Effect of Different External Stimuli on the release of Bioactive Molecules from Smart Nanohydrogels (Katime 2010).
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The latest research in the area of polymeric materials focus on the design of increasingly complex devices that have a specific objective (Dubé et al., 2002). The knowledge of a world beyond our simple fire vision of research that, in turn, have generated a more complete knowledge about the surrounding environment and the development of new sciences that attempt to explain the behavior of micro scale.
Among the new sciences of the XXI century are to nanotechnology, which is still being developed. The transition from micro to nano scale will provide significant improvements in the understanding of matter and its applications (Katime et al., 2004). Nanotechnology is the study, design, creation, synthesis, manipulation and application of materials, devices and functional systems through control of matter at the nano scale and the exploitation of phenomena and properties of matter at the nano scale.
Nanotechnology requires a new interdisciplinary approach to both research and in fabrication processes (Katime, 1994). We consider two routes: the first is the miniaturization of microsystems and the second mimics nature by building structures from atomic levels molecular (Thomson, 1983). Because of the latter need emerges nanotechnology to biomedicine, science that is now channeled to the study of biological systems, largely based on the science of polymers to achieve this goal (Mendizábal et al., 2000).
One of the areas in the twentieth century has been supplemented to the science of polymers is biomedicine within it, biomaterials have the most diverse types of devices, and that demonstrate the advantages over other materials traditionally used (Lee et al., 1996). Because of its versatility, polymeric hydrogels are a special type of biomaterials whose use has expanded rapidly in many areas of medicine (Lee & Wang, 1996). When designing a synthetic polymer is generally aimed at satisfying a need, in other words, it seeks to confer a characteristic end product that helps solve the problem for which it was designed.
There is a direct relationship between the properties of a hydrogel (or a polymer in general) and its structure, so that both features cannot be considered in isolation, since the method of synthesis has a decisive influence on them. Therefore, when evaluating the properties of the hydrogels is to be referred to the structural parameters that condition them8. In the field of polymers, the term biocompatibility concerns two different aspects, but those are directly related: (a) The high tolerance have to show the tissues to the foreign agent, mostly when the polymer is to be implemented, and (b) chemical stability, and especially physics polymer material during the time that is in contact with the body. There is no single definition of smart polymer; however we can say that is one that to an external stimulus undergoes changes in its physical and/or chemical. The first time I coined the term "smart polymer" was in a newspaper article of the year 1998 (Nata & Yamamoto, 1998). This paper described how a group of researchers from the University of Michigan using Electro-rheological fluids (ER) to create smart materials. These fluids have the potential to change viscosity almost instantly in response to an electrical current. The fact revealed the existence of a new type of material with the ability to modify its properties in a given time and adjust to changes in conditions. Two years later, in 1990, Hamada et al., Published an article in which phase transitions glimpsed a photo-induced gel (Mamada et al., 1990). A year later in 1991 appeared a review article on functional conducting polymers, which envisioned its potential application as intelligent materials (Kwon et al., 1991).
Currently there are several processes which can yield polymeric nanoparticles with a high yield of reaction, however, which allows the production of nanoparticles with high control of its features is the microemulsion polymerization. Microemulsion polymerization is a method with interesting perspectives and a type of polymerization alternative to existing processes to produce polymer latex of high molecular weight but with particle sizes smaller than those obtained in emulsion, which vary from 10 to 100 nm (Escalante et al., 1996; Candau & Buchert, 1990).
Microemulsions are fluid phases, microstructure, isotropic, optically transparent or translucent, at thermodynamic equilibrium, containing two immiscible fluids (usually water and oil) and surfactants (Candau & Zekhinini, 1987). Unlike emulsions are milky, opaque and thermodynamically unstable. The biggest difference between emulsion and microemulsion is given by the amount of surfactant needed to stabilize the system, which is much higher for the case of microemulsions ( 10% of the total mass). This restricts the potential use of microemulsions in most applications due to the requirement of a formulation as cheap as possible, characterized by a high proportion monomer/surfactant (Katime et al., 2001).
Hoar and Schulman were the first to introduce the concept of microemulsion and to postulate the first mechanism for the formation of a microemulsión (Corkhill et al., 1987). The reason for the formation of a stable microemulsion is to be found in the analysis of the energies present in dispersion, a fact which can be expressed in terms of Gibbs free energy necessary for the formation of a microemulsion (Hoar & Schulman, 1943).
The nano-hydrogels commonly exhibit volume changes in response to changing environmental conditions (Katime & Mendizábal, 1997). The polymer network can change its volume in response to a change in the environment such as temperature, pH, solvent composition, electrical stimulation, the action of electric fields, etc (Bokias et al., 1997). The combination of molecular interactions such as van der Waals forces, hydrophobic interactions, hydrogen bonds and electrostatic interactions, determine the degree of swelling of hydrogel at equilibrium. If a gel contains ionizable groups, is a pH sensitive gel, since the ionization is determined by the pH in terms of equilibrium ionization (Kurauchi et al., 1991). The variation of pH of the swelling induces changes in the degree of ionization of electrolytes and, therefore, a change in the degree of swelling of the hydrogel. Moreover, the temperature is one of the most significant parameters affecting the phase behavior of the gels. Recent studies show that it is possible to produce hydrogels with a particular transition temperature or even develop hydrogels with various transition temperatures (Kurauchi et al., 1991).
One of the most studied polymers, which respond to temperature changes in the external environment, is poly (N-isopropyl acrylamide) (PNIPA). This polymer undergoes a strong transition in water at 32°C, from a hydrophilic state below this temperature to a hydrophobic state above it. Currently the development of polymeric complexes have bioactive properties, that are able to interact with cellular mechanisms has grown considerably because of the many applications that can take the coupling of biological receptors within the polymer matrices. One of the biological receptor that has attracted interest from the scientific community is folic acid receptor Saunders & Vincent, 1999. The protein encoded by this gene is a member of the folate receptor family (FOLRF). The members of this family of genes have a high affinity for folic acid and reduction of various folic acid derivatives, in addition to mediate the delivery of 5-methyl tetrahydrofolate inside cells. This gene is composed of 7 exons, exons 1 to 4 encode the 5 \'UTR and exons 4 through 7 encode the open reading frame. Due to the presence of 2 promoters, there are multiple transcription start sites and alternative splicing of exons, there are several variants of the transcript derived from this gen (Choi et al., 1988).
The importance of folate receptor is that in various diseases this gene is overexpressed on the cell surface that makes it easy to capture through the cellular process of receptor-mediated endocytosis RME (Tannock & Rotin, 1989). Folic acid, in addition to high specificity towards the tumor tissue, offers potential advantages, including its small size, which carries favorable pharmacokinetics, reduced immunogenicity allowing repeated administration, high availability and safety (Vert, 1986). Devices for controlled release of drugs are an especially important application that exploits the collapse-swelling properties of the polymers in response. In this field are particularly important hydrogels containing poly (N-isopropyl acrylamide) (PNIP), which generate matrices that can exhibit thermally reversible collapse above the LCST of the homo polymer is taken as base (Stubbs et al., 2000).
The collapse in the structure of the matrix is accompanied by loss of water and any co-solute, as it may be a therapeutic agent or active ingredient. Drug expulsion and loss of water takes place at the initial stage of gel collapse, followed by a slower release of drug that diffuses from the gel visibly shrunken and physically compacted (Rivolta et al., 2005). A useful synthesis allows delivery systems be prepared to respond to a pre-designated value of pH and/or temperature to release some kind of drug. For drug delivery applications the response of the nanogels should be nonlinear with different levels of expectation and response, that is where the key is to develop materials that should show strong transitions to a small stimulus or change in the environment. One way to accomplish this is by defining the structures of micro and nano-scale.
One of the main challenges in designing a delivery system directed or specific control variables is necessary for the device you are thinking about getting this necessary features for use depending on which system to be used. The case of the current treatments for cancer therapy devices required to recognize a biological marker on the surface of tumor cells, so that this device can act as a mechanism Tipi "Trojan horse", which tumor cell invaginates the vehicle as if it were a necessary nutrient for cellular functions. Having recognized the growing problem: How can the vehicle be able to release their cargo within the cell cytoplasm? To answer this question it is necessary to consider some facts: a) new research has shown that folic acid specific ligand is over expressed in cancer cells and can be also referred to as a tumor marker. Also, as already mentioned in this work that the folate receptor is one of the 25 receptors that mediate the endocytosis process mediated by receptors (Mathur & Scranton, 1996) (previously described), b) the pH inside the tumor cell has a decrease to a value of 4.5 (Katime et al., 2009) and c) the average body temperature is near 36°C (Katime et al., 2008).
