Preparation and characterization of swellable polymer-based superporous hydrogel composite of poly (acrylamide-co-acrylic acid).
Abstract: The synthesis of superporous hydrogel composites (SPHCs) with carboxylmethylcellulose sodium (NaCMC) as a composite material was carried out by solution polymerization. The characterization studies were performed by measurement of apparent density, swelling studies, mechanical strength studies, and scanning electron microscopy (SEM). In double distilled water SPHCs showed tremendous increase in equilibrium swelling capacity. But, when SPHCs were placed in simulated gastric fluid showed less equilibrium swelling capacity. SPHCs showed improved penetration pressure as the NaCMC concentration increased. SEM images clearly indicate the formation of interconnected pore, capillary channels, and the adherence of NaCMC molecules around the periphery of pores.
Subject: Porosity (Chemical properties)
Polymerization (Chemical properties)
Drug delivery systems (Chemical properties)
Polymers (Chemical properties)
Drugs (Vehicles)
Drugs (Chemical properties)
Authors: Chavda, Hitesh V.
Patel, Chhaganbhai N.
Pub Date: 08/01/2010
Publication: Name: Trends in Biomaterials and Artificial Organs Publisher: Society for Biomaterials and Artificial Organs Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 Society for Biomaterials and Artificial Organs ISSN: 0971-1198
Issue: Date: August, 2010 Source Volume: 24 Source Issue: 2
Product: Product Code: 2910440 Polymerization; 2834030 Drug Delivery Systems NAICS Code: 32411 Petroleum Refineries; 325412 Pharmaceutical Preparation Manufacturing
Accession Number: 308129450
Full Text: Introduction

Hydrogels are cross-linked hydrophilic polymers, with a network structure, which are able to imbibe large amounts of water, and are water insoluble [1-3]. For the pharmaceutical applications they are unique carriers for controlled drug delivery, release control can be governed by both swelling and biodegrading properties [4-6]. The swelling properties of hydrogels are mainly related to the elasticity of the network, the presence of hydrophilic functional groups in the polymer chains, the extent of cross-linking, and porosity of the polymer. The physical characteristics of hydrogels including their swelling ratio also depend on the balance between attractive and repulsive ionic interactions and solvent-mediated effects [7, 8]. Owing to their high water affinity and biocompatibility, hydrogels based on poly (acrylic acid) and its derivatives [9, 10], chitosan [11], alginate [12] and collagen [13], have attracted the attention. However, these nonporous hydrogels swell slowly and exhibit low loading capacities [14, 15], which restrict their use in effective drug delivery. A new generation of hydrogels, which swell and absorb water very rapidly, has been developed. Examples of this new generation are superporous hydrogel (SPH), which swell to equilibrium size in a short period of time [16-20]. The first approach for SPH synthesis involves copolymerization/ crosslinking of co-monomers using multifunctional co-monomer, which acts as crosslinking agent. Chemical initiator initiates the polymerization reaction. Gas blowing techniques are used to synthesize SPHs. The commonly used foaming agents are inorganic carbonates such as sodium carbonate and sodium bicarbonates, which have been safely applied in drug delivery systems. The second method involves crosslinking of linear polymers by irradiation or by chemical compounds [21]. Several important properties of SPHs, such as fast swelling, large swelling ratio, and surface slipperiness, make them an excellent candidate material to develop gastric retention devices [22]. Due to poor mechanical strength of conventional SPHs (CSPHs) they are difficult to handle without breaking [23]. Superporous hydrogel composites (SPHCs) based on Ac-Di-Sol [24], carbopol [25] and o-carboxymethyl chitosan [26], as the second generation of SPHs, resulted in improvement of the properties of SPH.

The objective for the current investigation was to synthesis SPHCs containing carboxylmethylcellulose sodium (NaCMC) as a composite material to improve the characteristics of CSPHs. Acrylic acid and acrylamide were chosen as the base monomers for their high water affinity and fast co-polymerization velocity [27].

Materials and Methods

Acrylamide was obtained from Burgoyne Burbidges and Co. Pvt. Ltd., Mumbai, India. Acrylic acid, N,N'-methylenebisacrylamide, Span 80, ammo-nium persulphate, and N, N, N', N'-tetramethylethylenediamine, and NaCMC were purchased from SD Fine Chem Ltd, Mumbai, India. Double distilled water (DDW) was prepared in laboratory. Simulated gastric fluid (SGF) with pH of about 1.2 was prepared in laboratory by dissolving 2 g of sodium chloride, 3.2 g pepsin, and 6.8 ml of hydrochloric acid in DDW to make 1 L. All other chemicals used were of analytical grade and used as obtained.

