Solid-state thermal behavior and stability studies of theophylline–citric acid cocrystals prepared by neat cogrinding or thermal treatment

To investigate the thermal behavior of cocrystal formed between anhydrous theophylline (TP) and anhydrous citric acid (CA) by neat manual cogrinding or thermal treatment, DSC and FTIR microspectroscopy with curve-fitting analysis were applied. The physical mixture and 60-min ground mixture were stored at 55±0.5 °C/40±2% RH condition to determine their stability behavior. Typical TP–CA cocrystals were prepared by slow solvent evaporation method. Results indicate that the cogrinding process could gradually induce the cocrystal formation between TP and CA. The IR spectral peak shift from 3495 to 3512 cm−1 and the stepwise appearance of several new IR peaks at 1731, 1712, 1676, 1651, 1557 and 1265 cm−1 with cogrinding time suggest that the mechanism of TP–CA cocrystal formation was evidenced by interacting TP with CA through the intermolecular O–H···O hydrogen bonding. The stability of 60-min ground mixture of TP–CA was confirmed at 55±0.5 °C/40±2% RH condition over a storage time of 60 days. - Garphical abstract: Cogrinding, thermal and solvent-evaporation methods might easily induce the theophylline–citric acid cocrystal formation. Highlights: ► Cogrinding process could gradually induce the cocrystal formation between TP and CA. ► The TP–CA cocrystal was formed through the intermolecular O–H···O hydrogen bonding. ► The 60-min TP–CA ground mixture was similar to the solvent-evaporated cocrystal. ► The thermal-induced TP–CA cocrystal formation was confirmed by pre-heating the physical mixture to 152 °C. ► The 60-min TP–CA ground mixture was stable at accelerated condition over a storage time of 60 days.