Focusing on these facts we can say that the design of a nanostructure that can be used to treat diseases like cancer must submit specificity, sensitivity to pH and temperature.
If a gel contains ionizable groups, is a pH sensitive gel, since the ionization is determined by the pH in terms of ionization equilibrium. The variation of pH of the swelling induces changes in the degree of ionization of electrolytes and, therefore, a change in the degree of swelling of the hydrogel. Table 1 shows the functional groups that can induce changes in the polymer network to changes in pH.
Stimulus | Hydrogel Type | Release Mechanism |
pH | Acidic or basic hydrogel | Change in pH-swelling-release of drug |
Ionic Strength | Ionic hydrogel | Change in ionic strength-change in concentration of ions inside the gel-change in swelling-release of drug |
Chemical species | Hydrogel containing electron-accepting groups | Electron-donating compounds-formation of charge-transfer complexes-change in swelling-release of drug |
Thermal | Thermo-responsive hydrogel | Change in temperature-change in polymer-polymer and water-polymer interactions-change in swelling-release of drug |
Enzyme substrate | Hydrogel containing immobilized enzymes | Substrate present-enzymatic conversion-product changes swelling of gel-release of drug |
Electrical | Polyelectrolyte hydrogel | Applied electric field-membrane charging-electrophoresis of charged drug-change in swelling-release of drug |
Magnetic | Magnetic particles dispersed in microspheres | Applied magnetic field-change in pores in gel-change in swelling-release of drug |
Effect of Different External Stimuli on the release of Bioactive Molecules from Smart Nanohydrogels (Katime 2010).
Therefore, the understanding to the sensitivity to a change in pH for drug transport vehicle is based on the incorporation of ionizable groups within the polymer matrix. These groups will be responsible for ensuring, through its characteristics, the change in size in the pores of the polymer network with some variation of pH. Studies by Katime and colleagues (2009) show that depending on the type of ionizable structure, a polymer gel can change their swelling properties - collapse before a stimulation of pH, specifically the gels with more basic properties studied in recent years are those who owe their acid-base properties to the presence of pyridine rings in its structure molecular (Katime et al., 2005).
Pyridine is a cationic ionizable group has a pKa value of 5.2, so this functional group appears to be a strong candidate to obtain pH-sensitive cationic gels having a pH of swelling (pHs) around 5 (Figure 1).
Ionizing process of the pyridine ring.
One way to achieve the inclusion of pyridine functional groups is the copolymerization with vinyl monomers derived from the ionizable group, as is the case of 4-vinylpyridine (4VP) and 2-vinylpyridine (2VP). Polymerization and crosslinking leads to the obtaining of intersecting networks pyridine ring and ortho position respectively, with the carbonate skeleton of the network.
Synthetic procedure proposed by Katime and coworkers to obtain microgels with ionizable pyridine groups.
Loxley and Vincent (1997) synthesized microgels by copolymerizing 2-vinylpyridine and styrene, and found its swelling at pH values lower than 4531, while Fernandez-Nieves et al. (2000) studied the volume phase transition of microgels obtained from the direct polymerization of 2 vinyl pyridine, finding a pH of swelling of 4.032. Snowden et al. for their part, have been studied extensively in recent years cationic copolymer microgels of P (NIPA-co-4VP), and have found pH-sensitive properties of swelling with pH change 5.5. These microgels 4VP derivatives, obtained by different synthesis methods have also been recently studied by Vincent et al. (2005), also found pH-sensitive properties, although the pH of swelling were determined to be lower ( pH 3.5-4.0). More recently, several studies show that 4-aminomethyl pyridine (4AMP) coupled in post polymerization reactions to a crosslinked polymer network, can govern the collapse-swelling transition at a pH of 4.53-36 (Figure 2), by use of molecules with "good leaving groups" allowing the incorporation of 4AMP within the polymer network (Guerrero-Ramírez, 2008).
Schematic procedure proposed by Katime et al. (2010) for the synthesis of amine-based monomers.
Katime et al. (2010) have proposed the synthesis of vinyl monomers from amines for potential use in modification reactions that result in the ownership of pH sensitivity for polymeric gels (Agüero et al., 2010). The synthesis of monomers is a simple procedure that involves a nucleophilic substitution reaction by the use of a "good leaving group (Figure 3). Such reactions have a yield above 80%, which generates a good alternative to the inclusion of these compounds to drug transport vehicles.
Temperature is one of the most significant parameters affecting the phase behavior of the gels. Recent studies show that it is possible to produce hydrogels with a particular transition temperature or even develop hydrogels with various transition temperatures (Guerrero-Ramírez et al., 2008). One of the most studied polymers, which respond to temperature changes in the external environment, is poly(N-isopropyl acrylamide) (PNIPA). This polymer undergoes a strong transition in water at 32°C, from a hydrophilic state below this temperature to a hydrophobic state above it. Above the phase transition, as shown schematically in figure 4, is based on the entropic gain associated water molecules to the side chain isopropyl substituent.
The temperature at which this happens (called lower solution critical temperature or LCST) corresponds to the region in the phase diagram in which the enthalpic contribution of water bound to the polymer chain is less than the entropic gain of the system as whole and, therefore, depends largely on the ability to form hydrogen bonds and the chemical nature of constituent monomer units. Consequently, the LCST of a polymer can be adjusted to measure the variation in the content of hydrophilic or hydrophobic co-monomers.
Temperature behavior of typical pNIPA hydrogel.
A nanogel is polymer network that is ranged between 10 to 100 nm of particle size. The nanogeles can present well defined structures as a spherical structure or heterogeneous structure (non-defined structure). The synthesis of nanohydrogels besides the usual elements in any polymerization such as solvent, monomer or monomers and the initiator, it requires a crosslinking agent, who will be responsible for the crosslininked structure (Hervias et al., 2008; Guerrero-Ramírez et al., 2008; Guerrero-Ramírez et al., 2008; Bruck & Mueller, 1988; Agüero et al., 2010). For this purpose the synthetic procedure can be done using a large number of monomers that are classified divided in three different categories (Murray & Snowden, 1995): a) Monomer with no lateral ionizing groups, b) Monomers with ionizable functional groups and, c) Zwitterionic monomers.
There are several methods for preparing crosslinked hydrogels. One of this methods that is widely use is by a chemical reaction, this method is a copolymerization and crosslinking reaction between one or more monomers and multifunctional monomers which is present in very small quantities. Initiation systems that can be used are those used in conventional polymer synthesis: thermal decomposition of an initiator, temperature, ionic initiators, gamma radiation or redox.
Also it is possible to obtain crosslinking by the polymerization of a concentrated solution which can cause self-crosslinking through the elimination of hydrogen atoms in the polymer backbone, followed by combinations of radicals. The choice of the crosslinking agent is essential to optimize the properties of the hidrogel (Orrah et al., 1988).
There are different ways to reach a successful synthetic procedure: within which are precipitation polymerization, emulsion, microemulsion and nanoemulsion. Each is aimed at obtaining polymeric materials with different characteristics.
Among these, the microemulsion polymerization is offered more versatility because through it is possible to obtain very small particles (10-150 nm) by synthetic variation of different parameters within which we can find the surfactant system The oil phase, the aqueous phase, monomer ratio, the amount and type of crosslinking agent, the amount and type of initiator and the addition of compounds capable of reducing ionic micellar space.
Recently there have been reports of the synthesis of microgels using a new polymerization technique, microemulsion polymerization, which allows for smaller particle sizes (15-40 nm) than those obtained by emulsion polymerization (Zhang et al., 2002).
