Mirabegron Alpha-Form Crystallization Process
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Solution Overview
Problem
Existing methods for preparing the α-form crystal of Mirabegron suffer from reproducibility issues, require seed material, result in less yield, and lead to color development during preparation and storage, making them unsuitable for industrial use.
Innovation Solution
A process involving the dissolution of Mirabegron in a selected organic solvent, followed by cooling and drying under reduced pressure, with the optional addition of an antioxidant and/or chelating agent to prevent discoloration and reduce particle size for improved bioavailability and bioequivalence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If existing methods are used to prepare α-form crystal of Mirabegron, then the crystal can be obtained, but discoloration occurs during preparation and storage
Solution Approach 1:
An antioxidant is introduced as an intermediary substance to prevent oxidation and discoloration of Mirabegron during preparation and storage. The antioxidant acts as a mediator that protects the main substance from harmful chemical changes without interfering with the crystallization process.
Solution Approach 2:
The pH of the aqueous medium is adjusted to specific ranges (pH 2-4 or pH 7-9) to optimize crystal formation and stability. By changing the pH parameter, the process achieves both high yield of α-form crystals and prevention of discoloration through controlled chemical environment.
2Productivity
If existing methods are used to prepare α-form crystal of Mirabegron, then the crystal can be obtained, but the yield is low
Solution Approach 1:
The solvent system is changed from water/ethanol to aqueous media with specific pH control, and the temperature profile is optimized with controlled cooling rates. These parameter changes result in reproducible high-yield formation of α-form crystals without requiring seed material.
Solution Approach 2:
The process prepares the aqueous solution with appropriate pH adjustment and antioxidant addition before initiating crystallization. This preliminary preparation ensures optimal conditions are in place to achieve high and reproducible yields from the start of the crystallization process.
3Ease of manufacture
If water and ethanol are used as solvents with gradual or rapid cooling, then α-form crystal can be prepared, but seed material is required and reproducibility is poor
Solution Approach 1:
The solvent system is changed to aqueous media with controlled pH, and the cooling process is optimized with specific rate control. These parameter changes eliminate the requirement for seed material and achieve reproducible results, simplifying the manufacturing process while improving reliability.
4Strength
If existing methods are used to prepare α-form crystal of Mirabegron, then the crystal can be obtained, but particle size is large which reduces bioavailability
Solution Approach 1:
The crystallization process uses dynamic controlled cooling at optimized rates to produce crystals of reduced and more uniform particle size. This dynamic control during the crystallization process enhances bioavailability by creating smaller particles that are more readily absorbed.
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
The process yields α-form crystals of Mirabegron that are stable against discoloration, have high chemical purity, and reduced particle size, enhancing bioavailability and bioequivalence, thus providing an industrially feasible and cost-effective solution.
Implementation Method 1
preparing a solution of Mirabegron in an organic solvent
Implementation Method 2
cooling the solution obtained in step (a) to provide α-form crystal of Mirabegron
Implementation Method 3
cooling the solution obtained in step (a) to provide α-form crystal of Mirabegron
Implementation Method 4
drying the product under reduced pressure
Implementation Method 5
preparation of the hereinabove mentioned polymorphic form of Mirabegron in the presence of an antioxidant and/or a chelating agent
Data Source
AI summary
The present invention is directed to process for preparation of α-form crystal of Mirabegron, (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) acetamide of formula (1).