1.3 Stimuli-responsive Components
1.3.1 Phase Transitions
Polymers are the most widely used components of stimuli-responsive systems since they can be prepared with an unequalled richness of structures that enable many phase transitions to occur, leading to different states of conformation and association. Historically, the elucidation of the transitions began in 1940 when Flory71 and Huggins72 paid attention to the phase separations in polymer solutions caused by changes in the polymer–solvent or polymer–polymer interactions. These transitions are of first order except when near the critical point, where they can be of higher order. Later, the study of more complex systems and the evaluation of polypeptides and biological macromolecules attracted the interest of many researchers, who have notably contributed to identify more transitions and to elucidate their thermodynamics and kinetics.
Detailed historical reviews on the understanding of the phase transitions can be consulted elsewhere.73Up to now ten transitions have been discovered, more than half being exclusive to polymers. The phase transitions are mainly of first order or second order. In the first case, the extensive thermodynamic quantities of volume, energy, entropy or number of moles of the macromolecules show a discontinuity as a function of the intensive quantities of pressure, temperature, chemical potential, etc. In the second-order case, no discontinuity is evident, but it appears when the derivatives of the extensive thermodynamic quantities are plotted. Mainly, to be useful as a stimuli-sensitive component for drug delivery, the polymer has to respond to the appearance/disappearance of the stimulus undergoing a first-order phase transition, accompanied by a change in the specific volume of the polymer.74,75
The transitions can be classified as a function of the number of macro- molecules involved in the process, as follows:73
A) Transitions within one molecule, which occur because the sequential connectivity of the monomers along the polymer chain makes the monomers distinguishable from each other, differently from what happens when the monomers are free in a solution that behave similarly.
This set of transitions comprises:
i) Polymer threading a membrane, which occurs when a membrane that separates two solutions has holes that enable the passage of single polymer chains. Instead of completely diffuse from one solution to other, the chains remain in the holes attaching/detaching their ends to each side of the membrane. The transition is of first order.
ii) Helix to random coil transitions, typical of single-stranded poly- peptides, double-stranded DNA and triple-stranded collagen.
A change in temperature or chemical potential alters the intra- and inter-strands hydrogen bonds and triggers diffuse, first-order and second-order transitions in the polypeptides, collagen and DNA, respectively. It should be noted that the first-order transitions of collagen are responsible for their role as the main structural protein in animals, since they confer elasticity. Furthermore, DNA in the cells does not pack alone, but with other molecules to undergo first-order From Drug Dosage Forms to Intelligent Drug-delivery Systems 11
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transitions and to be more packed, since a second-order transition of naked DNA would lead to a random coil conformation with dimensions larger than those of the cells.36
iii) Adsorption of an isolated polymer, which refers to polymers that interact with surfaces being partially adsorbed forming trains and loops.76If one end of the polymer is attached to the surface, the other end remains free, and the monomers do not have attraction for the surface, so the number of contacts with the surface is limited to 1.
Above the transition temperature, the number of contacts increases proportionally to the molecular weight of the polymer. In this case, the transition is of second order.
iv) Equilibrium polymerization/1D crystallization, as occurs when polymer chains are immersed in a solution of monomers. The chains are far apart from each other and grow (decrease) by means of the addition (deletion) of monomers at one end. The addition of the monomers alters the energy of the polymer and thus, for a certain value, the chain length changes from finite to infinite, experiencing a first-order tran- sition. If the polymer chains interact with each other the scenario is more complicated and second-order transitions may be observed.77 v) Collapse transition, which refers to the competition between the
attractive interactions among monomers that drive the self-collapse of the polymer, and the entropy of the polymer chains (rubber elas- ticity) that tries to expand the polymer.78,79 Since each monomer occupies a certain volume in the polymer and the monomers cannot penetrate each other, there is repulsion at short distances. Such repulsion prevails in a good solvent and thus the polymer coils swell.80 A change in the environmental conditions, such as temperature, pH or solvent composition, can modify the balance between the free energy of the internal (polymer–polymer and polymer–solvent) interactions and the elasticity component. If the attractive interactions between monomers become strong enough, a coil–globule transition occurs at a condition calledypoint.36This is what occurs when the polymer chains are cross-linked forming a three-dimensional network (hydrogel). In a good solvent, the chains confined between two adjacent cross-linking points tend to behave as polymer coils. If the solvent conditions change towards they point, each subchain undergoes a coil-globule transition and, as a result, the network as a whole shrinks. Namely, a volume phase transition occurs, as proved experimentally for first time by T. Tanaka in 1978.81Hydrogel collapse can be driven by any one of the four basic types of inter-molecular interactions operational in water solutions and in biological systems, namely, by hydrogen bonds and van der Waals, hydrophobic and Coulomb interactions.82 The theoretical basis of the critical phenomena in cross-linked networks can be consulted in detail elsewhere.64,81,83The enormous number of papers about this transition, compared to the others, is mainly related to the
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wide scope of applications that the swelling–collapse phenomenon may have, since the volume phase transition can occur under physio- logical conditions and notably modifies the flow of fluids through the network and also the diffusion of solutes, such as drugs.84 The five transitions described above have in common that they are attributable to the fact that the monomers are connected into flexible long chains and, therefore, small changes in the intensive thermodynamic variables (namely, temperature, pressure, chemical potential) lead to drastic changes in the polymer conformation.
