Swellable hydrogels and cross linking Agents -Their role in drug delivery system

Research J. Pharm. and Tech. 10(3): March 2017 ISSN 0974-3618 (Print) 0974-360X (Online) www.rjptonline.org REVIEW ARTICLE Swellable hydrogels and cross linking Agents - Their role in drug delivery system K. Venkata Ramana Reddy1*, M.V. Nagabhushanam2, Eslaveth Ravindar Naik3 1 Asst.Professor, KVK College of Pharmacy, Himayath Nagar, R.R. Telangana State, India-501510 2 Professor, Hindu College of Pharmacy, Guntur, Andhra Pradesh. India522002. 3 Asst.Professor, Anurag College of Pharmacy, Hyderabad, Telangana State, India-501510. *Corresponding Author E-mail: srikanth.papa@gmail.com ABSTRACT: Hydrogels are cross linked polymers with the ability to swell in an aqueous medium. Cross linking in hydrogels occurs by chemical or physical means depending on the polymer properties and experimental conditions. PHResponsive Polymers containing carboxyl groups or amino groups respond to the pH changes by changing their size in the swollen state. At low pH values, the carboxyl containing anionic polymers display minimum ionization and hence reduced hydration. Once the pH of the swelling medium rises above the pKa of the polymer, the carboxyl groups start to ionize and hydrate, which results in polymer expansion and hence higher swelling. On the contrary, cationic polymers containing amino groups (quaternary ammonium salts) display a stronger ionization and hence higher swelling at low pH. Higher cross-link density increases the surface area and pore volume whereas decreases the pore size of polymer beads and vice-versa for lower cross-link density polymer. Further, rigid cross-linker maximizes whereas flexible cross-linker lowers both thermo stability and glass transition temperature. KEYWORDS: Hydrogel types, Characteristics, Cross Linking role. INTRODUCTION: Polyelectrolyte complexes may be formed when oppositely charged poly electrolytes are mixed and interact via electrostatic interactions. Recently, PEC from natural polysaccharides such as chitosan and sodium alginate1-7, carboxy methyl cellulose8 carrageenans Na, dextran etc. attracted considerable attention due to their, biodegradability, low toxicity, biocompatibility much availability of rich resources and potential applications in various biotechnological processes, controlled-release drugs or protein delivery systems, immobilization of drugs, enzymes, cells and proteins. These monomers are epimers resulting in a different configuration of the polymer chain; but, only the G units are oriented in a manner that ensures the carboxylate moieties accessible for ionic cross-linking. Addition of calcium ions to an aqueous solution of Na.Alg results in the formation of a three-dimensional calcium alginate complex hydrogel as the divalent calcium cations’ crosslink adjacent biopolymer chains9. Microcapsules/ particles, beads or membranes prepared from Chs/Alg complexes without a cross-linker10–15, Alg/Ch complexes with divalent compounds CaCl2or BaCl216-22 and Chs/Alg complexes with glutaraldehyde23 were used for encapsulation of drugs Sodium alginate has both anion and cation functional The ratio of M and G blocks in Na. alginate markedly groups in its strcture, these ions impart unique physical influenced by the physical properties of biopolymers. properties by means of electrostatic interactions. This one is added into a solutions of divalent(Cacl2,Bacl2,Sr2) or trivalent (Alcl3,Fecl3) metal ions it forms gels, which is due to the ionic interactions and intra molecular Received on 24.12.2016 Modified on 09.01.2017 bonding between the carboxylic groups which is located Accepted on 16.01.2017 © RJPT All right reserved Research J. Pharm. and Tech. 2017; 10(3): 937-943. on the polymer back bone and cations that are DOI: 10.5958/0974-360X.2017.00172.X 937 Research J. Pharm. and Tech. 10(3): March 2017 In atmosphere of di/tri valent ions, the calcium ion is substituted at site of carboxylic region. A second alginate strand can also connect at calcium ion site and forming a link at which ca2+ ion conjugate two alginate strands together, which forms complex solid gel. The trivalent cation orient into electronegative cavities like eggs arranged in egg box, this binds alginate polymer close together by forming tight/compact junction zones and thereby causing gelation of solution. Only half of carboxylic group engages in chelate binding of calcium if the egg box is a dimerization of molecules, the remaining of ca2+ is normally light bound. The interpretation is that dimeric junction zone binds ca2+ strongly and firmly inside egg box, where as calcium outside the egg box is less firmly bound with less intensity of interactions and multimeric junctions are occur less stable than dimeric zones. The divalent ions form two dimensional networks whereas trivalent cation gives three dimensional structures with alginate molecule. The ability of hydrogels to absorb water