*2.2. Theophylline Squarate*

The bulk powder of the hydrate form (**TS3w**) was obtained via LAG (liquid assisted grinding). Theophylline and Squaric Acid were weighed in an equimolar ratio (1:1, total mass 163 mg), the sample was transferred to a 4.0 mL vial with three grinding balls (5 mm φ, zirconia type) and the desired solvent was added (20 μL of water Milli-Q). Then, the mixture was ground for 1 h using a multi-sample vibrating ball mill (Pulverisette 6—Fritsch, Germany) under a rotational speed of 300 rpm and a temperature of 25 ◦C.

Along with **TS3w**, an anhydrous form was obtained (**TSan**). In order to obtain **TSan**, Theophylline (100 mg) and Squaric Acid (63 mg) were both dissolved in water (10 ml) at room temperature and lyophilized. An amorphous powder was obtained and crystallized through slurry in acetone 10 mg/mL at room temperature for three days.