SPHC synthesis

All ingredients except sodium bicarbonate and NaCMC were used as solution in DDW. For the synthesis of SPHC of poly (acrylamide-co-acrylic acid, P(AM-co-AA)) the following substances were added subsequently into a test tube at room temperature (25oC): AM 50%; AA 50%; BIS 2.5%; Span 80 10%; TEMED 20%; DDW; NaCMC as shown in Table 1. After adjusting the pH of reaction mixture to 5.0 with 5M sodium hydroxide solution, APS 20% was added. In this procedure, polymerization was allowed to continue for approximately 10 minute. After adding each substance to the test tube, the reaction mixture was vigorously shaken. Finally, 200 mg of sodium bicarbonate was added very quickly to the solution and mixed with a spatula. The synthesized SPHCs were removed with the forceps, allowed to dry in oven at 60[degrees]C for 4 days, and cut into pieces of required size. These SPHCs were stored in airtight container until further use.

Scanning electron microscopy analysis

Dried SPHCs were cut to expose their inner structure and used for SEM studies. The morphology and porous structures of the SPHCs were examined using ESEM EDAX XL-30 Scanning Electron Microscope (Philips, Netherlands), with an operating voltage of 30 kV.

Density measurements

For density measurement, the solvent displacement method was used. Dried SPHCs were used for density measurements, which actually show the apparent densities. Pieces of SPHCs were taken and weighed in order to determine the mass of each piece. A piece of polymer was immersed in a predetermined volume of hexane in a graduated cylinder, and the increase in the hexane volume was measured. The density was calculated from the eq 1:

Density = [M.sub.SPHC]/[V.sub.SPHC] (1)

where, [V.sub.SPHC] is the volume of solvent displaced by SPHC and [M.sub.SPHC] is the mass of SPHC.

Swelling studies

The dried SPHCs were used to determine their equilibrium swelling ratio in DDW and SGF. The equilibrium swelling ratio can be calculated from the following eq 2:

Q = ([M.sub.s] - [M.sub.d])/[M.sub.d] (2)

where, Q is the equilibrium swelling ratio, [M.sub.s] the mass in the swollen state and [M.sub.d] the mass in the dried state. At the beginning of each experiment, [M.sub.d] of a piece of polymer was measured by weight and then it was immersed in an excess of DDW for swelling. The swollen SPHCs were put on a grid boat with a mesh size of 1 mm. This technique allows to put the polymer in water and to weigh it without breaking. Each time the grid boat with the polymer was removed from water, it was gently dried by tissue paper in order to remove adhering water. At specific time intervals the polymer was removed from the water and weighed in order to measure [M.sub.s][16]. When the weight became constant it was considered as [M.sub.s] and the time was considered as swelling time.

Mechanical strength studies

The penetration pressure (PP) of the SPHCs was measured using a bench comparator as described by Chen et al. with modifications [24]. The fully swollen hydrogel was put longitudinally under the lower touch and weights were successively applied to the upper touch until the polymer completely fractured. The compressive force could be read from the gauge and the penetration pressure [25] could be calculated from the following eq 3:

PP = [F.sub.u]/S (3)

where, [F.sub.u] is the ultimate compressive force at complete breakage of the polymer and S is the area of the lower touch.

Results and Discussion

SPHC synthesis

In the synthesis procedure of SPHC, AA and AM are the monomers. BIS is used as a crosslinker, and span 80 is used as a foam stabilizer of the foam, which is formed by carbon dioxide originating from sodium bicarbonate. To obtain homogeneous SPHCs with as many pores as possible, polymerization should take place when the foam was stabilized. Here span 80 was used instead of Pluronic F127 as reported by Dorkoosh et al [28]. Span 80 does not contribute to the chemical structure of the polymer, but is very important as a surfactant to create the highly porous polymer structure. APS is used as a polymerization initiator and TEMED as a catalyst. One of the important factors that influence the synthesis of SPHCs was the pH of monomer solution. At the pH 5.0, SPHCs with well-distributed pores were produced because of the stability and the proper formation rate of the foam. The stirring after the addition of sodium carbonate further mixed NaCMC, and after the beginning of polymerization by addition of sodium carbonate, the viscosity increased quickly and the sedimentation of NaCMC particles was negligible. To obtain SPHCs with well distributed pores, polymerization and foaming involved in the preparation of polymers must be carefully controlled. The generation of foam was fine and uniform during the synthesis. The decrease in temperature during the synthesis is advantageous to stabilizing the foam. NaCMC enhanced the viscosity of the stock solution, which efficiently prevented bubbles from escaping from the solution and the residual gas bubbles were able to form inter-connected channels. It could be readily blended with the stock solution and well distributed in the SPHC, yielding a homogeneous SPHC.

