Avibactam Sodium Form C Crystallization via Low-Moisture Heating
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Solution Overview
Problem
Current methods lack an efficient and cost-effective process for producing polymorphically pure crystalline form C of avibactam sodium, which is essential for pharmaceutical applications due to its stability and manufacturability challenges, particularly in industrial-scale production without using large organic solvents or hazardous reagents.
Innovation Solution
A process involving a mixture of avibactam or its salt with a solvent having less than 2% water content, heated to at least 55°C under positive pressure, and optionally adding a sodium source, allows for the production of polymorphically pure avibactam sodium form C, characterized by specific powder X-ray diffractogram reflections.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If current methods are used to prepare crystalline form C of avibactam sodium, then the process lacks efficiency and cost-effectiveness, but the manufacturing precision and reliability are improved by using the new process with controlled water content and temperature
Solution Approach 1:
The patent applies parameter changes by controlling water content (less than 2% by weight) and temperature (at least 55°C) to transform avibactam or its salts into polymorphically pure crystalline form C. This specific parameter control resolves the contradiction by enabling efficient production while ensuring high polymorphic purity through defined thermal and compositional conditions.
Solution Approach 2:
The patent utilizes phase transitions by heating the mixture to at least 55°C under positive pressure to induce crystallization of form C from the solvent system. This controlled phase transition from dissolved state to crystalline form enables both efficient production and high polymorphic purity, resolving the technical contradiction.
2Ease of manufacture
If large quantities of organic solvents are used in the preparation process, then the ease of manufacture is improved, but the productivity and cost-effectiveness deteriorate due to increased processing complexity and hazardous reagent handling
Solution Approach 1:
The patent changes the solvent parameter by specifying a solvent with less than 2% water content, which enables efficient industrial-scale production without requiring large quantities of traditional organic solvents. This parameter optimization maintains manufacturing feasibility while significantly improving productivity and cost-effectiveness.
3Ease of manufacture
If hydrated forms of avibactam sodium are used, then the ease of manufacture is improved, but the stability against moisture and temperature stress deteriorates
Solution Approach 1:
The patent applies phase transition by dehydrating hydrated forms or starting from anhydrous materials and maintaining water content below 2% during crystallization. This controlled removal of water transforms the material into the stable anhydrous form C, which maintains manufacturability while providing superior stability against moisture and temperature stress.
Solution Approach 2:
The patent creates an inert environment by maintaining water content below 2% throughout the process, effectively protecting the avibactam sodium from moisture-induced degradation. This controlled low-moisture environment enables the production of form C that is highly stable against both moisture and temperature stress.
4Ease of manufacture
If the process is not optimized for polymorphic purity, then the ease of manufacture is improved, but the reliability and stability of the pharmaceutical product deteriorates
Solution Approach 1:
The patent optimizes reliability by defining specific parameters: water content less than 2% and temperature at least 55°C. These parameter specifications enable the straightforward production of polymorphically pure form C, achieving both ease of manufacture and high reliability without complex additional 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
This process enables the reliable and cost-effective production of polymorphically pure avibactam sodium form C, ensuring stability against moisture and temperature stress, and is suitable for industrial-scale manufacturing.
Implementation Method 1
increasing the temperature of the mixture provided in (i) to at least 55°C and providing a positive pressure
Implementation Method 2
thereby obtaining avibactam sodium in polymorphic form C
Data Source
AI summary
The invention relates to a process for the preparation of avibactam sodium in polymorphic form C comprising the steps (i) providing a mixture comprising avibactam or a salt thereof and a solvent, wherein the mixture has a water content of less than 2% by weight based on the weight of the mixture; (ii) increasing the temperature of the mixture provided in (i) to at least 55° C. and providing a positive pressure; adding a sodium source to the mixture in step (i) and/or (ii) if the form of avibactam provided in (i) is not avibactam sodium; thereby obtaining avibactam sodium in polymorphic form C.