**2.3.2 Hydrophilic plasticizers**

Hydrophilic plasticizers include the compounds which are without limitations or in a sufficient degree miscible with water. They are on the rule substances with very good biocompatibility, some are components of metabolic processes, and others can be easily eliminated from the organism. The most widely used are polyhydric alcohols, in the first place glycerol. The polymers plasticized with hygroscopic compounds receive water from the atmosphere in an increased degree and this water also possesses a plasticizing effect.

The thermoplastic starch is a material interesting for the use in pharmacy (Willet et al., 1997; Liu et al., 2009). It is produced by heating under pressure and under shear from a mixture of native granules and 20 % to 50 % glycerol. This composition named as opened starch was patented for implantation (Van De Wijdeven, 2010). In the temperatures of 150 to 180 °C the granules melt and a plastic amorphous material is produced (Carvalho et al. 2003). Glycerol and xylitol are important plasticizers of starch; in their presence the starch film is flexible regardless of the water content in it (Bader & Göritz, 1994). With the use of 11 % of water and glycerol or xylitol in low concentrations, an antiplasticizing action of polyalcohols on starch was observed; when a concentration of 15 % for glycerol and 20 % for xylitol was achieved, there occurred a significant decrease in Tg. Between the individual plasticizers there occurs competitive plasticization with three types of interactions: starch/plasticizer, plasticizer/water and starch/water (Chaudhary et al., 2011).

The tests for starch plasticization (cassava starch) included glycerol, sorbitol and a mixture of these two polyhydric alcohols in a ratio of 1:1 (Mali et al., 2005) in a concentration of 0, 20, and 40 g/100 g of starch. The combined effect of relative humidity and the plasticizer on the mechanical properties of films was tested. The hydrophilicity of the films of the plasticizer was the decisive factor influencing the affinity to water. The films plasticized with glycerol adsorbed more humidity and more rapidly, and they were more influenced by plasticization from the standpoint of mechanical properties. Glycerol in comparison with sorbitol and a

Plasticization is a concept which can be understood either as a physical phenomenon, or as a technological process (Kozlov & Papkov, 1982). Water is a natural plasticizer of biopolymers as well as their semisynthetic derivatives. A portion of this water is structural water, which has anomal properties (Coyle et al., 1996). Cotton cellulose at 60 % to 70 % crystallinity contains 6 % to 8 % of water, viscose does even more, and gelatin as collagen hydrolyzate

The water content influences also the properties of synthetic polymers. The polyacrylate polymer Eudragit RS used to coat the pellets with theophylline changes its mechanical and dissolution properties with the relative humidity on storage (Wu & McGinity, 2000). Tg values are decreased in the biodegradable poly(lactide-co-glycolide) in the environment of water vapours up to by 15 °C. Water content was within a range from 0.3 % to 2.6 %. It has been demonstrated that water responsible for plasticization effect was non-freezable and only a small fraction of this water absorbed from the environment caused degradation of the polymer in the same manner as bulk water. In dependence on temperature and concentration, water can act as a plasticizer and an antiplasticizer (Blasi

Hydrophilic plasticizers include the compounds which are without limitations or in a sufficient degree miscible with water. They are on the rule substances with very good biocompatibility, some are components of metabolic processes, and others can be easily eliminated from the organism. The most widely used are polyhydric alcohols, in the first place glycerol. The polymers plasticized with hygroscopic compounds receive water from the atmosphere in an increased degree and this water also possesses a plasticizing effect.

The thermoplastic starch is a material interesting for the use in pharmacy (Willet et al., 1997; Liu et al., 2009). It is produced by heating under pressure and under shear from a mixture of native granules and 20 % to 50 % glycerol. This composition named as opened starch was patented for implantation (Van De Wijdeven, 2010). In the temperatures of 150 to 180 °C the granules melt and a plastic amorphous material is produced (Carvalho et al. 2003). Glycerol and xylitol are important plasticizers of starch; in their presence the starch film is flexible regardless of the water content in it (Bader & Göritz, 1994). With the use of 11 % of water and glycerol or xylitol in low concentrations, an antiplasticizing action of polyalcohols on starch was observed; when a concentration of 15 % for glycerol and 20 % for xylitol was achieved, there occurred a significant decrease in Tg. Between the individual plasticizers there occurs competitive plasticization with three types of interactions: starch/plasticizer,

The tests for starch plasticization (cassava starch) included glycerol, sorbitol and a mixture of these two polyhydric alcohols in a ratio of 1:1 (Mali et al., 2005) in a concentration of 0, 20, and 40 g/100 g of starch. The combined effect of relative humidity and the plasticizer on the mechanical properties of films was tested. The hydrophilicity of the films of the plasticizer was the decisive factor influencing the affinity to water. The films plasticized with glycerol adsorbed more humidity and more rapidly, and they were more influenced by plasticization from the standpoint of mechanical properties. Glycerol in comparison with sorbitol and a

contains 5 % to 15 % of water, according to atmospheric humidity.

plasticizer/water and starch/water (Chaudhary et al., 2011).

