Multicomponent Crystals of Amitriptyline as Potential Controlled-Release Systems: Synthesis, Crystal Packing Analysis, and Dissolution Study

In the present work, for the first time, a crystal engineeringapproach was systematically applied to produce novel crystalline formsof the tricyclic antidepressant amitriptyline (AMT) with modifiedaqueous dissolution kinetics. Six novel multicomponent crystals, includingthree salts with dicarboxylic acid counterions, two salt cocrystals,and a salt hydrate, were obtained and structurally characterized bysingle-crystal X-ray diffraction analysis. The structural analysisrevealed 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 foundto differ significantly. The structure-directing role of 2D bilayersof AMT was discussed based on insights from periodic density functionaltheory (DFT) computations. The dissolution performance of the obtainedsolid forms was studied in the FaSSGF buffer solution under sink conditionsand compared to that of the commercial form AMT-HCl. The effect ofthe salt formation on the AMT release profile was assessed using fivedifferent dissolution models. The potential of the AMT maleate andAMT oxalate salts as a basis for the design of controlled-releaseforms was discussed. Forthe first time, a crystal engineering method was employedto comprehensively examine the solid-state landscape of amitriptylinewith the goal of altering the drug's aqueous dissolution kinetics.Six new multicomponent crystals were obtained and structurally characterized.The newly obtained solid forms have lower equilibrium solubility anda slower dissolution rate compared to the commercial form. AMT-Mle(1:1) and AMT-Ox (1:1) salts provide the sustained release of AMTfrom the tablet into the FaSSGF media without the need for additionalexcipients.

Automated summary

For the first time, a crystal engineering approach was used to create novel crystalline forms of the tricyclic antidepressant amitriptyline (AMT) with modified aqueous dissolution kinetics. Six new multicomponent crystals, including salts, salt cocrystals, and a salt hydrate, were obtained and studied. The obtained solid forms have lower solubility and slower dissolution rate compared to the commercial form, and AMT-Mle(1:1) and AMT-Ox(1:1) salts show potential for sustained release applications.