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

Abstract

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.

The Bioavailability of Drugs—The Current State of Knowledge

“…The utilization of a magnetic field enables the control of drug release, thus facilitating targeted drug delivery to an area of interest and limiting potential adverse effects [114]. Drug release control systems are designed to optimize the way in which the body absorbs and uses the API, which can lead to improved bioavailability and therapeutic effectiveness [115].…”

Salt Cocrystal and Salt of Marbofloxacin with Butenedioic Acid: Impact of cis–trans Isomerism of Coformer on the Conformation and Properties of Marbofloxacin

“…Pharmaceutical cocrystallization technology has the advantage of being faster, more cost-effective, and efficient as a means of improving the physicochemical properties of APIs without chemical modification. , In fact, the physicochemical properties of the crystal form of APIs are essentially dependent on the conformation of the molecules, packing arrangements, and the strength of the intermolecular interactions, , which implies that through the effective control of the crystal arrangement by suitable coformers, multiple and comprehensive tuning of the properties can be achieved. However, the regulation of API physical and chemical properties by pharmaceutical cocrystals/salts is not always better, and there are some cocrystals for which the solubility, dissolution, or permeability is reduced or remains unchanged. − The same is true for salt cocrystals, a pharmaceutical cocrystalline form that differs from pharmaceutical cocrystals (nonionic supramolecules) and salts (anion and cation) by having a salt structure with a neutral molecule. − As often happens, it is hard to predict the changes in the arrangement and physicochemical properties of pharmaceutical molecules in cocrystals/salt produced by coformers. This is because coformers with different configurations change intermolecular interactions during the cocrystallization process, which may result in the twisting of the flexible groups from the pharmaceutical molecules affecting the arrangement of the molecules in the crystals, which in turn leads to differences in their physicochemical properties after cocrystallization. − Changes in conformation have been shown to affect the optical properties of solid materials. , Regrettably, in the pharmaceutical industry, it is not clear how coformers affect the conformation, assembly, and physicochemical properties of molecules in pharmaceutical cocrystals/salts.…”