AZD9291 Tablet Dissolution via Diluent Ratio Control
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Solution Overview
Problem
The pharmaceutical composition of AZD9291 exhibits pH-dependent solubility, leading to variability in absorption rates and amounts when administered orally, resulting in inconsistent drug efficacy and potential safety risks due to variable drug levels in systemic circulation.
Innovation Solution
A novel pharmaceutical composition with a reduced amount of microcrystalline cellulose and the inclusion of other pharmaceutically acceptable diluents, disintegrants, solubilizing agents, and lubricants, such as mannitol, sodium stearyl fumarate, and low-substituted hydroxypropyl cellulose, to enhance dissolution and release characteristics, reducing pH-dependent solubility variability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If AZD9291 is formulated as a simple blend in capsule with microcrystalline cellulose, then manufacturing is simple and cost-effective, but dissolution is slow and incomplete leading to variable absorption
Solution Approach 1:
The patent changes the dissolution parameters by adjusting pH (using citric acid to create acidic environment) and temperature (incubation at 37°C), demonstrating that the formulation's dissolution behavior is sensitive to these parameters. This supports using parameter control to improve dissolution reliability
Solution Approach 2:
The patent uses composite materials by combining AZD9291 with multiple excipients including microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate in specific ratios. This composite approach optimizes both dissolution performance and manufacturing feasibility, resolving the contradiction between simplicity and reliability
2Ease of operation
If AZD9291 is administered orally, then patient compliance is improved, but pH-dependent solubility causes variability in drug levels in systemic circulation
Solution Approach 1:
The patent performs preliminary dissolution testing under simulated gastrointestinal conditions (pH 1.2, 4.5, 6.8) to characterize the drug's pH-dependent solubility behavior before clinical use. This preliminary characterization allows for formulation optimization to ensure consistent drug levels, addressing the reliability issue while maintaining oral administration convenience
Solution Approach 2:
The patent introduces excipients as intermediaries that mediate between the drug and gastrointestinal environment. These excipients modify the dissolution profile to reduce pH-dependent variability, ensuring more consistent drug release across different gastrointestinal pH conditions while maintaining oral administration
3Reliability
If dissolution is enhanced to reduce variability in absorption, then drug efficacy and safety are improved, but formulation complexity increases
Solution Approach 1:
The patent systematically evaluates the effect of excipient ratios on dissolution parameters, identifying optimal ranges that achieve reliable absorption without excessive complexity. By controlling parameters within specific ranges rather than using complex mechanisms, the formulation achieves reliability with manageable complexity
Solution Approach 2:
The patent uses moderate amounts of excipients (e.g., 5-20% microcrystalline cellulose, 5-15% mannitol) rather than large quantities or multiple complex components. This partial action approach achieves sufficient dissolution enhancement to reduce absorption variability while avoiding unnecessary formulation complexity
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 improved composition achieves faster and more complete dissolution of AZD9291, reducing inter-dose and inter-patient variability in absorption, thereby enhancing drug efficacy and safety by maintaining consistent drug levels in systemic circulation.
Implementation Method 1
The improved composition achieves faster and more complete dissolution of AZD9291
Implementation Method 2
AZD9291 exhibits significant pH dependent solubility
Implementation Method 3
from 0 to 15 parts of one or more pharmaceutical disintegrants
Data Source
AI summary
The present invention relates to pharmaceutical compositions suitable for oral administration, and more particularly to pharmaceutical compositions, including pharmaceutical tablet compositions, containing N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide (“AZD9291”) or a pharmaceutically acceptable salt thereof, wherein such compositions comprise a certain amount of microcrystalline cellulose and at least one other pharmaceutical diluent.