With the page file on a separate drive, there should be no need, or reason, to boot to safe mode to run defrag.
The primary reason for booting into safe mode for running scandisk and defrag is that Windows does not load many drivers, and does not load as much software as it does when you boot into normal mode.
In safe mode, Windows accesses the page file much less than it does in normal mode so scandisk and defrag are less apt to stop because drive contents have changed.
Also, if you are running a dynamic swap file, the swap file is it's smallest in safe mode.
What I do, is run defrag in normal mode for ALL drives except the drive with the page file.
I then temporarily switch the drive where the page file exists,
re-boot, and defrag the page file drive.
Since I seldom change the contents of the drive with the page file, I only need to defrag it once a year or so.
Chas