Cocrystallization improves the tabletability of ligustrazine despite a reduction in plasticity

Cocrystallization is an effective method for altering the tableting performance of crystals by modifying their mechanical properties. In this study, cocrystals of ligustrazine (LIG) with malonic acid (MA) and salicylic acid (SA) were investigated to better understand how modifying crystal structure can affect tableting properties. LIG suffered from overcompression at high pressures despite its high plasticity. Both LIG-MA and LIG-SA displayed lower plasticity than LIG, which was confirmed by both an in-die Heckel and energy framework analyses. The LIG-MA cocrystal displayed slightly worse tabletability than LIG, as expected from its lower plasticity. However, LIG-SA surprisingly showed improved tabletability despite its lower plasticity. This was explained by the higher bonding strength of LIG-SA compared with LIG. This work not only provided new examples of tabletability modulation through crystal engineering but also highlighted the risk of failed tabletability predictions based on plasticity alone. Instead, more reliable tabletability predictions of different crystal forms must consider the bonding area – bonding strength interplay.