Researchers from ISC RAS and IGIC RAS have prepared and studied novel forms of antidepressant drug amitriptyline. The authors have synthesized multicomponent crystals of the substance with maleic, fumaric, oxalic, gallic, and orthophosphoric acids that can affect the drug dissolution rate in the human body. The researchers were able to prepare novel sustained-release crystalline forms of the drug, in which the rate of the active ingredient release became almost 88% lower. The researchers' work can be applied in pharmacology and medicine: become the foundation for a novel, improved amitriptyline dosage form. The results of the study supported by a grant of the Russian Science Foundation (grant No. 22-13-00031) were published in the journal Crystal Growth & Design (https://pubs.acs.org/doi/abs/10.1021/acs.cgd.3c00751).
The object of the study was amitriptyline, a classical tricyclic antidepressant drug that has long been considered the standard in the therapy of a variety of mental disorders, including depression, panic attacks, insomnia, attention deficit and hyperactivity disorder (ADHD), bulimia, etc. Besides, the drug can be applied as a local anaesthetic to treat chronic pain syndromes, such as migraine or fibromyalgia. Amitriptyline is known to have much higher therapeutic efficiency than a lot of more modern antidepressants but also to produce stronger side effects. The main commercial form of amitriptyline is amitriptyline hydrochloride (a salt of amitriptyline and hydrochloric acid), which has a high dissolution rate and fast uptake. This leads to a quick noticeable effect, which disappears as quickly as it emerged. All this makes it necessary to design sustained-release drug forms, in which the medication is absorbed slowly. They reduce the severity of side effects (which can be rather bad in case of antidepressants) and overdose risks. Besides, sustained-release drugs have a longer dosing interval and are easier to administer. They also make the risks of missed doses lower (statistically, 30-60% of patients with depression or bipolar disorder skip doses of antidepressant drugs and 35-45% do not take prescribed medicines for three or more days).
One of the ways to change the dissolution rate can be multicomponent crystals, in which the active ingredient binds with substances that are harmless to the human body. In their work, the researchers have for the first time prepared and studied novel multicomponent crystals of amitriptyline with maleic, fumaric, oxalic, gallic, and orthophosphoric acids. The molecular packaging in the crystal was determined based on the X-ray diffraction data, whereas the role of intermolecular interactions in the crystal stabilization was studied by computational methods. The crystal dissolution experiment was made in conditions imitating dissolution of a tablet in the human stomach, and the dissolution profiles were processed based on five models.
The authors proposed a method of obtaining multicomponent crystals of amitriptyline. The obtained crystals were found to have a layered packing with the amitriptyline cation layers alternating with the layers of anions of the second component. The novel crystaline forms of amitriptyline demonstrated lower solubility and lower rate (by almost 88%) of the drug release from the tablet, which agrees with the ion packaging in the crystals. Amitriptyline is released from tablets evenly over time, which must lead to a steady therapeutic effect and reduce the need for auxiliary substances.
The obtained multicomponent crystals have great prospects as the basis for controlled sustained-release amitriptyline drug forms. When administered, such drug form will ensure a constant concentration of the active ingredient in the human body for a long time. Sustained-release forms do not require frequent doses, which is convenient for administration in hospitals, reduces side effects and risks of missed doses and accidental overdosage.
