Lyophilization of Hydrolysis-Susceptible Compounds Using Subzero Solvent Mixtures
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Solution Overview
Problem
Compounds susceptible to hydrolytic degradation, such as Azacitidine, Decitabine, and Bendamustine, face stability issues in aqueous solutions, leading to rapid degradation and limited shelf life, making their formulation and administration challenging.
Innovation Solution
A process involving the use of a mixture of aqueous and organic solvents, specifically Acetonitrile and Water in a 80:20 ratio, to lower the freezing point to −5±2°C, enhancing the stability of these compounds during lyophilization and maintaining solubility at subzero temperatures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If compounds are formulated in aqueous solutions for parenteral administration, then ease of administration is improved, but hydrolytic degradation increases leading to reduced stability
Solution Approach 1:
The patent changes the temperature parameter to subzero conditions (−5±2°C) during lyophilization to reduce the rate of hydrolytic degradation. This temperature parameter change allows the compound to maintain stability while still being formulated in an aqueous-compatible system that can be administered parenterally after reconstitution.
Solution Approach 2:
The patent utilizes the phase transition of water to ice during lyophilization at subzero temperatures. By freezing the aqueous solution and then lyophilizing, the compound is converted to a stable lyophilized powder form that prevents hydrolytic degradation while maintaining the ability to be reconstituted for administration.
2Ease of manufacture
If lyophilization is performed at conventional freezing points, then manufacturing simplicity is maintained, but degradation of hydrolysis-susceptible compounds increases
Solution Approach 1:
The patent modifies the freezing point parameter from conventional temperatures (0°C or above) to subzero temperatures (−5±2°C) during lyophilization. This parameter change reduces hydrolytic degradation of the compound while still using standard lyophilization equipment and procedures, maintaining manufacturing simplicity.
Solution Approach 2:
The patent introduces an intermediary step of cooling the solution to subzero temperatures before lyophilization. This intermediary temperature control step acts as a mediator that protects the hydrolysis-susceptible compound from degradation while allowing the lyophilization process to proceed with conventional equipment.
3Ease of manufacture
If solubility is maintained at higher temperatures, then ease of formulation is improved, but hydrolytic degradation rate increases
Solution Approach 1:
The patent changes the temperature parameter to subzero conditions (−5±2°C) during the formulation and lyophilization process. At this lower temperature, the rate of hydrolytic degradation is significantly reduced, and the compound can be formulated and processed with maintained solubility through the use of appropriate solvents and excipients.
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
This approach significantly reduces the degradation of hydrolysis-susceptible compounds, improving their stability profile and allowing for more stable pharmaceutical compositions suitable for parenteral administration with reduced reconstitution time and increased sterility assurance.
Implementation Method 1
A process involving the use of a mixture of aqueous and organic solvents, specifically Acetonitrile and Water in a 80:20 ratio, to lower the freezing point to −5±2°C
Implementation Method 2
by Lyophilization at the optimum subzero temperature
Data Source
AI summary
The present invention relates to a process of preparing a stable pharmaceutical composition of compounds which are susceptible to hydrolysis comprising a. Addition of required quantity of pharmaceutically acceptable lyophilization excipients optionally in Water for Injection in a formulation vessel; b. Addition of organic solvent to form a appropriate proportion of aqueous and organic solvent; c. Maintaining the temperature of the formulation vessel from the range −5±1° C. to −5±3° C.; d. Addition of required quantity of compound susceptible to hydrolysis to form a solution and lyophilizing the solution.