I experienced problems with 2 GB MS Access databases. When they reached a certain volume they just stopped responding or do anything at all. No warning nothing. That seems to stem from the time of 32 Bit systems but still is in force today.
And keep in mind the DB would also need some room for temporary operations and stuff.
The only workaround was to split the database into several files (which is not very elegant). So it might not be a problem related to KNIME.