**3. Free membranes**

72 Recent Advances in Plasticizers

There are two substantial forces which influence the polymer adhesion: the strength of the interfacial bonds between the polymeric film and the surface of the solid, and the internal stresses within the film coating. The interfacial bonding between the tablet surface and polymer coating is made primarily with hydrogen bonds, to a lesser extent with dipoledipole and dipole-induced dipole interactions. The addition of plasticizing agents to coating formulations generally decreases the internal stress in the film by decreasing both the elastic modulus and the glass transition temperature of the film coating (Johnson Hathaway,

The measured force of adhesion, therefore, would be expected to increase with increased plasticization of the polymer. The contradictory results may be due to the interaction of the plasticizing agent with the polar groups of the polymer within the film structure (Felton

The adhesive property of Eudragit films is effected with organic esters used as plasticizers (triacetin, diethyl phthalate, dibutyl phthalate and tributyl citrate were tested). The molecular weight and solubility parameters of the plasticizer seemed to play an important role in changing the adhesive strength of the Eudragit films. The adhesion of Eudragit films is markedly increased when the concentration of the plasticizer is greater than 25%. Tributyl citrate may be the best choice of the plasticizer for the Eudragit film, particularly for the

The molecular weight and solubility parameters of the plasticizer seemed to play an important role in changing the adhesive strength of the Eudragit films (Lina et al., 2000).

The water soluble plasticizers, triethyl citrate and polyethylene glycol 6000, lower the Tg of the films to a greater extent than the hydrophobic plasticizers, tributyl citrate and dibutyl sebacate, and the coatings with the hydrophilic plasticizers exhibit stronger adhesion

The study of the influence of plasticizers on the adhesion of the acrylic polymer to either hydrophilic or hydrophobic tablet compacts revealed that increasing tablet hydrophobicity decreased adhesion of both cellulosic and acrylic polymers (Felton McGinity, 1996, 1997;

Polymer-plasticizer incompatibility, plasticizer migration out of polymer (and particularly leaching of plasticizer) as well sticking and aging of the film coated dosage influence not only the mechanical properties, but also drug release (Amighi Moes, 1996; Arwidsson et al., 1991; Bodmeier Paeratakul, 1992; Skultety Sims, 1987). For example, dibutyl sebacate unlike triethyl citrate was found to remain within the polymeric coating upon exposure to the dissolution media and thus mechanical properties of coatings during drug release are maintained. Leaching of triethyl citrate out of the film resulting in decreased mechanical

A blend of polymers can be used in the coating of solid dosage forms, and then the type of plasticizer must be chosen responsibly to ensure good quality of the coating. If the plasticizer has different affinities to the individual polymers forming the blend, the

1991; Rowe, 1981, 1992).

McGinity, 1999).

Eudragit E film.

Rowe, 1977).

(Entwistle Rowe, 1979; Felton McGinity, 1997).

**2.2 Factors negatively influencing the coating** 

resistances facilitates crack formation.

A membrane can be in the form of a free film containing the active ingredient, or it can form the outer wall of the body which is its reservoir together with other excipients. The membrane has a defined thickness; it can be porous or compact, it can contain, in addition to the active ingredient, various excipients including plasticizers. In the case of dosage forms such as buccal and sublingual films, capsules intended for oral, rectal or vaginal administration, and inserts placed into cavities, their membranes and membrane systems possess the function of (1) the primary coating increasing stability and enabling administration, (2) separation from and protection against the influence of the biological environment after administration, or (3) controlled release.

Ethyl cellulose films of standard thickness were prepared by slow evaporation of the solvent from chloroform solutions of a 48.8% ethoxylated cellulose derivative and three plasticizers: classic dibutyl sebacate, vitamin D3 and vitamin E. The individual plasticizers were used in nine different concentrations up to 80 %. It has been demonstrated that primarily αtocopherol (vitamin E) in concentrations of 40 to 50 % is an advantageous and effective plasticizer of ethyl cellulose from the standpoint of toxicity, ultimate strength, toughness, and Young modulus (Kangarlou et al., 2008). Ethyl cellulose of the identical parameters was employed in the preparation of films using the same method, diethyl sebacate in a 40% concentration being used as the plasticizer. Chloroform was evaporated using the standard very slow evaporation procedure. A suitable velocity of stress action was found for the most conclusive stress-strain deformation diagrams (Sogol & Ismaeil, 2011).

Thin films made of poly(lactide-co-glycolide) were prepared from a dichloromethane solution with additions of 15%, 25%, or 50% polyethylene glycol 8 000 and 35 000, yielding potential implants of 40 µm in thickness containing the antitumor drug paclitaxel. Raman spectrometry was used to demonstrate partial separation of the plasticizer (Steele et al., 2011).

