**2.1.1 Toxicity**

In the selection of a plasticizer suitable for the formulation of dosage forms a great emphasis is laid on the criterion of toxicity. This problem is solved with regard to the mode of administration, dosing frequency and dosage size. For example, the tablet coating contains a plasticizer in the order of milligrams, whereas the implants *in situ* may contain hundreds of milligrams of plasticizers.

The primary role of all plasticizers as low molecular weight non-volatile additives is to improve the flexibility and processability of polymers by lowering the second order transition temperature (glass transition temperature, Tg) (Rosen, 1993). The extent of Tg reduction in the presence of a plasticizer can be used as a parameter to assess the

When incorporated into a polymeric material, a plasticizer improves the workability and flexibility of the polymer by increasing the intermolecular separation of the polymer molecules. This results in a reduction in elastic modulus, tensile strength, polymer melt viscosity and Tg. The polymer toughness and flexibility is improved and lower thermal

The attributes of an ideal plasticizer are changed with each application. When selecting an appropriate plasticizer, the compatibility with the polymer and plasticization efficiency are the pivotal criteria. Incompatibility is commonly evidenced by phase separation between the biopolymer and plasticizer, presented in the form of exudated drops on the surface of the

Historically the first plasticized polymer used as a medicinal preparation since the 19th century has been cellulose nitrate. Its solution in a mixture of ethanol and diethyl ether is called collodion and used to cover wounds. After administration, the solvents quickly evaporate and cause unpleasant tension. That is why its plasticizing with 5% castor oil was introduced (Murray, 1867). The composition after incorporation of an antimicrobial

Different requirements are important for the choice of a plasticizer for polymeric dosage forms in comparison with these for the technical plasticization. Pharmaceutically used plasticizers are selected according these criteria in the following order of importance

In the selection of a plasticizer suitable for the formulation of dosage forms a great emphasis is laid on the criterion of toxicity. This problem is solved with regard to the mode of administration, dosing frequency and dosage size. For example, the tablet coating contains a plasticizer in the order of milligrams, whereas the implants *in situ* may contain hundreds of

product immediately after its blending or during final application (Wilson, 1995).

**2.1 Criterions of the plasticizer selection in medicine and pharmacy** 

**2. Pharmaceutically used plasticizers** 

substance functions as a protective barrier.

effect of plasticizer on drug release

compatibility of a plasticizer with a given polymer

effect of plasticizer on mechanical properties

(Rahman Brazel, 2004):

 processing characteristics cost-benefit analysis.

milligrams of plasticizers.

biocompatibility

**2.1.1 Toxicity** 

plasticization efficiency (Senichev Tereshatov, 2004).

processing temperatures can be employed. (Zhu et al., 2002).

In the EU there exists the obligatory document ICH Topic Q3C titled Impurities: Guideline for Residual Solvents, which distinguishes three classes of solvents. Class 1 must not be used, Class 2 has a limited daily dose and concentration, and Class 3 includes solvents accepted in usual amounts in pharmaceutical products. The Class 3 residual solvents are accepted without marked restrictions in daily doses of up to 50 mg or in concentrations up to 0.5 %. Class 3 solvents are listed in Table 1 (European Medicines Agency, 2010). Many of the above mentioned solvents can be used as plasticizers of polymers which should be limited by GMP or pharmacopoeial requirements. The selection of plasticizers appropriate for dosage forms formulation is shown in their list in the 35th edition of the United States Pharmacopoeia (USP 35, 2011) (Table 2).


Table 1. Class 3 solvents with low toxic potential.


Table 2. List of plasticizers declared in USP 35-NF 30.

As there is no single universal mechanism of polymer plasticization, there is no universal criterion for its selection and for the evaluation of its efficacy. The use of internal plasticizers based on modifications of monomer units by decreasing the polarity of the groups, or modification with large side groups is problematic in pharmacy. The main cause is the fact that an introduction of new compounds into pharmacopoeias as the principal pharmaceutical standards is as complicated as an introduction of a new active substance. It is a process that lasts several years and is considerably costly.

On the rule, external plasticizers are used, which are less heterogeneously miscible, more frequently molecularly miscible with an amorphous phase of polymers. They are the solvents or thinners used in a minority concentration in a mixture with a polymer. The range of the concentrations of the plasticizer in the polymer is due to, besides other things,

Pharmaceutically Used Plasticizers 49

in the study of biocompatibility has been superseded from a major part by the standard ISO

The tests called in the USP as Biological Reactivity Tests are carried out with the pharmaceutical dosage form or the medical device or the extracts obtained from them at

The rate of plasticizer uptake is depended on the type and concentration of the plasticizer and the type of polymer dispersion, and also on the water solubility of the plasticizer. The plasticization time had a minimal effect on the rate of uptake of water-soluble plasticizers, while it had a strong effect on the uptake of water-insoluble plasticizers. Depending on plasticizer water-solubility and the added amount, when a plasticizer is added to an aqueous polymer dispersion, it is first dissolved and/or dispersed within the outer water phase. Subsequently, the plasticizer diffuses into the polymer particles. A sufficient amount of time for plasticizer uptake by the polymer particles is necessary to avoid forming an

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 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

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

10993. Tests following the USP are carried out on animals in three versions:

different temperatures for different periods of action of the extraction reagent.

inhomogeneous plasticized system (Bodmeier Paeratakul, 1997).

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

plasticized polymer system, notably the incorporated drug release patterns.

challenges regarding the research of plasticizers today.

Systemic injection test (intravenous and intraperitoneal)

 Intracutaneous test Implantation test

**2.1.3 Plasticizer uptake by polymer** 

the crystallinity of the polymer, usually 5 % to 30 %, but there exist also deviations from this range.

When plasticizers are present in low concentrations, their effect is often the exact opposite of what is typically expected. Low concentrations of plasticizer often result in an increase in the rigidity of the polymer instead of the expected softening effect. This effect is known as antiplasticization, or effect of low plasticizer concentrations (Chamarthy Pinal, 2008).

It is of advantage when plasticizers are low volatile. The size of the molecule of plasticizers includes a wide range from a water molecule to the molecules of low-molecular oligomers and polymers. Schematically, hydrophilic and hydrophobic plasticizers are distinguished; the border between them is not officially declared, the classification is subjective.

Because of the prevalence of fully biodegradable polymers, particularly for parenteral controlled-release systems as they do not require surgical retrieval from the body after completion of the drug release, recent research has focused on developing compatible plasticizers that also biodegrade.
