Influence of Superdisintegrants on the Rate of Drug Dissolution from Oral Solid Dosage Forms - Pharmaceutical Technology

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Influence of Superdisintegrants on the Rate of Drug Dissolution from Oral Solid Dosage Forms
The authors examine common superdisintegrants (i.e., crospovidone Type A, crospovidone Type B, croscarmellose sodium, and sodium starch glycolate) with a set of poorly soluble drug actives and evaluate in vitro drug dissolution.


Pharmaceutical Technology


Results and discussion


Figure 3
Although crospovidone, croscarmellose sodium, and sodium starch glycolate are used to provide the same function within the formulation, they differ in their chemical structure, particle morphology, and powder properties.


Figure 4
Croscarmellose sodium is the sodium salt of a cross-linked, partly O-(carboxymethylated) cellulose, and sodium starch glycolate is the sodium salt of a carboxymethyl ether of starch or of a cross-linked carboxymethyl ether of starch (5). Both materials are sodium salts and are anionic. In addition, their polymer backbones are composed mostly of glucose repeat units. In contrast, crospovidone is an insoluble, cross-linked homopolymer of N-vinyl-2-pyrrolidone and is nonionic. Chemically, the repeat structure of crospovidone is similar to that of N-methylpyrrolidone, a water-miscible, polar aprotic solvent with high interfacial activity used as a solubilizer in many applications.


Figure 5
When examined under a scanning electron microscope, croscarmellose sodium particles have a fibrous, nonporous structure; sodium starch glycolate particles are spherical and nonporous; and crospovidone particles (Type A and Type B) appear highly porous and granular (see Figures 1–4). Both crospovidone types have similar particle morphology, but differ in particle size. Table VI shows a comparison of the superdisintegrants' typical average particle size and surface area (Mastersizer, Malvern, Worcestershire, England) and Brunauer, Emmett, and Teller gas adsorption, respectively. Crospovidone Type B had the smallest particle size and the highest surface area. The high surface area increases interfacial activity that can aid in drug dissolution. Thus, the unique chemical structure and powder properties of crospovidone Type B may improve the dissolution of poorly soluble drugs.


Figure 6
Drug-dissolution profiles are increasingly used to evaluate drug-release characteristics of pharmaceutical products. The dissolution media adopted by the pharmacopeias or recommended by FDA for in vitro dissolution testing are designed to maximize drug release. Thus, the recommended medium for a given marketed drug becomes the quality-control standard to ensure that batch-to-batch consistency and continuing product quality and performance are maintained regardless of changes in the manufacturing process. Although the recommended media for in vitro dissolution testing can guide formulation development, it typically does not discriminate between formulation ingredients because a poorly soluble drug's release is usually affected more by the medium than the formulation ingredients.


Figure 7
Discriminatory dissolution profiles are highly desirable for distinguishing between products with different pharmaceutical attributes (e.g., formulation or manufacturing-process differences) (6). In the present study, dissolution testing was conducted in the recommended media for the drug as well as in modified dissolution media that were designed to produce drug-release profiles that discriminate between formulations with different superdisintegrants. The formulations for a given drug were produced using the same process, ingredients, and ingredient levels. In addition, tablets were compressed to equivalent hardness to minimize the effect of the tablet's physical properties on the dissolution results. Only the selection of superdisintegrant varied. The discriminating media were selected so that at least one formulation achieved 80% drug release. Table VII shows the recommended and discriminating media for each drug tested.


Figure 8
For the 13 poorly soluble drugs evaluated, no significant differences were observed in the breaking force and disintegration times of the tablets prepared using the various superdisintegrants for a given drug studied (see Table VIII).


Figure 9
Figures 5–12 show the dissolution profiles for the tablets with atorvastatin, loratadine, efavirenz, and ezetimibe in the recommended and discriminating media as examples. The dissolution profiles indicate that the tablets with crospovidone Type B, in both the recommended and discriminating media, had the fastest rate of dissolution. Thus, even though the superdisintegrants gave similar disintegration results, the choice of superdisintegrant had a significant effect on drug dissolution. Because the discriminating media showed even greater differences in dissolution rate between the superdisintegrants studied, the discriminating media were highly effective at identifying differences between the superdisintegrants selected.


Figure 10
Table IX shows the t 80 results for all 13 drugs studied in both media. In the recommended media, crospovidone provided the fastest t 80 for 12 of the 13 drugs studied. Crospovidone Type B provided the fastest t 80 for 10 of the 13 drugs studied. In the discriminating media, crospovidone Type B provided the fastest release for all drugs. A discriminating medium for raloxifene HCl tablets was not developed because the recommended medium was sufficiently discriminating. Therefore only 12 drugs were evaluated in a discriminatory medium. Furthermore, crospovidone Type B was often the only superdisintegrant to yield a formulation of the most poorly soluble drugs that achieved 80% drug release in the discriminating media. Overall, the results suggest that crospovidone Type B is more effective than the other superdisintegrants in enhancing the dissolution rate of poorly soluble drugs. Crospovidone Type B has solventlike chemistry and high surface area, resulting in high interfacial activity that enhances drug dissolution and release.


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