**1. Introduction**

Hydrogels can be defined as three-dimensional cross-linked polymer networks that have the property of swallowing a substantial amount of water without dissolving as an effect of their physical and/or chemical cross-linking matrix architecture [1, 2]. Besides excellent swelling capacity, other features of hydrogels include an outstanding biocompatibility, high permeability for water-soluble agents and adjustable mechanical properties. Consequently, these materials have been studied extensively for medical application purposes such as tissue engineering, drug delivery systems and biosensor fields [3]. Lately, polysaccharide-constructed hydrogels have gained more attention. The main disadvantage of polysaccharide hydrogels is the lack of mechanical strength, and for this reason, the introduction of a rigid synthetic polymer in order to develop interpenetrating or semi-interpenetrating polymer network hydrogels (IPN/SIPN) with improved strength is being recently studied. IPN or SIPN differs from other multicomponent systems through the highly intimate contact between the polymers, though no chemical bond exists between them. The unique properties of the final nanomaterials are given by the entanglement between the polymer chains. Moreover, the porous morphology of the structure allows numerous applications in various fields. The challenge of synthesizing clay mineral-containing nanocomposite hydrogels in an effective way is still present. More attention is necessary to be paid for combining the strong aspects of layered clay minerals and those of the polymers where both can be modified and functionalized as function of the final materials desired to be manufactured.

The hydrogen bonds between the hydroxyl groups in Salecan and the protonated acid groups in PMAA restrained the swelling of the hydrogel. When the pH is increased, the carboxyl groups of PMAA chains dissociated, undermining the H-bonds between the Salecan and

The Effect of Clay Type on the Physicochemical Properties of New Hydrogel Clay Nanocomposites

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On the other hand, clay nanocomposites have also attracted attention worldwide. The contact between the polymer and clay leads to better thermal and mechanical stability, durability or reduced permeability to small molecules and solvent uptake [4], thus being effectively used to modify drug delivery systems. As a hydrogel network component, clays have proven to act as a trap for the drug that would be released, preventing uncontrolled diffusion of the drug from the gel network and offering a better control of the release. In absence of clay, the drug-loaded hydrogels suffer a burst type of delivery [5]. Over the years, numerous studies demonstrated the outstanding properties of the clay-polymeric materials [6–8]. For instance, Pinnavaia et al. reported increased tensile strength, modulus and heat distortion temperature of polymerclay nanocomposites compared to the simple polymer [6]. Park et al. showed great enhancement in the release rate of the drug for the inorganic–organic hybrid successfully realized by intercalating donepezil molecules into smectite clays [9]. The improvement achieved with the clay inclusion is better defined when the silicate lamellas tend to an intercalated to exfoliated

All the aforementioned features and described techniques lead to the conclusion that on one hand, we have the semi-IPNs, in particular, Salecan/PMMA with outstanding potential for being designed as drug delivery systems, and on the other hand, there are claypolymeric nanocomposites intended for various medical applications. Therefore, we considered the advantages of both systems and decided to develop a novel synergic system suitable for oral delivery of drugs, by combining the hydrophilic networks composed of poly(methacrylic acid) and Salecan with clay mineral nanoparticles. The designed polymer nanocomposite carriers would be able to provide cancer treatment by direct delivery of the medicine to the colon. More than that, we aimed to investigate the effect of the initial clay composition upon the final properties of Salecan/PMMA semi-IPN. In most of the cases, the developing of clay/polymer nanocomposites with sodium montmorillonite (ClNa) was

Interesting investigations, in our opinion, would be regarding the structures obtained with ClNa but with hydrophobic montmorillonites as well. As the clays are basically hydrophilic compounds, the only way to turn them into a structure compatible with hydrophobic network is to functionalize them using ammonium salts [10] or by sol–gel process with various long alkyl chain silanes [11, 12]. The synthesis of various *in house* advanced modified Cloisites were previously reported starting from commercial clay by edge covalent bonding at the clay edges [13]. By measuring the static contact angle values for water, the modified clay minerals proved to have an enhanced hydrophobic behavior [12, 14]. But for this study, we have chosen the commercially available Cloisite Na and organomodified montmorillonite with different ammonium salts: (methyl, tallow, bis-2-hidroxyethyl)-Cloisite 30B, (dimethyl, dehydrogenated tallow)-Cloisite 20A and (dimethyl, dehydrogenated tallow)-

PMAA chains.

structure.

envisaged.

Cloisite 15A.

Salecan is a polysaccharide that possesses a high number of hydroxyl groups on the main chain, allowing this way to be accordingly managed in SIPN architecture. Antioxidant and nontoxic character as well as biocompatibility and biodegradability make it highly suitable for drug delivery purposes. Poly(methacrylic acid) (PMAA) is a synthetic polymer often investigated for being a desirable component of a SIPN. Methacrylic acid (MAA) is a watersoluble monomer that has the ability of polymerizing via *free radical polymerization* under convenient condition. PMAA is a synthetic polyelectrolyte capable of donating or accepting protons upon pH changes, accompanying reversible conformational alterations between the collapse and extension state [3]. Nontoxicity and outstanding mechanical strength sustain its usage in pharmaceutical industry.

