2 medium fuel canisters, or 1 large

The empty 500g can weighs less than two empty 250g cans, but it isn't much less.

I often take the small ones since they will pack inside my cook pot.

–B.G.–

All this is marginal: the 500 gram will cost less,
Because a half full 500 has more mass and more surface area, I think it will burn better than a half full 250. These canisters are cooled by evaporation as you use them and this slows the butane gasification. You probably only use the canister in short bursts so the bigger mass will stay warmer than the smaller so the bigger should burn better.
As Bob says the 500 empty is lighter than 2 x 250 empty. 2 x 220 coleman weigh 260 gram. I do not know the empty weight of a 500. I guess about 190 gram.
On the other hand you might find the opportunity to ethically discard a 250 empty during your trip. The nearly empty tail of a 500 is nearly twice as long as a single 250 and may seem longer.

…

That's a complex question. As you might expect, it depends on how the canister gets used.

If you are using the stove in warm weather then the 450 g canister is fine, and more weight-efficient. We found 1 x 450 g canister lasted two of us about 14 days across Europe (3 months walking).

If you are using the stove in really cold weather … complex. Best subscribe and read our articles on canister stoves.

Cheers

From my measurements, a 8oz (medium) canister weighs 142g and a 16oz (large) canister weighs 227g, so opting for the larger canister would save you 57g or 2oz. Those numbers were for primus canisters but it should be similar for all brands.

The most important thing with minimizing canister weight is to do a good job of estimating how much fuel you'll need. This can be hard and takes a bit of experience. It also can be hard to find a way to bring as much fuel as you want since you are constrained to 4oz increments (small canisters) unless you have partial ones on hand. The math gets complicated which is one of the main reasons why I like alcohol even though I don't really find it lighter.

My math:

For me, estimating fuel usage depends a lot on the weather forecast. In cool weather, there is more heat lost in cooking, plus the human needs more hot liquids.

I figure that it is better to take 25% extra and hope to bring some fuel home than it is to run out on a rainy day.

–B.G.–