Nintedanib Esylate is a synthetic indolinone derivative formulated as an ethylsulfate salt, functioning as an intracellular inhibitor of receptor tyrosine kinases. It targets vascular endothelial growth factor receptors, fibroblast growth factor receptors, and platelet-derived growth factor receptors, alongside Src and Flt-3 kinases. The raw material is synthesized via controlled multi-stage organic reactions with precise crystallization parameters to secure the required solid-state polymorphic form and particle dimensions for solid oral dosage manufacturing.
Chemical and Physical Specifications
|
Parameter |
Specification |
|
Chemical Name |
Ethanesulfonic acid compound with methyl 3-({[4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl]amino}(6-methoxy-2-methylindol-3-yl)methylidene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylate |
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CAS Number |
656247-18-6 (Esylate) / 287930-75-0 (Free Base) |
|
Molecular Formula |
C31H33N5O4 · C2H6O4S |
|
Molecular Weight |
649.76 g/mol |
|
Physical Appearance |
Bright yellow to yellow crystalline powder |
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Solubility |
Practically insoluble in water; slightly soluble in methanol; soluble in dimethyl sulfoxide |
Quality and Analytical Parameters
|
Parameter |
Acceptance Criteria / Method |
|
Assay (Dried Basis) |
98.5% to 101.5% (High-Performance Liquid Chromatography) |
|
Identity |
Confirmed by Infrared Absorption and HPLC retention time |
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Loss on Drying |
≤ 0.5% (105°C, Gravimetric Analysis) |
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Residue on Ignition |
≤ 0.1% (Sulfated Ash Test) |
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Heavy Metals |
≤ 10 ppm (Inductively Coupled Plasma Mass Spectrometry) |
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Individual Specified Impurity |
≤ 0.10% (Gradient HPLC) |
|
Total Impurities |
≤ 0.5% (Gradient HPLC) |
|
Residual Solvents |
Ethanol ≤ 5000 ppm, Dichloromethane ≤ 600 ppm, Ethyl Acetate ≤ 5000 ppm (Headspace Gas Chromatography) |
|
Particle Size Distribution |
D(0.5): 5 µm to 15 µm; d(0.9): ≤ 30 µm (Laser Diffraction) |
Manufacturing and Processing Standards
Synthesis Route: Convergent multi-stage organic synthesis using specialized reactor systems with continuous in-process chromatographic monitoring.
Purification Process: Multi-stage fractional crystallization and targeted solvent washing designed to isolate active fractions and remove process-related intermediates.
Facility Controls: Final isolation, micronization, and packaging executed within ISO Class 8 cleanroom environments utilizing localized barrier isolation technology.
Production Scale: Commercial manufacturing capabilities structured for continuous multi-kilogram to metric ton annual output under fully validated process parameters.
Regulatory Documentation and Support
Drug Master File: Comprehensive Type II documentation maintained to support global regulatory submissions and drug product registrations.
Analytical Certification: Complete Certificate of Analysis supplied with every commercial production batch.
Safety Data Sheet: Comprehensive hazard identification, handling guidelines, and toxicological documentation aligned with international standards.
Stability Profiles: Real-time (25°C / 60% RH) and accelerated (40°C / 75% RH) stability data packages available for technical evaluation.
Packaging and Storage
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Primary Packaging |
Double-layer pharmaceutical-grade low-density polyethylene bags, heat-sealed under positive nitrogen pressure. |
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Secondary Packaging |
Rigid high-density polyethylene drums equipped with tamper-evident security seals. |
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Moisture Control |
Food-grade silica gel desiccant packets positioned between packaging layers. |
|
Standard Net Weight |
1 kg, 5 kg, and 25 kg configurations per container. |
|
Storage Conditions |
Store in tightly sealed containers protected from light and moisture at controlled room temperatures between 15°C and 25°C. |
Pharmaceutical Applications
Idiopathic Pulmonary Fibrosis: Active pharmaceutical ingredient utilized in oral capsule formulations designed to slow pulmonary function decline through fibroblast proliferation inhibition.
Oncological Therapeutics: Incorporated into combination regimens targeting tumor angiogenesis and cell proliferation in specific histology types.
Interstitial Lung Disease: Applied in specialized solid oral dosage manufacturing aimed at reducing progressive decline of forced vital capacity.
Preclinical Research: Employed as an analytical reference standard and raw material in investigations of kinase cascade inhibition and tissue remodeling mechanisms.
FAQ
Q: What regulatory documentation is provided to support generic drug filing?
A: A comprehensive Drug Master File (DMF) prepared in Common Technical Document (CTD) format is available, containing complete chemistry, manufacturing, and controls (CMC) data, analytical methods, and impurity profiles.
Q: How is batch-to-batch consistency and polymorphic stability guaranteed?
A: Manufacturing follows a validated crystallization protocol utilizing standardized temperature gradients and automated stirring speeds, ensuring uniform particle size distribution and a single stable polymorphic form confirmed by X-ray powder diffraction (XRPD).
Q: What are the standard shipping and temperature control protocols for commercial quantities?
A: Shipments are packed in light-resistant, moisture-barrier containers with continuous temperature monitoring devices upon request, ensuring storage guidelines (2°C to 8°C) are maintained throughout transit.
Q: Are custom particle size distribution (PSD) profiles available for direct compression?
A: Yes, micronization and specialized milling parameters can be adjusted during the final processing stage to meet specific particle size distribution requirements for direct compression or specialized capsule filling.
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