Bivalirudin Formulation pH Control Lyophilization
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Solution Overview
Problem
Current bivalirudin formulation processes often result in high levels of impurities like Asp9-bivalirudin, which affect product stability and shelf-life, with existing methods failing to consistently maintain low impurity levels and efficient reconstitution times.
Innovation Solution
A compounding process involving dissolving bivalirudin in a solvent, efficiently mixing a pH-adjusting solution to minimize Asp9-bivalirudin levels, and removing the solvent through lyophilization, using high shear mixing and controlled pH conditions to achieve a pharmaceutical formulation with reduced impurities and rapid reconstitution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional compounding processes are used to prepare bivalirudin formulations, then the formulation can be produced, but high levels of impurities (up to 12% Asp9-bivalirudin) are generated which affect product stability and shelf-life
Solution Approach 1:
The patent applies parameter changes by optimizing the pH-adjusting step to maintain pH below 8.0 during compounding, and controlling temperature at 25°C or lower during storage. These parameter changes prevent deamidation of asparagine at position 9, reducing Asp9-bivalirudin impurity formation and improving both manufacturing precision and product stability.
Solution Approach 2:
The patent employs preliminary anti-action by adding pH-adjusting solution under controlled conditions (pH < 8.0, temperature ≤ 25°C) before impurity formation can occur. This preventive approach counteracts the deamidation reaction that would otherwise generate Asp9-bivalirudin impurities, thereby maintaining low impurity levels and ensuring product stability.
2Productivity
If conventional compounding processes are used, then formulation production is achieved, but reconstitution time exceeds acceptable limits (greater than 42 seconds)
Solution Approach 1:
The patent changes the physical state parameter by using lyophilization (freeze-drying) to create a porous solid structure that rapidly reconstitutes. This parameter change in the formulation's physical state enables fast reconstitution (≤42 seconds) while maintaining ease of manufacture through standardized lyophilization processes.
3Manufacturing precision
If pH-adjusting solution is added without controlled mixing, then the compounding process is simple, but Asp9-bivalirudin impurity levels increase significantly
Solution Approach 1:
The patent applies continuity of useful action by implementing continuous or thorough mixing during the pH-adjusting step. This ensures uniform pH distribution throughout the formulation, preventing localized high-pH zones that would catalyze deamidation and Asp9-bivalirudin formation, thereby achieving low impurity levels through controlled mixing processes.
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 process consistently produces bivalirudin formulations with maximum Asp9-bivalirudin levels below 0.6% and total impurities below 2%, along with reconstitution times not exceeding 42 seconds, enhancing stability and usability.
Implementation Method 1
Impurities such as Asp9-bivalirudin (deamidation of asparagine at position 9 of bivalirudin to aspartic acid)
Implementation Method 2
removing the solvent from the second solution
Data Source
AI summary
Pharmaceutical batch(es) or pharmaceutical formulation(s) comprising bivalirudin as the active ingredient, and a method of preparing the pharmaceutical batch(es) or pharmaceutical formulation(s). The pharmaceutical batch(es) or pharmaceutical formulation(s) may have a maximum impurity level of Asp9-bivalirudin that does not exceed about 0.6%. Also, the pharmaceutical batch(es) or pharmaceutical formulation(s) may have a reconstitution time that does not exceed about 42 seconds. The method of preparing the pharmaceutical batch(es) or pharmaceutical formulation(s) may comprise dissolving bivalirudin in a solvent to form a first solution, efficiently mixing a pH-adjusting solution with the first solution to form a second solution in which the pH-adjusting solution may comprise a pH-adjusting solution solvent, and removing the solvent and the pH-adjusting solution solvent from the second solution.