**Pharmaceutically Used Plasticizers**

Eva Snejdrova and Milan Dittrich

*Faculty of Pharmacy, Charles University in Prague Czech Republic* 

### **1. Introduction**

44 Recent Advances in Plasticizers

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biocompatibility of chitosan films modified by blending with PEG. *Biomaterials*,

chitosan composites. *Journal of Applied Polymer Science*, Vol.64, No.11, (December

properties of PAA/gelatin core-shell nanoparticles via template polymerization.

The extensive use of polymers in medical and pharmaceutical applications including particularly packaging, medical devices, drug carriers and coatings has caused a substantial demand for the proper plasticizers. Although there are many plasticizers used in the chemical industry, only a few of them have been approved for pharmaceutical applications. The natural-based plasticizers characterized by low toxicity and low migration are required nowadays not only for pharmaceutical and medical applications. In this respect, most of traditional plasticizers are not applicable in this area.

External plasticizers added to pharmaceutically used polymers interact with their chains, but are not chemically attached to them by primary bonds therefore their lost by evaporation, migration or extraction is possible. The benefit of using external plasticizers is the chance to select the right plasticizer type and concentration depending on the desired therapeutic system properties particularly drug release. Low volatile substances with average molecular weights between 200 and 400 such as diesters derived from dicarboxylic acids (e.g. sebacic acid, azelaic acid) or from ethylene glycol and propylene glycol, citric acid (tributylcitrate, triethylcitrate) or glycerol (triacetin, tributyrin) are used. Plasticizer as minor component of polymeric drug delivery systems has not been strictly defined. Even liquid drugs or liquids with a potential pharmacodynamic effect can serve as plasticizers.

As well structural water in the hydrophilic polymer seems to be an internal plasticizer of the polymeric drug delivery systems. In case of contact with body fluids after application the hydrophilic plasticizer can be released from polymer and thus conditions for the incorporated drug release are changed. The hydrophobic plasticizer remains in the system and ensures standard conditions during the process of drug release. On the other hand, hydrophilic plasticizer added to the polymeric drug carrier in high concentration can lead to an increase in water diffusion into the polymer, thus diffusivity parameters of the system are changed. As a consequence the kinetics of drug release is changed by elimination of lag time of drug release process. Plasticizers decrease viscosity and thus can enable or facilitate the application of some preparations; e.g. sufficient low viscosity at temperature bellow 50 °C is necessary for easy manipulation and simply and harmless application of implants in situ via an injection needle or trocar device.

Pharmaceutically Used Plasticizers 47

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

Alcohols 1-Butanol, 2-Butanol, Ethanol, 2-Methyl-1-butanol,

Ketones Acetone, Methylethyl ketone, Methylisobutyl ketone

Glycerin Acetyl Tributyl Citrate Polyethylene Glycols Acetyl Triethyl Citrate

Propylene Glycol Diacetylated Monoglycerides

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

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,

Esters Ethyl acetate, Ethyl formate, Isopropyl acetate, Methyl acetate, Propyl acetate Ethers Anisole, tert-Butylmethyl ether, Ethyl ether

Hydrophilic Hydrophobic

Polyethylene Glycol Monomethyl Ether Castor Oil

Triacetin

Sorbitol Sorbitan Solution Dibutyl Sebacate

2-Methyl-1-propanol, 1-Pentanol, 1-Propanol, 2-Propanol

Diethyl Phthalate

Tributyl Citrate Triethyl Citrate

Pharmacopoeia (USP 35, 2011) (Table 2).

Acids Acetic acid, Formic acid

Hydrocarbons Cumene, Heptane, Pentane

Others Dimethyl sulfoxide Table 1. Class 3 solvents with low toxic potential.

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

is a process that lasts several years and is considerably costly.
