Structural characterization of cevimeline and its trans-impurity by single crystal XRD

Area of Science:

• Pharmaceutical Chemistry
• Solid-State Chemistry
• Medicinal Chemistry

Background:

• Cevimeline is a muscarinic receptor agonist that enhances exocrine gland secretion.
• Cevimeline base is a liquid, necessitating a solid pharmaceutical formulation, specifically the hydrochloride hemihydrate.
• Cevimeline synthesis produces cis- and trans-isomers, with only the cis-isomer being the active pharmaceutical ingredient (API).

Purpose of the Study:

• To conduct structural and physicochemical investigations on the hydrochloride hemihydrates of both cis- and trans-cevimeline isomers.
• To characterize the solid-state properties of cevimeline isomers for pharmaceutical development.
• To provide the first single crystal X-ray analyses of cis- and trans-cevimeline isomers.

Main Methods:

• Single crystal X-ray diffraction analysis of cis- and trans-cevimeline hydrochloride hemihydrates.
• Determination of melting points for both isomers.
• Solubility studies in relevant solvents.
• Crystallographic analysis to compare packing efficiency.

Main Results:

• The cis-isomer, the API, displays less dense crystal packing compared to the trans-isomer.
• The cis-isomer exhibits a lower melting point than the trans-isomer.
• The cis-isomer demonstrates higher solubility than the trans-isomer.

Conclusions:

• The distinct solid-state properties of cis- and trans-cevimeline isomers are elucidated.
• The findings support the use of the cis-isomer as the API due to its favorable physicochemical characteristics.
• This study provides critical data for the formulation and development of cevimeline-based pharmaceuticals.