Swellingcontrolled Drug Delivery Systems

Various polymeric matrix formers show significant swelling once they come into contact with aqueous media. Hydroxypropyl methylcellulose (HPMC), which is often the first choice for oral controlled-release matrix tablets, is an example for a highly swellable polymer (14,27,28). The two most important consequences of polymer swelling for the resulting drug-release kinetics are:

1. The length of the diffusion pathways increases (increase in volume of the systems). This can lead to decreasing drug-concentration gradients and, thus, decreasing drug-release rates.

2. The polymer molecular mobility significantly increases, resulting in increasing drug diffusivities within the polymeric network (29,30). For example, in a dry HPMC tablet, the apparent drug-diffusion coefficient approaches zero, whereas in a fully swollen HPMC matrix, diffusivities can be achieved that are similar to those in aqueous solutions, in particular, in the case of small molecular weight drugs. This is due to the fact that the average mesh size of the fully swollen HPMC network is large in comparison to the drug molecule size. This increase in drug mobility can lead to increasing drug-release rates.

Depending on the type of polymer and type of drug, one of these two effects (increase in diffusion pathway length and increase in drug mobility) might dominate, resulting in either decreasing or increasing drug-release rates compared to a non-swellable drug delivery system.

Figure 4 schematically illustrates the phenomena that can be involved in the control of drug release from a highly swellable drug delivery system, for example, an HPMC matrix tablet. This can, for instance, be a schematic cross section through one-half of a cylindrical matrix tablet. On the left-hand side, the release medium (well-agitated bulk fluid) is shown, on the right-hand side, the still dry (non-swollen) tablet core. The curves represent the macromolecules, the stars dissolved (individualized) drug molecules, and the black circles drug excess (e.g., drug crystals and/or amorphous aggregates). Once the system comes into contact with aqueous body fluids, water diffuses into the device. With increasing water content, the mobility of the macromolecules increases (please note that the degree of polymer chain mobility is different in the dry tablet core compared to the

Swollen matrix Non-swollen matrix

Swollen matrix Non-swollen matrix

Figure 4 Schematic presentation of a swelling-controlled drug delivery system containing dissolved and dispersed drug (illustrated by the stars and black circles, respectively). Three moving boundaries can be distinguished: (z) an "erosion front," separating the bulk fluid from the delivery system; (zz) a "diffusion front," separating the swollen matrix containing dissolved drug only and the swollen matrix containing dissolved and dispersed drug; and (zzz) a "swelling front," separating the swollen and non-swollen matrix.

Figure 4 Schematic presentation of a swelling-controlled drug delivery system containing dissolved and dispersed drug (illustrated by the stars and black circles, respectively). Three moving boundaries can be distinguished: (z) an "erosion front," separating the bulk fluid from the delivery system; (zz) a "diffusion front," separating the swollen matrix containing dissolved drug only and the swollen matrix containing dissolved and dispersed drug; and (zzz) a "swelling front," separating the swollen and non-swollen matrix.

rest of the tablet, Fig. 2). Certain polymers, including HPMC, show steep, sudden increases in their mobility as soon as a critical, polymer-specific water concentration is reached ("polymer chain relaxation"). The front at which this phenomenon occurs is called "swelling front" (Fig. 2). This front separates the region of the tablet in which the macromolecules (and, thus, also dissolved drug molecules) are highly mobile from the region in which the drug is efficiently trapped within a rigid polymeric system. In the non-swollen part of the tablet, the water concentration is generally very low and the amount of dissolved drug often negligible. In contrast, in the swollen part of the tablet, the macromolecules are much more mobile and often significant amounts of water available for drug dissolution. Due to concentration gradients, the individualized, dissolved drug molecules diffuse out of the system. If the initial drug concentration in the device is greater than the solubility of the drug in the swollen matrix, dissolved and undissolved drug coexist directly next to the swelling front. In case drug dissolution is rapid compared to drug diffusion, saturated drug solutions are maintained in these parts of the system (released drug molecules are replaced by the partial dissolution of undissolved drug). However, once all drug excess is dissolved, the concentration of dissolved drug, also in this part of polymeric network, decreases with time. The front separating the region containing both dissolved and dispersed drug from the region containing only dissolved drug, is called "diffusion front" (31,32) (Fig. 2). If the polymeric matrix former is water soluble, the third front is called "erosion" front, separating the bulk fluid from the swollen polymer network. Importantly, these three fronts are not stationary but moving, and the distances between them determine the length of the diffusion pathways for the drug and water. For a more detailed mechanistic analysis and quantitative mathematical treatment, the reader is referred to the literature (14,19,33,34).

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