**2.1.4 Plasticizer leaching out of polymer and methods of reduction**

Plasticizer migration refers to any method by which a plasticizer leaves a polymer to a solid, liquid or gas phase, which includes solid–solid migration, evaporation of plasticizer, and liquid leaching. These mentioned processes signify the loss of plasticizers from the plasticized polymeric system. The most important way of plasticizer migration within the polymer drug delivery system represents its leaching by physiological fluids after application of the dosage form. Leaching is the major trouble encountered during the plasticizing of polymeric drug delivery systems, as it can eventually result in drastic alteration in all the functions of the plasticizer, and thus the properties of the initially plasticized polymer system, notably the incorporated drug release patterns.

Plasticized polymers used in drug delivery systems come to contact with liquid after application into the body. Plasticizers tend to diffuse down the concentration gradient to the interface between the polymer surface and the external medium. The interfacial mass transport to the surrounding medium has been found to be the limiting step rather than diffusion of the plasticizer through the matrix to the surface. This rate is usually a function of temperature and initial plasticizer concentration (Foldes, 1998). If plasticizers leach out to a liquid, polymers fail to retain their flexibility while the loss of plasticizers leaves the polymers inappropriate for the desired application. Leaching issue is one of the toughest challenges regarding the research of plasticizers today.

The most effective approaches how to reduce the leaching of plasticizers into physiological fluids are particularly surface modifications. Among a variety of surface modification techniques, (i) surface cross-linking, (ii) modification of surface hydrophilicity/lipophilicity

Pharmaceutically Used Plasticizers 51

classified it as 'possibly carcinogenic to humans' in 1980s (Murphy, 2001). The mechanisms by which DEHP may cause various adverse effects in humans are likely to be multiple and variable, and are not well understood. DEHP belongs to a class of chemicals called "peroxisome proliferators". The greater exposure source is particularly relevant for individuals who are ill, and therefore potentially less able to withstand any toxicant

Particular concern has been raised in neonatal care applications because newborns receive among the highest doses of DEHP from blood transfusions, extracorporeal membrane

Infants and children receiving intravenous total parenteral nutrition infused using the typical PVC-DEHP tubing and ethylene vinyl acetate bags with PVC-DEHP connections potentially receive considerable amounts of DEHP every day. DEHP is extracted from the bags and tubing due to the high solubility of DEHP in lipids and DEHP extraction by total parenteral nutrition depends on the lipid content of each total parenteral nutrition

Adults can also be subjected to DEHP exposure from medical plastics. Kambia et al. (Kambia et al., 2001) studied the leachability of DEHP from PVC haemodialysis tubing during maintenance haemodialysis of 10 patients with chronic renal failure. The patient blood obtained from the inlet and the outlet of the dialyzer was analyzed during a 4 h dialysis session. An average DEHP quantity of 123 mg was extracted from tubing during a single dialysis session, of which approximately 27 mg was retained in the patient's body. The detrimental dose for humans has been estimated at 69 mg/kg per day whereas the average daily exposure to DEHP is much lower (2.3–2.8 mg/kg in Europe and 4 mg/kg in the US). (Murphy, 2001). Application of DEHP as plasticizer was found to have adverse effects on the biocompatibility of the plastic materials used in medical devices. Upon contact with blood, albumin is instantly absorbed on the polymer surface, followed by globulin

There are a number of techniques which could help minimize health and environmental problems owing to the use of leachable plasticizers. One simple way to do this is to use alternative flexible polymers (e.g. polyolefins), which require less or no plasticizers, to accomplish some surface modification, or use plasticizers that have less volatility and leachability, and thus low toxicity. Because it is cheap, clear, and flexible, PVC remains the most widely used material by manufacturers and end users of medical bags and

Pharmaceuticaly used plasticizers are often distinguished into hydrophilic and hydrophobic, or low molecular weight, oligomeric and polymeric. Water insoluble plasticizers have to be emulsified in the aqueous phase of the polymer dispersions. Plasticizers are incorporated in the amorphous phase of polymers while the structure and size of any crystalline part remains unaffected (Fedorko et al., 2003). The water has an exceptional position as the inherent plasticizer of biopolymers, mainly polysaccharides

oxygenation and respiratory therapy. (Sjoberg et. al., 1985; Loff et al., 2000).

preparation and the flow rate (Kambia et al., 2003).

**2.3 Classification of pharmaceuticaly used plasticizers** 

exposure (Tickner et al., 1999).

(Baier, 1972).

tubing.

and proteins.

by grafting of water soluble polymers to the surface of biomaterials, (iii) surface coating and (iv) surface extraction have been used.

