I agree that 3D is more difficult but I was of the understanding that southpark is done on Maya and I believe a lot of 2D is similar. There are custom 2D packages for animation. I know that there is a company Cambridge Animation or something like that which specializes in high end 2D apps. You can also use 3D models and light them and then use a toon shader too which flattens the appearance. So you can do 3D, 3D looking 2D, 2D with a 3D program or 2D with a 2D program !
I would try to use a proper 2D animation package but in absence I think a 3D animation tool done in 2D is better than a 2D non animation package. Having key frames and time sync and all those anim things generally would probably save more time than by using a 2D paint app type thing. Tho my old light wave has no 2D view I know Blender has a proper Ortho camera view. To be honest a long focal length perspective is not much different tho.
Edit: Seems that these guys have bought CA...