Exploring the solubility of novel lamotrigine drug–drug salts: the role of pH and structural variability

Abstract

Lamotrigine (LAM) is a widely used first-line anti-epileptic drug with limitations due to its poor water solubility and side effects. Over the years, numerous attempts to modify LAM's physicochemical properties have been made, but the underlying reasons for the impact of newly formed salts on solubility remain unclear. This study aimed to address these issues by designing drug–drug salts of LAM with non-steroidal anti-inflammatory drugs (NSAIDs). The influence of structural factors on the pH-dependent solubility of LAM salts was investigated. Four novel drug–drug salts were successfully synthesized using flufenamic acid (FFA), diclofenac acid (DFA), mefenamic acid (MFA), and niflumic acid (NFA) as ligand molecules. The intrinsic dissolution rate and solubility of LAM and its corresponding salts were studied and compared to investigate the impact of structural factors on the pH-dependent solubility behavior. Results showed that the pH dependence of the newly formed salts decreased but did not alter the pH-dependent solubility tendency. Structural analysis revealed that O–H⋯O linked homodimers (LAM–LAM, FFA–FFA, DFA–DFA, MFA–MFA, NFA–NFA) exhibited a more stable spatial structure compared to N–H⋯O linked heterodimers (LAM–FFA, LAM–DFA, LAM–MFA, LAM–NFA). This stability led to a more stable arrangement of the salts and further reduced their solubility. In conclusion, this study provides valuable insights into the structural state of drug–drug salts and the effects of pH changes on their solubility.