Amorphous Dispersion of 4-Methyl-3-Quinolin-3-ylethynyl-Benzoic Acid Hydrazide
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Solution Overview
Problem
Conventional oral solid dosage forms of 4-Methyl-3-quinolin-3-ylethynyl-benzoic acid N′-(2-chloro-6-methyl-benzoyl)hydrazide fail to provide adequate bioavailability and stability, necessitating a new formulation that enhances both bioavailability and stability.
Innovation Solution
An amorphous dispersion of the compound in a fusible polymeric carrier, specifically polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, is created through melt processing, which is physically and chemically stable, maintaining the amorphous state during storage and improving bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional oral solid dosage forms are used, then manufacturing is simple, but bioavailability is inadequate
Solution Approach 1:
The patent changes the physical state parameter of the compound from crystalline to amorphous form. This parameter change significantly improves bioavailability by enhancing dissolution rate and solubility, while the amorphous state is maintained through specific formulation techniques that balance complexity and performance
Solution Approach 2:
The patent creates a composite system by combining the amorphous compound with a fusible polymeric carrier. This composite approach improves bioavailability through controlled release mechanisms and enhanced stability, while the polymer matrix manages the complexity of maintaining amorphous state during storage and processing
2Reliability
If conventional oral solid dosage forms are used, then formulation is simple, but stability is inadequate
Solution Approach 1:
The patent changes the physical state from crystalline to amorphous, which improves stability by reducing polymorphic transitions and degradation pathways. The amorphous state is stabilized through interaction with the polymeric carrier, managing the inherent instability of amorphous materials
Solution Approach 2:
The fusible polymeric carrier acts as an intermediary that stabilizes the amorphous compound. The polymer matrix prevents molecular rearrangement and degradation, while also providing a controlled release mechanism. This intermediary approach enhances stability without requiring complex external stabilization systems
3Reliability
If amorphous dispersion is used, then bioavailability is enhanced, but processing complexity increases
Solution Approach 1:
The patent utilizes phase transition of the polymeric carrier from solid to melt state during processing, then back to solid upon cooling. This phase transition approach allows for simple melt mixing and extrusion processes to create amorphous dispersions, avoiding complex processing while maintaining bioavailability benefits
Solution Approach 2:
The patent changes the temperature parameter during processing to facilitate melt extrusion of the polymeric carrier with the amorphous compound. By controlling temperature above the polymer's melting point during processing and then cooling, the system achieves easy manufacturing through phase change without compromising the amorphous state or bioavailability
4Reliability
If amorphous dispersion is used, then stability is improved, but storage requirements become more stringent
Solution Approach 1:
The fusible polymeric carrier serves as a protective intermediary that stabilizes the amorphous compound during storage. The polymer matrix restricts molecular mobility and prevents degradation even at elevated temperatures, allowing the formulation to maintain stability without requiring stringent cold storage conditions
Solution Approach 2:
The composite system of amorphous compound in polymeric matrix provides thermal stability through the polymer's glass transition temperature. The polymer network restricts molecular motion and prevents crystallization or degradation at storage temperatures, enabling stable storage without extreme temperature control while maintaining the stability advantages of the amorphous state
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The amorphous dispersion form achieves enhanced bioavailability, with plasma levels significantly higher than crystalline forms, and maintains stability with degradation impurities below 0.2% by weight, ensuring the compound remains stable and bioavailable for extended periods.
Implementation Method 1
the compound of formula I remained in an amorphous state during the period of storage
Implementation Method 2
An amorphous dispersion of the compound in a fusible polymeric carrier, specifically polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, is created through melt processing
Data Source
AI summary
An oral solid dosage form comprising a mixture of compound of formula I and a fusible polymeric carrier; and optionally pharmaceutically acceptable excipients, wherein the mixture is an amorphous dispersion.