Microemulsion polymerization is an alternative to existing processes to produce latex containing polymer of high molar mass but with particle sizes smaller than those obtained by emulsion polymerization (Kudela, 1987; Krane & Peppas, 1991). Microemulsions are fluid phases, microstructured, isotropic, optically transparent or translucent, at thermodynamic equilibrium, containing two immiscible fluids (usually water and oil), contrary to emulsion which are milky, opaque and thermodynamically unstable. An important difference between emulsion and microemulsion is that the amount of surfactant needed to stabilize the micromulsions (> 10% wt) is much greater than that used in the emulsions (1 to 2% wt). This greatly restricts the potential use of microemulsions in most applications, since it is required to use a formulation as cheap as possible (Franson & Peppas, 1991). However, since by microemulsion polymerization it is possible to obtain monodisperse spherical microgels with diameters less than 50 nm (Downey et al., 1999; Tanaka et al., 1984; Osada et al., 1989) there is a promissory future for this technique.
The most important part of a microemulsion is the surfactant. Usually mixtures of surfactants are used to take advantage of each of them and their sinergy (Pelton, 2000). Surfactants are organic compounds that are amphiphilic because they have hydrophobic groups (tails) and hydrophylic groups (heads). Therefore, they are soluble in both organic solvents and water.
There are four types of surfactants: a) Anionic, b) Cationic, c) Non ionic and, d) Amphoteric. Increasing the concentration of surfactant causes the formation of microstructures, which are aggregates of colloidal dimensions that exist in equilibrium with individual surfactant molecules. The concentration at which these microstructures (micelles) are formed is the critical aggregation concentration (CAC).
The micellization phenomena is a cooperative process in which a large number of surfactant molecules associate to form a closed aggregate. When forming the micelles, the critical aggregation concentration is called critical micelle concentration (CMC). The critical micelle concentration depends on the number, length, type, branching or substitution of the hydrophobic chain and the nature of the polar group. The effects favoring micellization produce a decrease in the critical micelle concentration and viceverse.
The type of micelles that are formed depends on the properties of the surfactant and dissolution. The micellization is a cooperative process in which a large number of surfactant molecules associate to form a closed aggregate in which the nonpolar parts of the surfactant are separated from the water. The micellization process occurs through a series of conflicting effects: 1) effect that tend to favor the formation of a micelle and the hydrophobic effect, which increases with the size of the hydrocarbon chain of surfactant, and 2) effect that tend to oppose the formation of a micelle, as the repulsion between the hydrophilic groups, particularly important in ionic surfactants.
The presence of alcohol, which is sandwiched between the surfactant molecules at the interface, or the addition of electrolytes to produce a screen effect that reduces the intermolecular electric field, reduces the repulsive forces favoring the micelización (Zhu et al., 1989).
The critical micelle concentration depends on the number, length, nature, saturation, branching or substitution of the hydrophobic chain and the nature of the polar group. The effects that favor the micellization produce a decrease in critical micelle concentration and vice versa.
When is added to the medium a salt or an ionic monomer, latex stabilization is achieved (Antonietti & Bremser, 1990). It is known that the addition of an electrolyte to an aqueous solution produces a variation in the cloud point, i.e. the point at which the solubility changes. When this addition causes a migration of surfactant molecules into the oil phase, increasing the packing of it at the interface, it favors the formation of the microemulsion, due to an increase in the solubility by the presence of salt (salting out). If instead there is a decrease in the cloud point, there is a decrease in solubility by the presence of the salt (salting in). These phenomena are usually related to changes in the water structure around the ions which modify the interactions between water and the surfactant (Funke et al., 1998). Ions such as Na+ and K+ decrease the of the surfactant polar head, while ions such as SCN-and I-, favor the solvation of the surfactant making it more water soluble (Kazakov et al., 2002). In general, the introduction of an electrolyte with salting out effect causes a change in the hydrophilic-lipophilic (HLB) balance of the surfactant, shifting the optimum HLB to form a microemulsion towards higher values. Regarding the preparation method, there is a difference between these two types of dispersions, which focuses on the order of addition of components. In the emulsion case the addition order is very important, contrary to what happens in the formation of microemulsions, where it is not important.
The inverse microemulsion polymerization is based on training, pre-polymerization, microemulsion system of water in oil, which include micromicelas containing monomers to react. Within this group, with globular structure and those with bicontinuous structure.
The inverse microemulsion polymerization of monomers soluble in water is a particularly suitable method for preparing high molecular weight polymers and fast reaction rates (Nata & Yamamoto, 1998), due to high local concentration of monomer within each particle as the growth of radical separate particles prevents termination by combination.
According to studies by Candau, throughout the reaction there is an excess of surfactant stabilizing micells (Candau & Leong, 1985). Two populations are shown as typical colloidal aggregates: a particle with a diameter of about 50 nm and a micelle. It has also been observed that the number of particles increases continuously throughout the polymerization reaction due to excess surfactant, which makes the amount of micelles is at all times well above the particle, allowing for entry of radicals nucleation into micelles. According to the kinetic mechanism for the inverse microemulsion polymerization is depicted in figure 5, the radicals are absorbed into the micelles. They react with the monomer to spread and form a polymer particle. This particle is growing due to the contribution of monomer from other micelles that act as reserve deposits. Eventually the system is reduced to two populations of polymer particles and a water swollen micelles.
Kinetic mechanism for the inverse microemulsion polymerization.
Currently the development of polymeric complexes have bioactive properties, i.e. that are able to interact with cellular mechanisms has grown considerably because of the many applications that can take the coupling of biological receptors within the polymer matrices. Among these recipients are: acetylcholine receptor, cytokine receptor, insulin receptor T cell receptor, recipient of transforming growth factor beta, receptor phosphotyrosine phosphatase, receptor guanylyl cyclase, muscarinic receptor, M1 muscarinic receptor, muscarinic receptor M2, muscarinic receptor M3, M4 muscarinic receptor, nicotinic receptor, mineralocorticoid receptor.
But a biological receptor that has attracted interest from the scientific community is folic acid receptor (Candau & Zekhinini, 1986). The protein encoded by this gene is a member of the folate receptor family (FOLRE). The members of this family of genes have a high affinity for folic acid and reduction of various folic acid derivatives, in addition to mediate the delivery of 5-methyl tetrahydrofolate inside cells. This gene is composed of 7 exons, exons 1 to 4 encode the 5 \'UTR and exons 4 through 7 encode the open reading frame. Due to the presence of 2 promoters, there are multiple transcription start sites and alternative splicing of exons, there are several variants of the transcript derived from this gene.
The importance of folate receptor is that in various diseases this gene is overexpressed on the cell surface that makes it easy to capture through the cellular process of receptor-mediated endocytosis EMR (Bleiberg et al., 1998). Folic acid, whose chemical structure is shown in figure 6, is a natural vitamin required for transfer reactions in many metabolic processes and is now a promise in the vectorization of anticancer drugs. Several investigations in recent decades have concluded that folic acid receptors have a preferential expression in ovarian, endometrial, lung, kidney, colon, among others, but are very limited in the normal tissues (Boggs et al., 1996; Castro et al., 2005; Alléman et al., 1993; Coney et al., 1991). This specific folate-cancer cell has been used for the design of anticancer using folic acid as the ligand molecule to the director of their tumoral cells (Weitman et al., 1992; Garin-Chesa et al., 1993; Ross et al., 1994; Anderson et al., 1992).
Molecular structure of folic acid.
Folic acid, in addition to high specificity towards the tumor tissue, offers potential advantages, including its small size, which carries favorable pharmacokinetics, reduced immunogenicity allowing repeated administration, high availability and safety. Moreover, folic acid is stable at very different temperatures and in a variety of solvents, and in slightly acidic or basic media, unlike antibodies that require careful handling to avoid distortion. Another point to note is that it is cheaper than the aforementioned monoclonal antibodies. All this, combined with its relatively simple chemical conjugation, makes it an interesting and promising molecule specific antitumoral therapies (Bronstein, 2004).
To determine at which pH these folate conjugates are subject to when passing into the intracellular environment, in studies it has been measured indirectly the pH of individual endosomes containing folate conjugates and it was found that although this value can vary considerably (4.7-5.3), the average pH is 5.0 (Brannon-Peppas, 1997; Tannock & Rotin, 1989; Vert, 1986; Stubbs et al., 2000; Katime et al., 2006). This pH is markedly different of the physiological pH of the blood stream and of any healthy tissue (pH = 7.4).