Surface modification of polymers not only prevents the plasticizer from leaching but also improve the biocompatibility of a polymer without compromising. Coating the polymer surface with some non-migrating material may often cause a reduction in flexibility of the polymeric materials due to the thickness of the coating layer. During surface extraction, a material is shortly exposed to some solvent for the plasticizer, and then dried. Subsequently the plasticizer distribution in the polymer is not homogenous and interfacial mass transfer of the plasticizer is blocked with the rigid surface. It follows that the mechanical properties of the polymer system are very often influenced in a negative way.

Leaching resistance of flexible PVC has also been improved by grafting polyethylene glycol, which is often used in biomaterials to prevent biological recognition and protein adhesion. The decrease in plasticizer leaching after polyethylene glycol-grafting is presumably due to the hydrophilic polyethylene glycol surface acting as a barrier to the diffusion of di(2 ethylhexyl) phthalate (DEHP) from the PVC matrix. (Lakshmi & Jayakrishnan 1998). There are radical possibilities of how to solve the plasticizer migration out, namely the use of polymeric or oligomeric plasticizers instead of the low molecular weight ones, or alternative (so called non-classical, non-traditional, multifunction) plasticizers, even alternative polymers which do not require plasticizers.

#### **2.2 The effect of plasticizers on human health**

Phthalic acid esters found applications as plasticizers for the first time in 1920s and continue to be the largest class of plasticizers in the 21st century (Rahman Brazel 2004). DEHP, also known as dioctyl phthalate (DOP), was introduced in 1930s and has been the most widely used plasticizer up to the present time. Thus, the use of plasticizers is being questioned due to their possible toxicity problems, related to their migration out of the polymer. Nowadays, there is increasing interest in the use of natural-based plasticizers that are characterized by low toxicity and low migration. This group includes epoxidized triglyceride vegetable oils from soybean oil, linseed oil, castor-oil, sunflower oil, and fatty acid esters (Baltacioğlu Balkose 1999).

Currently, there is a trend towards replacing DEHP by either diisononyl phthalate or diisodecyl phthalate, which are higher molecular weight phthalates and therefore are more permanent, have lower solubility and present slower migration rates. Although a total replacement of synthetic plasticizers by natural-based plasticizers is just impossible, at least for some specific applications such a replacement seems obvious and useful.

A number of medical devices as bags, catheters and gloves, intravenous (i.v.) fluid containers and blood bags, medical tubings, are made from the PVC plasticized with the use of DEHP. PVC i.v. bags typically contain 30-40% DEHP by weight; other devices may contain much as 80% DEHP by weight. Because DEHP is not chemically bound to the polymer in a PVC medical device, it can be released into the solutions and blood products transported by these devices.

DEHP leaching from medical plastics was first observed in the late 1960s (Jaeger Rubin, 1970). Extensive research began after the International Agency for Research on Cancer

by grafting of water soluble polymers to the surface of biomaterials, (iii) surface coating and

Surface modification of polymers not only prevents the plasticizer from leaching but also improve the biocompatibility of a polymer without compromising. Coating the polymer surface with some non-migrating material may often cause a reduction in flexibility of the polymeric materials due to the thickness of the coating layer. During surface extraction, a material is shortly exposed to some solvent for the plasticizer, and then dried. Subsequently the plasticizer distribution in the polymer is not homogenous and interfacial mass transfer of the plasticizer is blocked with the rigid surface. It follows that the mechanical properties

Leaching resistance of flexible PVC has also been improved by grafting polyethylene glycol, which is often used in biomaterials to prevent biological recognition and protein adhesion. The decrease in plasticizer leaching after polyethylene glycol-grafting is presumably due to the hydrophilic polyethylene glycol surface acting as a barrier to the diffusion of di(2 ethylhexyl) phthalate (DEHP) from the PVC matrix. (Lakshmi & Jayakrishnan 1998). There are radical possibilities of how to solve the plasticizer migration out, namely the use of polymeric or oligomeric plasticizers instead of the low molecular weight ones, or alternative (so called non-classical, non-traditional, multifunction) plasticizers, even alternative

Phthalic acid esters found applications as plasticizers for the first time in 1920s and continue to be the largest class of plasticizers in the 21st century (Rahman Brazel 2004). DEHP, also known as dioctyl phthalate (DOP), was introduced in 1930s and has been the most widely used plasticizer up to the present time. Thus, the use of plasticizers is being questioned due to their possible toxicity problems, related to their migration out of the polymer. Nowadays, there is increasing interest in the use of natural-based plasticizers that are characterized by low toxicity and low migration. This group includes epoxidized triglyceride vegetable oils from soybean oil, linseed oil, castor-oil, sunflower oil, and fatty acid esters (Baltacioğlu

