Organic Solvent-Free Lyophilized Cyclophosphamide Preparation
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Solution Overview
Problem
Cyclophosphamide lyophilized compositions prepared with organic solvents face issues of instability, solubility, and potential side effects due to residual solvent residues, and existing methods do not efficiently dissolve the drug without using organic solvents.
Innovation Solution
A method involving dissolving cyclophosphamide and a lyoprotectant like D-mannitol or lactose in a water solvent at 40° C. to 70° C., followed by lyophilization, which allows for rapid reconstitution of the lyophilized composition within 15 seconds when water is added, eliminating the need for organic solvents and enhancing stability and solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If organic solvents are used to prepare lyophilized cyclophosphamide composition, then the composition can be prepared, but residual solvent residues cause instability, poor solubility, and potential side effects
Solution Approach 1:
The patent removes organic solvents from the preparation system entirely, extracting the harmful component while maintaining the ability to prepare lyophilized cyclophosphamide composition through water-based dissolution and lyophilization processes
Solution Approach 2:
The patent introduces water as an intermediary solvent that enables dissolution of cyclophosphamide and lyoprotectants without leaving harmful residues, facilitating the formation of stable lyophilized composition through aqueous lyophilization
2Ease of manufacture
If organic solvents are used in lyophilized composition preparation, then the composition can be formed, but solubility and stability are compromised
Solution Approach 1:
The patent changes the solvent parameter from organic to aqueous, and optimizes temperature parameters (40-70°C) to achieve both easy composition formation and improved solubility/stability in the resulting lyophilized product
3Object-generated harmful factors
If cyclophosphamide is dissolved in water at room temperature, then no organic solvent is needed, but dissolution is incomplete and reconstitution is slow
Solution Approach 1:
The patent changes the temperature parameter from room temperature to 40-70°C, enabling complete dissolution of cyclophosphamide and lyoprotectants in water while maintaining organic solvent-free conditions and achieving rapid reconstitution within 15 seconds
Solution Approach 2:
The patent introduces lyoprotectants (D-mannitol or lactose) as intermediary substances that facilitate complete dissolution and rapid reconstitution of cyclophosphamide in aqueous solutions at elevated temperatures
Data Source
AI summary
The present invention relates to a method for preparing a lyophilized cyclophosphamide composition, wherein 99% or more of the finally prepared lyophilized cyclophosphamide composition is reconstituted within 15 seconds when water for pharmaceutical use is injected thereinto at a ratio of 50 mL per 1 g of anhydrous cyclophosphamide, comprising a step of dissolving D-mannitol or lactose, as a lyoprotectant, and cyclophosphamide in a water solvent in a selected reaction vessel; and a lyophilized cyclophosphamide composition for injection prepared thereof.