Endocytosis is a cellular process by which the cell introduces large molecules or particles, and does so by including them in an invagination of the cytoplasm membrane, forming a vesicle that eventually breaks off and enters the cytoplasm. When endocytosis leads to the capture of particles is called phagocytosis, and when only portions of liquid are captured is called pinocytosis. Pinocytosis traps substances indiscriminately, while receptor-mediated endocytosis only includes those molecules that bind to the receptor being this type of endocytosis very selective. The RME allows cells to take specific macromolecules called ligands, such as proteins that bind insulin (a hormone), transferrine (a protein that binds to iron), cholesterol carriers and low density lipoproteins.
1) The RME requires specific membrane receptors to recognize a particular ligand and link to it, 2) ligand-receptor complexes migrate along the surface of the membrane structures called coated pits. Just inside the cytoplasm, these pits are lined with a protein that can polymerize into a cage-shaped structure (membrane vesicle), and 3) The vesicles move within the cytoplasm, taking the ligand from the extracellular fluid to within the cell. The materials bound to the ligand, such as iron or cholesterol, are introduced into the cell, then the empty ligand returns to the surface.
Devices for controlled release of drugs are an especially important application that exploits the collapse-swelling properties of the polymers in response. In this field are particularly important hydrogels containing poly (N-isopropyl acrylamide) (PNIPA), which generate matrices that can exhibit thermally reversible collapse above the LCST of the homopolymer is taken as base (Mathur & Scranton, 1996).
The collapse in the structure of the matrix is accompanied by loss of water and any co-solute, as it may be a therapeutic agent or active ingredient. Drug expulsion and loss of water takes place at the initial stage of gel collapse, followed by a slower release of drug that diffuses from the gel shrunk visibly and physically compact.
When the polymer matrix has been incorporated into a co-monomer to respond when the polymer changes state, swelling of the gel can be exploited as a release mechanism to change as a result of the expansion of the polymer. The smart nanogels have the potential to be used with a variety of drug loading and release of active ingredients as well as features and release can be adapted to a wide range of different environments (Bruck & Mueller, 1988; Alléman et al., 1993; Bleiberg et al., 1998).
A useful synthesis allows delivery systems be prepared to respond to a pre-designated value of pH and/or temperature to release some kind of drug. For drug delivery applications the response of the nanogels should be nonlinear, i.e., with different levels of expectation and response, that is where the key is to develop materials that should show strong transitions to a small stimulus or change in the environment. One way to accomplish this is by defining the structures of micro and nano-scale.
Smart copolymeric nanoparticles can be synthesized using a microemulsion polymerization process using a reported method (Guerrero-Ramírez et al., 2008). The microemulsion solution was introduced in a mechanical reactor at 25 ± 1°C operated at 131 rpm and nitrogen was bubbled to maintain an inert atmosphere during the whole reaction. The monomers N (4-methyl pyridine) acrylamide (NPAM) and tert-butyl 2 acrylamidoethyl carbamate (2AAECM) are not commercial products, they were synthesized by a nucleophilic substitution reaction from the precursors, modified 4AMP and BOC, respectively. To obtain NPAM monomer, 4AMP reagent was previously prepared and reacted with acryloil chloride at -5°C under vigorous stirring to produce a nucleophilic substitution by the amino functional group and releasing HCl to the average reaction. The 2AAECM synthesis procedure involves several steps: the first was to obtain a di-tert-butyl dicarbonate (BOC) modified by reaction with ethylenediamine at -19°C using dichloromethane as a reaction medium and when all the BOC reactive was added the reaction was maintained for 16 hours at 25°C. Then, dichloromethane was evaporated and the diprotected amine formed as a secondary product was separated due is insoluble in water, so water was added to precipitate system. Diprotected amine was separated by filtration and the resulting solution was saturated with NaCl and extracted with ethyl acetate. Then the solution was dried by adding anhydrous sodium sulphate and the final product was obtained by rotoevaporation. Finally, the resulted product of the reaction was reacted with acryloil chloride to produce an active monomer (2AAECM).
This kind of particles can be used to load, transport and deliver active drugs. These characteristics permits that smart nanocarriers be use against different diseases including cancer or tuberculosis.
Polymerization kinetics for COP23 sample obtained using a gravimetric method.
In the case of anti-cancer therapies it is also necessary the functionalization with folic acid, as it has been described, this director molecule is widely used as a biological cellular marker due to it is overexpressed in a number of human tumors, including cancer of lung, kidney and blood cells.
Dissolution of folic acid is prepared by mixing it with 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) and tryethylamine, at 25°C, using magnetic stirring for one hour to produce activated folic acid. This mixture is dropped into a dispersion of nanogels in water to incorporate the guide molecule. The purification and the isolating procedure of the final product is carried out by dialysis using a phosphate buffer solution of pH = 7.4, and then distilled water. All of this procedure is performed in a dark environment to avoid degradation of the folic acid molecule.
The total reaction time for obtaining this type of system is estimated at an average of 3 minutes. Figure 7 can be seen that reaction times higher than the 3 minutes are not a significant change in conversion rate. As low curing times, with conversions above 97%, produce nanoparticles more efficiently.
An important fact is that in samples where the amount of initiator used in the synthesis is increased, decreased reaction time. For this system has not been given this trend, because as mentioned, the average reaction times for all cases are set at 3 minutes.
The particle size of several samples of smart nanogels have been synthesized, for all formulations, small particle sizes. Table 1 shows this behavior, in the same way, the remarkable effect of initiator concentration on particle size has a tendency that increasing the initiator concentration, particle size decreases. On the other hand, the particle size of the nanogels synthesized with different concentrations of crosslinking agent and different amounts of salt added, show that the particle diameter decreases nanogel depending on the content of crosslinking agent. As can be seen when the concentration of crosslinker increases, the particle diameter decreases. However, there is a concentration limit, both as crosslinking initiator, from which particle size can not decrease nanogel more.
Sample code | %crosslinker | %initiator | %KNO3 | Dp (nm) |
COP20 | 5 | 1 | 0 | 45 |
COP21 | 5 | 2 | 0 | 43 |
COP22 | 5 | 3 | 0 | 40 |
COP23 | 5 | 4 | 0 | 38 |
COP24 | 5 | 5 | 0 | 36 |
COP25 | 4 | 5 | 0 | 40 |
COP26 | 3 | 5 | 0 | 42 |
COP27 | 2 | 5 | 0 | 41 |
COP28 | 1 | 5 | 0 | 41 |
COP29 | 5 | 3 | 0 | 42 |
COP30 | 5 | 3 | 0 | 40 |
COP31 | 5 | 3 | 0 | 42 |
COP32 | 5 | 3 | 0 | 41 |
COP33 | 5 | 3 | 0 | 40 |
COP34 | 5 | 3 | 2 | 35 |
COP35 | 5 | 3 | 4 | 33 |
COP36 | 5 | 3 | 6 | 30 |
COP37 | 5 | 3 | 8 | 28 |
COP38 | 5 | 3 | 10 | 28 |
Particle sizes of smart nanogels obtained by QELS.
The addition of a soluble salt such as potassium nitrate (KNO3) produced a reduction of space inside the micelles because the salt creates a series of charges in the continuous phase. They produce a reduction in size of the micelle by the action of electrostatic forces external to that micelle, thereby limiting the size of the particles. This effect can be seen in the same table, so that when the concentration of KNO3 increases, the particle size is reduced, and when the concentration of KNO3 is greater than or equal to 5% (based on the total amount of monomers). Particle size has no appreciable change and remains constant.
The micrograph of a nano-synthesized samples is presented in figure 8, this figure shows the spherical nature of the obtained nanoparticles.
Variation of particle size of the nanogels. Samples COP25(6), COP26 (7), COP 28 (8) and COP29 (9).
Moreover, when these particles are subjected to changes in pH values can be clearly seen as the inclusion of molecules ionizing groups within the skeleton of the system allow the nanogel have an answer "smart" to these variations. This can be seen in Figure 8, which shows that at pH values lower than 4.5 the nanogel is in the swollen state while values close to 5 the gel collapses.
Because these nanoparticles are designed primarily for use in cancer therapy, the choice of the active ingredient can be transported by this system must comply with the desired characteristics of an anticancer drug. For this reason we have chosen the 5-fluorouracil (5FU). 5FU is a drug that blocks the methylation reaction of acid to convert deoxyuridylic thymidylic acid, by inhibiting an enzyme that is important for the synthesis of thymidine.
Chemical structure of 5-fluorouracil (5FU).