Soft gelatin capsules were formed by a wall of varying thickness containing about 40 to 45 % of gelatin, which is plasticized with water 20 to 30 % and glycerol, or sorbitol 30 to 35 % (Marques et al., 2009). The plasticizer increased the flexibility of gelatin, with increasing concentration to 45 % it decreased the sensitivity to humidity, decreased the tendency to recrystallization, decreased tensile strength and the elastic modulus, increases elongation at break (Bergo & Sobral, 2007).

Protein films possess good mechanical properties, but they are very sensitive to atmospheric humidity. Their hygroscopic character can be decreased by adding a hydrophobic plasticizer. Esters derived from citric acid such as triethyl citrate, tributyl citrate, acetyl triethyl citrate and acetyl tributyl citrate were tested in various concentrations (Andreuccetti et al., 2009). Their limited miscibility with an aqueous solution of gelatin was solved by

Pharmaceutical Applications of Plasticized Polymers 75

Matrix polymeric systems are heterogeneous systems composed of a polymer, plasticizers, other additives and the active ingredient, and they can be porous. They include primarily oral preparations with prolonged or retarded release of the active ingredient, or implants

Extrusion is a process of conversion of raw materials to form a product of a uniform shape and density by forcing it through a nozzle under controlled conditions (Breitenbach, 2002). Plasticizers facilitate the manufacture and improve the parameters of preparations such as porosity, tortuosity, mechanical resistance, diffusivity, or compatibility of the components. Hot-melt extrusion, in which it is possible to process materials with higher Tg values, is

Due to their little volatility, the plasticizers which are in the solid state in room temperature are advantageous. For plasticization of polyacrylate polymers, e.g. matrices from Eudragit RS PO, citric acid, in particular its monohydrate, turned out to be useful. Tensile strength and the elastic modulus were decreased, whereas elongation was increased. The plasticizing effect of citric acid achieved the plateau stage at its 25% concentration in polyacrylate, i.e. when achieving the solubility value of (Schilling et al., 2007). The continous process of extrusion and subsequent division of the extruded body into tablets was used in the formulation of enterosolvent preparations from the polyacrylate material Eudragit L100-55. Mixtures of two plasticizers, triethyl citrate and citric acid, were employed. Triethyl citrate markedly decreased the Tg value and thus decreased the temperatures in the individual zones of the extruder and the pressure during extrusion. The optimal concentration of citric acid was 17 %. 5-aminosalicylic acid was employed as the model active ingredient (Andrews

Subcutaneous implants of a diameter of 1.5 mm and length of 18 mm weighing 40 mg containing thermolabile recombinant proteins and peptides were prepared from plasticized poly(lactide-co-glycolide) as the carrier and ethanol as the plasticizer (Mauriac & Marion, 2006). First, a 10% solution of the polymer in ethanol was prepared, followed by drying to achieve an ethanol concentration of 20 %. The polymer plasticized in such a way was mixed with the unplasticized one and the mixture was extruded at 75 °C. The following step was grinding of the extrudate at -5 to -10 °C with an ethanol content of 8 %. The active ingredient and other additives were added to the powder and the mixture was extruded at a temperature up to 70 °C. Another example of extremely volatile plasticizer is supercritical carbon dioxide (Lakshman, 2008). This compoud is added to facilitate processing of

Starch is the biomaterial which has excellent parameters from the standpoint of availability, price and biocompatibility. In the presence of water and suitable polar hydrophilic compatible plasticizers during extrusions at temperatures over 100 °C amylopectin flows and at the same time native starch granules partially melt. The material can have two markedly different values of Tg. Interactions between starch and plasticizers with strong hydrogen bonds (Pushpadass et al., 2008) were demonstrated in it. The use of glycerol in a concentration of 25 % and secondary plasticizers such as stearic acid, sucrose or urea in markedly lower concentrations are advantageous. It thus yields a flexible material suitable

**5. Matrix polymeric systems** 

advantageous.

et al., 2008).

materials by extrusion method.

as a biodegradable drug carrier.

produced by extrusion or hot moulding or compression.

emulsification of plasticizers with soya lecithin. The tensile stress of the material was decreased with increasing concentrations of the plasticizer, permeability of water vapours was moderately increased.

Biodegradable films were prepared from a protein isolated from sunflower oil with additions of various polyalcohols, such as glycerol, ethylene glycol, propylene glycol, polyethylene glycols. The mixture was subjected to thermo-moulding at 150 °C using 150 MPa. Tensile strength of films was 6.3 to 9.6 MPa and elongation at break was 23 to 140 %. Permeability of water vapours was low; films were resistant against aqueous environment only in a limited degree, as migration of the plasticizer took place (Orliac et al., 2003). The plasticizers used were evaluated as suitable for protein films.