arises from hydrophilic functional groups attached to the polymer backbone while their resistance to dissolution arises from cross-links between network chains. Water inside the hydrogel permits free diffusion of few solute molecules, and the polymer serves as a matrix to hold water together. The gel is a state that is neither completely solid nor completely liquid solid. These half part of liquid-like and half solid-like properties cause much interesting relaxation behaviors that are not found in either a pure solid state or a pure liquid state. The amount of water absorbed in hydrogels is related to the presence of active groups such as –CONH2, –COOH, – OH, –CONH–, and –SO3H. The presence of capillary and osmotic pressure effect are other variables that also influence the equilibrium content of water uptake in hydrogels23. Hydrogels can be classified majorly as physically and chemically cross-linked gels on characteristic base. In the first category the networks are held together by existing of physical forces, like ionic, H2-bonding or hydrophobic forces, where in the second case the gel forms covalently cross linked networks. Advantages of Hydrogels: The advantage of hydrogel has many in its nature. They possess a degree of flexibility which is almost very to natural tissue, due to their water content. They are biodegradable, biocompatible, and can be injected. Hydrogels also possess good transport properties and are easy to modify. Environmentally sensitive hydrogels have the greater ability and sensitive in changes of pH, temperature, or the concentration of metabolite and release their load as result of such a change. Disadvantages of Hydrogels: The main disadvantage of hydrogel is that they are nonadherent and may need to be secured by a secondary dressing and also causes sensation felt by movement of the maggots. Hydrogels have low mechanical strength and sensitive to handle and are economical. Type of Stimuli-Sensitive Hydrogel: Thermo type: Release of medicine occurs, through abrupt decrease in surface area due to change in temperature. pH type : Swelling has controlled mechanism through the interactions among protons in solution and ions within hydrogel. Electro type: Drug release occurs when electric filed acts on the hydrogel Enzyme: After swelling occurs, from increase in pH, enzymes degrade hydrogel; therefore it releases medicine in designed manner. Classification of Hydrogel products: The Hydrogel products can be classified on different bases as mentioned below: Classification based on availability of source: Hydrogels can be classified into two groups based on their natural or synthetic origins24. Among many, one of the important classifications is based on their cross linking nature. The network stability of hydrogels in their swollen state is due to the presence of either physical chemical or cross linking. Chemically crosslinked hydrogels are also called as thermosetting or permanent hydrogels. They cannot be dissolved in any solvents unless when the covalent crosslink points are cleaved. Classification according to polymeric composition: The method of preparation leads to formations of some important classes of hydrogels. These can be exemplified by the following: (a) Homo polymeric hydrogels are referred to polymer network derived from a single species of monomer, which is a basic structural unit comprising of any polymer network25. Homo polymers may have crosslinked skeletal structure depending on the nature of the monomer and polymerization technique. (b) Co-polymeric hydrogels are comprised of two or more different monomer species with at least one hydrophilic component, arranged in a random, block or alternating configuration along the chain of thepolymer network26. 938 Research J. Pharm. and Tech. 10(3): March 2017 (c) Multi-polymer inter penetrating polymeric hydrogel (IPN), an important class of hydrogels, is made of two independent cross-linked synthetic and/or natural polymer component, contained in a network form. In semi IPN hydrogel, one component is a cross-linked polymer and other component is a non-cross-linked polymer27. Classification based on configuration The classification of hydrogels depends on their physical structure and chemical composition can be classified as follows: (a) Amorphous (non-crystalline state). (b) Semi crystalline: A complex mixture of amorphous and crystalline phases. (c) Crystalline state. Classification based on type of cross-linking: Hydrogels can be divided into two categories based on the chemical or physical nature of the cross-link junctions. Chemically cross-linked networks have permanent junctions, while physical networks have transient junctions that arise from either polymer chain entanglements or physical interactions such as ionic interactions, hydrogen bonds, or hydrophobic interactions28. When polymer chains are in solution, they tend to coil up. However, the hydrogel now has lots of negative