the tablets were evaluated to study the effect of the MPH on the release behavior of DS. Table 1 shows the composition of different formulations of the MPH.

Table 1 Composition of oral tablet formulations of DS based on MPH

Formulation composition (mg per tablet)	F1	F2	F3
MPH	100	150	200
DS	100	100	100
Microcrystalline cellulose	125	75	25
PVP K30	20	20	20
Magnesium stearate	5	5	5

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2.2.11 In vitro drug release study. The effect of the MPH on the release of DS tablets was studied in SGF (900 mL, pH 1.2) for 2 h using a USP Dissolution Apparatus II. The tablets were then shifted to SIF (900 mL, pH 7.4) and the release behaviour was studied for 14 h at 37 °C and 50 rpm. After fixed time intervals, from SGF and SIF media, samples (5 mL) were withdrawn, filtered, diluted (if necessary) and analyzed using a UV/Vis spectrophotometer (Shimadzu, Japan) at 276 nm. Fresh SGF or SIF was added to make up the withdrawn volume. The experiment was performed in triplicate and the cumulative percentages of drug release were expressed as mean values. The results of the MPH containing formulations were compared with a commercial formulation of DS (Voltral® SR 100 tablet).

The drug release from water-swellable polymers is mainly controlled by a diffusion mechanism which can be better explained by the power law equation (eqn (11))³² as follows;

where M_t/M_∞ is the fraction of the drug released in time t, k_p is the power law constant and n is the diffusion exponent.

The drug release mechanism corresponds to the value of this diffusion coefficient (n). The drug release from the hydrogel follows a Fickian diffusion mechanism if the value of n is 0.45. The mechanism will be non-Fickian diffusion (controlled by both swelling and diffusion) when the value of n ranges between 0.45 and 0.89. If the value of n is greater than 0.89, the mechanism is super case-II transport in which the rate remains constant for longer periods of time and shows an exponential increase in drug release at the end due to matrix erosion.^33,34

3 Results and discussion

3.1 Physical properties of MPH

Carr’s index, the Hausner ratio and the angle of repose indicated that powder MPH had poor flow-ability. The physical properties of the hydrogel are given in Table 2.

Table 2 Physical properties of MPH

Physical properties	MPH
Moisture content (%)	12 ± 0.20
Average particle size (μm)	≈259
Angle of repose	46 ± 0.25
Bulk density (g cm^−3)	0.2 ± 0.01
Tapped density (g cm^−3)	0.363 ± 0.01
Carr’s index (%)	44.1 ± 1.50
Hausner ratio	1.82 ± 0.06
Swelling capacity on 24 h (g g^−1)	55.42 ± 2.00
Centrifuge retention capacity (%)	87.28 ± 1.11

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3.2 pH responsive swelling of MPH

The swelling behavior of the MPH was evaluated in buffers of pH 1.2, 6.8 and 7.4, mimicking the pH values of the stomach, small intestine and large intestine, respectively (Fig. 1a). It was observed that the swelling in the acidic buffer (pH 1.2) is markedly less than the swelling in the basic buffers and deionized water. This is mainly due to the protonation of carboxylic acid groups present on the polymer chains. An increase in pH increases the ionization of the carboxylic acid groups resulting in anion–anion repulsion hence enhancing the swelling in alkaline media. Moreover, the swelling capacity was found to be low in basic buffers as compared to deionized water. This low swelling capacity in alkaline media may be due to a charge screening effect of excess cations that put a stop to anion–anion repulsion due to the shielding of carboxylate anions. The literature reveals that many other hydrogels show a pH dependent water absorbency.^35,36 Therefore, based on the pH dependent swelling of the MPH, it can be said that the MPH is a potential candidate for drug release formulations.

Fig. 1 (a) Swelling capacity and (b) swelling kinetics of MPH in deionized water and different buffers.

3.3 Swelling kinetics

The swelling of the hydrogel is controlled by the diffusion of the solvent and the relaxation of the polymer chain as explained by a 2^nd order kinetic model.³⁷ Kinetic studies were performed on the swelling data of the MPH obtained in water and at pH 6.8 and 7.4. Fig. 1b shows a plot of t/Q_t vs. t which is linear with a slope of 1/Q_e and an intercept of 1/kQ_e² indicating a best fit of the swelling data to a 2^nd order kinetic model.

3.4 Saline responsive swelling of MPH

The swelling of hydrogels mainly depends upon the salt concentration and charge on the ions along with the nature of the polymer, i.e., the presence of hydrophilic groups and the elasticity of the network, etc.³⁸ It was found that the swelling capacity of the MPH decreases abruptly with an increase in the concentration of salts (Fig. 2). This reduced swelling in salt solutions might be due to the charge screening effect of excess cations resulting in non-perfect anion–anion electrostatic repulsion.³⁹ Smaller ions with a greater charge density interact more strongly with carboxylate anions and decrease anion–anion repulsion.⁴⁰ Therefore, the MPH deswells more in NaCl solution as compared to KCl solution.

Fig. 2 Swelling behaviour of the MPH in different concentrations of NaCl and KCl.

3.5 Swelling–deswelling kinetics in response to external stimuli

3.5.1 Swelling–deswelling behaviour of MPH in water and ethanol. The hydrogel deswells in ethanol rapidly because ethanol has less affinity with the hydrogel than water (Fig. 3). The MPH forms fewer hydrogen bonds with ethanol because it has a lower polarity and dielectric constant (24.55) than water (80.40). This lesser dielectric constant decreases the ionization of ionizable groups and the swelling capacity of the polymer. The hydrogel swells again in water quickly due to the swift wash out of ethanol molecules and the formation of extensive hydrogen bonds with water.

Fig. 3 Swelling–deswelling behaviour of MPH in deionized water (filled circles) and ethanol (empty circles).

