Lyophilized Pharmaceutical Formulations for Poor Solubility
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Solution Overview
Problem
Compounds like glibenclamide, which are weak acids, exhibit poor solubility at low and medium pH values, making them difficult to use in pharmaceutical formulations due to stability and solubility issues in aqueous solutions, limiting their clinical effectiveness.
Innovation Solution
The development of methods and compositions for lyophilizing these compounds at high pH values to increase solubility, followed by freeze-drying to create stable lyophilized formulations that can be reconstituted for pharmaceutical use, including the use of pH adjusters like NaOH and bulking agents like mannitol, without the need for buffering agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If compounds like glibenclamide are formulated in aqueous solutions at low and medium pH values, then they can be used in standard pharmaceutical formulations, but their solubility is poor and stability is compromised
Solution Approach 1:
The patent changes the pH parameter from low/medium (standard pharmaceutical range) to high pH (greater than 9) to dramatically improve solubility of weak acid compounds like glibenclamide. This parameter change enables the compound to achieve adequate solubility (greater than 0.1 mg/mL) while maintaining stability, resolving the contradiction between formulability and reliability.
2Stability of the object's composition
If buffering agents are added to maintain pH stability, then pH instability is reduced, but the formulation becomes more complex and may interfere with the compound's solubility and stability
Solution Approach 1:
The patent removes buffering agents from the formulation entirely, extracting the problematic element that caused complexity. Instead of adding buffers to stabilize pH, the formulation relies on the inherent stability of high pH conditions combined with controlled water activity through freezing, achieving pH stability without the need for complex buffering systems.
3Reliability
If the compound is lyophilized at high pH values, then solubility and stability are enhanced, but additional processing steps are required
Solution Approach 1:
The patent utilizes the phase transition of water from liquid to solid (freezing) to control water activity and stabilize the compound during lyophilization. By freezing the high pH solution and then lyophilizing, the process achieves enhanced solubility and stability through controlled phase changes, making the additional processing steps worthwhile for the significant improvement in compound reliability.
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 enhances the solubility and stability of poorly soluble compounds, allowing for the creation of pharmaceutically acceptable formulations that maintain efficacy and stability over time, suitable for various storage conditions and reconstitution without pH instability.
Implementation Method 1
The compound is dissolved in aqueous solution at high pH values to increase solubility, then frozen and lyophilized to create a stable solid formulation
Implementation Method 2
dissolved in aqueous solution at high pH values to increase solubility
Data Source
AI summary
The present invention provides compositions, methods for lyophilizing compounds and making pharmaceutical compositions, and kits providing solutions and lyophilized formulations of compounds. The compositions, methods, and kits are particularly useful in pharmaceutical applications involving therapeutic agents that have low solubility at low and medium pH values. Certain embodiments provide methods for lyophilizing compounds in liquid solutions, which include the steps of: a) preparing aqueous solutions of a compound of interest in the absence of buffer; b) adjusting the pH to high values of pH in order to increase the solubility of the compound of interest; and c) freeze-drying the solution to provide a lyophilized solid composition. Aqueous solutions including buffer are also disclosed. Lyophilized formulations, including micronized and non-micronized powders, are provided.