Donna's exit was probably the most tragic for the obvious reasons from Donna's perspective but also from the Doctor's - I can't imagine what it's like to feel your best friend look at you and not know or care who you are.
I want to talk about Martha though because her goodbye is talked about less and her exit always gets me as the most real. In real life, people rarely just fall out of your life in one dramatic event like a mindwipe, being trapped in a parallel universe, being turned into a cyberman, being sent back in time, etc. They move on because your lives are going in different directions. You often still see each other a few times after someone's moved away or moved on, like Martha's returns in S4 but you drift apart and it's never the same again. It's not a closed door, it's a slowly closing door that you've both realised you don't want to hold open anymore. For me, Martha's exit - just moving on - is the most human ending and the one that hits closest to home and therefore hardest.
Bonus snippet: on Amy and Rory
The build up to Amy and Rory's exit is the really heartbreaking part of their goodbye, as the Doctor slowly realises he's losing them and one day he's not going to be part of their family anymore. He's left on the outside wanting them to be happy and knowing for that to happen, he can't be part of it. And again: that can be a very real situation for people when their best friends start families of their own.
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