**2.3.3 Plasticizers with limited miscibility with water**

The border between hydrophilic and hydrophobic plasticizers is not sharp, being connected with its solubility in water. Plasticizers which possess solubility in water lower than 10 % are frequently employed for the formulation of dosage forms either in the form of solutions or they are emulsified in the aqueous phase. On the rule they are highly biocompatible esters of dicarboxylic and tricarboxylic acids or glycerol esters. These items are mentioned below. In the selection of a suitable plasticizer of this category of less polar compounds, two principal criteria are taken into consideration, (1) depression of the glass transition temperature and (2) the parameter of solubility. In the next order of importance are the mechanical properties of plasticized polymers, such as decreased strength, decreased elastic modulus and increased elongation at break. Another parameter for the selection for formulation studies is a decrease in the internal stress or the effect on the permeability of the material and for the release of the active ingredient.

Diesters and triesters of acids:


Diesters and triesters of alcohols:

Triacetin (TA)

54 Recent Advances in Plasticizers

increased with sorbitol content. The origin of gelatin was important from the standpoint of measured parameters only at a sorbitol concentration higher than 25 g/100 g of gelatin. The samples containing 15 g to 35 g of sorbitol/100 g of gelatin heated in the first cycle possessed a marked glass transition followed by a sol-gel transition. With increasing sorbitol concentration, the glass transition was wider, typical of the system with phase separation. To predict Tg values in the function of sorbitol concentration, the model according to

The effect of glycerol in a concentration of 3 – 7 % and sorbitol 4 – 8 % on the permeability of water vapours, humidity content, solubility and optical transparency of films prepared from the protein isolated from pea seeds was investigated. With an increasing glycerol content the permeability of vapours and humidity content in the films was increased, their solubility was not influenced, films plasticized with sorbitol, on the other hand, possessed lower permeability and humidity content and higher solubility. Different behaviour of plasticized films was explained by different hygroscopic plasticizers. A change in the pH value of solutions in the preparation of films from 7.0 to 11.0 did not influence most parameters

Glycerol serves a number of functions in soft gelatin capsules – it is a humectant, plasticizer, in a higher concentration it serves as a preservative. It influences the helix formation from linear protein chains of gelatin in dependence on concentration. Its effect on the formation of helices decreases to 10 %, and then increases, on storage the degree of organization of the structure grows more in hard capsules than in the soft ones. With an increasing glycerol concentration, the extent of changes in the structure on storage is increased (Hüttenrauch &

The border between hydrophilic and hydrophobic plasticizers is not sharp, being connected with its solubility in water. Plasticizers which possess solubility in water lower than 10 % are frequently employed for the formulation of dosage forms either in the form of solutions or they are emulsified in the aqueous phase. On the rule they are highly biocompatible esters of dicarboxylic and tricarboxylic acids or glycerol esters. These items are mentioned below. In the selection of a suitable plasticizer of this category of less polar compounds, two principal criteria are taken into consideration, (1) depression of the glass transition temperature and (2) the parameter of solubility. In the next order of importance are the mechanical properties of plasticized polymers, such as decreased strength, decreased elastic modulus and increased elongation at break. Another parameter for the selection for formulation studies is a decrease in the internal stress or the effect on the permeability of the

Couchman and Karasz for the ternary system was employed (Sobral et al., 2001).

(Kovalczyk & Baraniak, 2011).

**2.3.3 Plasticizers with limited miscibility with water** 

material and for the release of the active ingredient.

Diesters and triesters of acids:

 Acetyl triethyl citrate (ATEC) Dibutyl sebacate (DBS)

 Triethyl citrate (TEC) Tributyl citrate (TBC)

Fricke, 1984).


They are the plasticizers which are added to synthetic polymers with lower polarity in different fields of human activity. Many of them are encountered in foodstuffs. The team of analytical chemists of the Japanese National Institute of Health Sciences carried out an analysis of 93 samples of foodstuffs from the standpoint of the presence of 10 plasticizers (4 phthalates, 3 adipates, 1 sebacate, 1 citrate, and 1 triglyceride) and used as additives to the covers and vessels of various Japanese manufacturers. The method of gas chromatography/mass spectrometry revealed higher concentrations of diacetylauroyl glycerol, which did not originate from contamination with plastics, but it was used in children's food as an additive. Acetyl tributyl citrate was found in the bottles with sake, migrating from the bottle caps seals. This one as well as the other plasticizers were deep below the maximal tolerated concentrations (Tsumura et al., 2002).

Triesters of citric acid are considered to be very safe. They possess very advantageous parameters of biocompatibility. Their acetylated forms are markedly hydrophobic, mainly acetyl tributyl citrate. In acute, short-term, subchronic and chronic testing they are relatively non-toxic. After ocular and dermal administration to rabbits they were non-irritating, in guinea-pigs acetyl triethyl citrate acted as a sensitizer, whereas acetyl tributyl citrate did not. According to Cosmetic Ingredient Review Expert Panel, esters of citric acid are not considered to be sensitizers (Johnson, 2002). After intravenous administration they decrease blood pressure and spasms of intestinal muscles. The compounds were not genotoxic in the tests on bacteria and on mammals, they did not induce tumours.

Dibutyl sebacate is a widely used plasticizer in pharmacy. Its solubility in water is 40 mg/l at 20 °C, it is odourless and colourless. It possesses very favourable thermal characteristics, above -10 °C it is liquid, at 344 °C is boiling point. The toxicological data indicate that this compound is practically non-toxic after oral administration and also non-irritating in dermal contact (Clayton & Clayton, 1993-1994).

