**4. Conclusions**

Theophylline salt was treated with squaric acid giving two different forms: anhydrous theophylline squarate and theophylline squarate trihydrate, whose crystal structure has been elucidated allowing to interpret its thermal behavior. Thermal analysis, VH-XRPD, and VT-XRPD experiments allowed us to characterize the stability of **TS3w** and the evolution of the various forms. Indeed, TS3w was stable until 70 ◦C and it dissociated into the two starting components only above 70 ◦C, making it suitable for a tablet manufacturing process for instance. Complementary, theophylline, and squaric acid alone led to the salt formation in a high RH% ambient.

During the dissolution study, **TS3w** showed a relevant decrease in the percentage of drugs released in the vehicle. This allows a better control of the administrated dose, reducing the adverse effects without losing efficacy.

Salification of Theophylline can thus be considered a valuable strategy to modify its physio-chemical properties and it can be taken into account as an alternative method for controlled release of the drug.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/ 10.3390/cryst12020201/s1, Table S1. Summary of crystallographic data for Theophylline Squarate trihydrate (TS3w); Figure S1. DSC thermogram of TS3w ; Figure S2. TGA thermogram of TS3w; Figure S3. DVS of TS3w; Figure S4. XRPD of TS3w after DVS (a) compared to its pattern before DVS (b); Figure S5. DSC thermogram of TSan; Figure S6. TGA thermogram of TSan. Figure S7. FTIR of Theophylline (red), Squaric Acid (black) and Theophylline squarate trihydrate (blue). Figure S8. Asymmetric unit of Theophylline squarate trihydrate (a) and molecular structure highlighting the HB connections and distances (b). Figure S9. VH-XRPD of pure Theophylline.

**Author Contributions:** Project administration, L.M., I.B., F.A. and A.B.; data curation, L.B. and L.F.; formal analysis, L.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Chiesi Farmaceutici S.p.A. (CHF-RES-00228).

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

**Informed Consent Statement:** Not applicable.

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