Retigabine API, also known as Ezogabine, is a synthetic small-molecule active pharmaceutical ingredient belonging to the neuronal potassium channel opener class. It acts primarily on Kv7/KCNQ potassium channels and was developed for anticonvulsant therapy. FDA regulatory documentation identifies Retigabine as a first-in-class neuronal potassium channel opener.
Retigabine has the molecular formula C16H18FN3O2 and molecular weight 303.3 g/mol, with CAS Number 150812-12-7. The API is described as a non-hygroscopic, white to slightly colored crystalline powder with very poor water solubility.
Retigabine is chemically identified as N-[2-Amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester. It is an achiral synthetic compound and exists in multiple crystalline polymorphic forms. Regulatory assessment identified five polymorphic forms, with Form A selected for commercial use and controlled using X-ray diffraction.
Retigabine is weakly basic with a reported pKa of 3.7. FDA data report water solubility of approximately 0.04–0.05 mg/mL above pH 5, while solubility increases substantially under acidic conditions.
| Parameter | Retigabine |
|---|---|
| Product Name | Retigabine |
| Synonym | Ezogabine |
| CAS Number | 150812-12-7 |
| Molecular Formula | C16H18FN3O2 |
| Molecular Weight | 303.33 g/mol |
| Chemical Class | Neuronal potassium channel opener |
| API Type | Synthetic small molecule |
| Physical Form | Crystalline powder |
| Appearance | White to slightly colored / off-white powder |
| pKa | 3.7 |
| Water Solubility | Approximately 0.04–0.05 mg/mL above pH 5 |
| Polymorphism | Five polymorphic forms identified |
| Commercial Form | Form A |
| Chirality | Achiral |
| Melting Point | Approximately 142°C |
| BCS Classification | Class II |
The molecular and physicochemical values above are supported by FDA and Australian regulatory assessments.
Retigabine was developed as an anticonvulsant and neuronal potassium channel opener for the treatment of partial-onset seizures. Its pharmacological activity is associated with enhancement of neuronal Kv7/KCNQ potassium-channel currents.
The API is therefore relevant to pharmaceutical development and analytical research involving:
Retigabine drug substance quality control involves identity, assay, related-substance analysis, polymorphic-form control and residual-solvent testing. FDA documentation reports the use of reverse-phase HPLC methods for assay and ordinary related substances, while potentially genotoxic impurities were controlled using LC-MS analytical procedures.
The regulatory documentation also identifies control of the crystalline form by X-ray diffraction and control of particle size. For the commercial process, the Australian assessment reports a D50 particle-size limit of ≤35 µm. Residual methanol was revised to a limit of 3000 ppm.
Commercial analytical references report Retigabine purity of ≥98% by HPLC, while a Tocris certificate of analysis for a research batch reported 99% HPLC purity. These are commercial/reference values rather than a universal pharmacopoeial API specification.
Retigabine API manufacturing and analytical control should address the chemical identity, assay, related substances, residual solvents, polymorphic form and particle-size characteristics of the active ingredient. Regulatory development history demonstrates the importance of controlling process-related and potentially genotoxic impurities in Retigabine drug substance.
Analytical characterization can include HPLC/UV, LC-MS, IR, UV, mass spectrometry and X-ray diffraction according to the attribute being evaluated. FDA documentation confirms that Retigabine was characterized using elemental analysis, mass spectrometry, NMR, X-ray crystal structure, UV and IR techniques.
Retigabine API should be stored in a tightly closed, appropriately protective pharmaceutical container under controlled conditions that protect the material from contamination, moisture and excessive heat.
The regulatory assessment describes Retigabine as non-hygroscopic. Commercial analytical material is commonly stored at room temperature, while some research-grade material is stored under refrigerated conditions according to the manufacturer's certificate.
Typical API documentation can include:
Retigabine API requires controlled analytical characterization because its quality profile includes polymorphism, related substances, residual solvents and particle-size attributes. Regulatory assessments specifically document control of Form A, particle size and process-related impurities.
A quality-focused Retigabine API manufacturing program should therefore emphasize:
| Parameter | Specification |
|---|---|
| Appearance | white to off-white crystalline powder |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | 98.0% – 102.0% |
| pH (1% Solution) | 5.5 – 6.5 |
| Water Content | Approximately 0.04–0.05 mg/mL above pH 5 |
| Melting Point | Approximately 142°C |