Phthalates are effective plasticizers of many polymers. With regard to the fact that in the case of some pharmaceutical applications, in particular in film coating of tablets, they are used in very small amounts they are still in use; it is, above all, dibutyl phthalate (Lowell Center for Sustainable Production, 2011) and diethyl phthalate (World Health Organization, 2003).

Triacetin has been very often used as a plasticizer and a solvent in pharmaceutical and cosmetic products. It has been affirmed as a GRAS product by FDA for human use in the food industry, and it is safe for cosmetic products (Zondlo & Fiume, 2003). After acute shortterm oral administration and dermal exposure it is not toxic or mutagenic; it feebly irritates the guinea pig skin and rabbit eye.

Pharmaceutically Used Plasticizers 57

The influence of methylparaben, ibuprofen, chlorpheniramine maleate and theophylline on the mechanical properties of polymeric films of Eudragit® RS 30 D was studied. The results demonstrated that the glass transition temperature of the Eudragit® RS 30 D decreased with increasing levels of methylparaben, ibuprofen and chlorpheniramine maleate in the polymeric coatings. The addition of methylparaben to Eudragit® RS 30 D resulted in significant changes in the mechanical properties, making the polymer softer and more

Drug release from polymer drug delivery system is modified by the method of their formation, or by using an appropriate polymer or additive, which could also be a plasticizer. Modified release includes delayed release, extended release (prolonged, sustained), and

Dosage forms based on polymeric carriers can be classified according to the mechanism of drug release into the following categories: (i) Diffusion-controlled drug release either from a non-porous polymer drug delivery system or (ii) from a porous polymer drug delivery system, and (iii) disintegration controlled systems (Khandare & Haag, 2010). Diffusion of a drug within a non-porous polymer drug delivery system occurs predominantly through the void spaces between polymer chains, and in the case of a porous polymer drug delivery system by diffusion of a drug through a porous or swelling polymer drug delivery system. The plain fact is that the plasticizer type and concentration must influence the drug release as plasticizers reduce polymer-polymer chain secondary bonding, and provide more mobility for the drug. Plasticizer leaching out of the polymer results in pore formation for burst release of the drug. Subsequent release stage of drug is based on diffusion through the

Non-biodegradable polymers are characterized by their durability, tissue compatibility, and mechanical strength, which endure under in vivo conditions without erosion or considerable degradation. Polyurethane, poly(ethylene vinyl acetate), and polydimethylsiloxane are examples of polymer films that follow predictable Fickian diffusion or can be modified for linear or near zero order release. One drawback of these non-biodegradable polymer devices is an occasional need for a second surgical procedure to remove the device, which leads to an increased cost and associated discomfort /

Drug release from biodegradable polymers is depended on the way of erosion and degradation. The most commonly employed class of biodegradable polymers are the polyesters, which consist mainly of poly(caprolactone), poly(lactic acid), poly(glycolic acid) and copolymers of lactic and glycolic acids. Their degradation mechanism is non-enzymatic random hydrolytic chain scission established. Polymer drug delivery system can be classified in bulk-eroding systems, surface-eroding systems, or systems undergoing both surface and bulk erosion. Polyanhydrides and polyorthoesters degrade only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the drug delivery system. Poly(lactic acid) and poly( lactic-co-glycolic acid) are reported to undergo

both surface and bulk erosion which probably disturbs an even rate of drug delivery.

flexible. The Tg of the polymer was significantly reduced (Wu McGinity, 1999).

**3. Drug release influenced by plasticizers** 

pulsatile release (Chamarthy & Pinal, 2008).

dense polymer phase.

inconvenience for the patient.

### **2.3.4 Oligomeric and polymeric plasticizers**

An advantage of the plasticizers of this type is a decrease in or a full prevention of their migration from materials (Rasal et al., 2010).

Polyesters derived from aliphatic hydroxy acids are compounds which have been very intensively studied and employed as biodegradable and renewable thermoplastic materials with a potential of replacing the conventional polymers based on mineral oil products. These polyesters are used as carriers of active ingredients with a period of release of these substances for weeks to months. They are the products of polymerization of cyclic dimers, lactones via ring opening method, or the substances developed by a polycondensation reaction, e.g. poly(lactic acid), poly(lactide-co-glycolide). They are mostly polymers which in the glassy state have a small elongation at break. For their plasticization highly biocompatible, if possible completely biodegradable compounds are suitable. As the very suitable ones were demonstrated oligoesters or low-molecular polyesters of identical or similar aliphatic hydroxy acids as plasticized polymers (Martin & Avérous, 2001), and polyesteramides were also proposed (Ljungberg et al., 2005). Polyethylene glycols (PEG) are also suitable for these purposes, their miscibility decreases with molecular mass (Baiardo et al., 2003). PEG with a value of Mn 20 000 very effectively plasticized in a 40 % concentration of poly(L-lactic acid) (Kim et al., 2001). PEG in a concentration above 50 % possesses increased crystallinity, an increased module and decreased ductility (Sheth et al., 1997). Polypropylene glycol also exerts a plasticizing effect on poly(L-lactic acid), its effect on a decrease in crystallinity is lower than in PEG (Kulinski et al., 2006). A blend of two plasticizers called multiple plasticizer, triacetin and oligomeric poly(1,3-butanediol), significantly influences the elastic properties and tensile strength (Ren et al., 2006).
