Levothyroxine Liquid Formulation Stability via pH Control
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Solution Overview
Problem
Conventional lyophilized formulations of levothyroxine sodium for injection require reconstitution, leading to limited stability and potential contamination, making them unsuitable for long-term storage and use.
Innovation Solution
A ready-to-use liquid formulation of levothyroxine sodium, tromethamine, sodium iodide, and water with a pH of 9.0 to 11.5, which is stable for extended periods without reconstitution, reducing impurity formation and ensuring patient safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional lyophilized formulations are used, then storage stability is improved, but reconstitution is required which introduces contamination risk and limited post-reconstitution stability
Solution Approach 1:
The formulation is prepared in advance as a ready-to-use liquid solution with optimized pH (9.0-11.5) and stabilizing agents, eliminating the need for reconstitution at the point of use. This preliminary preparation ensures sterility and stability are maintained throughout storage without requiring contamination-prone reconstitution steps.
Solution Approach 2:
The patent changes the pH parameter to 9.0-11.5 and incorporates specific stabilizing agents to improve levothyroxine stability in liquid form. This parameter optimization allows the formulation to maintain stability without reconstitution, resolving the contradiction between storage stability and contamination risk.
2Duration of action of stationary object
If conventional lyophilized formulations are used, then long-term storage is possible, but post-reconstitution stability is limited to a few hours
Solution Approach 1:
The patent optimizes pH to 9.0-11.5 and incorporates stabilizing agents to extend the stability duration of the liquid formulation. This allows the product to maintain stability throughout the entire shelf life without reconstitution, eliminating the short post-reconstitution stability window.
Solution Approach 2:
Stabilizing agents are introduced as intermediaries to protect levothyroxine from degradation in liquid form. These agents mediate between the drug substance and the aqueous environment, preventing degradation and extending stability duration.
3Ease of operation
If levothyroxine is formulated in aqueous solutions, then ready-to-use convenience is improved, but degradation occurs leading to reduced stability
Solution Approach 1:
The patent formulates the aqueous solution at pH 9.0-11.5 and includes stabilizing agents to prevent degradation. This parameter optimization maintains ready-to-use convenience while significantly improving degradation resistance compared to conventional formulations.
Solution Approach 2:
Stabilizing agents serve as intermediaries that protect levothyroxine from degradation in the aqueous environment. These agents mediate the interaction between the drug and water, preventing harmful degradation reactions while maintaining the ready-to-use liquid form.
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 formulation maintains at least 90% of the labeled concentration of levothyroxine after storage for up to 36 months, with reduced impurities, enhancing storage stability and safety.
Implementation Method 1
The liquid formulation has a pH of about 9.0 to about 11.5
Implementation Method 2
aqueous solutions of levothyroxine sodium have been shown to be more stable at basic pH than at acidic pH
Implementation Method 3
levothyroxine in oral tablets and in aqueous solutions undergoes degradation. Aqueous solutions of levothyroxine sodium have been shown to be more stable at basic pH than at acidic pH
Data Source
AI summary
The present invention is directed to a pharmaceutical product which includes a liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof. The formulation of the present invention includes a cyclodextrin, water, and an amine, and has a pH above the buffering range of the amine. The liquid formulation of the invention is stable and ready-to-use.