B) Transitions within collections of molecules
i) Liquid crystals/plastic crystals. It has been shown that, above a certain concentration, a dispersion of rigid rods changes from isotropic (random) to nematic (parallel alignment) phase; namely, the rigid rods cannot freely orient. In the isotropic phase, the centre of the mass is liquid and the rods can adopt any orientation. By contrast, in the nematic phase the freedom of the rods to orientate is restricted, although the centre of the mass still has liquid-like freedom (namely, the translational degrees of freedom are maintained). The ordered alignment enables maximum packaging (entropy driven process) and the side groups of the rods to stabilize the nematic phase through favorable interactions between each other. If the system is cooled down, the centre of the mass loses its translational degrees of freedom and a crystal is formed.
ii) Glass transitions/sol-gel transitionsare due to a drastic decrease in the configurational entropy. As the temperature of a polymer goes down, the small mobile rods that form each chain and make the polymer flexible (rubber phase) become fewer and larger and therefore more difficult to pack. At a certain temperature, close to the conditions of zero configurational entropy, the rigid rods become stuck in a randomly ordered structure, because each rigid portion cannot accommodate the energetic preferences of all its neighbors simul- taneously. This second-order transition leads to the formation of a glass phase. This phenomenon is similar to the situation in which more cross-linking points are introduced among the chains of a polymer dispersed in a solvent and a sol-gel transition is triggered.
iii) Crystallization. Diluted polymer solutions crystallize when the constituent rods align to form ordered, lamellar structures, instead of the disordered ones reported above.85
iv) Liquid–liquid transitions/polymer blends. Phase separation phenomena in randomly mixed polymers are dictated by the fact that each polymer prefers to interact with itself and only the entropy favors the mixing. The entropy of mixing is quite large for short polymers, but becomes negligible for large polymers. Thus, in the latter case, the enthalpy component is predominant and triggers the separation of the polymers into nearly pure phases of each one.
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v) Block copolymers/membranes-micelles-vesicles. Incompatible polymers can be attached together in the form of block copolymers to prevent each of them moving far away. Nevertheless, the tendency to phase separate persists and it leads to microphase separation, namely, a pattern of microdomains, each containing mainly one of the blocks, separated by thin inter-phase regions.36 Depending on the relative length of each block, the microdomains can take different shapes, forming lamellar, cylindrical or spherical phases. Free-standing membranes, micelles and vesicles can be considered as block copolymer-based phase systems, to which enough solvent has been added to maintain individualized the layers, the cylinders or the spheres.
In addition to the ten classes of transitions described above, it might occur that a material suddenly changes its chemical nature (e.g. rupture of certain bonds by hydrolysis or oxidation/reduction) and transforms into another material with different groups. Obviously, thermodynamic transitions can accompany such chemical transformation. Furthermore, it should be taken into account that one transition does not exclude the occurrence of others.
Conversely, the transitions are frequently coupled and there are many examples in Nature of such couplings; some of those that refer to natural macromolecules are the cause of detrimental effects on human health (e.g. sickle-cell anemia, phi cell body cancers, scleroderma,etc.).73In fact, it could be stated that organic polymers that can undergo phase transitions are essential for all evolved life- forms, since they are the only material that can fulfill the three main requirements of living systems: i) minimal complexity to form and function, ii) ability to produce different structures in a reproducible way and iii) ability to transmit all information necessary to the forms and functions.