Xanomeline is a synthetic muscarinic receptor agonist belonging to the tetrahydropyridine and thiadiazole chemical classes. The compound is also known by the development code LY-246708 and has been investigated for its activity at muscarinic acetylcholine receptors, particularly M1 and M4 receptors. Xanomeline is supplied in pharmaceutical development and commercial drug products primarily in its tartrate salt form, known as Xanomeline Tartrate.
Xanomeline Tartrate is the xanomeline form used in the FDA-approved combination product COBENFY, which combines xanomeline with trospium chloride. COBENFY was approved by the U.S. FDA in September 2024 for the treatment of schizophrenia in adults. Xanomeline provides the muscarinic agonist component, while trospium chloride is included to reduce peripheral muscarinic effects associated with xanomeline.
Xanomeline free base has the molecular formula C14H23N3OS and molecular weight 281.42 g/mol. Its CAS number is 131986-45-3 and its FDA UNII is 9ORI6L73CJ. Xanomeline Tartrate has the molecular formula C18H29N3O7S and molecular weight approximately 431.5 g/mol, reflecting the association of xanomeline with tartaric acid.
The chemical structure contains a tetrahydropyridine ring connected to a substituted thiadiazole moiety and a hexyloxy side chain. This structural arrangement contributes to the compound's interaction with muscarinic acetylcholine receptors.
For pharmaceutical manufacturing and development, the distinction between xanomeline free base and Xanomeline Tartrate is important. The marketed pharmaceutical product uses xanomeline tartrate, and API documentation should identify the actual salt form being supplied.
Xanomeline acts as a muscarinic receptor agonist. It has been characterized particularly for activity at M1 and M4 muscarinic receptors. Its pharmacological profile is different from conventional dopamine D2 receptor antagonist antipsychotic medicines.
The current pharmaceutical relevance of xanomeline increased substantially following the development and FDA approval of COBENFY. The FDA describes COBENFY as a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist, for adults with schizophrenia.
The FDA-approved dosage forms contain 50 mg/20 mg, 100 mg/20 mg and 125 mg/30 mg of xanomeline/trospium chloride, respectively. The corresponding amounts of xanomeline tartrate are higher because xanomeline is administered as its tartrate salt.
Xanomeline is primarily associated with central nervous system and neuropsychiatric pharmaceutical development. Its muscarinic receptor activity has historically resulted in research interest in Alzheimer's disease, cognition and other neurological disorders.
More recently, xanomeline has become an important pharmaceutical ingredient in the treatment of schizophrenia through the xanomeline/trospium combination. The FDA review identified xanomeline tartrate and trospium chloride as the two active components of COBENFY.
The combination represents a non-dopaminergic pharmacological approach to schizophrenia treatment. Xanomeline provides the central muscarinic agonist activity, while trospium chloride acts primarily as a peripheral muscarinic antagonist.
Xanomeline Tartrate is associated with CAS number 152854-19-8 and molecular formula C18H29N3O7S. PubChem reports a molecular weight of approximately 431.5 g/mol. It is also identified by synonyms including LY-246708 tartrate and Xanomeline (+)-L-hydrogen tartrate.
Reported physical data should be interpreted according to the specific salt, hydration state and analytical grade. Literature and chemical-reference sources report a melting point around 95.5°C for Xanomeline Tartrate, while commercially available Xanomeline L-tartrate may be supplied as a hydrate. Therefore, the exact thermal behavior should be confirmed against the specification and solid form of the supplied API.
Xanomeline free base has substantially different physical properties from the tartrate salt. For example, published chemical supplier data describe the free base as water-insoluble, while Xanomeline L-tartrate hydrate has been reported to form a clear aqueous solution at 10 mg/mL when warmed.
Xanomeline API and Xanomeline Tartrate require appropriate analytical characterization during pharmaceutical development and manufacturing. Identification can be performed using orthogonal analytical techniques such as HPLC, FTIR and LC-MS, depending on the applicable quality-control strategy.
Chromatographic methods are particularly important for assay and related-substance evaluation. Published analytical literature has described HPLC and LC-MS methods for determination of xanomeline and its metabolites.
For pharmaceutical API quality control, assay, related substances, water content, residual solvents, elemental impurities and other applicable parameters should be controlled according to the approved product specification and relevant regulatory requirements. A universal pharmacopoeial acceptance range should not be assumed where no applicable public monograph establishes one.
Xanomeline's aqueous solubility is highly dependent on the chemical form and experimental conditions. FDA chemistry documentation for xanomeline reported substantially different solubility values across dissolution media, including high solubility in acidic media and considerably lower solubility in biorelevant media near neutral pH. For example, FDA data reported 242 mg/mL in 0.1 N HCl and 303 mg/mL in 50 mM sodium acetate, while lower values were observed in FaSSIF and phosphate buffer.
Because salt form, pH, temperature and medium composition affect measured solubility, API specifications should identify the analytical conditions rather than presenting a single universal water-solubility value as an intrinsic property.
Xanomeline API and Xanomeline Tartrate are relevant to pharmaceutical research, development and manufacturing programs involving muscarinic receptor agonists and CNS products. A reliable API supply program should provide appropriate identity testing, assay determination, impurity profiling, moisture or water determination, residual-solvent control and documentation supporting the applicable quality requirements.
Xanomeline Tartrate should be clearly identified by its salt form and molecular characteristics to avoid confusion with xanomeline free base. For commercial pharmaceutical applications, the supplied material should be accompanied by appropriate batch-specific documentation and analytical data.
Xanomeline and its salts should be stored according to the validated storage conditions established for the specific API form. Protection from excessive moisture, heat and unsuitable environmental conditions is appropriate for maintaining chemical quality. Where a hydrate or other solid form is supplied, storage conditions should be established with consideration of water content and solid-state stability.
| Parameter | Specification |
|---|---|
| Appearance | white to off-white crystalline powder |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | ≥98.0% HPLC |
| Loss on Drying | NMT 1.0% |
| Residue on Ignition | NMT 0.5% |
| Melting Point | Approx. 95.5°C |