5-fluorouracil is involved in DNA synthesis and inhibits the formation of RNA. Both actions are combined to promote a metabolic imbalance that ultimately kills the cell. The inhibitory activity of the drug, by analogy with uracil nucleic acid affect the growth of neoplastic cells, preferably taking advantage of the molecule of uracil for nucleic acid biosynthesis. The effects of DNA and RNA deprivation are more affected cells grow and multiply without control over the normal. Its effectiveness is that it binds irreversibly to the enzyme thymidylate synthase, essential for the synthesis of thymine nucleotides. Thymine is one of four nitrogenous bases that make up the DNA, and lack means that DNA cannot replicate, which inhibits cell division and therefore tumor growth. 5FU structure shown in figure 9.
To keep track of the release rate of 5FU from the NIPA copolymer nanogels NPAM-2AAECM-HPLC was previously required a calibration with standards of 5-FU. 5FU standards were prepared at concentrations of 0, 10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 ppm, and injected into a liquid chromatograph, using the method described in the experimental section. After obtaining the chromatograms of standards, chromatographic peaks were integrated to obtain the area under the curve, the data obtained for this calibration is shown in table 2.
STD | Concentration (ppm) | Peak area (A.U.) | Retention time TR (minutes) |
1 | 100 | 37366 | 6,58 |
2 | 90 | 33256 | 6,58 |
3 | 80 | 30749 | 6,56 |
4 | 70 | 26572 | 6,55 |
5 | 60 | 22294 | 6,53 |
6 | 50 | 17353 | 6,51 |
7 | 40 | 14176 | 6,51 |
8 | 30 | 11406 | 6,51 |
9 | 20 | 7615 | 6,51 |
10 | 10 | 3751 | 6,51 |
Data obtained for calibration standards of 5-FU.
Before performing the action for the release of 5FU, the nanogels of NIPA-NPAM-2AAECM were loaded with the drug. Recall that the swelling of our nanogels depends on the pH of the medium in which it is, so a simple yet effective to carry the burden of these the nanogels is to introduce a known amount of nanogel in a concentrated solution of 5FU (known concentration) to a pH below 4.5 which guarantees that the nanogel will be swollen in the middle. The set is kept under constant magnetic stirring for 2 hours. After the loading time, changing the pH of the medium to a value greater than 6, which ensures that the nanogel will be collapsed. Thus, when the nanogel collapses, 5FU is retained in the polymer network and water solution ejected from the macromolecular matrix.
To quantify the total burden of nanogels was necessary to take a sample of the remaining load, as the difference in concentration, both initial (before loading) and final (after loading), will indicate the amount 5FU retained in the nanogel.
In the first instance, two experiments were conducted 5FU release two different pH values. The first experiment was performed at pH 7.4, in a release time of 2 hours. In this experiment, there should be no release from the nanogel, since, as mentioned above, the nanogel above a value of 5 on the pH scale is collapsed. However, in this experiment we can see that there is little sign of 5FU in the chromatogram obtained by HPLC, which indicates that in the release medium are molecules of 5FU. This can be attributed to the release of 5-FU molecules absorbed on the surface of nanogel, since the concentration at which 5FU is in the release medium is very small. This behavior can be seen in figure 10.
Furthermore, this experiment was to perform the release at pH 4 during a time of 2 hours, which in our case ensures that the polymer network is in a swollen state, allowing the contents within the nanogel 5FU out release to the environment by diffusion effects. As expected, the chromatogram of this test presents a significant peak of 5FU in a retention time of 6.7 minutes, characteristic of this compound. The chromatogram of this test is shown in figure 11. The total area of this peak has a value of 16,890 A.U.
Chromatogram of a sample of nanogel after 2 hours of release at pH 7.4.
Chromatogram of a sample of nanogel after 2 hours of release at pH 4.
We have synthesized a new pH- and T-responsive smart copolymeric nanohydrogel by inverse microemulsion polymerization. The size particle was determinate by QELS showing an average value of 33 nm. The success of the synthesis was confirmed by FTIR, 1H NMR and DSC. A versatile and successful synthetic strategy to obtain potential nanodevices for targeted drug delivery has been designed. NPA-based copolymeric microgels have been employed as reactive substrate for specific derivatization that led to a smart biomedical function. These precursor microgels were easily chemically modified by aminolysis reaction with amino derivatives to achieve two purposes: firstly, to introduce linkage sites for bonding with the tumor guiding molecule folic acid, which is coupled to the folate receptors in the surface of tumor cells and once internalized by receptor-mediated endocytosis, swell as result of the difference of pH and secondly, to get a specific swelling behavior that determines the capability of the microgels for intelligent therapy. The functionalization with 4-MP leads to an interesting pH-driven swelling transition. This pH-selective swelling potentially leads to an exclusive release of antitumoral drug into the cancer cells. The networks drastically swell when external pH varies from neutral to pH values around 5. There are some facts that influence this swelling behavior, such as copolymer composition.
The financial support from the Ministerio de Ciencia y Tecnología of Spain is gratefully acknowledged.
Stability constant of the formation of metal complexes is used to measure interaction strength of reagents. From this process, metal ion and ligand interaction formed the two types of metal complexes; one is supramolecular complexes known as host-guest complexes [1] and the other is anion-containing complexes. In the solution it provides and calculates the required information about the concentration of metal complexes.
Solubility, light, absorption conductance, partitioning behavior, conductance, and chemical reactivity are the complex characteristics which are different from their components. It is determined by various numerical and graphical methods which calculate the equilibrium constants. This is based on or related to a quantity, and this is called the complex formation function.
During the displacement process at the time of metal complex formation, some ions disappear and form a bonding between metal ions and ligands. It may be considered due to displacement of a proton from a ligand species or ions or molecules causing a drop in the pH values of the solution [2]. Irving and Rossotti developed a technique for the calculation of stability constant, and it is called potentiometric technique.
To determine the stability constant, Bjerrum has used a very simple method, and that is metal salt solubility method. For the studies of a larger different variety of polycarboxylic acid-, oxime-, phenol-containing metal complexes, Martel and Calvin used the potentiometric technique for calculating the stability constant. Those ligands [3, 4] which are uncharged are also examined, and their stability constant calculations are determined by the limitations inherent in the ligand solubility method. The limitations of the metal salt solubility method and the result of solubility methods are compared with this. M-L, MLM, and (M3) L are some types of examples of metal-ligand bonding. One thing is common, and that is these entire types metal complexes all have one ligand.
The solubility method can only usefully be applied to studies of such complexes, and it is best applied for ML; in such types of system, only ML is formed. Jacqueline Gonzalez and his co-worker propose to explore the coordination chemistry of calcium complexes. Jacqueline and et al. followed this technique for evaluate the as partial model of the manganese-calcium cluster and spectrophotometric studies of metal complexes, i.e., they were carried calcium(II)-1,4-butanediamine in acetonitrile and calcium(II)-1,2-ethylendiamine, calcium(II)-1,3-propanediamine by them.
Spectrophotometric programming of HypSpec and received data allows the determination of the formation of solubility constants. The logarithmic values, log β110 = 5.25 for calcium(II)-1,3-propanediamine, log β110 = 4.072 for calcium(II)-1,4-butanediamine, and log β110 = 4.69 for calcium(II)-1,2-ethylendiamine, are obtained for the formation constants [5]. The structure of Cimetidine and histamine H2-receptor is a chelating agent. Syed Ahmad Tirmizi has examined Ni(II) cimetidine complex spectrophotometrically and found an absorption peak maximum of 622 nm with respect to different temperatures.
Syed Ahmad Tirmizi have been used to taken 1:2 ratio of metal and cimetidine compound for the formation of metal complex and this satisfied by molar ratio data. The data, 1.40–2.4 × 108, was calculated using the continuous variation method and stability constant at room temperature, and by using the mole ratio method, this value at 40°C was 1.24–2.4 × 108. In the formation of lead(II) metal complexes with 1-(aminomethyl) cyclohexene, Thanavelan et al. found the formation of their binary and ternary complexes. Glycine,
Using the stability constant method, these ternary complexes were found out, and using the parameters such as Δ log K and log X, these ternary complex data were compared with binary complex. The potentiometric technique at room temperature (25°C) was used in the investigation of some binary complex formations by Abdelatty Mohamed Radalla. These binary complexes are formed with 3D transition metal ions like Cu2+, Ni2+, Co2+, and Zn2+ and gallic acid’s importance as a ligand and 0.10 mol dm−3 of NaNO3. Such types of aliphatic dicarboxylic acids are very important biologically. Many acid-base characters and the nature of using metal complexes have been investigated and discussed time to time by researchers [7].
