Category: Formulation and Quality
Purpose: To discover and explain the synergistic and antagonistic effects of polymers order of addition on the precipitation of amorphous indomethacin from solid dispersions in different dissolution medias
Methods: We prepared different indomethacin dispersions and tested their solubility and dissolution in different media as following:
Indomethacin was first prepared as amorphous form in binary solid dispersions with either Eudragit 100 or PVP K 90 in a weight ratio of 1:1. Indomethacin was also prepared as a ternary solid dispersion with Eudragit 100 and PVP K 90 in a weight ratio of 1:1:1.
The pH solubility profiles of amorphous indomethacin from binary and ternary solid dispersion were studied in pH range 2-7 using different buffers.
The dissolution profiles of the binary and ternary solid dispersion systems were studied in 0.1 N HCl at pH 1.8 as well as in fasted simulated small intestine fluid (FaSSIF) at pH 6.5 using USP dissolution apparatus 2.
To investigate the effect of the order of addition, the following method was invented: in studying the dissolution of indomethacin from PVP K 90 binary solid dispersion, Eudragit 100 was added to the dissolution media and when running the dissolution study of indomethacin in Eudragit 100 binary solid dispersion, PVP K 90 was added to the media. The ternary solid dispersion of indomethacin, Eudragit 100 and PVP K 90 had no polymer in the dissolution media.
Samples were withdrawn at predetermined time points and analyzed.
The UV spectra was used to determine the indomethacin concentration through the study.
Results: Indomethacin is a week acid with pKa of 4.6. It is expected to have higher solubility at pH higher than its pKa. This was observed when we had the indomethacin prepared as a binary solid dispersion with PVP since there is no interaction between the indomethacin and the PVP. Thus, the solubility of the indomethacin increased when the pH increased.
On the other hand, indomethacin showed a high solubility at pH lower than its pKa when prepared as a solid dispersion with Eudragit 100, which is likely due to the pH dependant solubility of the Eudragit 100. The latter is more soluble in acidic media.
In studying the dissolution profile at pH 1.8, we observed minimal release of the indomethacin when prepared as a binary solid dispersion with PVP K 90 despite the presence of Eudragit 100 in the media. On the other hand, we observed almost 80 % release of indomethacin when prepared as a binary solid dispersion with Eudragit 100 with PVP being added to the dissolution media.
To our surprise, in absence of PVP K 90 from the media, decrease in release of indomethacin to 35 % was observed. This proves that PVP is has a synergistic effect even when only added to the media and not used to prepare the solid dispersion.
The Eudragit 100 hydrophobic site interacts with the indomethacin and binds to it closely, thus, and because Eudragit 100 is highly soluble in pH 1.8, we saw a high release of indomethacin at that pH.
The ternary solid dispersion showed a lowered release compared to the binary solid dispersion. This is because the PVP is reducing the interaction between the hydrophobic sites of indomethacin and Eudragit.
In pH 6.5 and FaSSIF media, the results were inverted. We observed almost 95% release of indomethacin when prepared as a binary solid dispersion with PVP K 90 without Eudragit in the media. The letter dropped to 80 % when Eudragit was added to the media.
Furthermore, we observed a minimal release from indomethacin and Eudragit 100 binary dispersion. This can be explained by Eudragit 100 having minimal solubility at that pH. Furthermore, at pH 6.5 the indomethacin carboxylic acid group has ionic interaction with the protonated ternary amine group of Eudragit 100.
Conclusion: We achieved higher release of indomethacin when prepared as binary solid dispersion. The PVP K 90 has a synergistic effect on the release of indomethacin when added to the dissolution media at pH 1.8. Unlike what was reported, ternary solid dispersion does not have higher release profile compared to the binary solid dispersion in both pH 1.8 and 6.5.
The suggested ionic interaction between Eudragit 100 and indomethacin needs to be further investigated as it plays a crucial rule in predicting the dissolution profile of weak acid drugs when prepared as a binary solid dispersion with Eudragit 100.