Polymorphic Form B of NXL104 Sodium Salt
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Solution Overview
Problem
The sodium salt of (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, a beta-lactamase inhibitor, is unstable in the amorphous form and hygroscopic, making it difficult to handle, store, and scale up industrially, and its preparation methods, such as ion exchange and lyophilization, are costly and inefficient.
Innovation Solution
Development of novel crystalline forms, specifically polymorphic form 'B', which is stable, easy to isolate, handle, and store, and can be prepared using methods that avoid ion exchange and lyophilization, such as crystallization in the presence of seed crystals and controlled water content, allowing for industrial-scale production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the amorphous form of NXL104 is used, then it can be obtained through simple concentration, but it is unstable, hygroscopic, and difficult to handle and store
Solution Approach 1:
The patent transforms the amorphous form into a crystalline form by changing the physical state parameters. The crystalline form 'B' is obtained through specific crystallization conditions (solvent system, temperature, pH control) that transform the unstable amorphous material into a stable crystalline structure with defined XRPD patterns, thereby improving stability while maintaining manufacturability
Solution Approach 2:
The patent creates a composite crystalline structure where the sodium salt of NXL104 forms a specific polymorphic form 'B' with characteristic crystal lattice arrangement. This composite crystalline structure incorporates the active ingredient in a stable matrix that prevents hygroscopy and degradation, resolving the contradiction between ease of manufacture and stability
2Manufacturing precision
If ion exchange and lyophilization are used to prepare the sodium salt, then the product can be obtained in high purity, but the process is costly and of low productivity
Solution Approach 1:
The patent extracts and eliminates the need for ion exchange resin and lyophilization steps from the process. By using direct crystallization from aqueous solution under controlled conditions, the method removes these costly and time-consuming intermediate steps while still achieving high purity crystalline product through selective crystallization
Solution Approach 2:
The patent changes the process parameters from complex multi-step procedures (ion exchange, lyophilization) to a simplified crystallization process controlled by solvent composition, temperature, and pH. This parameter optimization achieves both high purity and high productivity by allowing direct crystallization from aqueous solution without intermediate purification steps
3Ease of manufacture
If the racemic mixture is used, then the synthesis is simpler, but only one enantiomer is active and the other is inactive
Solution Approach 1:
The patent segments the racemic mixture into individual enantiomers through chiral resolution. By using chiral chromatography or chiral resolving agents, the mixture is separated into the active (1R,2S,5R) enantiomer and the inactive enantiomer, allowing isolation and use of only the pharmacologically active component while maintaining synthetic accessibility
Data Source
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AI summary
The invention relates to the sodium salt of (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide of formula (I) in crystallised polymorphic form "B". The compound of the invention can be used as a medicament, in particular as a beta-lactamase inhibitor.