*2.1. Non-Bonding Interactions Analysis*

The intramolecular geometry analysis was conducted using V1.7.5 *Mogul*, as described in a paper by Galek et al., together with some adjustments to optimize the results [20]. During this investigation, all organometallic entries were excluded, as their geometric parameters may have introduced a bias in the histograms provided in *Mogul* when analyzing a purely organic molecule. In cases where few fragments were available, the relevance threshold was reduced from 1.00 to 0.75.

The electrostatic potential was calculated through *Mercury* by means of the MOPAC (Molecular Orbital Package) interface, using the RM1 semi-empirical Hamiltonian method, and was mapped onto the VdW molecular surface [21–23].

*IsoStar* V2.2.5 was utilized for initial examination of the interactions within ganciclovir, with functional groups acting as the central groups [24]. The analysis of possible intermolecular interactions was taken further by means of the construction of full interaction maps in

*Mercury*, taking into consideration the environmental effects of collective factors and steric exclusion to produce maps that are unique to each form and conformation [25,26].

The detection of any intramolecular and intermolecular hydrogen bonding in the asymmetric unit was investigated using *Mercury* for both anhydrous forms individually. The definition of a hydrogen bond was modified to have an angle of more than 120◦, and the distance range was slightly extended further to be less or equal to the sum of VdW radii + 1.00 Å, to ensure that all potential interactions were included [27].

Hirshfeld surfaces were plotted for each of the anhydrous forms using *CrystalExplorer*, so as to gain a better understanding of the network of non-bonding contacts, beyond conventional hydrogen bonds [28]. The participants of such contacts were identified through fingerprint scatterplots, which map the distance from a point on the surface to the closest nucleus inside the surface, *di*, against the distance outside the surface, *de*. Further details about the calculation of each descriptive variable used can be found elsewhere [29].

Crystal packing similarity was investigated through *Mercury*, using both anhydrous forms as reference, and the whole database was explored for any entry having sufficient packing similarity. Default selection options were retained, including a molecular cluster size of 15, 20% distance tolerance and 20◦ angle tolerance.
