*Article* **Understanding Conformational Polymorphism in Ganciclovir: A Holistic Approach**

**Lorella Spiteri, Ulrich Baisch \* and Liana Vella-Zarb \***

> Department of Chemistry, University of Malta, MSD, 2080 Msida, Malta; lorella.spiteri@um.edu.mt

**\*** Correspondence: ulrich.baisch@um.edu.mt (U.B.); liana.vella-zarb@um.edu.mt (L.V.-Z.)

**Abstract:** We present a holistic crystallographic study of the antiviral ganciclovir, including insights into its solid-state behavior, which could prove useful during drug development, making the process more sustainable. A newly developed methodology was used incorporating a combination of statistical and thermodynamic approaches, which can be applied to various crystalline materials. We demonstrate how the chemical environment and orientation of a functional group can affect its accessibility for participation in hydrogen bonding. The difference in the nature and strength of intermolecular contacts between the two anhydrous forms, exposed through full interaction maps and Hirshfeld surfaces, leads to the manifestation of conformational polymorphism. Variations in the intramolecular geometry and intermolecular interactions of both forms of ganciclovir were identified as possible predictors for their relative thermodynamic stability. It was shown through energy frameworks how the extensive supramolecular network of contacts in form I causes a higher level of compactness and lower enthalpy relative to form II. The likelihood of the material to exhibit polymorphism was assessed through a hydrogen bond propensity model, which predicted a high probability associated with the formation of other relatively stable forms. However, this model failed to classify the stability of form I appropriately, suggesting that it might not have fully captured the collective impacts which govern polymorphic stability.

**Keywords:** supramolecular structure; conformational polymorphism; intermolecular contacts

**Citation:** Spiteri, L.; Baisch, U.; Vella-Zarb, L. Understanding Conformational Polymorphism in Ganciclovir: A Holistic Approach. *Chemistry* **2021**, *3*, 126–137. https:// doi.org/10.3390/chemistry3010010

Received: 22 December 2020 Accepted: 20 January 2021 Published: 26 January 2021

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