**3.5 Effect of plasticization technology on drug release**

Drug release profile can be modified by the preplasticization step, which is often necessary when incorporating plasticizer into the formulation in order to achieve uniform mixing of the polymer and plasticizer, to effectively reduce the polymer Tg, and to lower the processing temperatures. For instance, citric acid monohydrate combined with triethyl citrate in the powder blend was found to plasticize Eudragit S 100. Tablets containing citric acid released drug at a slower rate as a result of the suppression of polymer ionization due to a decrease in the micro-environmental pH of the tablet. The drug release profiles of the extruded tablets were found to fit both diffusion and surface erosion models (Bruce et al., 2005).

Theophylline or chlorpheniramine maleate pellets were coated with an aqueous ethylcellulose dispersion, Aquacoat. The influence of the plasticization time, curing conditions, storage time, and core properties on the drug release were investigated. The plasticization time (time between plasticizer addition to the polymer dispersion and the spraying process) did not affect the drug release, when the water-soluble plasticizer triethyl citrate was used, because of its rapid uptake by the colloidal polymer particles. In contrast, with the water-insoluble plasticizer acetyltributyl citrate, plasticization time (½ h vs 24 h) influenced the drug release, the longer plasticization time resulted in a slower drug release because of a more complete plasticizer uptake prior to the coating step. However, a thermal aftertreatment of the coated pellets at elevated temperatures (curing step) eliminated the effect of the plasticization time with acetyltributyl citrate. In general, curing reduced the drug release and resulted in stable drug release profiles. The time period between the coating and the curing step was not critical when the pellets were cured for a longer time. The structure of the pellet core (high dose matrix vs low dose layered pellet) strongly affected the drug release. A slow, zero-order drug release was obtained with high dose theophylline pellets, while a more rapid, first-order release pattern was obtained with low dose theophylline-layered nonpareil pellets (Wesseling & Bodmeier, 2001).

A pharmaceutical paste composition comprising the active ingredient such as an additive substance a control release agent and suitable carrier was patented (Odidi I. & Odidi A., 2009). The composition may be filled into a capsule or other dispensing device. Oily, waxy, or fatty substances were applied as plasticizers. Other invention relates to an oral pulse release comprising a polymer micromatrix, a first active ingredient distributed substantially uniformly within polymer micromatrix and a second active ingredient deposited on the surface of the polymer matrix (Gadre et al., 2006).

#### **3.6 Drug release from plasticized polyesters**

Films from poly(L-lactide) and poly(lactide-co-glycolide) were plasticized with polyethylene glycol. The plasticizer accelerated the degradation of polyester, its effect on the beginning of the release of the contained heparin significantly differed in dependence on the parameters of the polymer. In the homopolymer it decreased the burst-effect and accelerated the drug release in the phase controlled by diffusion, in copolymer the plasticizer did not exert a significant effect on the kinetics of release. The differences were explained by the influence of plasticizer on polymer hydrophilicity and crystallinity (Tan et al., 2004).

Drug release profile can be modified by the preplasticization step, which is often necessary when incorporating plasticizer into the formulation in order to achieve uniform mixing of the polymer and plasticizer, to effectively reduce the polymer Tg, and to lower the processing temperatures. For instance, citric acid monohydrate combined with triethyl citrate in the powder blend was found to plasticize Eudragit S 100. Tablets containing citric acid released drug at a slower rate as a result of the suppression of polymer ionization due to a decrease in the micro-environmental pH of the tablet. The drug release profiles of the extruded tablets were found to fit both diffusion and surface erosion

Theophylline or chlorpheniramine maleate pellets were coated with an aqueous ethylcellulose dispersion, Aquacoat. The influence of the plasticization time, curing conditions, storage time, and core properties on the drug release were investigated. The plasticization time (time between plasticizer addition to the polymer dispersion and the spraying process) did not affect the drug release, when the water-soluble plasticizer triethyl citrate was used, because of its rapid uptake by the colloidal polymer particles. In contrast, with the water-insoluble plasticizer acetyltributyl citrate, plasticization time (½ h vs 24 h) influenced the drug release, the longer plasticization time resulted in a slower drug release because of a more complete plasticizer uptake prior to the coating step. However, a thermal aftertreatment of the coated pellets at elevated temperatures (curing step) eliminated the effect of the plasticization time with acetyltributyl citrate. In general, curing reduced the drug release and resulted in stable drug release profiles. The time period between the coating and the curing step was not critical when the pellets were cured for a longer time. The structure of the pellet core (high dose matrix vs low dose layered pellet) strongly affected the drug release. A slow, zero-order drug release was obtained with high dose theophylline pellets, while a more rapid, first-order release pattern was obtained with low

dose theophylline-layered nonpareil pellets (Wesseling & Bodmeier, 2001).

of plasticizer on polymer hydrophilicity and crystallinity (Tan et al., 2004).

surface of the polymer matrix (Gadre et al., 2006).

