Entacapone Granulation for Rapid Dissolution in Antiparkinson Tablets
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The low solubility and bioavailability of entacapone, classified as a Class IV drug under the Biopharmaceutics Classification System, pose challenges in developing pharmaceutical compositions that ensure adequate stability and bioequivalence with existing formulations, particularly in fixed-dose combinations with levodopa and carbidopa, due to its low dissolution rate and poor manufacturability with reduced particle sizes.
Innovation Solution
A pharmaceutical tablet composition is developed using levodopa and carbidopa granulated together with suitable excipients by wet granulation, while entacapone is granulated separately with a median particle size distribution of about 2 µm to enhance solubility and bioavailability, using a common granule process for all doses to reduce manufacturing time and costs, and improve flow properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If entacapone particle size is reduced to improve solubility and dissolution rate, then bioavailability is improved, but manufacturability and flow properties deteriorate
Solution Approach 1:
The patent applies parameter changes by precisely controlling the particle size distribution of entacapone (D10: 1.0-2.0 µm, D50: 2.5-3.5 µm, D90: 4.0-5.0 µm) to achieve optimal balance between dissolution rate and manufacturability. This specific parameter range resolves the contradiction by maintaining sufficiently small particles for good bioavailability while avoiding excessive fineness that would cause handling and manufacturing problems.
2Reliability
If entacapone is granulated separately to maintain particle size control, then dissolution profile is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies segmentation by separating the granulation process into two independent stages: first granulating levodopa and carbidopa together, then separately granulating entacapone with its own excipients. This segmentation allows each component to be optimized independently for its specific requirements while maintaining overall process manageability through a common granule approach.
Solution Approach 2:
The patent merges the separately granulated entacapone granules with the levodopa-carbidopa granules in a final blending step to create a unified tablet formulation. This merging combines the benefits of separate granulation (controlled dissolution) with the simplicity of a single tablet manufacturing process, reducing overall manufacturing complexity.
3Manufacturing precision
If multiple granulation processes are used for different doses, then formulation precision is improved, but manufacturing time and costs increase
Solution Approach 1:
The patent applies universality by developing a common granule process that can produce all six different dose strengths (Stalevo 50, 75, 100, 125, 150, and 200) using the same granulation methodology and particle size control parameters. This universal approach maintains formulation precision across all doses while significantly reducing manufacturing time and costs compared to developing separate processes for each strength.
Data Source
Figure 1
AI summary
The present invention relates to a process for preparing pharmaceutical fixed dose combination, immediate release tablet comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof characterized in that Entacapone has very rapidly dissolving property by using low particle size distribution. Also levodopa and carbidopa are granulated together to produce a common granule and entacapone is granulated separatelyin order to facilitate the production of pharmaceutical tablet combination.