The above acids (gallic and aliphatic dicarboxylic acid) were taken to determine the acidity constants. For the purpose of determining the stability constant, binary and ternary complexes were carried in the aqueous medium using the experimental conditions as stated above. The potentiometric pH-metric titration curves are inferred for the binary complexes and ternary complexes at different ratios, and formation of ternary metal complex formation was in a stepwise manner that provided an easy way to calculate stability constants for the formation of metal complexes.
The values of Δ log K, percentage of relative stabilization (% R. S.), and log X were evaluated and discussed. Now it provides the outline about the various complex species for the formation of different solvents, and using the concentration distribution, these complexes were evaluated and discussed. The conductivity measurements have ascertained for the mode of ternary chelating complexes.
A study by Kathrina and Pekar suggests that pH plays an important role in the formation of metal complexes. When epigallocatechin gallate and gallic acid combine with copper(II) to form metal complexes, the pH changes its speculation. We have been able to determine its pH in frozen and fluid state with the help of multifrequency EPR spectroscopy [8]. With the help of this spectroscopy, it is able to detect that each polyphenol exhibits the formation of three different mononuclear species. If the pH ranges 4–8 for di- or polymeric complex of Cu(II), then it conjectures such metal complexes. It is only at alkaline pH values.
The line width in fluid solutions by molecular motion exhibits an incomplete average of the parameters of anisotropy spin Hamilton. If the complexes are different, then their rotational correlation times for this also vary. The analysis of the LyCEP anisotropy of the fluid solution spectra is performed using the parameters determined by the simulation of the rigid boundary spectra. Its result suggests that pH increases its value by affecting its molecular mass. It is a polyphenol ligand complex with copper, showing the coordination of an increasing number of its molecules or increasing participation of polyphenol dimers used as ligands in the copper coordination region.
The study by Vishenkova and his co-worker [8] provides the investigation of electrochemical properties of triphenylmethane dyes using a voltammetric method with constant-current potential sweep. Malachite green (MG) and basic fuchsin (BF) have been chosen as representatives of the triphenylmethane dyes [9]. The electrochemical behavior of MG and BF on the surface of a mercury film electrode depending on pH, the nature of background electrolyte, and scan rate of potential sweep has been investigated.
Using a voltammetric method with a constant-current potential sweep examines the electrical properties of triphenylmethane dye. In order to find out the solution of MG and BF, certain registration conditions have been prescribed for it, which have proved to be quite useful. The reduction peak for the currents of MG and BF has demonstrated that it increases linearly with respect to their concentration as 9.0 × 10−5–7.0 × 10−3 mol/dm3 for MG and 6.0 × 10−5–8.0 × 10−3 mol/dm3 for BF and correlation coefficients of these values are 0.9987 for MG and 0.9961 for BF [10].
5.0 × 10−5 and 2.0 × 10−5 mol/dm3 are the values used as the detection limit of MG and BF, respectively. Stability constants are a very useful technique whose size is huge. Due to its usefulness, it has acquired an umbrella right in the fields of chemistry, biology, and medicine. No science subject is untouched by this. Stability constants of metal complexes are widely used in the various areas like pharmaceuticals as well as biological processes, separation techniques, analytical processes, etc. In the presented chapter, we have tried to explain this in detail by focusing our attention on the applications and solutions of stability of metal complexes in solution.
Stability or formation or binding constant is the type of equilibrium constant used for the formation of metal complexes in the solution. Acutely, stability constant is applicable to measure the strength of interactions between the ligands and metal ions that are involved in complex formation in the solution [11]. A generally these 1-4 equations are expressed as the following ways:
Thus
K1, K2, K3, … Kn are the equilibrium constants and these are also called stepwise stability constants. The formation of the metal-ligand-n complex may also be expressed as equilibrium constants by the following steps:
The parameters K and β are related together, and these are expressed in the following example:
Now the numerator and denominator are multiplied together with the use of [metal-ligand] [metal-ligand2], and after the rearranging we get the following equation:
Now we expressed it as the following:
From the above relation, it is clear that the overall stability constant βn is equal to the product of the successive (i.e., stepwise) stability constants, K1, K2, K3,…Kn. This in other words means that the value of stability constants for a given complex is actually made up of a number of stepwise stability constants. The term stability is used without qualification to mean that the complex exists under a suitable condition and that it is possible to store the complex for an appreciable amount of time. The term stability is commonly used because coordination compounds are stable in one reagent but dissociate or dissolve in the presence of another regent. It is also possible that the term stability can be referred as an action of heat or light or compound. The stability of complex [13] is expressed qualitatively in terms of thermodynamic stability and kinetic stability.
In a chemical reaction, chemical equilibrium is a state in which the concentration of reactants and products does not change over time. Often this condition occurs when the speed of forward reaction becomes the same as the speed of reverse reaction. It is worth noting that the velocities of the forward and backward reaction are not zero at this stage but are equal.
If hydrogen and iodine are kept together in molecular proportions in a closed process vessel at high temperature (500°C), the following action begins:
In this activity, hydrogen iodide is formed by combining hydrogen and iodine, and the amount of hydrogen iodide increases with time. In contrast to this action, if the pure hydrogen iodide gas is heated to 500°C in the reaction, the compound is dissolved by reverse action, which causes hydrogen iodide to dissolve into hydrogen and iodine, and the ratio of these products increases over time. This is expressed in the following reaction:
For the formation of metal chelates, the thermodynamic technique provides a very significant information. Thermodynamics is a very useful technique in distinguishing between enthalpic effects and entropic effects. The bond strengths are totally effected by enthalpic effect, and this does not make any difference in the whole solution in order/disorder. Based on thermodynamics the chelate effect below can be best explained. The change of standard Gibbs free energy for equilibrium constant is response:
Where:
R = gas constant
T = absolute temperature
At 25°C,
ΔG = (− 5.708 kJ mol−1) · log β.
The enthalpy term creates free energy, i.e.,
For metal complexes, thermodynamic stability and kinetic stability are two interpretations of the stability constant in the solution. If reaction moves from reactants to products, it refers to a change in its energy as shown in the above equation. But for the reactivity, kinetic stability is responsible for this system, and this refers to ligand species [14].
Stable and unstable are thermodynamic terms, while labile and inert are kinetic terms. As a rule of thumb, those complexes which react completely within about 1 minute at 25°C are considered labile, and those complexes which take longer time than this to react are considered inert. [Ni(CN)4]2− is thermodynamically stable but kinetically inert because it rapidly exchanges ligands.
The metal complexes [Co(NH3)6]3+ and such types of other complexes are kinetically inert, but these are thermodynamically unstable. We may expect the complex to decompose in the presence of acid immediately because the complex is thermodynamically unstable. The rate is of the order of 1025 for the decomposition in acidic solution. Hence, it is thermodynamically unstable. However, nothing happens to the complex when it is kept in acidic solution for several days. While considering the stability of a complex, always the condition must be specified. Under what condition, the complex which is stable or unstable must be specified such as acidic and also basic condition, temperature, reactant, etc.
A complex may be stable with respect to a particular condition but with respect to another. In brief, a stable complex need not be inert and similarly, and an unstable complex need not be labile. It is the measure of extent of formation or transformation of complex under a given set of conditions at equilibrium [15].
Thermodynamic stability has an important role in determining the bond strength between metal ligands. Some complexes are stable, but as soon as they are introduced into aqueous solution, it is seen that these complexes have an effect on stability and fall apart. For an example, we take the [Co (SCN)4]2+ complex. The ion bond of this complex is very weak and breaks down quickly to form other compounds. But when [Fe(CN)6]3− is dissolved in water, it does not test Fe3+ by any sensitive reagent, which shows that this complex is more stable in aqueous solution. So it is indicated that thermodynamic stability deals with metal-ligand bond energy, stability constant, and other thermodynamic parameters.
