Design Of The Lamotrigine Multicomponent Supramolecular Complex And Its PH-Dependent Solubility Mechanism

Objective Lamotrigine(LAM)is a medication that is frequently prescribed for epilepsy,bipolar disorder and other neuropsychiatric disorders.However,LAM is a Class Ⅱmedicine under the Biopharmaceutics Classification System,whose low solubility and dissolution rate in the acute phase of the disease would restrict its curative efficacy,while it need to be delivered steadily and slowly to prevent long-term drug adverse reactions in patients.To improve the solubility and dissolution rate of LAM for various phases of the disease,this thesis presents synthon to construct multicomponent supramolecular complexes with LAM based on the theory of supramolecular chemistry,deeply investigates the solid chemical forms of LAM complexes,and then clarifies the process of their solubility change.Methods By the introduction of synthons with high water solubility and antiinflammatory activity,multicomponent solid forms with better physiochemical properties were synthesized by wet grinding crystallization,slow solvent evaporation crystallization and rotary evaporation crystallization.The confirmation of multicomponent solid forms was carried out through various basic solid-state characterizations such as single crystal X-ray diffraction.The solubility,intrinsic dissolution rate and dynamic vapour sorption were carried out to evaluate their property changes.The theoretical calculations such as energy decomposition analysis were used to verify their property change.Results Seven novel multicomponent solid forms of LAM were first successfully designed and synthesized,including lamotrigine-2,5 dihydroxybenzoate acid(LAMDA),lamotrigine-Isonicotinic acid(LAM-IA),lamotrigine-Shikimic acid(LAM-SA),and lamotrigine-Tolfenamic acid(LAM-TOL)polymorphic system,including LAMTOL Form Ⅰ,LAM-TOL Form Ⅱ,LAM-TOL methanol solvate and LAM-TOL ethanol solvate.Further research on physiochemical properties revealed that LAM-DA,LAMIA,and LAM-SA had higher water solubilities than LAM,measuring 3.37,6.44,and 7.90 times,respectively,while the intrinsic dissolution rate was 1.23,2.25,and 3.96 times that of LAM.The solubility of LAM-IA and LAM-SA solubility rose significantly with decreasing pH values in various buffer solutions,although the solubility LAM-DA varied slowly with pH.LAM salts were pH-dependent,and the solubility was correlated with the pH of the solution and the pKa of components.The LAM-TOL polymorphic system had typical multicomponent thermodynamic behavior and considerable crystal morphology differences.Rhombohedral(Form Ⅰ),block(Form Ⅱ),rods(methanol solvate)and flakes(ethanol solvate)could all be clearly seen in the experiment.The experimental solvent content of LAM-TOL methanol and LAMTOL ethanol was determined by thermogravimetric analysis to be consistent with the theoretical value of the crystal structure.Infrared spectroscopy rerealed a carboxylate stretching vibration peak(1377 cm-1)in Form Ⅰ,whereas Form Ⅱ lacked a comparable absorption peak,indicating the presence of the Form Ⅱ carboxylate proton.Singlecrystal X-ray diffraction suggested that Form Ⅱ was a rare conjugate acid-base cocrystal,that is,the complex was not a traditional complete proton transfer salt or a cocrystal without proton transfer,rather,but one proton from each pair of TOL in the carboxyl group was transferred to LAM,forming a TOL--TOL conjugate acid-base pair.The energy decomposition analysis of polymorphs indicated that Form Ⅰ was a metastable crystal form,which was consistent with the experimental findings.The water solubility of Form Ⅰ,Form Ⅱ,methanol solvate,and ethanol solvate were 0.19,0.19,0.18,and 0.20 times that of LAM,respectively,while the intrinsic dissolution rates were 0.13,0.03,0.16,and 0.25 times that of LAM,showing a decrease tread.The dynamic vapour sorption showed that the polymorphic system had good hygroscopic stability(RH<1%).Conclusion This thesis reported the first identification of seven novel LAM salts,conjugate acid-base cocrystal,and solvates.This study demonstrated the pH-pKa dependent dissolution mechanism of LAM salts,and the pH-solubility curve provided a theoretical basis and evidence to support predictions of LAM’s solubility.It was worth pointing out that the solubility and intrinsic dissolution rate of LAM-DA,LAMIA and LAM-SA were significantly improved compared with LAM,which was of scientific significance for improving the release behavior of the drug in the early stage of disease treatment.This thesis also provided new solid forms of drug with excellent physiochemical properties for the treatment of mental diseases.