The enhanced pH-dependent solubility behavior of three novel lamotrigine-acid salts

Lamotrigine (LAM), a Biopharmaceutics Classification System (BCS) class II drug, is widely used to treat epilepsy, bipolar disorder and neuropathic pain. However, its low solubility and dissolution rate limit its absorption and bioavailability. This study aims to enhance the solubility of LAM by forming salts with different acids and elucidate the mechanism underlying the solubility changes. Herein, three new salt forms as lamotrigine-2, 5-dihydroxybenzoic acid (LAM-DA), lamotrigine-isonicotinic acid (LAM-IA), and lamotrigine-shikimic acid (LAM-SA) were discovered and characterized. We investigated and compared the intrinsic dissolution rate (IDR) and solubility between LAM and its corresponding salts. Significantly improved solubility was observed for all three LAM salts, which were 3.37 (LAM-DA), 6.44 (LAM-IA), and 7.90 (LAM-SA)-fold greater than LAM in water, respectively. Accordingly, the IDR parameters of all the salts exhibit a similar pattern, indicating an overall improvement over LAM. In order to investigate the solubility mechanism, solution were prepared at different pH values (1.2, 3.0, 5.0, 6.8 buffered solutions, and water) and their changes were measured. Our findings indicated that the solubility of LAM salts was influenced by the pH. The results demonstrate that the solubility of LAM salts is pH-dependence. The solubility of salts was negatively correlated with the pH of the solution. In this regard, the solubility of LAM-DA, LAM-IA and LAM-SA increased from 326.7, 330.8, and 320.1 μg/mL at pH = 6.8 to 1238.2, 6527.9, and 7854.9 μg/mL at pH = 3.0, respectively. Analyzing the pH-dependent curves can help to comprehend the mechanisms underlying the solubility changes of LAM salts. Overall, this approach can serve as a valuable tool in predicting their potential oral bioavailability.