**3.6 Drug release from plasticized polyesters** 

A pharmaceutical paste composition comprising the active ingredient such as an additive substance a control release agent and suitable carrier was patented (Odidi I. & Odidi A., 2009). The composition may be filled into a capsule or other dispensing device. Oily, waxy, or fatty substances were applied as plasticizers. Other invention relates to an oral pulse release comprising a polymer micromatrix, a first active ingredient distributed substantially uniformly within polymer micromatrix and a second active ingredient deposited on the

Films from poly(L-lactide) and poly(lactide-co-glycolide) were plasticized with polyethylene glycol. The plasticizer accelerated the degradation of polyester, its effect on the beginning of the release of the contained heparin significantly differed in dependence on the parameters of the polymer. In the homopolymer it decreased the burst-effect and accelerated the drug release in the phase controlled by diffusion, in copolymer the plasticizer did not exert a significant effect on the kinetics of release. The differences were explained by the influence

**3.5 Effect of plasticization technology on drug release** 

models (Bruce et al., 2005).

Thin films of a thickness of 40 μm from poly(lactide-co-glycolide) containing 10 % paclitaxel were plasticized with polyethylene glycols Mw 8,000 and 35,000 in various concentrations. The plasticizer with a lower molecular mass exerted a great influence on a more rapid release of paclitaxel. Polyethylene glycol was phase separated from copolymer (Steele et al., 2011).

The active ingredients were demonstrated to act as plasticizers of the polymer. The kinetics of dissolution in phosphate buffer of pH 7.4 and apparent diffusion coefficient including mathematical analysis of data resulted in the expression of the quantitative relationship between the diffusivity of drugs and the initial composition of medicinal substances with a possibility of prediction of the effect of thickness of the membrane and its composition on the kinetics of drug release (Siepmann et al., 2006).

Oligoester carrier compound of the equimolar ratio of glycolic acid and lactic acid branched with dipentaerythritol was synthesised by polycondensation (Snejdrova, E. & Dittrich, M., 2011). Table 3 shows the basic characteristic of the carrier.


Table 3. Relevant characteristics of oligoester carrier.

The carrier was plasticized using methyl salicylate in concentration of either 10 %, or 20 %, or 30 %. The increase of methyl salicylate concentration in the oligoester matrices influences the aciclovir release *in vitro* in the obvious manner. At 10 % concentration of the plasticizer the 90 % portion of active substance released was achieved after 15 days, at its 20 % concentration after 9 days , and at 30 % concentration after three days (Fig. 1).

Fig. 1. Acyclovir release from oligoester carrier plasticized by methyl salicylate (MS).

Ethyl salicylate as more hydrophobic plasticizer in comparison to methyl salicylate was used in various concentrations for plasticizing of the oligoester carrier. It influences the aciclovir release kinetics in the more complicated way. The partition coefficient matrix/dissolution medium for drug is in the consequence a character of plasticizer and aqueous medium influx changed. During the drug release process small portion of

Pharmaceutically Used Plasticizers 63

The "tailor made method" of selection the proper polymer for drug formulation has its limitations due to the demanding registration procedure of new polymers. Blending of two polymers or mixing of polymers with plasticizers and other additives are relatively simple and promising methods providing new biomaterials used in drug delivery with advantageous properties. Aliphatic polyesters are the most frequently used polymers in drug delivery systems. Star-like copolymers of hydroxy acids with polyhydric alcohols such as dipentaerythritol are particularly interesting. They possess good mechanical properties, however the brittleness is their major drawback for many applications. This is the reason for their blending with common and even non-traditional plasticizers. Viscosity of these drug carriers must be sufficiently low for good workability or in order their application via an injection needle or trocar applicator. The plasticizer type and concentration influence the

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**4. Conclusion** 

whole profile of drug release.

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**5. References** 

plasticizer is separated as liquid heterophase containing aciclovir in the swelled matrices. The viscosity of matrices is dominant factor in the initial phase of drug release (Fig. 2).

Fig. 2. Acyclovir release from oligoester carrier plasticized by ethyl salicylate (ES).