3.5.2 Swelling–deswelling behaviour of MPH in acidic and basic buffers. Evaluation of the swelling–deswelling behaviour of the hydrogel was carried out using different buffers. The MPH swells in a basic buffer (pH 7.4) whereas it deswells in an acidic buffer (pH 1.2). This swelling–deswelling behaviour of the MPH was noted four times and the results of these on–off experiments are shown in Fig. 4. The mechanism of the swelling–deswelling behaviour of the MPH has already been discussed in Section 3.2.

Fig. 4 Swelling–deswelling behavior of MPH in basic (filled circles) and acidic (empty circles) buffers.

3.5.3 Swelling–deswelling behaviour of MPH in deionized water and NaCl solution. The swelling and deswelling of the MPH was studied by immersing the MPH in water and NaCl solution (0.9%) respectively. It was found that the MPH shows swelling in water while shrinking in salt solution when studied at regular intervals (Fig. 5). Actually, the addition of salt decreases the osmotic pressure between the hydrogel and water. In this way, the water molecules move out of the hydrogel and the swelling decreases.^39,40

Fig. 5 Swelling–deswelling behaviour of MPH in deionized water (filled circles) and NaCl solution (empty circles).

3.6 Scanning electron microscopy (SEM)

The surface morphology and porosity of the swollen then freeze-dried MPH were investigated using SEM. The SEM images of the transverse cross sections of the hydrogel (Fig. 6) confirm the presence of interconnected macropores in the size range of 5–147 μm. The average pore size (of the macropores) measured with Image J software was 62.94 μm. The SEM analysis of the longitudinal cross sections of the hydrogel reveals that the interconnected macropores are arranged in the form of hollow macroporous channels, responsible for the fast transportation of water or other solvents. It is therefore expected that the MPH may be used in drug release, cosmetics, diapers and pharmaceuticals.

Fig. 6 Scanning electron micrographs of transverse (a–c) and longitudinal (d–f) cross sections of swollen then freeze-dried MPH (with average pore size 62.94 μm) at different magnifications. Size distribution of macropores (g) and (h); of transverse (a) and longitudinal (d) cross sections.

3.7 In vitro drug release mechanism

Drug release from water-swellable polymeric drug delivery systems is mainly controlled by the swelling capability of the hydrogel, the solubility of the drug in the dissolution media and the interaction between the hydrogel and the drug.⁴¹ The release behaviour of DS from the MPH containing tablets was evaluated in SGF and SIF for 2 and 14 h, respectively. For this purpose, different formulations of DS were prepared by varying the amount of the MPH (see Table 1). The release in SGF was found to be lesser due to the low swelling capacity of the hydrogel and the insolubility of DS in acidic media. The release of DS in SGF was found to be 4.8, 4.5 and 3.75% for F1, F2 and F3, respectively. In SIF, the swelling capacity of the hydrogel and the dissolution of DS increases due to the slightly basic media, and therefore, the release of DS (after 14 h in SIF) was noted to be 97.21, 96.3 and 80.8% for F1, F2 and F3, respectively. It was also observed that with an increase in concentration of the MPH in DS formulations, the release of the drug decreases. Formulation F3 sustained the drug better than the commercially available Voltral® SR tablet formulation. The results of the drug release studies are shown in Fig. 7a.

Fig. 7 (a) Drug (DS) release profile from MPH matrix tablets in SGF and SIF, (b) swelling capacity of MPH tablets containing DS, (c) photographs exhibiting swelling behaviour (aerial and axial view) of F1 formulation in water and (d) SEM images of air-dried hydrogel (i and ii) and tablet (F1) surface (iii).

The values of n and k_p were calculated from the slope and intercept of the plot of ln(M_t/M_∞) vs. ln t, respectively, and given in Table 3. The values of n range from 0.894–0.944 for the given formulations, which indicates that the drug release follows the super case-II transport mechanism in which the release of the drug is governed by the erosion of the delivery system.

Table 3 Mathematical data of power law

Formulation	n	kp	r^2
F1	0.899	12.554	0.9699
F2	0.894	11.603	0.9745
F3	0.944	9.966	0.9752

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The swelling behaviour of all three formulations (F1, F2 and F3) was evaluated in water and the results are depicted in Fig. 7b. It was observed that the swelling of the tablets are directly proportional to the concentration of the MPH in the tablet formulations. Fig. 7c shows the condition of the tablet (F1) during the swelling process in water after selected time intervals.

The morphology of the MPH (air-dried) and the tablet of DS containing MPH (F3) were observed using SEM analysis (see Fig. 7d). The results of SEM revealed that the appearance of the MPH was like micro-flakes. On pressing into the tablet the surface becomes smooth but shows some nanopores and micro-cracks which further supports the superporous and superabsorbent nature of MPH which is a prerequisite for polysaccharidal materials for the sustained/controlled release of drugs.⁴²

4 Conclusions

Mimosa pudica hydrogel has shown high swelling in deionized water, at pH 6.8 and 7.4 while unable to show reasonable swelling at pH 1.2. Furthermore, the excellent stimuli responsive swelling–shrinking behaviour of the Mimosa pudica hydrogel in water and ethanol, in basic (pH 7.4) and acidic (pH 1.2) media and in water and normal saline solution has proven its potential as an intelligent drug delivery system. SEM analysis has confirmed the macroporous nature of the freeze dried hydrogel which makes it a superabsorbent material for many pharmaceutical applications. An in vitro drug release study has shown that the Mimosa pudica hydrogel is a potential candidate for the sustained and targeted delivery of drugs in the small intestine and colon.

Acknowledgements

G. Muhammad gratefully acknowledges the Higher Education Commission, Pakistan, for funding under the scheme “HEC Indigenous 5000 Fellowships”.

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