Clopidogrel Stability via Acidic Microenvironment
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Solution Overview
Problem
Thienopyridine derivatives like Clopidogrel are prone to degradation in alkaline environments, leading to reduced stability and effectiveness in pharmaceutical compositions, especially when combined with certain excipients, which complicates the production of stable solid oral formulations.
Innovation Solution
Incorporating an effective amount of citric acid to create an acidic pH micro-environment around the active ingredient, which stabilizes Clopidogrel and prevents degradation, along with the use of compatible excipients like hydroxypropyl cellulose and crospovidone, to enhance the stability and bioavailability of the formulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Clopidogrel is formulated with conventional excipients in solid oral dosage forms, then the formulation can be manufactured and administered, but the active ingredient degrades in alkaline environments leading to reduced stability and effectiveness
Solution Approach 1:
The patent changes the pH parameter of the microenvironment by incorporating acidifying agents (citric acid, fumaric acid, or tartaric acid) to create an acidic pH microenvironment (pH 2-4) around Clopidogrel particles. This parameter change prevents degradation by maintaining the active ingredient in an acidic environment where it is stable, even when surrounded by alkaline excipients like stearic acid or magnesium stearate.
Solution Approach 2:
The acidifying agents act as intermediary substances that create a protective acidic microenvironment between Clopidogrel and alkaline excipients. These intermediaries (citric acid, fumaric acid, or tartaric acid) buffer the local pH around the active ingredient, preventing direct interaction with alkaline degradation sources while allowing the formulation to maintain conventional excipients for manufacturing.
2Reliability
If acidifying agents are added to protect Clopidogrel from degradation, then stability is improved, but the formulation complexity and manufacturing process become more complicated
Solution Approach 1:
The patent modifies the chemical environment parameter by adding small amounts of acidifying agents (0.1-10% w/w) to create an acidic microenvironment. This simple parameter change achieves protection without requiring complex formulation structures, special coating technologies, or multiple processing steps.
Solution Approach 2:
The acidifying agents self-buffer the microenvironment around Clopidogrel particles, automatically maintaining acidic conditions without requiring external control systems, pH monitoring, or complex release mechanisms. The formulation self-regulates the pH through the buffering capacity of the acidifying agents.
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 use of citric acid in the formulation significantly increases the stability of Clopidogrel, maintaining its effectiveness over prolonged storage periods and ensuring rapid and quantitative drug release, as demonstrated by enhanced stability and dissolution profiles compared to compositions without citric acid.
Implementation Method 1
Incorporating an effective amount of citric acid to create an acidic pH micro-environment around the active ingredient, which stabilizes Clopidogrel and prevents degradation
Data Source
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Figure 3
AI summary
The present invention relates to an improved solid dosage form such as tablets and in particular to a pharmaceutical formulation for oral administration comprising a therapeutically effective quantity of an anti-platelet agent, such as Clopidogrel or pharmaceutical acceptable salt or derivative thereof in combination with an acidifying agent, such as citric acid to protect the active ingredient from degradation and a method for the preparation thereof.