I’ve looked at the drawings of several full size locos, and they all conform to Julian’s advice on relative position of crankpins.
However, if we take a 4 coupled inside cylinder loco with 16” * 24” cylinders and 6 ft wheels, running at 120 psi cylinder pressure, the piston thrust is 10.8 tons. Assuming the tractive effort is shared between the 2 coupled axles, the coupling rod force is half of this, ie 5.4 tons, and the force at the wheel rim is 5.4 * 24/72 = 1.8 tons. With the rods set out as per Julian and the main crankpin at 12 o’clock, the combined force at the axlebox is (10.8 + 5.4 + 1.8) = 18 tons. In the same position with the pins in line, the force at the axlebox is (10.8 – 5.4 + 1.8) = 7.2 tons. This calculation is a little simplified as the forces are not in the same vertical plane, and I haven't allowed for the other cylinders/wheels. The loco dimensions/ pressure used do not affect the direction of the argument, having the inside and outside crankpins aligned would seem to give the axle boxes a much easier time. Yes it probably requires bigger balance weights, but outside cylinder locos managed, and you can put quite a bit of balance onto the inside crank.