Crystalline Form B Anxiolytic Polymorph Control
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Solution Overview
Problem
The challenge lies in controlling and predicting polymorphism in drug compounds, as different crystalline forms can affect shelf life, solubility, and biological activity, leading to potential toxicity and contamination during manufacture and storage.
Innovation Solution
A stable crystalline hemihydrate form of the anxiolytic compound 1-ethyl-6-(indan-2-ylamino)-3-(morpholine-4-carbonyl)-1,8-naphthyridin-4-one, denoted as Form B, is characterized by specific XRPD patterns and is used in pharmaceutical compositions to treat anxiety disorders, offering improved stability and reduced impurities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If a drug compound is allowed to exist in multiple crystalline forms (polymorphism), then the drug can exhibit varying biological activity and solubility, but this leads to contamination during manufacture and storage, and potential toxicity
Solution Approach 1:
The patent applies parameter changes by controlling the crystallization conditions (temperature, solvent composition, pH, rate of cooling) to selectively obtain and stabilize a specific polymorphic form (Form B) of the anxiolytic compound. By adjusting these parameters, the desired crystalline form is achieved while preventing the formation of unwanted polymorphs, thus resolving the contradiction between biological activity variation and manufacturing stability.
Solution Approach 2:
The patent employs preliminary action by conducting thorough polymorph screening and stability studies during the early development phase to identify and select the most stable and suitable crystalline form (Form B) before scale-up manufacturing. This preliminary characterization and selection prevent contamination by other polymorphs during subsequent manufacture and storage, ensuring reliability while maintaining desired biological properties.
2Ease of manufacture
If different crystalline forms are produced during manufacture, then solubility and formulation properties may be optimized, but unknown polymorphic forms can cause toxicity and contamination
Solution Approach 1:
The patent implements feedback by establishing comprehensive analytical methods (X-ray powder diffraction, NMR spectroscopy, HPLC) to monitor and detect the presence of specific polymorphic forms during manufacturing and storage. This feedback mechanism allows for real-time identification and control of the desired Form B while detecting and preventing contamination by unknown polymorphs, thus optimizing formulation properties without compromising safety.
Solution Approach 2:
The patent replaces mechanical mixing and traditional filtration methods with advanced analytical techniques (XRPD, NMR, DSC) to characterize and control polymorphic forms. This substitution enables precise identification and control of crystalline structures, ensuring only the desired form is produced while eliminating the need for complex mechanical separation processes, thereby improving ease of manufacture while preventing contamination.
3Productivity
If polymorphism is not controlled, then the drug can be manufactured simpler, but shelf life and solubility are compromised
Solution Approach 1:
The patent applies parameter changes by optimizing crystallization parameters (temperature profiles, solvent selection, anti-solvent addition rates) to facilitate the formation of the stable Form B polymorph. These controlled parameter adjustments ensure high shelf life and consistent solubility while maintaining relatively simple manufacturing processes, resolving the contradiction between productivity and compositional stability.
Solution Approach 2:
The patent utilizes phase transitions (dissolution, crystallization, melting) to control polymorph formation and stabilize the desired crystalline form (Form B). By carefully managing these phase changes through temperature and solvent control, the patent achieves stable shelf life and consistent solubility properties while maintaining manufacturing simplicity, thus resolving the contradiction between productivity and stability.
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 B provides a therapeutically effective and stable anxiolytic agent with reduced impurities, enhancing solubility and stability, thus addressing the issues of polymorphism and contamination, and offering a viable alternative to traditional anxiolytics like diazepam.
Implementation Method 1
Form B is characterized at least by having four or more peaks in its XRPD pattern selected from the Angle 2-Theta ° values of 13.94, 14.52, 16.27, 16.60, 17.62, 18.76, 19.02, 19.29, 19.64, 22.32, 22.77, 23.02 and 23.16
Data Source
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AI summary
The present invention provides a crystalline Form B of compound 1, and pharmaceutically compositions thereof. The present invention also provides methods of treating a disease (e.g., a disease of the central nervous system) using the pharmaceutical compositions.