charges down in its length. Technical Features of Hydrogels: The functional features of an ideal hydrogel material can be listed as follows29. The highest absorption capacity (maximum equilibrium swelling) in saline. • Desired rate of absorption (preferred particle size and porosity) depending on the application requirement. • The highest absorbency under load. • The lowest soluble content and residual monomer. • The lowest price. • The highest durability and stability in the swelling environment and during the storage. • The highest biodegradability without formation of toxic • PH-neutrality after swelling in water. • Species following the degradation. • Colorlessness, odorless, and absolutely non-toxic. • Photo stability. • Have ability to give back the imbibed solution or to maintain it. • Re-wetting capability (if required) the hydrogel has to be depending on the application requirement (e.g., in agricultural or hygienic applications). Classification based on physical appearance: Hydrogels appeared in multi forms naming matrix, film, Swelling behavior of hydrogels: or microsphere depend on the type of polymerization When a hydrogel in its initial state is placed in an aqueous solution, water molecules will penetrate into the involved in the preparation process. polymer network. The entering molecules are going to occupy some space, and as a result some meshes of the Classification according to electrical charge: Hydrogels may be categorized into four groups on the network will start expanding, allowing other water basis of presence or absence of their electrical charge molecules to enter within the network. Evidently, swelling is not a continual process, the elasticity of the which located on the cross linked chains: physically (e.g. hydrogen bonding) or chemically (a) Nonionic (neutral). (covalent, atomic, ionic) cross-linked network will (b) Ionic (including anionic or cationic). (c) Amphoteric electrolyte (ampholytic) containing both counter-balance the infinite stretching of the network to prevent its destruction. Thus, by balancing these two acidic and basic groups. (d) Zwitterionic (polybetaines) containing both anionic opposite forces, a net force, known as the swelling pressure (Psw) is produced, which is equal to zero at and cationic groups in each structural repeating unit. equilibrium obtained with pure water, and that can be expressed as30. Structure and bonding: Scientists still have been on research how hydrogels Psw = k × Cn manage to absorb so much water, and there is still plenty Where, k and n are constants, and C is the polymer of ongoing research into their properties and uses. concentration. At the equilibrium there is no additional Understanding the structure and bonding of these swelling. In the case of ionic polymers, the swelling advanced materials helps to explain these properties; this equilibrium of the polymeric matrix is more complicated in turn helps chemists to design and new hydrogels as it heavily depends also on the ionic strength which can perform in different functions. Many hydrogels are polymers of carboxylic acids types. The Preparation of Hydrogels: acid group sticks off the main chain of the polymer. Hydrogels are usually prepared from polar monomers. When these polymers are put into water, the hydrogen According to their starting materials, they can be divided atoms reacts and come off as positive ions. This gives into natural polymer hydrogels, synthetic polymer negative ions along the length of the polymer chain. hydrogels and combinations of the two classes. 939 Research J. Pharm. and Tech. 10(3): March 2017 Hydrogels can be classified as physically and chemically cross-linked gels. In the first case the networks are held together by physical forces, including ionic, H2-bonding or hydrophobic forces, while in the second case the gel has covalently crosslinked networks Characteristics of hydrogels: Hydrogels can be divided into several groups based on their stimuli-sensitivity. Stimuli sensitivity is related to how different groups of hydrogels express varying degrees of response (continuous or discontinuous changes in swelling) to minor changes in environment conditions, such as pH, temperature, ionic strength, quality of solvent31. Temperature responsive hydrogels: Temperature responsible hydrogels can be hydrogels containing polymers such as chitosan PEG-poly, N-isopropyl acryl amide hydrogel methyl cellulose and tetronics. These hydrogels are characterized by temperature dependent sol-gel transition Tgel, which corresponds to the lower critical solution temperature (LCST), and by the gel-sol transition temperature Tp (UCST), which corresponds to precipitation of a gel. When the temperature is below LCST, the water molecules make H2 bond with the polar groups of the polymer. These bonds shape kind of hydrophobic groups as iceberg water. When the temperature increases above the LCST, these hydrogen bonds are released to