Currently, there is a trend towards replacing DEHP by either diisononyl phthalate or diisodecyl phthalate, which are higher molecular weight phthalates and therefore are more permanent, have lower solubility and present slower migration rates. Although a total replacement of synthetic plasticizers by natural-based plasticizers is just impossible, at least

A number of medical devices as bags, catheters and gloves, intravenous (i.v.) fluid containers and blood bags, medical tubings, are made from the PVC plasticized with the use of DEHP. PVC i.v. bags typically contain 30-40% DEHP by weight; other devices may contain much as 80% DEHP by weight. Because DEHP is not chemically bound to the polymer in a PVC medical device, it can be released into the solutions and blood products

DEHP leaching from medical plastics was first observed in the late 1960s (Jaeger Rubin, 1970). Extensive research began after the International Agency for Research on Cancer

for some specific applications such a replacement seems obvious and useful.

of the polymer system are very often influenced in a negative way.

(iv) surface extraction have been used.

polymers which do not require plasticizers.

Balkose 1999).

transported by these devices.

**2.2 The effect of plasticizers on human health** 

classified it as 'possibly carcinogenic to humans' in 1980s (Murphy, 2001). The mechanisms by which DEHP may cause various adverse effects in humans are likely to be multiple and variable, and are not well understood. DEHP belongs to a class of chemicals called "peroxisome proliferators". The greater exposure source is particularly relevant for individuals who are ill, and therefore potentially less able to withstand any toxicant exposure (Tickner et al., 1999).

Particular concern has been raised in neonatal care applications because newborns receive among the highest doses of DEHP from blood transfusions, extracorporeal membrane oxygenation and respiratory therapy. (Sjoberg et. al., 1985; Loff et al., 2000).

Infants and children receiving intravenous total parenteral nutrition infused using the typical PVC-DEHP tubing and ethylene vinyl acetate bags with PVC-DEHP connections potentially receive considerable amounts of DEHP every day. DEHP is extracted from the bags and tubing due to the high solubility of DEHP in lipids and DEHP extraction by total parenteral nutrition depends on the lipid content of each total parenteral nutrition preparation and the flow rate (Kambia et al., 2003).

Adults can also be subjected to DEHP exposure from medical plastics. Kambia et al. (Kambia et al., 2001) studied the leachability of DEHP from PVC haemodialysis tubing during maintenance haemodialysis of 10 patients with chronic renal failure. The patient blood obtained from the inlet and the outlet of the dialyzer was analyzed during a 4 h dialysis session. An average DEHP quantity of 123 mg was extracted from tubing during a single dialysis session, of which approximately 27 mg was retained in the patient's body. The detrimental dose for humans has been estimated at 69 mg/kg per day whereas the average daily exposure to DEHP is much lower (2.3–2.8 mg/kg in Europe and 4 mg/kg in the US). (Murphy, 2001). Application of DEHP as plasticizer was found to have adverse effects on the biocompatibility of the plastic materials used in medical devices. Upon contact with blood, albumin is instantly absorbed on the polymer surface, followed by globulin (Baier, 1972).

There are a number of techniques which could help minimize health and environmental problems owing to the use of leachable plasticizers. One simple way to do this is to use alternative flexible polymers (e.g. polyolefins), which require less or no plasticizers, to accomplish some surface modification, or use plasticizers that have less volatility and leachability, and thus low toxicity. Because it is cheap, clear, and flexible, PVC remains the most widely used material by manufacturers and end users of medical bags and tubing.

#### **2.3 Classification of pharmaceuticaly used plasticizers**

Pharmaceuticaly used plasticizers are often distinguished into hydrophilic and hydrophobic, or low molecular weight, oligomeric and polymeric. Water insoluble plasticizers have to be emulsified in the aqueous phase of the polymer dispersions. Plasticizers are incorporated in the amorphous phase of polymers while the structure and size of any crystalline part remains unaffected (Fedorko et al., 2003). The water has an exceptional position as the inherent plasticizer of biopolymers, mainly polysaccharides and proteins.

Pharmaceutically Used Plasticizers 53

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

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

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

The invention provided an orally dissolving capsule comprising pullulan, a plasticizer, and a dissolution enhancing agent (Rajewski & Haslam, 2008). Polyhydric alcohols such as

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

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

glycerol, propylene glycol, polyvinyl alcohol, sorbitol and maltitol were proposed.

with increasing atmospheric humidity (Bourtoom, 2008).

structure of starch.

humidity (57 % RH).

20 % was not demonstrated (Liu et al., 2011).

### **2.3.1 Water as a plasticizer**

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

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 et al., 2005).
