Amlodipine Mesylate Monohydrate Seeded Crystallization for Direct Tableting
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Solution Overview
Problem
Existing methods for preparing amlodipine mesylate monohydrate result in poor particle size distribution, fluidity, and compressibility, making it unsuitable for direct tablet pressing using High-Speed Rotary Tablet Press Machines, and are prone to explosive crystallization and impurities.
Innovation Solution
A method involving dissolving amlodipine free base in a water-containing organic solvent, adding methanesulfonic acid dropwise under low temperature, and using seed crystals to control crystallization, followed by centrifugation and vacuum drying, to achieve a uniform particle size distribution and improved fluidity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If high supersaturation condition is used to precipitate crystals, then crystal precipitation occurs, but explosive crystallization happens resulting in overfine crystallization and agglomeration
Solution Approach 1:
The patent applies preliminary action by adding seed crystals before achieving high supersaturation. The seed crystals provide pre-formed nucleation sites that guide controlled crystallization, preventing explosive nucleation when high supersaturation is reached. This allows the process to benefit from high supersaturation-driven precipitation while avoiding the harmful explosive crystallization effect.
Solution Approach 2:
The seed crystals act as an intermediary between the supersaturated solution and the crystal formation process. Instead of direct explosive nucleation from the supersaturated state, the seed crystals mediate the transition by providing controlled growth surfaces, thereby achieving uniform particle size distribution while maintaining crystallization efficiency.
2Ease of manufacture
If amlodipine free base is used, then the drug can be manufactured, but poor water solubility and moisture absorption characteristics result
Solution Approach 1:
The patent applies parameter changes by converting the chemical form of amlodipine from free base to mesylate salt through salt formation reaction. This chemical parameter change fundamentally alters the solubility characteristics and moisture stability while maintaining the pharmacological activity, thereby resolving the contradiction between manufacturability and stability.
3Quantity of substance
If small particle size API is used, then the drug can be produced, but poor fluidity and compressibility make it unsuitable for direct tablet pressing
Solution Approach 1:
The patent applies preliminary action by controlling the crystallization process from the beginning to form particles of optimal size directly, rather than producing fine particles and attempting to improve them later. The seed crystal addition and controlled supersaturation ensure that particles nucleate and grow to a size range suitable for direct tablet pressing, preventing the need for subsequent size modification steps.
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 method produces amlodipine mesylate monohydrate with a controlled particle size distribution, high purity, and excellent fluidity and compressibility, suitable for direct tablet pressing, ensuring high-quality tablet production.
Implementation Method 1
adding methanesulfonic acid under a cooling condition under water bath condition to conduct a salt-forming reaction
Implementation Method 2
the crystal is not easy to precipitate and a high supersaturation condition is needed; explosive crystallization is likely to occur once the crystals are precipitated
Implementation Method 3
centrifugation and vacuum drying
Implementation Method 4
centrifugation and vacuum drying
Data Source
AI summary
Amlodipine mesylate monohydrate, a preparation method therefor and a use thereof. The described amlodipine mesylate monohydrate has high purity, has good fluidity and compressibility, and is suitable for direct tableting processing by a high-speed tablet press.