(336b) ­­­­the Effect of Inorganic Salt on Disintegration of Tablets with High Loadings of Kollidon® VA64-Based Amorphous Solid Dispersion

Xi, H., Merck & Co., Inc.
Ren, J., Merck & Co., Inc.
Novak, J., Merck & Co., Inc.
Kemp, E., Merck & Co., Inc.
Johnson, G., Merck & Co., Inc.
Klinzing, J. R., Merck & Co., Inc.
Johnson, M. A., Merck & Co., Inc.
Xu, W., Merck & Co., Inc.
Amorphous solid dispersions (ASDs) can improve dissolution of many poorly soluble drugs, and potentially enhance bioavailability in oral formulations. While the inclusion of ASDs in tablet formulations is increasingly common, tablets with high ASD loadings are often associated with slow disintegration, which hinders the development of immediate-release formulations with high drug loading. This slowdown of disintegration is believed to come from gel formation of the polymer, a major constituent of the ASD, upon exposure to aqueous media. In this study, we use a model ASD, composed of a hydrophobic drug with Kollidon® VA64 (a polyvinylpyrrolidone/ vinyl acetate copolymer) and a non-ionic surfactant, to explore formulation options that prevent such disintegration slowdown. We found that the pH, the ASD loading, and quite interestingly, the inclusion of inorganic salts in the tablet, all play important roles in the dissolution of VA64, and hence the tablet disintegration dynamics. We demonstrated that certain kosmotropic salts, when added in the formulation outside of the ASD, can significantly accelerate tablet disintegration. Contrary to expectation, we showed that the rank order of these salts in their effectiveness to help disintegration does not exactly follow the Hofmeister series; in addition to ionic effects, it also depends on other factors like particle size and dissolution rate of the salts. This highlights the dynamic nature of the tablet disintegration process, which is not to be fully predicted by steady-state properties. From our results, we provided a mechanistic explanation of the disintegration process: fast-dissolving kosmotropic salt builds high local concentration inside the restrained tablet matrix, thus lowering the cloud point of the polymer and preventing it from quickly dissolving and gelling, thereby helping the tablet break apart. This fundamental understanding has enabled design of a new platform formulation that accommodates higher ASD loadings for immediate release of poorly-soluble drug compounds.