Deep Eutectic Solvent Crystallization for API Polymorph Control
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Solution Overview
Problem
Current methods for producing active pharmaceutical ingredients (APIs) face challenges in achieving scalable and cost-effective production of higher energy polymorphs, which are often more soluble and efficacious but difficult to crystallize, due to their complex crystallization requirements and mechanical instability during processing.
Innovation Solution
A solidification method using deep eutomic solvents (DXS) is developed, where a first organic compound and a volatile co-former organic compound form hydrogen bonds, allowing the mixture to liquify below the components' melting points, and subsequent evaporation of the volatile co-former leads to controlled crystallization of the first organic compound, enabling the formation of eutectic mixtures and co-crystalline solids at room temperature and pressure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional crystallization methods are used to produce higher energy polymorphs, then solubility and efficacy are improved, but crystallization complexity and production cost increase
Solution Approach 1:
The patent introduces deep eutectic solvents as intermediary media to facilitate the crystallization of higher energy polymorphs. These solvents act as mediators that enable controlled formation of desired polymorphs under simpler conditions, resolving the contradiction between achieving high solubility/efficacy and maintaining crystallization complexity.
Solution Approach 2:
The patent utilizes changes in thermodynamic parameters through deep eutectic solvent formation to control polymorph selection. By altering the chemical environment and thermodynamic stability landscape, the method enables preferential formation of higher energy polymorphs with improved solubility without requiring complex crystallization procedures.
2Ease of operation
If mechanical processes such as milling are used to reduce particle size, then processability is improved, but mechanically induced solid-state transformations and agglomeration occur
Solution Approach 1:
The patent applies preliminary crystallization action under controlled deep eutectic solvent conditions to form stable crystals before mechanical processing. This preliminary structuring reduces the susceptibility of the material to mechanically induced transformations and agglomeration during subsequent milling operations, while still achieving desired particle size reduction.
3Stability of the object's composition
If the most thermodynamically stable polymorph is produced, then crystalline stability is improved, but solubility decreases compared to higher energy metastable polymorphs
Solution Approach 1:
The patent employs deep eutectic solvents to change the thermodynamic parameters of the crystallization process. This parameter modification enables the formation of higher energy metastable polymorphs that would normally be unstable, achieving both improved solubility and controlled crystalline structure through precise thermodynamic control.
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
This method provides greater control over crystal polymorph and morphology, allowing for the production of eutectic mixtures and co-crystalline solids, enhancing bioavailability, processing ability, and stability of APIs, while reducing the need for complex crystallization conditions.
Implementation Method 1
either the first organic compound or the volatile co-former organic compound comprises a hydrogen acceptor moiety and the other comprises a hydrogen donor moiety, thereby allowing the formation of hydrogen bonds between the first organic compound and the volatile co-former organic compound
Implementation Method 2
forming a mixture of at least the first organic compound and the co-former organic compound, allowing the mixture to stand for sufficient time for the mixture to liquify at a temperature below that of the melting points of the components
Implementation Method 3
allowing the volatile co-former organic compound to evaporate, thereby resulting in crystallization of at least the first organic compound
Implementation Method 4
allowing the volatile co-former organic compound to evaporate, thereby resulting in crystallization of at least the first organic compound
Data Source
AI summary
A solidification or crystallization method is disclosed, which includes providing at least a first organic compound and at least one volatile co-former organic compound. A mixture of at least the first organic compound and the co-former organic compound is formed, wherein either the first organic compound or the volatile co-former organic compound includes a hydrogen acceptor moiety and the other includes a hydrogen donor moiety, thereby allowing the formation of hydrogen bonds between the first organic compound and the volatile co-former organic compound. The mixture is allowed to stand for sufficient time for the mixture to liquify at a temperature below that of the melting points of the components, thereby forming a liquid mixture. The volatile co-former organic compound is allowed to evaporate, thereby resulting in crystallization of at least the first organic compound. The method can be a co-crystallization method if there are two organic compounds.