In the present work, for the first time, a crystal engineering approach was systematically applied to produce novel crystalline forms of the tricyclic antidepressant amitriptyline (AMT) with modified aqueous dissolution kinetics. Six novel multicomponent crystals, including three salts with dicarboxylic acid counterions, two salt cocrystals, and a salt hydrate, were obtained and structurally characterized by single-crystal X-ray diffraction analysis. The structural analysis revealed that all of the investigated crystals contain two-dimensional (2D) bilayers of AMT cations separated by organic counterions; however, the packing arrangements of AMT cations within the bilayers were found to differ significantly. The structure-directing role of 2D bilayers of AMT was discussed based on insights from periodic density functional theory (DFT) computations. The dissolution performance of the obtained solid forms was studied in the FaSSGF buffer solution under sink conditions and compared to that of the commercial form AMT-HCl. The effect of the salt formation on the AMT release profile was assessed using five different dissolution models. The potential of the AMT maleate and AMT oxalate salts as a basis for the design of controlled-release forms was discussed.