The influence of triethyl citrate concentration on acyclovir release from the branched oligoester carrier is shown in Fig. 3. Triethyl citrate differs from above mentioned plasticizers, methyl salicylate and ethyl salicylate, by its higher solubility in aqueous medium. The value of triethyl citrate solubility is 6.5 %, whilst for salicylic acid esters it is under 0.1 %. The accleration of dissolution process after 10 % triethyl citrate addition is expected situation. The hydrophilisation of matrices and their higher swelling is possible explanation for this behaviour. Opposite relation between concentration of triethyl citrate and velocity of drug release is reached at higher plasticizer concentrations. The possible hypothesis of this atypical situation is based on rapid collapse of matrices structure and formation of supramolecular structure based on more dense random coil conformation of molecules.

Fig. 3. Effect of triethyl citrate (TEC) on acyclovir release from branched oligoester carrier.

#### **4. Conclusion**

62 Recent Advances in Plasticizers

plasticizer is separated as liquid heterophase containing aciclovir in the swelled matrices. The viscosity of matrices is dominant factor in the initial phase of drug release (Fig. 2).

Fig. 2. Acyclovir release from oligoester carrier plasticized by ethyl salicylate (ES).

molecules.

The influence of triethyl citrate concentration on acyclovir release from the branched oligoester carrier is shown in Fig. 3. Triethyl citrate differs from above mentioned plasticizers, methyl salicylate and ethyl salicylate, by its higher solubility in aqueous medium. The value of triethyl citrate solubility is 6.5 %, whilst for salicylic acid esters it is under 0.1 %. The accleration of dissolution process after 10 % triethyl citrate addition is expected situation. The hydrophilisation of matrices and their higher swelling is possible explanation for this behaviour. Opposite relation between concentration of triethyl citrate and velocity of drug release is reached at higher plasticizer concentrations. The possible hypothesis of this atypical situation is based on rapid collapse of matrices structure and formation of supramolecular structure based on more dense random coil conformation of

Fig. 3. Effect of triethyl citrate (TEC) on acyclovir release from branched oligoester carrier.

The "tailor made method" of selection the proper polymer for drug formulation has its limitations due to the demanding registration procedure of new polymers. Blending of two polymers or mixing of polymers with plasticizers and other additives are relatively simple and promising methods providing new biomaterials used in drug delivery with advantageous properties. Aliphatic polyesters are the most frequently used polymers in drug delivery systems. Star-like copolymers of hydroxy acids with polyhydric alcohols such as dipentaerythritol are particularly interesting. They possess good mechanical properties, however the brittleness is their major drawback for many applications. This is the reason for their blending with common and even non-traditional plasticizers. Viscosity of these drug carriers must be sufficiently low for good workability or in order their application via an injection needle or trocar applicator. The plasticizer type and concentration influence the whole profile of drug release.

#### **5. References**


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**4** 

*Czech Republic* 

**Pharmaceutical Applications** 

*Faculty of Pharmacy, Charles University in Prague* 

The modern pharmaceutical technology is not conceivable without plasticized polymers. The pharmaceutical applications of polymers range from packaging materials or auxiliary substances in conventional dosage forms to membranes or matrices modifying and controlling the drug release characteristics in therapeutic systems. Recently, a great variety of plasticized polymeric systems have been studied as microparticles, matrices, free membranes, membranes for transdermal systems and *in situ* forming implants. Not only the polymer itself but thorough choice of other ingredients of the polymer system is necessary for required quality of drug delivery system. The plasticizer has the unsubstitutable place in drug polymer system due to its primary role, i. e. improve the flexibility and processability of polymers by lowering the glass transition temperature. The supramolecular structure and relevant properties of specific plasticized polymer drug delivery systems has attracted the

It is common practice to coat oral solid dosage forms with polymeric materials for several purposes, such as modifying drug release, affording gastroprotection, protecting from environmental agents, masking unpleasant taste or just enhancing product aesthetics. A film coating is defined as a thin and uniform polymer based-layer of about 20 to 100 µm in thickness, which is applied to the surface of substrates such as tablets, granules, powders,

Polymers used in coating can be categorized into two types: (i) non-functional or conventional film coating polymers for immediate release coatings; which improve the appearance, the handling, prevent dusting or (ii) functional coating polymers, which can be used to modify the pharmaceutical function of the dosage forms, and include the delayed release dosage forms and sustained release (or extended or prolonged) dosage forms.

Coating films can be usually prepared from organic solvent-based polymers or aqueous solvent-based latex dispersions. However, the aqueous film coating have been favoured in coating technology because of its wide applications, low environmental concerns, efficiency of the process, and wide commercial availability of coating materials. The cellulose ethers and esters are the major group of polymers used in the film coating process. The

**2. Plasticized polymers used as coatings of the dosage forms** 

**1. Introduction** 

interest of many researchers.

capsules, particles or pellets (Porter, 1995).

**of Plasticized Polymers** 

Eva Snejdrova and Milan Dittrich