Scanning electron microscopy analysis

Figures 1 and 2 shows the SEM pictures of SPHC and CSPH. Both CSPH and SPHC possessed large numbers of pores, indicating that formation of hydrogel would not destroy the superporous structure. The pore size of SPHC was less compared that of CSPH, indicating that the presence of NaCMC molecules not allowed the gas bubbles to escape easily, due to its viscosity, and so accumulated around the peripheries of the pores resulting in decreased pore size. White fibers on the peripheries of the inner pores were clearly observed in SPHC while not in CSPH, which was primarily determined to be the NaCMC fibers. The fully swollen CSPH was transparent in water and lots of bubbles could be seen within the hydrogel. By comparison, white structure could be observed in the swollen SPHC, which appeared as netlike distribution. Such difference indicated that the white fibers should be the NaCMC molecules and they were well distributed in the polymer to form a three-dimensional network, which primarily confirmed formation of the SPHC.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Density measurements

The density of SPHCs should be lower compared with the conventional hydrogels, as SPHCs possess lots of pores. As shown in Table 2, the increase in the NaCMC amount decreased the density of the synthesized SPHCs. When NaCMC was mixed with the monomer solution, it swelled so that monomers and crosslinker were absorbed into the cellulose network. After polymerization is complete, the cellulose network of NaCMC particulates and the crosslinked poly (AA-co-AM) network formed. SPHCs contained some of pores connected each other, thus leading to larger occupied volume. Increased concentration of NaCMC prevented the bubbles from escaping from the solution mixture as well as it decreases the pore size of SPHC. But at the same the numbers of interconnected pores were increased and so the volume occupied was increased. The superporous hydrogels with higher NaCMC content had higher porosity and better capillary channels. SPHCs shrank less during the drying process, because the network structure was maintained by rigid fibers of NaCMC.

Swelling studies

Swelling parameters of SPHCs in DDW and in SGF are shown Table 3. An increase in the NaCMC concentration led to a slower swelling and decreased equilibrium swelling ratio of the SPHCs. Through entanglement with the cross-linked NaCMC network, flexibility of the polymeric chains was greatly restricted. Bonds between NaCMC and P (AA-co-AM) reduced the ability of the polymer to form hydrogen bonds with water molecules, thus limiting its water absorption. Therefore, a dense NaCMC network would further restrict the swelling of the polymer. The increase in NaCMC dramatically decreased the swelling time. As the concentration of NaCMC increased, probably it helped in retaining the capillary channels, which was supported by the lower density of SPHCs. The reason for fast swelling was hydrophilicity and high wettability of NaCMC [29]. Thus, incorporation of NaCMC made the surface of superporous hydrogels more hydrophilic and with better wettability.

Mechanical strength studies

A SPHC should be able to withstand the pressure expected in the stomach during repeated gastric contractions, especially the housekeeper waves. Formulation variables, such as the amount of crosslinker, type of monomer, amount of blowing agent as well as process variables all affect the mechanical properties of the SPHCs. The maximum pressure during the gastric contraction was reported to range from 50-70 cm water [4]. Penetration pressures of SPHCs are shown in Table 4. SPHCs when swollen in DDW showed mechanical strength that can not withstand the pressure during gastric contraction. When swollen in SGF, SPHCs showed too good penetration pressure more than 1000 gf/[cm.sup.2]. It is thought that the addition of NaCMC increases the effective cross-linking density of the superporous hydrogel. NaCMC is also thought to function as filler in the superporous hydrogel. Increase in the amount of NaCMC helped bring about a denser NaCMC networks and a smaller equilibrium swelling ratio, thus enhancing the elasticity of the polymer. At higher concentration of NaCMC, more than 196 mg, the viscosity of the reaction mixture became too high and proper mixing of all the ingredients difficult.

