Atorvastatin Purification via Concentration and Crystallization
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Solution Overview
Problem
The production of atorvastatin hemi calcium salt faces challenges in reducing impurities to levels below 0.1% as required by USP and European Pharmacopoeia standards, particularly when using iso-propyl group protection, which differs from tert-butyl ester protection in chemical reactivity and impurity profiles.
Innovation Solution
A method involving treating a compound with an acid, followed by an alkali metal hydroxide, and then a calcium salt, with concentration steps under controlled temperature and solvent conditions to minimize impurities, including the use of seed crystals and optional washing steps, effectively reduces impurities to 0.0001% to 0.05%.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If iso-propyl group protection is used for carboxylic acid, then different chemical reactivity and impurity profiles are obtained compared to tert-butyl ester, but impurity levels reach up to 0.2% which exceeds pharmacopeial requirements
Solution Approach 1:
The patent applies parameter changes by concentrating the reaction mixture to specific gravity ranges (1.05-1.08 g/mL) and controlling temperature parameters (0-30°C) to selectively precipitate atorvastatin while leaving impurities in solution, thereby reducing impurity levels from 0.2% to below 0.1%
Solution Approach 2:
The patent utilizes phase transitions by inducing precipitation of atorvastatin hemi calcium salt from the concentrated solution through controlled cooling and pH adjustment, separating the solid product from liquid impurities, achieving purification to pharmacopeial standards
2Manufacturing precision
If concentration step is added to reduce impurities, then impurity levels drop to 0.0001%-0.05%, but process time and energy consumption increase
Solution Approach 1:
The patent optimizes concentration parameters by targeting specific gravity ranges (1.05-1.08 g/mL) and temperature ranges (0-30°C) to achieve efficient precipitation within 1-8 hours, balancing purification effectiveness with reasonable process time
Solution Approach 2:
The patent implements continuous concentration and precipitation processes where the reaction mixture is continuously concentrated and cooled to maintain optimal precipitation conditions, ensuring complete purification without unnecessary process interruptions
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 significantly lowers impurity levels in atorvastatin hemi calcium salt, enhancing its purity and reducing side effects during treatment, while adhering to stringent pharmacopeial requirements.
Implementation Method 1
Treating a solution of said compound of general formula (1) in a first solvent with an acid
Implementation Method 2
Treating the mixture obtained in step (a) with an alkali metal hydroxide
Implementation Method 3
The unique chemical nature of the tert-butyl ester function has leads to a unique spectrum of impurities
Implementation Method 4
Atorvastatin hemi calcium salt precipitates after step (c) and can be isolated by filtration, centrifugation or other techniques known to the skilled person
Implementation Method 5
Treating the mixture obtained in step (b) with a calcium salt or with calcium hydroxide
Implementation Method 6
Concentration may be carried out by evaporation under reduced pressure. Concentration times are from 1 to 4 h
Data Source
AI summary
The present invention relates to a method for the production of atorvastatin having decreased levels of impurities of general formulae (3) and (4) by means of a concentrating step.