Crystalline Polymorph A of 15ß-Hydroxy-Osaterone Acetate
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Solution Overview
Problem
Conventional crystalline polymorphic form B of 15β-hydroxy-osaterone acetate has insufficient stability, poor powder flow properties, and rapid pharmacokinetic absorption leading to safety concerns due to varying active ingredient content and high maximum plasma concentration reached quickly.
Innovation Solution
The development of crystalline polymorphic form A, characterized by specific diffraction peaks and produced through crystallization in a mixed solvent of ethanol and water, offering improved stability, powder flow, and controlled pharmacokinetic profile.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If crystalline polymorphic form B is used, then the compound can be obtained through conventional synthesis methods, but the crystal has insufficient storage stability and decreases in purity with storage
Solution Approach 1:
The patent applies parameter changes by modifying the crystallization conditions, specifically using a mixed solvent system of ethanol and water in a controlled temperature process to transform the crystal structure from form B to form A, thereby improving storage stability while maintaining manufacturability
Solution Approach 2:
The patent utilizes phase transitions by controlling the crystallization process to induce formation of a new polymorphic form (form A) with superior stability characteristics, achieving a transition from the less stable form B to the more stable form A through controlled solvent removal and temperature management
2Ease of manufacture
If crystalline polymorphic form B is used, then the compound can be produced through existing processes, but the crystal fails to maintain the crystal form by pressure action such as pulverization or crushing and decreases in purity
Solution Approach 1:
The patent modifies physical parameters of the crystal lattice by changing the crystallization solvent system and temperature profile, resulting in form A which possesses enhanced mechanical strength and resistance to pressure-induced degradation during pulverization and crushing operations
3Ease of manufacture
If crystalline polymorphic form B is used, then the compound can be obtained through conventional methods, but the crystal has low powder flow property and varying active ingredient content in preparation
Solution Approach 1:
The patent changes the physical parameters of the crystal through controlled crystallization in ethanol-water mixed solvent, producing form A with modified surface characteristics and particle morphology that significantly improve powder flow properties and enable uniform active ingredient distribution in pharmaceutical preparations
4Ease of manufacture
If crystalline polymorphic form B is used, then the compound can be synthesized through established processes, but the crystal has high C max and short T max leading to rapid absorbability and safety concerns
Solution Approach 1:
The patent modifies the bioavailability parameters by changing the crystal structure from form B to form A through controlled crystallization, resulting in altered dissolution characteristics that reduce C max and extend T max, thereby decreasing rapid absorbability and associated safety concerns
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
Crystalline polymorphic form A exhibits enhanced stability, workability, and safety with reduced rapid absorbability, maintaining active ingredient consistency and prolonged maximum plasma concentration, suitable for stable pharmaceutical preparations.
Implementation Method 1
heating and dissolving 15β-hydroxy-osaterone acetate in a mixed solvent of ethanol and water, and cooling (particularly, gradually cooling) the resulting solution
Data Source
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Figure 5
AI summary
Provided is a crystalline polymorphic form A of 15β-hydroxy-osaterone acetate having an improved stability (storage stability, pulverization stability, and absorption characteristics). In a powder X-ray diffraction spectrum, characteristic diffraction peaks of the crystalline polymorphic form A of 15β-hydroxy-osaterone acetate appear at diffraction angles 2θ of 9.6° ± 0.2°, 17.1° ± 0.2°, and 20.2° ± 0.2°. The crystalline polymorphic form A has a melting point of 280 to 283°C and is a prism crystal.