**3. Drug release influenced by plasticizers**

Drug release from polymer drug delivery system is modified by the method of their formation, or by using an appropriate polymer or additive, which could also be a plasticizer. Modified release includes delayed release, extended release (prolonged, sustained), and pulsatile release (Chamarthy & Pinal, 2008).

Dosage forms based on polymeric carriers can be classified according to the mechanism of drug release into the following categories: (i) Diffusion-controlled drug release either from a non-porous polymer drug delivery system or (ii) from a porous polymer drug delivery system, and (iii) disintegration controlled systems (Khandare & Haag, 2010). Diffusion of a drug within a non-porous polymer drug delivery system occurs predominantly through the void spaces between polymer chains, and in the case of a porous polymer drug delivery system by diffusion of a drug through a porous or swelling polymer drug delivery system. The plain fact is that the plasticizer type and concentration must influence the drug release as plasticizers reduce polymer-polymer chain secondary bonding, and provide more mobility for the drug. Plasticizer leaching out of the polymer results in pore formation for burst release of the drug. Subsequent release stage of drug is based on diffusion through the dense polymer phase.

Non-biodegradable polymers are characterized by their durability, tissue compatibility, and mechanical strength, which endure under in vivo conditions without erosion or considerable degradation. Polyurethane, poly(ethylene vinyl acetate), and polydimethylsiloxane are examples of polymer films that follow predictable Fickian diffusion or can be modified for linear or near zero order release. One drawback of these non-biodegradable polymer devices is an occasional need for a second surgical procedure to remove the device, which leads to an increased cost and associated discomfort / inconvenience for the patient.

Drug release from biodegradable polymers is depended on the way of erosion and degradation. The most commonly employed class of biodegradable polymers are the polyesters, which consist mainly of poly(caprolactone), poly(lactic acid), poly(glycolic acid) and copolymers of lactic and glycolic acids. Their degradation mechanism is non-enzymatic random hydrolytic chain scission established. Polymer drug delivery system can be classified in bulk-eroding systems, surface-eroding systems, or systems undergoing both surface and bulk erosion. Polyanhydrides and polyorthoesters degrade only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the drug delivery system. Poly(lactic acid) and poly( lactic-co-glycolic acid) are reported to undergo both surface and bulk erosion which probably disturbs an even rate of drug delivery.

Pharmaceutically Used Plasticizers 59

increase in the rigidity of the polymer instead of the expected softening effect. This effect, known as antiplasticization*,* can be used as a formulation strategy which can modulate drug

The antiplasticizing effect of water on the transport properties of disintegration controlled systems such as tablets is highly relevant during the manufacturing, handling and storage of the product; water does not antiplasticize during drug release. Once in the body, pharmaceutical formulations are subjected to a water saturated environment. Consequently, water will act exclusively as a plasticizer under such conditions (Chamarthy & Pinal, 2007). The theophylline release profile from soluble starch plasticized with sorbitol exhibits two valleys, which can be explained as a simultaneous plasticizing effect of water penetrating from the dissolution medium and the antiplasticizing effect of sorbitol contained in the

Antiplasticization can be expected to significantly affect drug release and thus a factor that

The drug-polymer or drug-plasticizer interaction within the polymer drug delivery system can significantly influence the drug release profile. For instance, when triacetin was added to indomethacin loaded poly(methyl methacrylate) (PMMA) microspheres, a desired drug release profile lasting 24 h was achieved. Originally biphasic release profile, an initial burst effect from the surface of the microspheres followed by a slower drug release phase was surmounted by addition of a plasticizer. There might be a hydrogen bonds formation between the indomethacin hydroxyl group and PMMA, no interaction between triacetin and indomethacin or PMMA as the effects of secondary bonds was observed. The release enhancement of indomethacin from microspheres was attributed to the physical plasticization effect of triacetin on PMMA and, to some extent, the

The plasticization effect of triacetin on PMMA increased the diffusivity of indomethacin from PMMA. However, this effect was not dependent on the formation of secondary bonds between triacetin and PMMA. This indicates that the triacetin molecules physically separate

An example of how drug-polymer interaction can affect the drug release can be piroxicamloaded Eudragit E film. The drug-polymer interaction occurring between piroxicam and Eudragit E seems to cause a drag effect, leading to a delay of the piroxicam release from the

Similarly, ibuprofen interacts with the Eudragit RS 30 D polymer through hydrogen bonding, thus ibuprofen acts both as the active ingredient and as the plasticizer for the polymer also. The glass transition temperature of the Eudragit RS 30 D polymer decreased with increasing levels of ibuprofen in the polymeric film. The drug release rate was reduced by increasing the amount of ibuprofen in the polymeric film and by increasing the coating

permeability of polymers used in pharmaceutical systems.

has to be taken into consideration in formulation development.

the PMMA chains by locating within them (Yuksel et al., 2011).

**3.4 Effect of drug-polymer or drug-plasticizer interaction on drug release** 

formulation (Chamarthy & Pinal, 2008).

amorphous state of the drug.

Eudragit E film (Lin et al., 1995).

level on the coated beads (Wu & McGinity, 2001).

The release profile of the drug from degradable matrices is typically triphasic. The three phases can be summarized by an initial rapid drug release (burst effect) from the matrix surface, followed by a phase where the incorporated drug diffuses more slowly out of the inner bulk matrix and then, the remaining drug release phase due to bulk degradation of the polymer. The extent of the initial burst release can be controlled by plasticizers. High burst release can be minimized by hydrophobic plasticizers; the opposite effect is achieved by hydrophilic plasticizers, which leach out of polymer in the hydrophilic medium.

Biodegradation rate and thus the release of incorporated drugs depend on the polymer molecular weight parameters. Low molecular weight polymers or oligomers are preferred as drug carriers, as their hydrolysis may proceed simultaneously or just somewhat slower than drug release. A low molecular weight poly(D,L-lactic) acid with a linear molecule constitution is not suitable as a carrier due to a lag-time. Star-like copolymers of hydroxy acids with polyhydric alcohols, such as pentaerythritol, mannitol, glucose, polyvinyl alcohol and others are particularly advantageous. These branched carriers unlike the linear are endowed with low gyration radius (Kissel et al. 1991). Drug release from this type of carriers can be modified not only by molecular weight, but also more significantly by the degree of their branching (Pistel et al., 2001).
