Regorafenib is an orally active, multikinase inhibitor belonging to the diphenylurea/pyridinecarboxamide class of anticancer agents. It inhibits multiple protein kinases involved in tumor proliferation, angiogenesis and the tumor microenvironment. Regorafenib is used in the treatment of metastatic colorectal cancer, advanced gastrointestinal stromal tumors (GIST) and hepatocellular carcinoma in approved clinical settings.
The anhydrous API has the molecular formula C₂₁H₁₅ClF₄N₄O₃ and molecular weight 482.8 g/mol. Its CAS Registry Number is 755037-03-7. Regorafenib also exists as a monohydrate, CAS 1019206-88-2, with molecular weight 500.83 g/mol.
| Parameter | Details |
|---|---|
| Product Name | Regorafenib |
| CAS Number – Anhydrous | 755037-03-7 |
| CAS Number – Monohydrate | 1019206-88-2 |
| Molecular Formula – Anhydrous | C₂₁H₁₅ClF₄N₄O₃ |
| Molecular Weight – Anhydrous | 482.8 g/mol |
| Molecular Formula – Monohydrate | C₂₁H₁₇ClF₄N₄O₄ |
| Molecular Weight – Monohydrate | 500.83 g/mol |
| PubChem CID | 11167602 |
| UNII | 24T2A1DOYB |
| ChEBI ID | CHEBI:68647 |
| ChEMBL ID | CHEMBL1946170 |
| Drug Class | Multikinase inhibitor |
| Therapeutic Class | Antineoplastic agent |
| Administration | Oral |
PubChem and USP identify both the anhydrous and monohydrate forms; the USP drug-substance monograph specifically defines Regorafenib against the anhydrous and solvent-free basis.
Regorafenib is chemically identified as 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide. It contains a pyridinecarboxamide structure, an aromatic ether, a phenylurea moiety, a chlorine substituent and trifluoromethyl group.
Key chemical properties include:
Regorafenib is used in approved indications including:
The FDA's current labeling includes the approved HCC indication and continues to identify regorafenib as the active ingredient in STIVARGA.
Regorafenib inhibits multiple kinases involved in tumor growth and angiogenesis. Its pharmacological activity includes inhibition of signaling pathways associated with VEGFR1, VEGFR2, VEGFR3, TIE2, KIT, RET, RAF, BRAF, PDGFR and FGFR.
Through inhibition of these signaling pathways, regorafenib can reduce tumor-cell proliferation, tumor vascularization and signaling within the tumor microenvironment.
Regorafenib has an established USP drug-substance monograph. USP defines the API as containing NLT 97.5% and NMT 101.5% regorafenib, calculated on an anhydrous and solvent-free basis.
Appropriate pharmaceutical quality testing can include:
USP currently lists reference standards for Regorafenib, Regorafenib Related Compound A, Regorafenib Related Compound D and Regorafenib Related Compound E.
Regorafenib is a synthetic small-molecule API manufactured through controlled chemical synthesis followed by purification and isolation of the required solid form.
A pharmaceutical-grade manufacturing process should control:
Particular attention should be given to the monohydrate/anhydrous distinction, since USP expresses assay on an anhydrous and solvent-free basis.
| Property | Value |
|---|---|
| Molecular Formula – Anhydrous | C₂₁H₁₅ClF₄N₄O₃ |
| Molecular Weight – Anhydrous | 482.8 g/mol |
| Molecular Formula – Monohydrate | C₂₁H₁₇ClF₄N₄O₄ |
| Molecular Weight – Monohydrate | 500.83 g/mol |
| Exact Mass | 482.0768807 Da |
| XLogP3-AA | 4.2 |
| H-Bond Donors | 3 |
| H-Bond Acceptors | 8 |
| Rotatable Bonds | 5 |
| TPSA | 92.4 Ų |
| Formal Charge | 0 |
| Stereocenters | 0 |
For the marketed finished product, the current FDA label specifies storage at 25°C, with permitted excursions from 15°C to 30°C. Tablets should remain in the original bottle with the desiccant, and the bottle should be tightly closed after opening.
For bulk Regorafenib API, storage should follow the validated API-specific stability specification, particularly because the API may be supplied in a defined solid/hydrate form.
Typical pharmaceutical documentation may include:
A qualified Regorafenib API manufacturing program should emphasize high chemical purity, impurity control and consistent management of the API's solid form.
Key quality considerations include:
| 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 0.5% |
| Heavy Metals | NMT 20 ppm |
| Individual Impurity | NMT 0.5% |
| Total Impurities | NMT 1.0% |
| Water Content | NMT 1.0% |