This example also suggests that thermodynamic stability refers to the stability and instability of complexes. The measurement of the extent to which one type of species is converted to another species can be determined by thermodynamic stability until equilibrium is achieved. For example, tetracyanonickelate is a thermodynamically stable and kinetic labile complex. But the example of hexa-amine cobalt(III) cation is just the opposite:
Thermodynamics is used to express the difference between stability and inertia. For the stable complex, large positive free energies have been obtained from ΔG0 reaction. The ΔH0, standard enthalpy change for this reaction, is related to the equilibrium constant, βn, by the well thermodynamic equation:
For similar complexes of various ions of the same charge of a particular transition series and particular ligand, ΔS0 values would not differ substantially, and hence a change in ΔH0 value would be related to change in βn values. So the order of values of ΔH0 is also the order of the βn value.
Kinetic stability is referred to the rate of reaction between the metal ions and ligand proceeds at equilibrium or used for the formation of metal complexes. To take a decision for kinetic stability of any complexes, time is a factor which plays an important role for this. It deals between the rate of reaction and what is the mechanism of this metal complex reaction.
As we discuss above in thermodynamic stability, kinetic stability is referred for the complexes at which complex is inert or labile. The term “inert” was used by Tube for the thermally stable complex and for reactive complexes the term ‘labile’ used [16]. The naturally occurring chlorophyll is the example of polydentate ligand. This complex is extremely inert due to exchange of Mg2+ ion in the aqueous media.
The nature of central atom of metal complexes, dimension, its degree of oxidation, electronic structure of these complexes, and so many other properties of complexes are affected by the stability constant. Some of the following factors described are as follows.
In the coordination chemistry, metal complexes are formed by the interaction between metal ions and ligands. For these type of compounds, metal ions are the coordination center, and the ligand or complexing agents are oriented surrounding it. These metal ions mostly are the transition elements. For the determination of stability constant, some important characteristics of these metal complexes may be as given below.
Ligands are oriented around the central metal ions in the metal complexes. The sizes of these metal ions determine the number of ligand species that will be attached or ordinated (dative covalent) in the bond formation. If the sizes of these metal ions are increased, the stability of coordination compound defiantly decreased. Zn(II) metal ions are the central atoms in their complexes, and due to their lower size (0.74A°) as compared to Cd(II) size (0.97A°), metal ions are formed more stable.
Hence, Al3+ ion has the greatest nuclear charge, but its size is the smallest, and the ion N3− has the smallest nuclear charge, and its size is the largest [17]. Inert atoms like neon do not participate in the formation of the covalent or ionic compound, and these atoms are not included in isoelectronic series; hence, it is not easy to measure the radius of this type of atoms.
The properties of stability depend on the size of the metal ion used in the complexes and the total charge thereon. If the size of these metal ions is small and the total charge is high, then their complexes will be more stable. That is, their ratio will depend on the charge/radius. This can be demonstrated through the following reaction:
An ionic charge is the electric charge of an ion which is formed by the gain (negative charge) or loss (positive charge) of one or more electrons from an atom or group of atoms. If we talk about the stability of the coordination compounds, we find that the total charge of their central metal ions affects their stability, so when we change their charge, their stability in a range of constant can be determined by propagating of error [18]. If the charge of the central metal ion is high and the size is small, the stability of the compound is high:
In general, the most stable coordination bonds can cause smaller and highly charged rations to form more stable coordination compounds.
When an electron pair attracts a central ion toward itself, a strong stability complex is formed, and this is due to electron donation from ligand → metal ion. This donation process is increasing the bond stability of metal complexes exerted the polarizing effect on certain metal ions. Li+, Na+, Mg2+, Ca2+, Al3+, etc. are such type of metal cation which is not able to attract so strongly from a highly electronegative containing stable complexes, and these atoms are O, N, F, Au, Hg, Ag, Pd, Pt, and Pb. Such type of ligands that contains P, S, As, Br and I atom are formed stable complex because these accepts electron from M → π-bonding. Hg2+, Pb2+, Cd2+, and Bi3+ metal ions are also electronegative ions which form insoluble salts of metal sulfide which are insoluble in aqueous medium.
Volatile ligands may be lost at higher temperature. This is exemplified by the loss of water by hydrates and ammonia:
The transformation of certain coordination compounds from one to another is shown as follows:
A ligand is an ion or small molecule that binds to a metal atom (in chemistry) or to a biomolecule (in biochemistry) to form a complex, such as the iron-cyanide coordination complex Prussian blue or the iron-containing blood-protein hemoglobin. The ligands are arranged in spectrochemical series which are based on the order of their field strength. It is not possible to form the entire series by studying complexes with a single metal ion; the series has been developed by overlapping different sequences obtained from spectroscopic studies [19]. The order of common ligands according to their increasing ligand field strength is
The above spectrochemical series help us to for determination of strength of ligands. The left last ligand is as weaker ligand. These weaker ligand cannot forcible binding the 3d electron and resultant outer octahedral complexes formed. It is as-
Increasing the oxidation number the value of Δ increased.
Δ increases from top to bottom.
However, when we consider the metal ion, the following two useful trends are observed:
Δ increases with increasing oxidation number.
Δ increases down a group. For the determination of stability constant, the nature of the ligand plays an important role.
The following factors described the nature of ligands.
The size and charge are two factors that affect the production of metal complexes. The less charges and small sizes of ligands are more favorable for less stable bond formation with metal and ligand. But if this condition just opposite the product of metal and ligand will be a more stable compound. So, less nuclear charge and more size= less stable complex whereas if more nuclear charge and small in size= less stable complex. We take fluoride as an example because due to their smaller size than other halide and their highest electro negativity than the other halides formed more stable complexes. So, fluoride ion complexes are more stable than the other halides:
As compared to S2− ion, O22− ions formed more stable complexes.
It is suggested by Calvin and Wilson that the metal complexes will be more stable if the basic character or strength of ligands is higher. It means that the donating power of ligands to central metal ions is high [20].
It means that the donating power of ligands to central metal ions is high. In the case of complex formation of aliphatic diamines and aromatic diamines, the stable complex is formed by aliphatic diamines, while an unstable coordination complex is formed with aromatic diamines. So, from the above discussion, we find that the stability will be grater if the e-donation power is greater.
Thus it is clear that greater basic power of electron-donating species will form always a stable complex. NH3, CN−, and F− behaved as ligands and formed stable complexes; on the other hand, these are more basic in nature.
We know that if the concentration of coordination group is higher, these coordination compounds will exist in the water as solution. It is noted that greater coordinating tendency show the water molecules than the coordinating group which is originally present. SCN− (thiocynate) ions are present in higher concentration; with the Co2+ metal ion, it formed a blue-colored complex which is stable in state, but on dilution of water medium, a pink color is generated in place of blue, or blue color complex is destroyed by [Co(H2O)6]2+, and now if we added further SCN−, the pink color will not appear:
Now it is clear that H2O and SCN− are in competition for the formation of Co(II) metal-containing complex compound. In the case of tetra-amine cupric sulfate metal complex, ammonia acts as a donor atom or ligand. If the concentration of NH3 is lower in the reaction, copper hydroxide is formed but at higher concentration formed tetra-amine cupric sulfate as in the following reaction:
For a metal ion, chelating ligand is enhanced and affinity it and this is known as chelate effect and compared it with non-chelating and monodentate ligand or the multidentate ligand is acts as chelating agent. Ethylenediamine is a simple chelating agent (Figure 1).
Structure of ethylenediamine.
Due to the bidentate nature of ethylenediamine, it forms two bonds with metal ion or central atom. Water forms a complex with Ni(II) metal ion, but due to its monodentate nature, it is not a chelating ligand (Figures 2 and 3).
Structure of chelating configuration of ethylenediamine ligand.
Structure of chelate with three ethylenediamine ligands.
The dentate cheater of ligand provides bonding strength to the metal ion or central atom, and as the number of dentate increased, the tightness also increased. This phenomenon is known as chelating effect, whereas the formation of metal complexes with these chelating ligands is called chelation:
or
Some factors are of much importance for chelation as follows.
The sizes of the chelating ring are increased as well as the stability of metal complex decreased. According to Schwarzenbach, connecting bridges form the chelating rings. The elongated ring predominates when long bridges connect to the ligand to form a long ring. It is usually observed that an increased a chelate ring size leads to a decrease in complex stability.