**2.3.1 Water as a plasticizer** 

et al., 2005).

**2.3.2 Hydrophilic plasticizers** 

mixture of both was the most effective plasticizer, much reduced the internal hydrogen bonds between the polymer chains and enlarged the internal space in the molecular structure of starch.

Amylose and starch were plasticized with glycerol or xylitol in various concentrations up to 20 %. On the basis of water sorption, the competition of the plasticizer and water under different activities of water was evaluated. Starch interacts with plasticizers and water by changing its crystallinity. The samples of lower concentrations of the plasticizers contain more humidity in the values of the activity of water in a range of 0.11 to 0.65. With a low activity of water there occurs association of amylose and exclusion of the molecules of the plasticizer. With increasing activity of water over 0.55, lower concentrations of the plasticizer exert no effect on a balanced content of water. It was explained by a strong bondings of glycerol and xylitol on starch chains with the development of cross-linking by means of hydroxyl bonds. Water is thus excluded from the polymer matrix. With a lower activity of water, starch binds both the plasticizer and water. Its antiplasticizing limit for glycerol was found between 10 % and 15 %, for xylitol this effect at its concentrations up to 20 % was not demonstrated (Liu et al., 2011).

Chitosan, partially deacetylated chitin is a biopolymer which has been studied very intensively as a potential carrier of active ingredients for more than two decades. Chitosan salts, in particularly chloride, lactate or gluconate are surface active and filmogenic. Elasticity of films can be improved by their plasticizing. Glycerol was used as a plasticizer of chitosan on a 25% concentration. The material was tested as suitable for the preparation of matrices by mechanical kneading as an alternative procedure to the traditional procedures based on the methods of solvent casting (Epure et al., 2011). Sorption of water, changes in crystallinity and thermomechanical properties were examined when the samples with and without the plasticizer were stored in the surroundings with a different relative humidity. Glycerol has been demonstrated to increase the hydrophilic character of films and acts in a plasticizing manner on the mechanical properties. The most suitable for film storage is the environment of the atmosphere with medium values of relative humidity (57 % RH).

The invention provided an orally dissolving capsule comprising pullulan, a plasticizer, and a dissolution enhancing agent (Rajewski & Haslam, 2008). Polyhydric alcohols such as glycerol, propylene glycol, polyvinyl alcohol, sorbitol and maltitol were proposed.

The biodegradable film was prepared from a blend of native rice starch-chitosan with an addition of various plasticizers in concentrations from 20 % to 60 %, using sorbitol, glycerol and polyethylene glycol 400. With an increased activity of water, a higher content of absorbed water was demonstrated. With increasing relative humidity the time of achievement of a balanced concentration of water was prolonged from 13 days to 24 days. Polymer films plasticized with polyethylene glycol 400 did not increase the content of water with increasing atmospheric humidity (Bourtoom, 2008).

Gelatin is a biopolymer produced by hydrolysis of collagen. Its surface activity and ability to form elastic and firm films are used. Its mechanical properties can be improved by adding plasticizers. Permeability of water vapours, mechanical and thermal properties of gelatin films of the gelatin produced from bovine and porcine hides were measured. The films contained 15 g to 65 g of sorbitol per 100 g of gelatin. Permeability of the conditioned films

Pharmaceutically Used Plasticizers 55

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

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

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

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

below the maximal tolerated concentrations (Tsumura et al., 2002).

tests on bacteria and on mammals, they did not induce tumours.

contact (Clayton & Clayton, 1993-1994).

the guinea pig skin and rabbit eye.

 Diethyl phthalate (DEP) Dibutyl phthalate (DBP)

 Fractionated coconut oil Acetylated monoglycerides

 Triacetin (TA) Vegetable oils

Diesters and triesters of alcohols:

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

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 (Kovalczyk & Baraniak, 2011).

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 & Fricke, 1984).
