Amorphous Atorvastatin Freeze-Drying Process
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Solution Overview
Problem
Current processes for producing amorphous atorvastatin are suboptimal due to the use of toxic or environmentally concerning solvents and are not suitable for large-scale synthesis, necessitating improved methods for preparation.
Innovation Solution
A process involving the dissolution of atorvastatin in non-hydroxylic or hydroxylic solvents with additives like solubilizing agents, alkalizing agents, or antioxidants, followed by lyophilization to produce amorphous atorvastatin, utilizing solvents such as dimethyl sulfoxide, tetrahydrofuran, or water with agents like polysorbate 80 and cyclodextrin, which enhances solubility and allows for effective large-scale manufacturing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If current processes for producing amorphous atorvastatin are used, then amorphous atorvastatin can be formed, but the process uses toxic or environmentally concerning solvents and is not suitable for large-scale synthesis
Solution Approach 1:
The patent changes the solvent parameters by selecting solvents with favorable toxicity and environmental profiles while maintaining adequate solubility for the lyophilization process. This allows the process to be both safe for large-scale manufacturing and environmentally acceptable.
Solution Approach 2:
The patent employs solvents that are safer, more environmentally friendly, and suitable for large-scale use, replacing toxic solvents with alternatives that can be easily handled and disposed of, reducing environmental burden and safety concerns in manufacturing.
2Manufacturing precision
If amorphous atorvastatin is produced from crystalline atorvastatin using non-hydroxylic solvents, then amorphous form is obtained, but the process is not optimal for large-scale production
Solution Approach 1:
The patent optimizes process parameters including solvent selection, concentration, pH adjustment, and lyophilization conditions to enable efficient large-scale production of amorphous atorvastatin while maintaining the desired amorphous form and high calcium salt content.
Solution Approach 2:
The patent performs preliminary optimization of the formulation and process conditions before scaling up, ensuring that the amorphous form is successfully produced and that the process can be effectively transferred to large-scale manufacturing operations.
3Reliability
If atorvastatin is dissolved in solvents and lyophilized to form amorphous form, then dissolution characteristics and bioavailability are improved, but the process complexity increases
Solution Approach 1:
The patent optimizes key parameters such as solvent type, drug concentration, pH level, and lyophilization cycle conditions to achieve the desired amorphous form with improved bioavailability while keeping the process manageable and not excessively complex.
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 method increases the atorvastatin calcium load and ensures the process is amenable to large-scale manufacturing while providing improved bioavailability and efficacy, particularly for treating hypercholesterolemia, hyperlipidemia, osteoporosis, benign prostatic hyperplasia, and Alzheimer's disease.
Implementation Method 1
lyophilizing the solution to afford said amorphous atorvastatin
Data Source
AI summary
A process for forming amorphous atorvastatin comprising the steps of dissolving atorvastatin in a non-hydroxylic solvent and removing the solvent by freeze-drying, as well as processes of dissolving atorvastatin in a hydroxylic solvent with a solubilizing agent or an alkalizing agent or an antioxidant and removing the solvent by freeze-drying to afford amorphous atorvastatin.