Polymer Dissolution

The dissolution of polymers, regardless of whether they are cellulose based, methacrylates, or other, depends on a variety of factors that may also influence the release of the drug. These are discussed in detail following. Some of these factors are important in vivo, whereas others play a role in vitro.

1. Thickness

To achieve enteric protection of the core, at least 3-4 mg/cm2 of polymer have to be applied (Figure 4). The precise amount of film coating depends on the type of polymer that is applied. Cellulose derivatives usually require higher amounts of polymer to obtain the same protection as methacrylic acid copolymers. A thin layer of 4 mg/cm2 of methacrylate copolymer will dissolve within approximately 10 minutes. However, if increasing layers of polymer are applied, the dissolution time will be prolonged, which can be used to delay the dissolution of the drug in the small intestine (Figure 5).

The salt form of the polymer may also play a role in determining the performance of the formulation. Kane et al. [32] found that cellulose acetate phthalate was more effective than cellulose acetate trimellitate in controlling the dissolution of sulfothiazole-sodium tablets with cellulose acetate. The enteric properties of hydroxypropylmethylcellulose phthalate (HPMCP) were found to depend on the solubility of the drug that was coated.

Figure 4 SEM of an aspirine crystal film coated with EUDRAGIT L 30 D-55.

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Figure 4 SEM of an aspirine crystal film coated with EUDRAGIT L 30 D-55.

Dissolution of polymers intended for enteric targeting depends on the pH of the dissolution medium [33, 34]. This is mainly influenced by the composition of the polymer, the monomers, or the type and degree of substitution. pH dissolution profiles can also be modified by the addition of other polymers, as demonstrated for EUDRAGIT L 100 and EUDRAGIT S 100 [35] (Figure 6). Such mixtures provide a variety of different pH dissolution profiles, which allows for specific targeting anywhere between the pylorus and the colon. This is also illustrated in Figure 2.

3. Other Excipients

Other excipients used in film-coating may influence the dissolution of the polymers [36]. For instance, plasticizers may increase or decrease dissolution rate, depending on whether a lipophilic or a hydrophilic plasticizer was used. Using this effect, the time-to-action of a drug may be improved (e.g., by using a hydro-philic plasticizer like triethyl citrate). Usually these effects are not detectable, if

Figure 5 In vitro dissolution profile of different dosage forms at pH 6.8, simulating the small intestine. Dosage forms that are film coated with an enteric polymer, EUDRAGIT L, (Salofalk, Claversal), show a delay in drug release at the dissolution pH of the polymer, which is probably due to the higher amounts of polymer that are applied (Rudolph et al., in press). Other film coatings: Pentasa (Ethylcellulose), Ascacolitin (EUDRAGIT S 100).

Figure 5 In vitro dissolution profile of different dosage forms at pH 6.8, simulating the small intestine. Dosage forms that are film coated with an enteric polymer, EUDRAGIT L, (Salofalk, Claversal), show a delay in drug release at the dissolution pH of the polymer, which is probably due to the higher amounts of polymer that are applied (Rudolph et al., in press). Other film coatings: Pentasa (Ethylcellulose), Ascacolitin (EUDRAGIT S 100).

5 5,5 6 6,5 7 7,5 8 8,5 9

-»-EUDRAGIT L 100 EUDRAGIT US 1:1 -«-EUDRAGIT S 100

Figure 6 Different dissolution rates from different methacrylate copolymers and mixtures of these polymers from their organic solutions (Rohm GmbH, technical information).

the USP 23 dissolution test [37] is used. However, in vivo, the dissolution times may vary between 10 minutes and 40 minutes, which might cause a considerable delay in the action of the drug. As a caveat, it is worth mentioning here that many of the pharmacopoeial dissolution tests for dosage form release do not take into consideration the in vivo conditions in some of the important aspects like the composition.

4. Ionic State

It could be shown [5] that the dissolution of polymers depends on the type of ions present in the dissolution medium. Dissolution is base catalyzed and can be described by the Bronstedt dissolution law [38]. At a given pH, a linear relationship exists between the logarithm of the dissolution rate and the pKa of the acidic component of the salt present in the dissolution medium. Cellulose acetate phosphate, especially, showed a strong dependency of the dissolution rate on the type of ions added. Sodium chloride prevented the dissolution of some polymers, because the base catalysis was at a minimum level.

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