Regarding Salecan/PMMA semi-IPN, the study conducted by Qi et al. [3] showed, besides a successful incorporation of the components in a semi-IPN architecture, several features: (1) Salecan addition leads to a better thermal stability of the network; (2) an increment in the Salecan dose resulted in an increase in the average pore size, resulting in an enhanced hydrophilicity of the construction; at the same time, an increase in the cross-linker agent leads to a decrease in pore size as a consequence of a higher density of the network; (3) Salecan facilitates the penetration of water molecules into the network, thus higher equilibrium swelling ratio is obtained while the cross-linker has a completely opposite effect; (4) the pH effect of swelling is assigned to the protonation and ionization balance of the carboxyl acid groups appearing in the hydrogel chains, whose pKa value was approximately 5.5; and (5) at lower pH, the acid groups in the hydrogel cannot be easily ionized.

The hydrogen bonds between the hydroxyl groups in Salecan and the protonated acid groups in PMAA restrained the swelling of the hydrogel. When the pH is increased, the carboxyl groups of PMAA chains dissociated, undermining the H-bonds between the Salecan and PMAA chains.

**1. Introduction**

148 Current Topics in the Utilization of Clay in Industrial and Medical Applications

materials desired to be manufactured.

usage in pharmaceutical industry.

pH, the acid groups in the hydrogel cannot be easily ionized.

Hydrogels can be defined as three-dimensional cross-linked polymer networks that have the property of swallowing a substantial amount of water without dissolving as an effect of their physical and/or chemical cross-linking matrix architecture [1, 2]. Besides excellent swelling capacity, other features of hydrogels include an outstanding biocompatibility, high permeability for water-soluble agents and adjustable mechanical properties. Consequently, these materials have been studied extensively for medical application purposes such as tissue engineering, drug delivery systems and biosensor fields [3]. Lately, polysaccharide-constructed hydrogels have gained more attention. The main disadvantage of polysaccharide hydrogels is the lack of mechanical strength, and for this reason, the introduction of a rigid synthetic polymer in order to develop interpenetrating or semi-interpenetrating polymer network hydrogels (IPN/SIPN) with improved strength is being recently studied. IPN or SIPN differs from other multicomponent systems through the highly intimate contact between the polymers, though no chemical bond exists between them. The unique properties of the final nanomaterials are given by the entanglement between the polymer chains. Moreover, the porous morphology of the structure allows numerous applications in various fields. The challenge of synthesizing clay mineral-containing nanocomposite hydrogels in an effective way is still present. More attention is necessary to be paid for combining the strong aspects of layered clay minerals and those of the polymers where both can be modified and functionalized as function of the final

Salecan is a polysaccharide that possesses a high number of hydroxyl groups on the main chain, allowing this way to be accordingly managed in SIPN architecture. Antioxidant and nontoxic character as well as biocompatibility and biodegradability make it highly suitable for drug delivery purposes. Poly(methacrylic acid) (PMAA) is a synthetic polymer often investigated for being a desirable component of a SIPN. Methacrylic acid (MAA) is a watersoluble monomer that has the ability of polymerizing via *free radical polymerization* under convenient condition. PMAA is a synthetic polyelectrolyte capable of donating or accepting protons upon pH changes, accompanying reversible conformational alterations between the collapse and extension state [3]. Nontoxicity and outstanding mechanical strength sustain its

Regarding Salecan/PMMA semi-IPN, the study conducted by Qi et al. [3] showed, besides a successful incorporation of the components in a semi-IPN architecture, several features: (1) Salecan addition leads to a better thermal stability of the network; (2) an increment in the Salecan dose resulted in an increase in the average pore size, resulting in an enhanced hydrophilicity of the construction; at the same time, an increase in the cross-linker agent leads to a decrease in pore size as a consequence of a higher density of the network; (3) Salecan facilitates the penetration of water molecules into the network, thus higher equilibrium swelling ratio is obtained while the cross-linker has a completely opposite effect; (4) the pH effect of swelling is assigned to the protonation and ionization balance of the carboxyl acid groups appearing in the hydrogel chains, whose pKa value was approximately 5.5; and (5) at lower On the other hand, clay nanocomposites have also attracted attention worldwide. The contact between the polymer and clay leads to better thermal and mechanical stability, durability or reduced permeability to small molecules and solvent uptake [4], thus being effectively used to modify drug delivery systems. As a hydrogel network component, clays have proven to act as a trap for the drug that would be released, preventing uncontrolled diffusion of the drug from the gel network and offering a better control of the release. In absence of clay, the drug-loaded hydrogels suffer a burst type of delivery [5]. Over the years, numerous studies demonstrated the outstanding properties of the clay-polymeric materials [6–8]. For instance, Pinnavaia et al. reported increased tensile strength, modulus and heat distortion temperature of polymerclay nanocomposites compared to the simple polymer [6]. Park et al. showed great enhancement in the release rate of the drug for the inorganic–organic hybrid successfully realized by intercalating donepezil molecules into smectite clays [9]. The improvement achieved with the clay inclusion is better defined when the silicate lamellas tend to an intercalated to exfoliated structure.

