Obeticholic Acid Form A Crystallization Stability
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Solution Overview
Problem
Current crystalline forms of obeticholic acid, such as Form C, exhibit poor stability and purity, making them unsuitable as final products for treating primary biliary cirrhosis and nonalcoholic steatohepatitis, and are often used as intermediates for purification.
Innovation Solution
A novel crystalline form of obeticholic acid (Form A) with specific X-ray powder diffraction patterns and thermal properties is developed, which is stable and suitable for storage and usage as a final product, achieved through crystallization methods using solvents like ethyl acetate and n-heptane, methyl ethyl ketone, and chloroform, resulting in high purity and minimal solvent residue.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If Form C of obeticholic acid is used as an intermediate for purification, then the purity can be improved, but the stability deteriorates
Solution Approach 1:
The patent changes the crystalline form parameter from Form C to Form A, which has different molecular packing and intermolecular interactions. This parameter change results in improved stability while maintaining high purity, as Form A exhibits better chemical and physical stability characteristics compared to Form C
Solution Approach 2:
The patent develops Form A as a stable crystalline form that can be used directly as final product rather than as intermediate. This composite approach combines purification and stability requirements into a single crystalline form that satisfies both demands simultaneously
2Quantity of substance
If amorphous obeticholic acid is prepared from crystalline forms, then the solubility can be improved, but the stability deteriorates
Solution Approach 1:
The patent changes the physical state parameter from amorphous to crystalline (Form A), which typically reduces solubility but dramatically improves stability. The specific crystalline structure of Form A is designed to provide optimal balance between these properties for clinical use
3Manufacturing precision
If multiple crystallization solvents are used for preparation, then the purity can be improved, but the device complexity increases
Solution Approach 1:
The patent optimizes the solvent system parameters by selecting specific solvents (ethyl acetate, n-heptane, methyl ethyl ketone, or chloroform) and their ratios to achieve high purity Form A crystallization. This parameter optimization simplifies the process by eliminating the need for multiple purification steps while maintaining high purity levels
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 A demonstrates excellent stability and high purity, preventing bioavailability and efficacy changes during storage and development, making it suitable for clinical use in treating biliary cirrhosis and nonalcoholic steatohepatitis, with improved industrial production feasibility.
Implementation Method 1
adding obeticholic acid powder into a crystallizing solvent to get Form A via crystallization
Implementation Method 2
adding obeticholic acid powder into a crystallizing solvent to get Form A via crystallization
Implementation Method 3
evaporation, anti-solvent addition or the like
Data Source
Figure 1~2
Figure 3
AI summary
The present invention relates to crystalline Form A of obeticholic acid and the preparation method thereof. The present invention provides Form A having characteristic peaks at 2theta value of 4.9 ° ± 0.2 °, 5.2 ° ± 0.2 °, 9.9 ° ± 0.2 °. The present invention provides a novel crystalline form of obeticholic acid, which has good stability, good processability and other favorable properties, is suitable for storage and usage as a final product. In addition, the preparation method is simple, low cost, and has a great value for the future optimization and development of obeticholic acid.