Anhydrous Neratinib Maleate Composition for Stable Dry Granulation
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Solution Overview
Problem
Neratinib maleate formulations face challenges due to degradation and polymorphic transformation, leading to instability and inconsistent dissolution profiles, which are exacerbated by the use of water and high temperatures during preparation, posing risks to drug quality and therapeutic efficacy.
Innovation Solution
A pharmaceutical composition comprising anhydrous neratinib maleate with specific excipients, such as copovidone, mannitol, and microcrystalline cellulose, is prepared using dry granulation to maintain stability and consistent dissolution, avoiding water and high temperatures, ensuring uniform particle size and controlled crystallinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If water is used during preparation, then granulation and binding are improved, but neratinib maleate undergoes polymorphic transformation from anhydrous to hydrated form and chemical degradation occurs
Solution Approach 1:
The patent uses a water-miscible organic solvent (acetonitrile, ethanol, or isopropanol) as an intermediary binding agent instead of water. This intermediary performs the granulation and binding functions while avoiding the polymorphic transformation to hydrated form and chemical degradation that occur with water exposure.
Solution Approach 2:
The patent changes the physical-chemical parameter of the binding agent from aqueous (water-based) to organic solvent-based. This parameter change eliminates the water-induced polymorphic transformation while maintaining the granulation and binding effectiveness needed for tablet formation.
2Quantity of substance
If high temperature drying is used to remove moisture, then moisture content is reduced, but neratinib maleate degradation increases
Solution Approach 1:
The patent uses a water-miscible organic solvent as an intermediary that allows for effective drying at lower temperatures. The organic solvent can be removed more gently than water, reducing the need for high-temperature drying that causes degradation, while still achieving the required low moisture content levels.
Solution Approach 2:
The patent changes the drying temperature parameter from high temperature (70-90°C) to lower temperature ranges (40-60°C). This parameter change reduces thermal degradation of neratinib maleate while still achieving adequate moisture removal through the use of organic solvent-based granulation.
3Strength
If fluidized-bed granulation with water is used, then binding properties are improved, but dissolution rate becomes too fast and stability decreases
Solution Approach 1:
The patent uses a water-miscible organic solvent as an intermediary binding agent that provides adequate granulation strength without causing excessive dissolution. The organic solvent creates granules with binding properties similar to water-based granulation but with controlled dissolution characteristics that match the reference product.
Solution Approach 2:
The patent changes the dissolution rate parameter by using organic solvent-based granulation instead of water-based granulation. This parameter change slows down the dissolution rate from >80% in 15 minutes to a profile consistent with the reference product, while maintaining adequate binding strength through the organic solvent binding mechanism.
Data Source
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AI summary
Disclosed in the present invention are a pharmaceutical composition containing an EGFR inhibitor, and a preparation method therefor and the use thereof. The pharmaceutical composition contains particles, wherein the particles contain the following components in mass fraction: 30%-45% of anhydrous neratinib maleate, 7%-28% of copovidone, 25%-48% of a filler, 1.0%-8.0% of a disintegrant, 0.5%-4.0% of a glidant and 0.5%-4.0% of a lubricant. The pharmaceutical composition of the present invention has good stability and in-vivo biological activity equivalent to that of a reference preparation, and has a good application prospect.