the bulk with a large gain in entropy resulting in collapse of the polymer network. They can be used in sustained drugs, gene delivery and tissue engineering32. PH Responsive hydrogels: In pH responsive hydrogels, the functional group of the polymer gets fixed to a week acidic group such as week basic groups such as amines acrylic acid or acrylic acid such as amines. Changes subject in pKa and pH value of these polymers make sudden swelling. Some polymers have carboxylic acids as their functional groups.These polymers accept hydrogen at low pH ie.acidic medium but exchange it for other cations above the pKa value. They become ionized at higher pH. The hydrodynamic volume and swelling capacity of these polymers increase gradually (relaxation) when these carboxylic groups becomes ionized and the highest plateau approaches near pH 7(alkaline medium). Degree of ionization of the functional groups dictates its swelling profile and hence the volume change. Polyacrylic acid is such type of pH sensitive hydrogel where swelling ratio changes due to the ionization of carboxyl groups on the polymer chain. Analyte responsive hydrogels: The analyte responsive hydrogels should function under physiologically relevant temperature, pH and ionic strength. Mono and disaccharides, enzymes, antigens and various ions are among the stimulus for analytic responsive Hydrogels33. Properties of Hydrogel: Hydrophilic gels called hydrogels receive considerable attention for their use in the field of pharmaceutical and biomedical engineering. This material can be used as a carrier for drug and other therapeutic bio-molecule only if it is biodegradable, biocompatible and non-toxic in situ. Thus once the biomaterials are prepared one must evaluate the characteristic properties like swelling behavior, mechanical properties and toxicity studies etc so that the hydrogel could be used successfully in the concerned biomedical field. 1) Swelling properties: All polymer chains in hydrogels are cross linked to each other either physically or chemically and thus, considered as one molecule regardless of its size. For this reason, there is no concept of molecular weight of hydrogels and therefore, sometimes called infinitely lar ge molecules or super macromolecules. A small change in environmental condition may trigger fast and reversible changes in hydrogel. The alteration in environmental parameters like temperature, pH, electric signal, and presence of enzyme or other ionic species may lead to a change in physical texture of the hydrogel. These changes may occur at macroscopic level as precipitate formation, changes in its morphology and water content of hydrogels. The difference in concentration of mobile ions in the hydrogel interior relative to external solution (osmotic pressure), changes in solvent pH, drives the volume change. Hydrogels with acidic or basic functional groups respond to the fluctuations in the external environmental pH. Degree of ionization of the functional groups decides/dictates its swelling profile and hence the volume change ratio. Polyacrylic acid is such type of pH sensitive hydrogel where swelling ratio changes due to the ionization of carboxyl groups on the polymer chain. 2) Mechanical properties: Mechanical properties of hydrogels are wide important from the pharmaceutical and biomedical point of view. The evaluation of mechanical property is essential in various biomedical applications viz. ligament and tendon repair, wound dressing material, matrix for drug delivery, tissue engineering and as cartilage replacement material. The mechanical properties of hydrogels should be such that it can maintain its physical texture during the delivery of therapeutic moieties for the predetermined period of time. Changing the degree of cross linking and desired mechanical property of the hydrogel could be achieved. Increasing the degree of 940 Research J. Pharm. and Tech. 10(3): March 2017 Increasing the degree of cross linking a stronger hydrogel could be achieved though the higher degree of cross linking decreases the % elongation of the hydrogels creates a more brittle structure. Hence there is an optimum degree of cross linking to achieve a relatively strong and yet elastic hydrogel. Copolymerization with co-monomer may result into hydrogen bonding within the hydrogel which has also been utilized by many researchers to achieve desired mechanical properties. Recently, Grassi et al. determined the mechanical properties of calcium alginate hydrogel. The mechanical characterization consisted of the relaxation experiments (normal stress relaxation at constant deformation) to determine the hydrogel linear viscoelastic range and to define the relaxation spectra and Young modulus by using the generalized Maxwell model. On the basis of Young modulus and Flory’s theory, it was possible to determine the hydrogels crosslinking density 34. The parameters of physical and Changing the degree of cross