MacOS – way to limit external hard-drive random spin-up

Ideally, you should set a longer spin-down time so that it is not occuring constantly. A time to spin down of after being idle for 4-6 hours would be better. This gives you the benefit of saving power for long periods when little is being done on the drives, e.g. during the night or while you are away from home at work, etc. Having longer times also allows for less slow down when you are using your drive since you will have a reasonable time-frame to get files and work done before the drive trys to spins down on you.

Use pmset from the terminal to set up a custom interval that works best for you.

Others our claiming that spin down or not is really not that big of a deal in a home / SMB environment.

As for the differences between the 3.5" and 2.5" drives its safe to assume they are the same or similar. Even a comparison between what you said was a 3.5" server drives is not the same as a comparison between a 3.5" consumer desktop drive, they are not on equal ground just because of form factor. It really comes down to the manufacture quality and is really one of those you get what you pay for kind of situations and OEM drives even in Macs are still a lowest bidder kind or process. Here is a discussion on the reliability of 2.5" vs. 3.5" drives.

As for the differences in trying to set internal or external drives independently it looks like its not possible since the setting is really only intended for the startup disk according to The X Lab -- Hard Disk Sleep

Another undocumented aspect of Put the hard disk(s) to sleep when possible is that this option generally applies only to the startup disk. Non-startup hard disk drives — external FireWire® or USB® drives or additional drives installed in a Mac desktop — may ignore this setting.

The solution was to disable the internal trackpad. The trackpad, one of the older style pads with the separate button along the bottom edge, had a malfunctioning button and that seemed to be at the heart of the problem.

As soon as I disabled the trackpad the mouse would word. And as soon as I re-enabled the trackpad the mouse would cease to work.

For details on how to disable the trackpad see this question and answer.