No matter how much RAM your computer has, TS3 can only use ~3.7 GB at a time before it gets unstable and prone to crashing. Even a temporary memory spike into the danger zone can cause an Error 12 or corrupt the game data so that saving properly becomes impossible. Large worlds use more memory than small ones, long-running saves use more memory than new ones, and more expansion packs add to the overhead no matter how you're playing. TS3 also has memory leak issues, meaning it takes more and more RAM as the play session goes on. So maybe your ongoing save demands too much RAM for you to play for very long before saving properly becomes impossible.
If you're interested in getting help with this particular save, people here can offer it, but some details would help. What world are you playing in, for how long, which packs do you have installed, do you use mods, etc.? If you have a strong graphics card, have you taken steps to limit your in-game frame rates? TS3's fps limiter doesn't work on its own.