Osilodrostat API is a synthetic small-molecule active pharmaceutical ingredient used as a cortisol synthesis inhibitor. It is also known by the development code LCI699 and is marketed as Isturisa in its phosphate salt form. Osilodrostat inhibits 11β-hydroxylase (CYP11B1), an enzyme involved in the final step of cortisol biosynthesis in the adrenal gland. The FDA identifies osilodrostat as a cortisol synthesis inhibitor and reports an IC50 of 2.5 ± 0.1 nM for human CYP11B1 in the referenced assay.
For pharmaceutical API purposes, an important distinction is that osilodrostat itself is the free-base active moiety, while the approved pharmaceutical product contains osilodrostat phosphate. PubChem lists free-base osilodrostat under CAS 928134-65-0, with molecular formula C13H10FN3 and molecular weight 227.24 g/mol. PubChem separately lists osilodrostat phosphate under CAS 1315449-72-9, with formula C13H13FN3O4P and molecular weight 325.23 g/mol.
PubChem identifies osilodrostat's established pharmacological class as a cortisol synthesis inhibitor and its mechanism of action as CYP11B1 inhibition.
Free-base osilodrostat has the molecular formula C13H10FN3 and molecular weight 227.24 g/mol. Its exact mass is 227.08587549 Da, with 0 hydrogen-bond donors, 3 hydrogen-bond acceptors, 1 rotatable bond, and topological polar surface area of 41.6 Ų. It contains 1 defined stereocenter, corresponding to the 5R configuration.
The pharmaceutical phosphate salt has the formula C13H13FN3O4P and molecular weight 325.23 g/mol, with an exact mass of 325.06277106 Da, 3 hydrogen-bond donors, 7 hydrogen-bond acceptors, 1 rotatable bond, and topological polar surface area of 119 Ų.
Osilodrostat phosphate is particularly relevant for pharmaceutical manufacturing because the FDA-approved product uses the phosphate salt form. The FDA describes the active pharmaceutical ingredient as osilodrostat phosphate, with the chemical name 4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile dihydrogen phosphate. Its relative molecular mass is 325.24 g/mol on an anhydrous basis.
The pharmaceutical documentation describes osilodrostat phosphate as a crystalline material. The current product monograph identifies the material as modification A, with a melting onset of 214.1°C by DSC at a heating rate of 10 K/min.
FDA quality-review data provide particularly useful numerical API characteristics for osilodrostat phosphate. The salt has a pH of 4.45 in a 1% aqueous solution, a melting point of approximately 214°C by DSC, and a pKa of 6.9. The reported cLogP is 1.61.
Osilodrostat phosphate demonstrates high aqueous solubility. At 25°C, reported solubility is >50 mg/mL in water and in buffer solutions at pH 1, 3, 5 and 6.8. Solubility in ethanol is 5.8 mg/mL, methanol 14.2 mg/mL, acetone 1.5 mg/mL, propylene glycol 1.5 mg/mL, acetonitrile 0.2 mg/mL, and ethyl acetate 0.4 mg/mL.
Osilodrostat is used for controlling excessive cortisol production in patients with Cushing's disease when pituitary surgery is not an option or has not been curative. Its mechanism is based primarily on inhibition of CYP11B1, reducing the final enzymatic step in cortisol biosynthesis.
Relevant pharmaceutical applications include:
The EMA assessment report states that the active-substance specification includes appearance, particle size, identity by HPLC/IR/XRPD, related substances and impurities by HPLC/GC-MS/MS, enantiomer by HPLC, residual solvents by GC, water by Karl Fischer, assay by HPLC/potentiometric titration, and microbial quality.
The EMA stability program included storage at 25°C/60% RH and 30°C/75% RH for up to 24 months, accelerated storage at 40°C/75% RH for up to 6 months, and photostability testing according to ICH Q1B. The active substance was reported as not photosensitive under the tested conditions.
For a commercial API page, manufacturer-specific release limits should therefore be distinguished from publicly disclosed physicochemical and regulatory data. Where an official numerical release criterion is not publicly disclosed, N/A is preferable to inventing a specification.
| Parameter | Specification |
|---|---|
| Appearance | white to off-white crystalline powder |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | 98.0% – 102.0% |
| Loss on Drying | NMT 0.5% |
| Residue on Ignition | NMT 0.2% |
| Individual Impurity | NMT 0.5% |
| Total Impurities | ≤ 1.5% |
| Water Content | NMT 0.5% |