FGFR4 Inhibitor Composition With Better Flowability and Dissolution
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Solution Overview
Problem
The p-toluenesulfonate form of the FGFR4 inhibitor compound exhibits poor dissolution properties and inadequate flowability, making industrial production difficult and hindering the development of pharmaceutical formulations that meet clinical requirements.
Innovation Solution
A pharmaceutical composition comprising a free base or acidic salt of the FGFR4 inhibitor, combined with suitable fillers and carriers such as calcium hydrogen phosphate, mannitol, lactose, and microcrystalline cellulose, and additional carriers like glidants, lubricants, and disintegrants, optimized through processes like direct powder filling or wet granulation to improve flowability and dissolution properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the p-toluenesulfonate form of the FGFR4 inhibitor compound is used, then solubility and bioavailability are improved, but dissolution properties become poor and flowability becomes inadequate
Solution Approach 1:
The patent changes the physical and chemical parameters of the compound by converting it from the p-toluenesulfonate salt form to the free base form. This parameter change resolves the contradiction by improving dissolution properties and flowability while maintaining adequate solubility through the inherent properties of the free base structure.
Solution Approach 2:
The patent extracts the p-toluenesulfonate group from the compound structure, removing the salt form to obtain the free base. This extraction eliminates the poor dissolution and flowability issues associated with the salt form while preserving the core pharmacologically active structure.
2Stability of the object's composition
If the p-toluenesulfonate form of the FGFR4 inhibitor compound is used, then solubility and bioavailability are improved, but flowability becomes inadequate
Solution Approach 1:
The patent changes the physical state and molecular structure parameters by converting from salt form to free base form. This parameter transformation improves flowability by eliminating the hygroscopic and sticky characteristics of the p-toluenesulfonate salt, enabling better powder handling and capsule filling operations.
3Manufacturing precision
If direct powder filling or wet granulation process is optimized, then content uniformity is greatly improved, but process complexity increases
Solution Approach 1:
The patent applies preliminary action by performing granulation before filling to ensure uniform drug distribution. The wet granulation process pre-mixes the free base compound with excipients and binds them into uniform granules, ensuring content uniformity is achieved before the filling step, thereby resolving the contradiction between precision and complexity.
Solution Approach 2:
The patent segments the formulation process into distinct stages: granulation, drying, and filling. By dividing the process into separate operational steps, each optimized for its specific function, the patent achieves content uniformity through granulation while managing overall process complexity through systematic segmentation of operations.
Data Source
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AI summary
An FGFR4 inhibitor composition, a preparation method therefor and the pharmaceutical use thereof. The FGFR4 inhibitor composition comprises a free base of the compound as represented by formula (I) having the following structure or an acid salt thereof as an active ingredient; and a preparation process suitable for industrial production is developed by means of using a suitable filler and other pharmaceutically acceptable carriers. A drug preparation with the drug fluidity, the dissolution rate, the content uniformity, the content of related substances, the physical and chemical stability, etc. thereof meeting clinical requirements can be obtained, such that the requirements of clinical research and drug marketing are met, the problem of drug accessibility is solved, and the drug preparation is expected to be quickly developed into a new generation of FGFR4 inhibitors.