Fluvastatin Sodium Salt Crystalline Form Stabilization
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Solution Overview
Problem
The existing methods for preparing Fluvastatin sodium salt crystalline forms, such as Form XIV and Form LXXXI, face reproducibility and robustness issues due to ease of interconversion among various forms and instability during drying operations, leading to inconsistent product outcomes.
Innovation Solution
A specific process involving recrystallization of Fluvastatin sodium salt in an acetonitrile/water mixture, followed by washing with an organic solvent, vacuum drying, and controlled re-equilibration at specific temperature and humidity conditions to produce a stable crystalline form characterized by distinct X-ray powder diffraction peaks.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If literature preparation methods are used to obtain FLVNa Form XIV, then the desired crystalline form can be obtained, but the drying operation converts it into a different crystalline form due to water content variation, temperature and relative humidity changes
Solution Approach 1:
The patent applies preliminary action by performing a specific washing step with acetone or ethanol before drying to remove surface water and stabilize the crystalline form. This preliminary treatment prevents the conversion to different crystalline forms during subsequent drying operations, ensuring the desired Form XIV is maintained throughout the process.
Solution Approach 2:
The patent employs parameter changes by optimizing and controlling specific parameters during the drying operation, including temperature, relative humidity, and duration. By carefully adjusting these parameters within defined ranges, the process maintains the stability of FLVNa Form XIV and prevents transformation to other crystalline forms while still achieving effective drying.
2Adaptability or versatility
If minimal condition variation is applied, then interconversion among various crystalline forms occurs easily, but this makes the preparation method less robust and reliable
Solution Approach 1:
The patent resolves this contradiction by identifying and controlling critical parameters (temperature, relative humidity, washing solvent composition, and drying duration) within optimized ranges. This controlled parameter management allows the process to reliably produce Form XIV despite the inherent ease of interconversion, transforming the situation from unreliable to robust through precise parameter specification.
Solution Approach 2:
The patent implements feedback control by monitoring the crystalline form characteristics during the preparation process and adjusting parameters accordingly. This ensures that even with minimal condition variations, the process remains on track to produce the desired Form XIV, enhancing reliability while maintaining the ability to adapt to small fluctuations.
3Loss of substance
If drying operation is performed to remove organic solvents, then solvent removal is achieved, but the variation of water content, temperature and relative humidity produced by drying converts the crystalline form
Solution Approach 1:
The patent applies preliminary action by washing with acetone or ethanol before drying to pre-stabilize the crystalline form and remove surface water. This preparatory step creates a more stable starting condition that resists transformation during the subsequent drying operation, allowing effective solvent removal while maintaining form stability.
Solution Approach 2:
The patent controls the drying parameters (temperature, relative humidity, duration) within optimized ranges to achieve solvent removal without causing crystalline form conversion. By carefully balancing these parameters, the process accomplishes both objectives: effective removal of organic solvents and water while maintaining the stability of the desired crystalline form.
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 process reliably produces Fluvastatin sodium salt Form XIV or equivalent Form LXXXI, ensuring consistent product quality by stabilizing the crystalline form and preventing conversion to other forms during drying.
Implementation Method 1
dissolving Fluvastatin Sodium salt of any crystalline form in a mixture of acetonitrile/water
Implementation Method 2
cooling the solution to a temperature comprised in the range from 65° C. to 35° C. to promote Fluvastatin sodium salt crystallization
Implementation Method 3
drying the wet solid obtained in step e) under vacuum
Implementation Method 4
re-equilibrate the solid obtained in step f) by treating the solid for a time comprised between 1 hour and 11 days at a temperature comprised in the range from 15° C. to 35° C. under relative humidity (RH) comprised in a range between 40% and 80%
Data Source
AI summary
The present invention refers to an improved process for the preparation of a crystalline form of Fluvastatin sodium salt. Moreover, it is also related to a novel Fluvastatin sodium salt crystalline form and a process for the preparation thereof.