Ionic, Neutral, and Hybrid Acid–Base Crystalline Adducts of Lamotrigine with Improved Pharmaceutical Performance

Abstract

Lamotrigine (L) is a known drug in the treatment of epilepsy and bipolar disorder. Due to its unique structure and functionalities, L is able to form both salts and cocrystals. The present study reports ionic, neutral, and hybrid crystalline forms of L with improved material properties and modified drug release rates. Novel forms of L with cinnamic acid (CA), ferulic acid (FRA), salicylic acid (SAC), and vanillin (VN) were successfully prepared and characterized using single crystal XRD, SEM, FT–IR, DSC, TGA, and powder XRD. LCA and LVN crystallized in P21/c space group, whereas LSAC crystallized in P1̅ space group. Pseudo-quadruple hydrogen bond with R4 2 (16) graph set notation were observed in all three crystal structures of L. The characteristic FT–IR stretching peaks at 3326.53, 3341.53, and 3340.65 cm–1 corresponding to N+–H bond were observed in LCA, LFRA, and LSAC. Comparison of dissolution profiles using similarity factor (f2) analysis revealed that the dissolution profiles of LCA, LFRA, and LVN were significantly different from that of L. LVN exhibited improved dissolution rate compared to L and LCA revealed a sustained release profile. Both these properties are important in designing oral dosage forms for neuropathic pain and bipolar disorder therapy. Further, LCA can be used in the development of extended release drug delivery systems for treating epileptic disorders.

Pharmaceutical cocrystals: walking the talk

“…Compressibility studies were performed (Fig. 7a) on cocrystals of lamotrigine using three different blends: A = blending time (BT) 5 min and dwell time (DT) 2 s, B = BT 5 min and DT 30 s, and C = BT 30 min and DT 2 s. 34 The capping tendency of the blends despite changes in lubrication time and dwell time is an indication of the elastic nature of the cocrystal material (Fig. 7b).…”

Hot melt extrusion: An emerging manufacturing method for slow and sustained protein delivery

“…HME has drawn attention for its use in mechanochemistry because it is a solvent‐free continuous manufacturing process and has applications in cocrystal synthesis and reactive extrusion (Chavan et al, 2018; Crawford et al, 2017). Cocrystallization is a process to engineer the molecular interactions between components, and results in unique structural composition with an aim of achieving enhanced bioactivity without affecting its physiological action by providing superior solubility and stability, desirable drug release (Thipparaboina et al, 2015). Ibuprofen and nicotinamide were successfully produced using HME to form cocrystal agglomerates.…”

Towards medicinal mechanochemistry: evolution of milling from pharmaceutical solid form screening to the synthesis of active pharmaceutical ingredients (APIs)

“…Importantly, all four three-component solids were isostructural, demonstrating previously unprecedented robustness of a particular crystal structure to modification of component building blocks. 151 Lamotrigine attracted further attention from Thipparaboina et al, 152 who carried out solid form screening by LAG to generate new salt forms based on cinnamic acid, ferulic acid, salicylic acid and vanillin.…”