Stable Liquid Cyclophosphamide Formulations via Non-Aqueous Solvents
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Solution Overview
Problem
Current formulations of cyclophosphamide are unstable in aqueous solutions, leading to rapid degradation and the lack of commercially available liquid formulations, which poses challenges in manufacturing and administration, and there is a need for stable liquid formulations that can maintain stability over a longer period.
Innovation Solution
Development of novel impurities of cyclophosphamide with structures V, VI, and VII, along with their stabilization and incorporation into stable liquid formulations using suitable solvents and stabilizers, such as polyols and organic acids, to reduce moisture content and enhance stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If cyclophosphamide is formulated in aqueous solutions, then it can be administered parenterally, but it degrades rapidly and loses stability
Solution Approach 1:
The patent changes the physical-chemical parameters of the formulation by using non-aqueous solvents (ethanol, propylene glycol, polyethylene glycol) instead of aqueous solutions. This parameter change prevents hydrolysis and maintains cyclophosphamide stability while still enabling parenteral administration. The solvent system is specifically designed to maintain drug stability over extended periods.
Solution Approach 2:
The patent creates an inert environment by excluding water from the formulation system. Non-aqueous solvents provide a water-free environment that prevents hydrolytic degradation of cyclophosphamide. The formulation maintains stability by keeping the drug in an inert, non-reactive solvent matrix that does not promote degradation.
2Stability of the object's composition
If cyclophosphamide is prepared as solid formulations, then it maintains stability, but it requires reconstitution and double handling increasing exposure risk
Solution Approach 1:
The patent creates a ready-to-use liquid formulation that eliminates the need for reconstitution. Although liquid formulations traditionally have shorter stability, this invention uses stable non-aqueous solvents to extend shelf life, making the formulation effectively disposable and ready-to-administer without requiring complex reconstitution procedures that expose personnel to the drug.
Solution Approach 2:
The patent performs preliminary action by pre-mixing cyclophosphamide with stable non-aqueous solvents during manufacturing to create ready-to-use liquid formulations. This eliminates the need for healthcare personnel to perform reconstitution and handling operations, thereby reducing occupational exposure risks while maintaining stability through the specialized solvent system.
3Ease of operation
If reconstituted solutions are prepared from dry powder, then they can be used immediately, but they are stable only for short periods at room temperature or refrigerated conditions
Solution Approach 1:
The patent fundamentally changes the formulation parameters by using non-aqueous solvents with different chemical properties than water. This parameter change extends the shelf life of the liquid formulation from hours (in aqueous systems) to months or years, while maintaining immediate usability. The formulation is stable at both room and refrigerated temperatures over extended periods.
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 stable liquid formulations of cyclophosphamide maintain pharmaceutical effectiveness and stability for extended periods, reducing the risk of degradation and improving handling safety for medical personnel, while allowing for effective parenteral administration of cyclophosphamide.
Implementation Method 1
incubating the bulk solution of cyclophosphamide of step a) with molecular sieves until the moisture content of the solution is less than about 2.0% by weight of the composition
Implementation Method 2
incorporation into stable liquid formulations using suitable solvents and stabilizers, such as polyols and organic acids, to reduce moisture content and enhance stability
Data Source
AI summary
The present invention relates to novel impurities of cyclophosphamide having structure V, VI or VII, stabilized form of these novel impurities, a process of preparing a stabilized form and isolating thereof. The invention also relates cyclophosphamide formulations which include cyclophosphamide, at least one pharmaceutically acceptable excipient, and a certain level of these impurities having structure V, VI or VII. The invention further relate to method of using such stable liquid formulations of cyclophosphamide for parenteral administration in treating various cancer disorders.