Tafamidis Meglumine is the meglumine salt form of tafamidis, a small-molecule transthyretin (TTR) stabilizer used in the management of transthyretin-mediated amyloidosis. The substance is also known as FX-1006A. FDA identifies tafamidis meglumine as the active ingredient in VYNDAQEL and describes tafamidis as a selective stabilizer of transthyretin.
Tafamidis meglumine has CAS No. 951395-08-7, molecular formula C21H24Cl2N2O8, and molecular weight 503.33 g/mol. PubChem identifies it as an organoammonium salt formed from tafamidis and one molar equivalent of meglumine (N-methyl-D-glucamine).
Tafamidis meglumine consists of tafamidis free acid combined with one equivalent of meglumine. The tafamidis component has the molecular formula C14H7Cl2NO3 and molecular weight 308.12 g/mol, while the complete meglumine salt has a molecular weight of approximately 503.33 g/mol.
The chemical name reported by FDA is 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid mono (1-deoxy-1-methylamino-D-glucitol).
Tafamidis is a selective transthyretin stabilizer. It binds to the thyroxine-binding sites of transthyretin and stabilizes the normal tetrameric structure of the protein. This reduces tetramer dissociation into monomers, which is the rate-limiting step in the amyloidogenic process. By stabilizing the TTR tetramer, tafamidis reduces the formation of misfolded TTR aggregates and subsequent amyloid deposition.
Tafamidis meglumine is associated with the treatment of transthyretin-mediated amyloidosis, particularly hereditary transthyretin amyloidosis. FDA's original VYNDAQEL labeling identifies tafamidis meglumine as the active pharmaceutical substance in the 20 mg capsule formulation. Each 20 mg tafamidis meglumine capsule corresponds to 12.2 mg of tafamidis free acid.
Tafamidis is also available as the free-acid drug substance in the 61 mg formulation. FDA's pharmacology review confirms that tafamidis free acid 61 mg was demonstrated to be therapeutically equivalent to 80 mg of tafamidis meglumine.
Tafamidis meglumine is reported as a solid material. FDA's CMC assessment describes the drug substance as poorly soluble in water and non-hygroscopic, and reports that it exists as one known polymorph in the reviewed manufacturing process.
Commercial analytical-reference material is described as a white to pink powder, while a research-grade source reports DMSO solubility of approximately 2 mg/mL when warmed. This research-grade solubility should not be confused with a pharmacopoeial API release specification.
Tafamidis meglumine manufacturing requires control of the tafamidis active moiety, meglumine ratio, process-related impurities and solid-state properties. FDA's CMC review states that the manufacturing process was adequately understood and that the process controls were designed to control known impurities and the tafamidis-to-meglumine ratio.
The FDA assessment also reports that stability studies supported the drug-substance stability under the reviewed container-closure and storage conditions.
Quality testing for Tafamidis Meglumine API should include identity, assay, related substances, residual solvents, water content, elemental impurities and appropriate solid-state characterization.
A particularly relevant quality consideration is meglumine-related nitrosamine risk. Recent analytical publications have described methods for monitoring N-nitroso-meglumine (NNM) in tafamidis meglumine drug substance and finished dosage forms.
Because the proprietary FDA drug-substance specification limits are not fully disclosed in the public CMC review, numerical release limits should not be invented for CMS publication.
Tafamidis Meglumine API should be packaged in suitable pharmaceutical-grade, well-closed containers that protect the material from contamination and environmental exposure. Storage should follow validated stability data and the applicable registered drug-substance specification.
FDA's CMC assessment describes the substance as non-hygroscopic and reports satisfactory stability under the reviewed conditions.
A pharmaceutical-grade Tafamidis Meglumine API package may include a Certificate of Analysis, specification sheet, analytical methods, safety documentation, batch information, stability information and other regulatory documentation applicable to the intended market.
A qualified Tafamidis Meglumine API manufacturer in India should maintain robust controls over tafamidis identity, meglumine stoichiometry, assay, related substances, residual solvents, water content and solid-state characteristics. Particular attention should also be given to nitrosamine-risk assessment and appropriate analytical control of N-nitroso-meglumine.
| Parameter | Specification |
|---|---|
| Appearance | white to off-white crystalline powder |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | 98.0% |
| Loss on Drying | NMT 0.5% |
| Residue on Ignition | NMT 0.1% |
| Melting Point | 195–198°C |