Conclusion

SPHCs as candidates for gastric retentive drug delivery were prepared from polymerization using APS and TEMED as an initiator system at various amounts of NaCMC. SPHCs possessed the porous structure approved by SEM analysis. The mechanical stability of CSPH is too poor, the presence of NaCMC improved mechanical stability, which prevent the breakage of SPHC during gastric contraction. Mechanical properties of the SPHCs were significantly improved and could be altered by varying the NaCMC content in DDW and SGF. The equilibrium swelling ratio and size of SPHCs decreased with the increase in NaCMC content in DDW and SGF. The equilibrium swelling ratio of the SPHC was found to be pH dependent, as in SGF with pH 1.2 it was less compared to DDW with pH about 7.0 for all the concentration of NaCMC.

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Hitesh V. Chavda * (1), Chhaganbhai N. Patel (1)

(1) Shri Sarvajanik Pharmacy College, Nr. Arvind Baug, Mehsana, Gujarat-384001, India

Corresponding author: hvchavda@sspcmsn.org (Hitesh V. Chavda)

Received 25 August 2009, Accepted 21 December 2009, Published online 27 January 2010.
Table 1: Formulation of SPHCs

Ingredients                                 Batch

                              B1             B2             B3

AM (50% w/v)             300 [micro]l   300 [micro]l   300 [micro]l
AA (50% v/v)             200 [micro]l   200 [micro]l   200 [micro]l
BIS (2.5% w/v)           100 [micro]l   100 [micro]l   100 [micro]l
Span 80 (10% v/v)        30 [micro]l    30 [micro]l    30 [micro]l
TEMED (20% v/v)          20 [micro]l    20 [micro]l    20 [micro]l
Double distilled water   330 [micro]l   330 [micro]l   330 [micro]l
NaCMC                         -            49 mg          98 mg
APS (20% w/v)            45 [micro]l    45 [micro]l    45 [micro]l
Sodium bicarbonate          200 mg         200 mg         200 mg

Ingredients                         Batch

                              B4             B5

AM (50% w/v)             300 [micro]l   300 [micro]l
AA (50% v/v)             200 [micro]l   200 [micro]l
BIS (2.5% w/v)           100 [micro]l   100 [micro]l
Span 80 (10% v/v)        30 [micro]l    30 [micro]l
TEMED (20% v/v)          20 [micro]l    20 [micro]l
Double distilled water   330 [micro]l   330 [micro]l
NaCMC                       147 mg         196 mg
APS (20% w/v)            45 [micro]l    45 [micro]l
Sodium bicarbonate          200 mg         200 mg

AM: Acrylamide; AA: Acrylic acid; BIS: N,N'-methylenebisacrylamide,

APS: Ammo-nium persulphate, TEMED:
N,N,N',N'-tetramethylethylenediamine

Table 2: Apparent density of
SPHCs

Batch    Apparent density
          (g/[cm.sup.3])

B1      0.79 [+ or -] 0.03
B2      0.61 [+ or -] 0.04
B3      0.49 [+ or -] 0.04
B4      0.42 [+ or -] 0.03
B5      0.36 [+ or -] 0.03

Data are expressed as the mean
[+ or -] SD of three experiments.

Table 3: Swelling parameters of SPHCs

Batch                 In DDW

        Size of swollen     Swelling
        SPHC ([mm.sup.2])   ratio

B1      1658 [+ or -] 63    152 [+ or -] 21
B2      1011 [+ or -] 84    51 [+ or -] 7
B3      875 [+ or -] 43     32 [+ or -] 7
B4      684 [+ or -] 45     22 [+ or -] 5
B5      607 [+ or -] 37     19 [+ or -] 6

Batch                 In SGF

        Size of swollen     Swelling
        SPHC ([mm.sup.2])   ratio

B1      394 [+ or -] 23     19 [+ or -] 3
B2      274 [+ or -] 32     9 [+ or -] 2
B3      250 [+ or -] 11     6 [+ or -] 2
B4      186 [+ or -] 24     3 [+ or -] 1
B5      168 [+ or -] 17     3 [+ or -] 1

Data are expressed as the mean [+ or -] SD
of three experiments. Initial size of all
the SPHCs is 100 [mm.sup.2].

Table 4: Penetration pressure of SPHCs

Batch   Penetration pressure (gf/[cm.sup.2])

            In DDW             In SGF

B1            a *         514 [+ or -] 93
B2      91 [+ or -] 14    1449 [+ or -] 78
B3      104 [+ or -] 13   1698 [+ or -] 65
B4      112 [+ or -] 15   1825 [+ or -] 95
B5      117 [+ or -] 09   1978 [+ or -] 98

a * Penetration pressure was less than 10
gf/[cm.sup.2]. Data are expressed as the
mean [+ or -] SD of three experiments.
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