Cocrystallization improves the tabletability of ligustrazine despite a reduction in plasticity

Abstract

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.

Introduction

Ligustrazine (LIG, Fig. 1a) is the main active compound of a Chinese traditional medicine, Ligusticum chuanxiong. It has been clinically used for treating cerebral thrombosis, coronary heart disease, and angina pectoris due to its effects of vasodilation, platelet aggregation inhibition, thrombosis prevention, and cerebral ischemia improvement (Gao et al., 2015, Kao et al., 2006, Li et al., 2017, Liao et al., 2004, Lin et al., 2015, Ren et al., 2012). Both injections and oral solid dosage forms (tablets or capsules) of LIG are available. Injection administration of LIG has been applied to treat cardiovascular diseases in China, but the safety problems on the herbal injection have usually been a serious concern. Thus, oral delivery of LIG is preferable for treating chronic diseases (Guo et al., 2016, Zhao et al., 2016). In contrast, oral administration of LIG offers higher patient compliance due to its convenience and pain-free nature. Oral administration also eliminates the risk of cross infection through needles, making it more preferred for administering LIG. These advantages are particularly important for treating chronic diseases using LIG (Cao et al., 2016). However, the commercial hydrochloride salt form of LIG (LIG-HCl) is challenging for tablet development because of its high sublimation tendency under ambient conditions and poor tabletability (Hu et al., 2020). Thus, new crystal forms of LIG exhibiting improved physical stability and compaction properties would be useful for developing high quality tablets of LIG.

Having previously addressed the high sublimation tendency issues of solid LIG through salt formation with acesulfame (Hu et al., 2020), we now turn our attention to enhancing its tabletability using crystal engineering. Several examples have shown the effectiveness of cocrystallization in modifying mechanical properties and, hence, tableting performance of active pharmaceutical ingredients (API) (Karki et al., 2009, Sun, 2009, Wang et al., 2020). In pursuit of enhancing LIG’s tabletability, we synthesized two new cocrystals: one with malonic acid (MA, Fig. 1b) and another with salicylic acid (SA, Fig. 1c). Crystals with higher plasticity are typically assumed to exhibit superior tabletability by promoting a larger bonding area (BA) between neighboring particles during compression (Chow et al., 2012, Liu et al., 2018, Sun and Hou, 2008). However, we observed that the LIG-SA salt cocrystal is an exception where a less plastic cocrystal exhibits better tabletability because of a higher bonding strength (BS). Although this scenario is expected from the BA-BS interplay model (Osei-Yeboah et al., 2016, Sun, 2011), no examples have been reported in the literature. This work emphasizes the importance of applying a holistic, scientific understanding in guiding effective crystal engineering to overcome tabletability challenges of APIs. By including candidate crystal forms with lower plasticity, an expanded crystal engineering design space is introduced, offering new avenues for improving tabletability.

Read also the article Simultaneous taste-masking and oral bioavailability enhancement of Ligustrazine by forming sweet salts here:

excipients formulation