(M0930-05-25) Cocrystallization Improves the Tabletability of Ligustrazine Despite a Reduction in Plasticity

Purpose: Ligustrazine (LIG), the main active compound of the Chinese traditional medicine Ligusticum chuanxiong, has been clinically used for treating ischemic cardiovascular and cerebrovascular diseases [1]. While LIG is available in both injection and oral solid dosage forms, oral delivery is preferrable due to patient convenience [2]. However, commercial forms of LIG, LIG hydrochloride (HCl), present challenging tablet development problems due to its high sublimation tendency and poor tabletability [3]. Crystal engineering, like salt formation and cocrystallization, has previously been employed to address stability and tabletability deficiencies in numerous crystal systems [4,5]. Salt formation with acesulfame was previously shown to effectively address LIG’s sublimation issues [3]. In this work, we similarly employ cocrystallization and salt formation to enhance the tabletability of LIG crystal systems using malonic acid and salicylic acid as coformers, resulting in an observation of a rare relationship between crystal mechanical property and tabletability.

Methods: Malonic acid (MA) and salicylic acid (SA) were used as received. Anhydrous LIG was prepared from LIG-HCl by neutralizing a dissolved LIG-HCl solution, extracting the LIG using ethyl acetate followed by rotary evaporation. Single crystals of LIG-MA and LIG-SA cocrystals were obtained using slow evaporation in a 6:1 (v:v) ethanol-acetone mixture. Powders for each crystal system were obtained by slurrying stoichiometric ratios of each component in the same 6:1 (v:v) ethanol-acetone mixture. Single crystal structures were solved using single crystal x-ray diffractometry. Their energy frameworks were computed using CrystalExplorer21 [6]. Thermogravimetric analysis (TGA) was used to assess cocrystal stability against sublimation at a heating rate of 10 °C/min from room temperature to 200 °C. Tablets were prepared on a Styl’One Compaction simulator using a 2 sec force-controlled symmetrical compression and 8 mm round, flat-faced tooling and tabletability was assessed via diametrical breaking following a standard procedure [7]. Powder plasticity was assessed using the in-die Heckel analysis [8,9].

Results: The LIG-MA cocrystal crystallized in a 1:1 stoichiometric ratio (Fig. 1a), while the LIG-SA system crystallized in 2:1 SA to LIG stoichiometric ratio (Fig. 1b). Interestingly, the LIG-SA is a salt-cocrystal, with a proton transfer from the carboxyl group of one SA molecule to the nitrogen on the adjacent LIG and a neutral SA molecule on a perpendicular plane to the LIG molecule. The energy framework of LIG reveals multiple orthogonal columnar slip structures, while MA has a single corrugated slip plane and SA has a unidirectional slip column. Compared to the individual coformers, the LIG-MA and LIG-SA have a highly interlocked energy framework (Fig. 1c), indicating inferior plasticity. This energy framework analysis aligns well with the powder plasticity of each component, as measured by the mean yield pressure from the in-die Heckel analysis (LIG: 52.5 MPa < MA: 66.4 < SA: 68.3 MPa < LIG-MA: 74.2 MPa < LIG-SA: 90.1 MPa), where a more plastic material has a lower mean yield pressure. A conventional interpretation of component plasticity would conclude that the cocrystals, having a lower plasticity, would not form strong tablets and would thus be undesirable for formulation. This is reasonably consistent with the LIG-MA cocrystal system, which exhibits low tabletability similar to that of MA alone (Fig. 2a). However, LIG-SA exhibited superior tabletability of both LIG and SA, despite being the least plastic powder (Fig. 2b). This may be reasonably explained by the higher bonding strength, as measured by its higher σ₀ (LIG: 2.0 MPa, SA: 3.8 MPa, LIG-SA: 5.7 MPa) via a compactibility analysis (Fig. 2c), highlighting the importance of the interplay between plasticity and bonding strength. While LIG alone is reasonably plastic and exhibits decent tensile strength at pressures below 150 MPa, it suffers from overcompression at pressures above 150 MPa, and is unable to attain a tensile strength of 2 MPa, which is a desired strength for acceptable tablets [10]. Additionally, the LIG-MA and LIG-SA cocrystals are reasonably stable, as indicated by their TGA compared with the commercial LIG-HCl (Fig. 3).

Conclusion: Two cocrystals of LIG, LIG-MA and LIG-SA, were shown to significantly modify tabletability compared with the individual components. While LIG was reasonably plastic, it exhibited overcompression and low physical stability. While both cocrystals showed improved physical stability, they exhibited vastly different tabletability profiles compared to LIG alone. The LIG-MA cocrystal had reduced plasticity and a tabletability similar to that of pure MA. The LIG-SA system crystallized as a unique salt-cocrystal and exhibited superior tabletability, despite a reduction in powder plasticity. This exemplifies the significance of considering the interplay between plasticity and bonding strength when predicting tabletability.

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Cocrystal structures of (a) LIG-MA and (b) LIG-SA cocrystals, and (c) the energy framework analysis for the coformers and cocrystals.


Tabletability of the (a) LIG-MA cocrystal (b) LIG-SA cocrystal and coformers, and (c) the cocrystal and coformer compactibilities.


TGA of the LIG-MA and LIG-SA cocrystals compared with the commercial LIG-HCl.