Drospirenone Crystallization for Fine Powder Without Grinding
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Solution Overview
Problem
Existing methods for reducing the particle size of Drospirenone in pharmaceutical compositions, such as mechanical grinding, lead to uncontrolled changes in crystalline structure, affecting API content uniformity and bioavailability due to mechanical stress.
Innovation Solution
A process involving a double change of crystalline form: from Crystalline Form I to Crystalline Form II and back to Crystalline Form I, using a suspension of Drospirenone in acetone and diisopropyl ether, followed by cooling and stirring to form needle-like crystals, and subsequent drying, without mechanical grinding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Length of moving object
If mechanical grinding is used to reduce particle size of Drospirenone, then particle size is reduced, but crystalline structure is altered leading to uncontrolled changes in solid form
Solution Approach 1:
The patent replaces mechanical grinding methods with a chemical/crystallization-based approach. The process uses solvent systems (acetone and diisopropyl ether) and controlled temperature changes to induce crystallization, thereby reducing particle size without applying mechanical stress that would alter the crystalline structure.
Solution Approach 2:
The patent employs parameter changes in the form of temperature control and solvent composition adjustment to achieve particle size reduction. By cooling the solvent mixture to specific temperatures and controlling the crystallization process, fine particles are obtained while maintaining the stability of Crystalline Form I.
2Length of moving object
If mechanical grinding is used to reduce particle size, then particle size is reduced, but API content uniformity and bioavailability are affected
Solution Approach 1:
The patent replaces mechanical grinding with a crystallization process that produces fine particles without mechanical stress. This substitution ensures that the crystalline structure remains intact, thereby maintaining API content uniformity and bioavailability while achieving the desired fine particle size.
Solution Approach 2:
The patent utilizes phase transitions during the crystallization process. By controlling the temperature and solvent conditions, the Drospirenone transitions from dissolved state to crystalline solid, forming fine particles with controlled morphology that maintain consistent API properties and bioavailability.
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
Achieves fine particle size of Drospirenone suitable for pharmaceutical formulations, maintaining crystalline stability and bioavailability, eliminating the need for mechanical treatments.
Implementation Method 1
stirring the suspension at the temperature of point b) until the formation of Crystalline Form II needle-like crystals is observed
Implementation Method 2
a double change of crystalline form: from Crystalline Form I to Crystalline Form II; and from Crystalline Form II to Crystalline Form I
Implementation Method 3
cooling the suspension to a temperature equal to or lower than −5° C.
Implementation Method 4
drying the obtained crystalline solid at a temperature above +5° C., thereby obtaining Drospirenone Crystalline Form I having fine particle size
Data Source
AI summary
The present invention refers to a process for the industrial-scale preparation of 17β-hydroxy-6β,7β; 15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone, known by the common name of Drospirenone, in the form of a fine powder without the use of mechanical grinding or micronization techniques, but rather exploiting a double change of crystalline form, from Crystalline Form I to Crystalline Form II and from Crystalline Form II to Crystalline Form I. The invention also refers to the new Crystalline Form II of Drospirenone obtained in the process.