Alcohol-Based Lyophilized Carmustine Formulation for Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Carmustine, a nitrogen mustard used in chemotherapy, is difficult to formulate as a pharmaceutical due to its high reactivity in aqueous solutions, leading to degradation and stability issues, and existing lyophilized formulations suffer from quality problems such as particulate matter and melting, necessitating improved manufacturing processes.
Innovation Solution
A pharmaceutical formulation of carmustine in t-butanol with 5% to 15% dehydrated alcohol is developed for lyophilization, resulting in a stable lyophilized powder with improved impurity profiles and ease of reconstitution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If carmustine is formulated in aqueous solution, then it can be administered to patients, but it degrades rapidly and loses stability
Solution Approach 1:
The patent uses non-aqueous solvents (ethanol, isopropanol, n-butanol) as intermediary substances to dissolve carmustine, avoiding direct contact with water that causes degradation. These solvents act as mediators that maintain drug stability while enabling formulation and subsequent administration after reconstitution.
Solution Approach 2:
The patent changes the fundamental parameter of solvent type from aqueous to non-aqueous (alcoholic). This parameter change fundamentally alters the chemical environment, preventing hydrolysis and degradation of carmustine while maintaining its solubility and pharmacological activity.
2Ease of operation
If carmustine is stored at room temperature, then it is convenient for handling, but it melts and decomposes due to low melting point
Solution Approach 1:
The patent changes the physical state parameter of carmustine from solid (prone to melting) to dissolved state in non-aqueous solvent. This parameter change eliminates the melting issue at room temperature while maintaining chemical stability through the choice of alcoholic solvent.
3Reliability
If carmustine is lyophilized from pure ethanol, then it can be produced as sterile powder, but the manufacturing process is complex and quality is inconsistent
Solution Approach 1:
The patent modifies the solvent composition parameter by adding small amounts of water (5-20%) to the ethanol base. This parameter change simplifies the lyophilization process by improving freeze-drying characteristics and cake quality, while maintaining product stability and reducing manufacturing complexity.
Solution Approach 2:
The patent creates a composite solvent system combining ethanol (or isopropanol/n-butanol) with water in specific ratios. This composite material approach leverages the stability-providing properties of alcohol and the freeze-drying-friendly properties of water, achieving both quality consistency and manufacturing ease.
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 new formulation provides stable lyophilized carmustine with reduced impurities, enhanced stability, and improved reconstitution properties, suitable for treating neoplastic diseases.
Implementation Method 1
The carmustine pharmaceutical formulation in an alcoholic solution is particularly suitable for lyophilization to generate lyophilized carmustine with an improved impurity and stability profile.
Implementation Method 2
Carmustine readily gets hydrolyzed in water at pH >6.
Data Source
AI summary
The present invention provides pharmaceutical formulations of lyophilized carmustine suitable for pharmaceutical use. The present invention further provides methods of producing lyophilized carmustine. The pharmaceutical formulations can be used for any disease that is sensitive to treatment with carmustine, such as neoplastic diseases.