All the aforementioned features and described techniques lead to the conclusion that on one hand, we have the semi-IPNs, in particular, Salecan/PMMA with outstanding potential for being designed as drug delivery systems, and on the other hand, there are claypolymeric nanocomposites intended for various medical applications. Therefore, we considered the advantages of both systems and decided to develop a novel synergic system suitable for oral delivery of drugs, by combining the hydrophilic networks composed of poly(methacrylic acid) and Salecan with clay mineral nanoparticles. The designed polymer nanocomposite carriers would be able to provide cancer treatment by direct delivery of the medicine to the colon. More than that, we aimed to investigate the effect of the initial clay composition upon the final properties of Salecan/PMMA semi-IPN. In most of the cases, the developing of clay/polymer nanocomposites with sodium montmorillonite (ClNa) was envisaged.

Interesting investigations, in our opinion, would be regarding the structures obtained with ClNa but with hydrophobic montmorillonites as well. As the clays are basically hydrophilic compounds, the only way to turn them into a structure compatible with hydrophobic network is to functionalize them using ammonium salts [10] or by sol–gel process with various long alkyl chain silanes [11, 12]. The synthesis of various *in house* advanced modified Cloisites were previously reported starting from commercial clay by edge covalent bonding at the clay edges [13]. By measuring the static contact angle values for water, the modified clay minerals proved to have an enhanced hydrophobic behavior [12, 14]. But for this study, we have chosen the commercially available Cloisite Na and organomodified montmorillonite with different ammonium salts: (methyl, tallow, bis-2-hidroxyethyl)-Cloisite 30B, (dimethyl, dehydrogenated tallow)-Cloisite 20A and (dimethyl, dehydrogenated tallow)- Cloisite 15A.

These hydrophilic-hydrophobic complex systems are foreseen to find application in controlled drug release where *co*-delivery of polar-unpolar substances at the target site is mandatory.

**3.2. X-ray diffraction**

**3.3. Thermal gravimetric analysis**

**3.4. Swelling behavior measurements**

immersed into the same recipient.

Powder X-ray diffraction was used for phase identification of the crystalline material and to determine the lattice parameters of the crystal structure. A multifunctional system powder X-ray diffractometer, Rigaku Ultima IV (Tokyo, Japan), was used to perform the measurements. The equipment conditions were as follows: X-ray generator was operated at 40 kV voltage and 30 mA current, using Cu target (CuKα radiation, λ = 1.5406 Å); the goniometer was set in parallel beam geometry system, with cross beam optics (CBO), θ-θ scanning mode and with a step width of 0.02°; a scintillation counter was used. For low angle measurements, the optics used were DS and SS (divergence and scattering slits) = 1°, RS (receiving slit) = 0.2° and receiving side Soller slit 0.5°, collecting data between 0.6 < 2θ < 6° measuring range, with a scanning speed of 1°/min. For wide angle measurements, the optics used were DS (divergence slit) = 1°, SS and RS (scattering and receiving slits) = open and receiving side Soller slit 0.5°, collecting data between 3 < 2θ < 50° measuring range, with a scanning speed of 2°/min. The measurements were per-

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formed in the continuous mode, at room temperature and atmospheric pressure.

Thermogravimetric (TGA) measurements were performed with a TGA Q5000 instrument.

The isotherms of equilibrium swollen hydrogel disks were carried at 37°C for 10 mL/min in

Swelling studies of semi-IPNs were conducted by immersing the dried samples in deionized water at 37± 1°C. The samples were removed from the thermostatic bath at regular intervals of time, their surface was dried with filter paper and then weighed; afterward, they were

*SD* = (*Wh* − *Wi*)/*Wi* (1)

where *Wh* is the weight of swelled hydrogel at a certain time and *Wi* is the weight of initial

ESEM-FEI Quanta 200 (Eindhoven, Netherlands) instrument was used to record SEM images in low vacuum mode with GSED detector. Micrographs were taken in vacuum conditions,

The morphologies of PMAA nanocomposites were obtained by transmission electron microscopy using TEM, Tecnai™ G2 F20 TWIN Cryo-TEM, FEI Company™, at 200 kV acceleration

The samples were heated, in nitrogen atmosphere 10 ml/min with a rate of 10°C/min.

nitrogen atmosphere. All experiments were realized in triplicate.

The swelling degree (*SD*) was calculated using Eq. (1):

**3.5. Electron microscopy analyses: SEM and TEM**

dried hydrogel. All experiments were performed in triplicate.

operating pressure of 2 torr, 25–30 KV accelerating voltage.

voltages. Powdered samples were deposited on carbon film grids.