He interpreted this statement. The entropy of complex will be change if the size of chelating ring is increased, i.e., second donor atom is allowed by the chelating ring. As the size of chelating ring increased, the stability should be increased with entropy effect. Four-membered ring compounds are unstable, whereas five-membered are more stable. So the chelating ring increased its size and the stability of the formed metal complexes.
The number of chelating rings also decides the stability of complexes. Non-chelating metal compounds are less stable than chelating compounds. These numbers increase the thermodynamic volume, and this is also known as an entropy term. In recent years ligands capable of occupying as many as six coordination positions on a single metal ion have been described. The studies on the formation constants of coordination compounds with these ligands have been reported. The numbers of ligand or chelating agents are affecting the stability of metal complexes so as these numbers go up and down, the stability will also vary with it.
For the Ni(II) complexes with ethylenediamine as chelating agent, its log K1 value is 7.9 and if chelating agents are trine and penten, then the log K1 values are 7.9 and 19.3, respectively. If the metal ion change Zn is used in place of Ni (II), then the values of log K1 for ethylenediamine, trine, and penten are 6.0, 12.1, and 16.2, respectively. The log βMY values of metal ions are given in Table 1.
Metal ion | log βMY (25°C, I = 0.1 M) |
---|---|
Ca2+ | 11.2 |
Cu2+ | 19.8 |
Fe3+ | 24.9 |
Metal ion vs. log βMY values.
Ni(NH3)62+ is an octahedral metal complex, and at 25 °C its log β6 value is 8.3, but Ni(ethylenediamine)32+ complex is also octahedral in geometry, with 18.4 as the value of log β6. The calculated stability value of Ni(ethylenediamine)32+ 1010 times is more stable because three rings are formed as chelating rings by ethylenediamine as compared to no such ring is formed. Ethylenediaminetetraacetate (EDTA) is a hexadentate ligand that usually formed stable metal complexes due to its chelating power.
A special effect in molecules is when the atoms occupy space. This is called steric effect. Energy is needed to bring these atoms closer to each other. These electrons run away from near atoms. There can be many ways of generating it. We know the repulsion between valence electrons as the steric effect which increases the energy of the current system [21]. Favorable or unfavorable any response is created.
For example, if the static effect is greater than that of a product in a metal complex formation process, then the static increase would favor this reaction. But if the case is opposite, the skepticism will be toward retardation.
This effect will mainly depend on the conformational states, and the minimum steric interaction theory can also be considered. The effect of secondary steric is seen on receptor binding produced by an alternative such as:
Reduced access to a critical group.
Stick barrier.
Electronic resonance substitution bond by repulsion.
Population of a conformer changes due to active shielding effect.
The macrocyclic effect is exactly like the image of the chelate effect. It means the principle of both is the same. But the macrocyclic effect suggests cyclic deformation of the ligand. Macrocyclic ligands are more tainted than chelating agents. Rather, their compounds are more stable due to their cyclically constrained constriction. It requires some entropy in the body to react with the metal ion. For example, for a tetradentate cyclic ligand, we can use heme-B which forms a metal complex using Fe+2 ions in biological systems (Figure 4).
Structure of hemoglobin is the biological complex compound which contains Fe(II) metal ion.
The n-dentate chelating agents play an important role for the formation of more stable metal complexes as compared to n-unidentate ligands. But the n-dentate macrocyclic ligand gives more stable environment in the metal complexes as compared to open-chain ligands. This change is very favorable for entropy (ΔS) and enthalpy (ΔH) change.
There are so many parameters to determination of formation constants or stability constant in solution for all types of chelating agents. These numerous parameters or techniques are refractive index, conductance, temperature, distribution coefficients, refractive index, nuclear magnetic resonance volume changes, and optical activity.
Solubility products are helpful and used for the insoluble salt that metal ions formed and complexes which are also formed by metal ions and are more soluble. The formation constant is observed in presence of donor atoms by measuring increased solubility.
To determine the solubility constant, it involves the distribution of the ligands or any complex species; metal ions are present in two immiscible solvents like water and carbon tetrachloride, benzene, etc.
In this method metal ions or ligands are present in solution and on exchanger. A solid polymers containing with positive and negative ions are ion exchange resins. These are insoluble in nature. This technique is helpful to determine the metal ions in resin phase, liquid phase, or even in radioactive metal. This method is also helpful to determine the polarizing effect of metal ions on the stability of ligands like Cu(II) and Zn(II) with amino acid complex formation.
At the equilibrium free metal and ions are present in the solution, and using the different electrometric techniques as described determines its stability constant.
This method is based upon the titration method or follows its principle. A stranded acid-base solution used as titrate and which is titrated, it may be strong base or strong acid follows as potentiometrically. The concentration of solution using 103− M does not decomposed during the reaction process, and this method is useful for protonated and nonprotonated ligands.
This is the graphic method used to determine the stability constant in producing metal complex formation by plotting a polarograph between the absences of substances and the presence of substances. During the complex formation, the presence of metal ions produced a shift in the half-wave potential in the solution.
If a complex is relatively slow to form and also decomposes at measurable rate, it is possible, in favorable situations, to determine the equilibrium constant.
This involves the study of the equilibrium constant of slow complex formation reactions. The use of tracer technique is extremely useful for determining the concentrations of dissociation products of the coordination compound.
This method is based on the study of the effect of an equilibrium concentration of some ions on the function at a definite organ of a living organism. The equilibrium concentration of the ion studied may be determined by the action of this organ in systems with complex formation.
The solution of 25 ml is adopted by preparing at the 1.0 × 10−5 M ligand or 1.0 × 10−5 M concentration and 1.0 × 10−5 M for the metal ion:
The solutions containing the metal ions were considered both at a pH sufficiently high to give almost complete complexation and at a pH value selected in order to obtain an equilibrium system of ligand and complexes.
In order to avoid modification of the spectral behavior of the ligand due to pH variations, it has been verified that the range of pH considered in all cases does not affect absorbance values. Use the collected pH values adopted for the determinations as well as selected wavelengths. The ionic strengths calculated from the composition of solutions allowed activity coefficient corrections. Absorbance values were determined at wavelengths in the range 430–700 nm, every 2 nm.
For a successive metal complex formation, use this method. If ligand is protonate and the produced complex has maximum number of donate atoms of ligands, a selective light is absorbed by this complex, while for determination of stability constant, it is just known about the composition of formed species.
Bjerrum (1941) used the method stepwise addition of the ligands to coordination sphere for the formation of complex. So, complex metal–ligand-n forms as the following steps [22]. The equilibrium constants, K1, K2, K3, … Kn are called stepwise stability constants. The formation of the complex metal-ligandn may also be expressed by the following steps and equilibrium constants.
Where:
M = central metal cation
L = monodentate ligand
N = maximum coordination number for the metal ion M for the ligand
If a complex ion is slow to reach equilibrium, it is often possible to apply the method of isotopic dilution to determine the equilibrium concentration of one or more of the species. Most often radioactive isotopes are used.
This method was extensively used by Werner and others to study metal complexes. In the case of a series of complexes of Co(III) and Pt(IV), Werner assigned the correct formulae on the basis of their molar conductance values measured in freshly prepared dilute solutions. In some cases, the conductance of the solution increased with time due to a chemical change, e.g.,
It is concluded that the information presented is very important to determine the stability constant of the ligand metal complexes. Some methods like spectrophotometric method, Bjerrum’s method, distribution method, ion exchange method, electrometric techniques, and potentiometric method have a huge contribution in quantitative analysis by easily finding the stability constants of metal complexes in aqueous solutions.
All the authors thank the Library of University of Delhi for reference books, journals, etc. which helped us a lot in reviewing the chapter.
Edited by Jan Oxholm Gordeladze, ISBN 978-953-51-3020-8, Print ISBN 978-953-51-3019-2, 336 pages,
\nPublisher: IntechOpen
\nChapters published March 22, 2017 under CC BY 3.0 license
\nDOI: 10.5772/61430
\nEdited Volume
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\\n\\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\\n\\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\\n\\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\\n\\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\\n\\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\\n\\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\\n\\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\\n\\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\\n\\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\\n\\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\\n\\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
\\n"}]'},components:[{type:"htmlEditorComponent",content:'This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\n\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\n\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\n\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\n\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\n\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\n\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\n\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\n\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\n\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\n\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\n\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
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