linking the desired chemical stimuli response affects hydrogel well predict mechanical property of the hydrogel could be achieved. in following figure. cross linking a stronger hydrogel could be achieved though the higher degree of cross linking decreases the percentage elongation of the hydrogels creates a more brittle structure. Hence there is an optimum degree of cross linking to achieve a relatively strong and yet elastic hydrogel. Copolymerization with co -monomer, may result into hydrogen bonding within the hydrogel, which has also been utilized by many researchers to achieve desired mechanical properties. Mechanical properties of hydrogels are very important from the pharmaceutical and biomedical point of view. The evaluation of mechanical property is essential in various biomedical applications viz. ligament and tendon repair, wound dressing material, tissue engineering, matrix for drug delivery. The mechanical properties of hydrogels should be such that it can maintain its physical texture during the delivery of therapeutic moieties for the predetermined period of time. Fig. 1. Stimuli response swelling hydrogel Fig 2: Mechanism of cross linking 941 Research J. Pharm. and Tech. 10(3): March 2017 Once sodium alginate has been put in a solution that contains calcium ions, then the calcium ions will replace the sodium ions in the polymer. Each calcium ion can confer maximum two of the polymer threads 35.This mechanism is known as cross-linking and can be symbolized as given in above figure. Drug release from Hydrogels: The drug release from hydrogel upon contact to different aqueous medium is controlled /sustained pattern with respect to time. The release of drug will restrict its rapid diffusion by forming rigid matrix layer, it slows down diffusion of core particles from bulk as well as surface of swelled micro particles. The sequesence of events occurs in following manners. • Upon contacting of aqueous medium (water) to hydrogel beads it forms wetting of device. • Initiation of pores formation takes place soon after it contact with surrounding atmosphere • Creation of pores depends upon concentration/viscosity of selected polymers. • Formed pores will alter morphology of hydrogel beads and thereby makes degradation of drug and excipients. • Degradation leads to makes diffusion of drug particles within hydrogel unit. • Drug will start to diffuse out of surface in sustained pattern and causes gradual degradation of entire unit. • Upon complete degradation it makes micro environmental pH changes and causing autocatalytic effects during hydrogel matrix degradation. • A slight change occurs along/across surface of hydrogel and makes relaxation i.e. swelling of polymer occurs, this leads to cause closing of pores. • Due to difference in pressure gradient it develops hydrostatic pressure within unit. • Upon surrounding atmosphere or micro environmental conditions hydrogel will undergoes contraction and swelling mechanism with time. Cross-Linked Polymers: Polymer cross-linking may be reversible or irreversible depending upon the nature of the cross-linking. Three main types of cross-linking methods are broadly studied36-38. These cross-linking methods are chemical, physical, and biological39. Chemical cross linking is irreversible and cannot be reversed whereas physical and biological cross-linking can be reversed by applying temperature, pressure, light, electricity, magnetic field, stress, or by changing pH. Chemical cross-linking is a function of primary forces like covalent bond formation whereas and these known as cross-linking methods. Of all types, ionic interaction is the powerful interaction of the physical cross-linking compared to rest of the physical methods. Chemical cross-linking is much stronger and stable towards heat, mechanical, or any other action. Effect of cross linking on polymer swelling: Polymer swelling is depending on degree of crosslinking, surface area, and porosity. Higher the polymer cross-linking, lower is the polymer swelling and viceversa for lower crosslink polymer. This is mainly because of lower cross-link polymers have longer chain length and easy to expand. In contrast, in higher crosslink polymer, chain length is smaller and makes difficult to swell. Surface area and porosity of a polymer are tunable by changing physico-chemical parameters. High surface area and porosity also encourages the polymer swelling. CONCLUSION: Hydrogels have played a very interest role in biomedical applications. New revised synthetic methods have been used to design homo- and co-polymeric hydrogels for a wide category of drugs, protein, and peptides delivery applications. Of pH-sensitive and/or temperaturesensitive hydrogels can be used for site-specific controlled drug delivery. Polymer solutions in water that transform into a gel phase on changing the temperature offer a very exciting field of research. 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