Pitavastatin Calcium Form K Stability
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Solution Overview
Problem
Current polymorphic forms of pitavastatin calcium, such as Form A, are sensitive to drying conditions and prone to conversion to amorphous forms, leading to instability during storage and processing, which complicates large-scale production and pharmaceutical formulation.
Innovation Solution
A new polymorphic form (Form K) of pitavastatin calcium is developed, characterized by high polymorphic purity and stability, achieved through a process involving the mixing of an aqueous calcium source with a water-soluble pitavastatin salt at controlled temperatures, which results in crystalline particles with specific X-ray diffraction peaks and improved chemical and physical stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If polymorphic form A of pitavastatin calcium is prepared and dried under usual conditions, then water content is reduced, but crystallinity decreases and converts to amorphous form, leading to poor stability
Solution Approach 1:
The patent changes the drying parameters (temperature, time, atmosphere) to achieve water removal without causing polymorphic conversion. By carefully controlling these parameters, the patent maintains crystallinity while reducing water content, resolving the contradiction between water removal and stability preservation.
Solution Approach 2:
The patent employs protective measures during the drying process, such as using controlled atmosphere (inert gas or vacuum) and gradual temperature increase, to prevent the formation of amorphous form before it can occur. This cushioning approach prevents the harmful conversion while achieving water removal.
2Stability of the object's composition
If polymorphic form A is subjected to strict drying conditions to maintain crystallinity, then stability is improved, but water content control becomes extremely difficult and process complexity increases
Solution Approach 1:
The patent optimizes drying parameters to find a balance point where effective water removal occurs without requiring extremely strict control. By adjusting temperature, time, and atmosphere parameters to specific ranges, the patent achieves both stability maintenance and process simplicity.
Solution Approach 2:
The patent develops a drying process that is self-regulating to some extent, where the material itself provides feedback on its drying state through observable properties, reducing the need for complex external monitoring and control systems.
3Stability of the object's composition
If polymorphic forms are converted during storage or processing, then stability is compromised, but preventing conversion requires complex process controls and monitoring
Solution Approach 1:
The patent implements preventive measures in the formulation and processing steps that protect against polymorphic conversion before it can occur during storage or handling. This includes using protective excipients, controlling particle size, and establishing buffer conditions that maintain stability without requiring continuous monitoring.
Solution Approach 2:
The patent identifies and controls critical parameters (temperature, humidity, stress) within specific ranges that prevent polymorphic conversion. By establishing these parameter windows during development, the patent simplifies ongoing process control while maintaining stability.
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
Form K exhibits enhanced stability under various technological processes and storage conditions, maintaining crystallinity and chemical stability, and shows improved thermal stability and reduced hygroscopicity compared to existing forms, making it suitable for large-scale production and pharmaceutical formulations.
Implementation Method 1
a process involving the mixing of an aqueous calcium source with a water-soluble pitavastatin salt at controlled temperatures, which results in crystalline particles
Implementation Method 2
characterized by a powder X-ray diffraction pattern with the following peaks
Data Source
AI summary
The present invention relates to a new polymorphic form of pitavastatin calcium, a process for its preparation and a pharmaceutical composition comprising it. The new polymorphic form is characterized by an X-ray powder diffraction pattern as shown in Figure 1.