This is a question that has bugged me for quite a time, and I think it's an interesting subject to discuss.
One problem of the realm was the seleucid king being away for fighting nearly everytime, so administration was a nightmare, satraps had to be independent which fed thoughts of complete independence. The seleucid kings should have been more like the ptolemaic pharaos, staying in the capital and sending trustworthy generals to conquer regions . With this steps, more regions could have been put under the direct control of the king.
The other problem was that during the reign of nearly every king, some stupid relative came and made himself king in anatolia or somewhere, so he had to be ''persuaded'' to leave that post. Unfortunately I do not know any way how that could have been prevented.
Another problem: A lot of eastern provinces were under the controle of easterners. They had no thoughts of loyalty, why should they? More Makedonians should have been there to keep loyalty up.
And of course: The degeneration of the cavalry in the ''Hammer and Anvil'' tactic. Easy to erase.

But that are just my thoughts, I'm not a gigantic expert anyway, all what I know do I know from Wikipedia. So feel free to make suggestions.