Usually word look-up is done through what is called a index. I don't know exactly what kind of index is used in Kindles, but I know for sure that they do use one (indexing file can be found in the system folders in your Kindle).
In general, indexes are made in such a way to minimize the time required for a look-up even when dealing with a great amount of data (search engines online are an example of that). This means that the dimension of the file, in general, should NOT affect much the time required for a word look-up.
Now, considering that the elaboration power of a Kindle is not as the one of a PC, there might be a number of contingent factors that might influence the time required for a word look-up. Perhaps the two most significant ones are:
- background processing (syncing with cloud, WiFi detection, etc.) that might absorb at least part of the computational power,
the way the data is stored on the local memory (Kindle main partition uses a FAT filesystem, which means that significant fragmentation is a possibility) that might influence the time required to access the index file. EDIT: this is not the case for flash drives, so this is not actually influencing performances
In order to optimize word look-up in general you might try to go off-line (in order to reduce background processing)
and to defragment the memory of your Kindle. This done, the speed of word look-up should be very similar for all e-books (with a difference of maybe some milliseconds).