**4. Conclusions**

This investigation presents an extensive study of ganciclovir from a crystallographic point of view, ranging from a structural to energy framework analysis. The methodology developed has proven how the use of multiple computational tools which target the examination of different characteristics, can be successful in providing a reasonable insight into the mechanism of polymorphism. Furthermore, it can be implemented to extract information about the influence of specific bonds and substituents on the formation of a particular form, regardless of the complexity or nature of the molecule.

Such a dominant impact was observed through the folding of the chain moiety in form II, which intrinsically affects its intramolecular and intermolecular characteristics. On the other hand, full interaction maps and Hirshfeld surfaces demonstrated how the extended chain moiety in form I enables the molecule to have an extensive network of non-covalent contacts, with a significant degree of directionality. These properties were identified as significant factors responsible for the known thermodynamic behavior of both forms, ultimately resulting in the conformational polymorphism present between them. The collective analysis of results from all molecular levels and energy frameworks provides a plausible explanation for the stability of both polymorphs at different temperature ranges.

The nature of this methodology makes it applicable to a wide range of crystal forms, even beyond active pharmaceutical ingredients. Such knowledge would facilitate the selection of co-formers or environmental conditions to selectively target the formation of a particular co-crystal. It would also aid navigation through the possibility of forming other relatively stable polymorphs, as suggested by the putative landscape in the case of ganciclovir. Therefore, the utilization of such data could lead to a more sustainable process of drug development, as well as possibly improving the pharmacokinetic properties of this active pharmaceutical ingredient.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/2624-8549/ 3/1/10/s1. Detailed information about the computational methods applied as well as a list of all results.

**Author Contributions:** Conceptualization, L.V.-Z. and L.S.; methodology, L.S.; software, L.S.; validation, L.V.-Z., L.S. and U.B.; formal analysis, L.S.; investigation, L.S.; resources, L.V.-Z.; data curation, L.S.; writing—original draft preparation, L.S.; writing—review and editing, U.B. and L.V.-Z.; visualization, L.S.; supervision, L.V.-Z. and U.B.; project administration, L.V.-Z.; funding acquisition, L.S. and L.V.-Z. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Tertiary Education Scholarships Scheme (TESS) (L.S.) and by the project: "Setting up of transdisciplinary research and knowledge exchange (TRAKE) complex at the University of Malta (ERDF.01.124)", which is being co-financed through the European Union through the European Regional Development Fund 2014–2020 (L.V.-Z. and U.B.).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available in the Supplementary Materials.

**Conflicts of Interest:** The authors declare no conflict of interest.
