API Cocrystallization via Stronger Hydrogen Bonding
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Solution Overview
Problem
Current methods for identifying and forming cocrystals of active pharmaceutical ingredients (APIs) are unpredictable and often result in unsuitable physical properties, leading to challenges in drug formulation and development.
Innovation Solution
The development of novel cocrystallization methods that involve selecting a guest molecule to coordinate more strongly with the counterion of an API, replacing weak hydrogen bonds with stronger ones, and using techniques like evaporation or grinding to form cocrystals, which can modify physical properties such as solubility and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional cocrystallization methods are used to form cocrystals of APIs, then new solid state phases can be created, but the process is unpredictable and often results in unsuitable physical properties
Solution Approach 1:
The patent applies preliminary action by pre-identifying suitable guest molecules based on their ability to form strong hydrogen bonds with counterions before attempting cocrystallization. This preliminary selection process increases the reliability and predictability of forming cocrystals with desirable physical properties, rather than relying on random or conventional screening methods
Solution Approach 2:
The patent changes the key parameter of hydrogen bond strength by selecting guest molecules that form stronger hydrogen bonds with counterions than the original API molecules do. This parameter change (increasing hydrogen bond strength) leads to more stable and predictable cocrystal formation with improved physical properties
2Strength
If guest molecules are selected to coordinate more strongly with counterions, then stronger hydrogen bonds are formed and physical properties are improved, but the selection process becomes more complex
Solution Approach 1:
The patent employs a library approach where multiple guest molecules are screened, and those that do not form suitable cocrystals are discarded. This allows for efficient testing of many candidates without committing extensive resources to each individual screening attempt, making the complex selection process more manageable
Solution Approach 2:
The patent simplifies the complex selection process by establishing clear parameter criteria for guest molecule selection - specifically focusing on hydrogen bond donor/acceptor capabilities and structural compatibility with counterions. This parameter-based approach provides a systematic framework that reduces the complexity of evaluating potential guest molecules
3Reliability
If cocrystals are formed to modify physical properties like solubility and stability, then drug formulation performance is enhanced, but the manufacturing process requires precise control
Solution Approach 1:
The patent applies preliminary action by pre-determining the optimal API-to-guest ratio and crystallization conditions based on the selected guest molecule's properties. This preliminary optimization reduces the need for extensive trial-and-error during manufacturing, thereby enhancing physical property reliability while reducing manufacturing precision requirements
Solution Approach 2:
The patent designs the cocrystallization process to be self-directing, where the selected guest molecules naturally guide the formation of the desired cocrystal structure through their specific hydrogen bonding patterns. This self-organizing behavior reduces the need for precise external control during crystallization, simplifying manufacturing while maintaining product quality
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 approach allows for the creation of new solid state phases with improved physical properties, such as modified solubility and stability, enhancing the performance and development of drug formulations.
Implementation Method 1
One may then select a guest to coordinate more strongly with the negative counterion than the coordination within the crystal. If a strong hydrogen bond acceptor is interacting with a weak hydrogen bond donor in a crystal, a cocrystal could be created by adding a strong hydrogen bond donor molecule to the system which would replace the weak donor and bond to the strong acceptor site
Implementation Method 2
The solution or melt is subjected to a crystallization process, such as evaporation, cooling, or any of the many well-known processes for forming a crystal from a solution or melt
Implementation Method 3
The solution or melt is subjected to a crystallization process, such as evaporation, cooling, or any of the many well-known processes for forming a crystal from a solution or melt
Implementation Method 4
The physical mixture can be ground to form the cocrystal
Data Source
AI summary
The present disclosure relates to novel cocrystals and novel methods for cocrystallization. In particular, the disclosure includes cocrystals comprising a salt of an active agent, such as a chloride salt of an active pharmaceutical ingredient. The present disclosure also relates to methods of preparing cocrystals and methods for screening for solid state phases.