I've faced a shocking situation some minutes ago and thats reproducable.
If you package an App using "sencha package run *.json" with iPad as Device target
the simulator comes up normally. You can quit the simulator, restart the app - all fine.

But if you choose "Window -> Size -> 100%" and afterwards "Hardware -> Turn right"
the simulator cannot be started again after you quit the current simulator session.
No Simulator session at all can be started again. Whatever App you want to simulate (even non-sencha-touch apps, native apps etc.) It quits directly after startup with a popup dialog where you can switch the SDK, quit or try to restart the simulator.

After an OS X restart, all is fine again. I'm running OS X Lion, Xcode 4.1, build 4B110; latest native packager (the one from abe, not the release one).

Thanks & regards