In order to assess the internal consistency and reliability of the method in this specific application, a free energy profile is calculated for each of the four biasing strategies outlined in Tab.2 for the case of an ibuprofen detachment from the {100} apolar crystal face in the presence of water. Tab.2 also reports the average difference between any two free energy surfaces calculated, as well as the standard deviation of that mean. The maximum average difference between any two cases is found to be just under 2k B T, with a standard deviation within 0.5k B T. These results demonstrate a consistent reconstruction of the FES associated with the removal An example free energy surface for the case of a molecule removal from the {100} apolar crystal surface in water for biasing protocol No.2 is shown in Fig. . The free energy is dominated by the starting configuration of a perfectly aligned solute molecule incorporated into the crystal surface which can be found at low distance, high solute coordination number and an alignment angle of ±π, referred to as the crystalline configuration in Fig. . The value of the angle here is arbitrary with respect to how the reference has been defined. This configuration accounts for 99.5% of the probability distribution of states in the reactant basin. On the given free energy profile a local minimum at an angle of 0 rad can be identified, which corresponds to a configuration in which the molecule has flipped orientation within the crystal surface and the opposite para-substituents of the aromatic ring are exposed to the solution, whilst the overall alignment of the molecule is crystal-like. This configuration accounts for 0.04% of all microstates within the reactant basin for this particular setup. The remaining 0.01% of configurations within the basin account for intermediate states for which the molecule has lost order within the crystal surface but is not fully detached, labelled as disordered state in Figure . : Sampling region for three different trajectories of a molecular detachment from the {100} apolar surface in water in collective variable space. In green, a direct detachment from crystalline state out of the crystal slab along the distance and coordination number coordinate is illustrated. A detachment mechanism involving rearrangement of the molecule within the crystal surface before detachment is illustrated in blue and orange, where the former depicts a particular case of mechanism going via a flipped configuration as shown in Figure .