Ixazomib Citrate Solid-State Forms for Low-Residual-Solvent Crystallization
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Solution Overview
Problem
Existing processes for producing Ixazomib Citrate result in high levels of residual solvents and mixtures with other forms, making it difficult to achieve pure and stable solid state forms suitable for pharmaceutical applications.
Innovation Solution
A novel process using catalytic amounts of mineral acid and a ketone solvent as a pinanediol leaving group acceptor, allowing for direct crystallization in a one-phase system without the need for anti-solvents, resulting in high-yield, low-residual-solvent forms of Ixazomib Citrate.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing processes are used to produce Ixazomib Citrate, then production can be achieved, but high levels of residual solvents and mixtures with other forms are obtained, making it difficult to achieve pure and stable solid state forms
Solution Approach 1:
The patent changes the chemical parameters of the reaction system by using catalytic amounts of mineral acid (changing acid concentration from stoichiometric to catalytic levels) and selecting specific ketone solvents with particular properties. These parameter changes enable the reaction to proceed while minimizing residual solvent incorporation into the crystal lattice, directly resolving the contradiction between achieving pure solid state forms and eliminating residual solvents
Solution Approach 2:
The ketone solvent acts as an intermediary substance that facilitates the reaction between the starting materials while being easily removable. The specific selection of ketone solvents and their use in controlled amounts allows them to mediate the reaction without becoming permanently trapped in the final product, thus reducing residual solvent levels while maintaining manufacturing efficiency
2Manufacturing precision
If existing processes are used to produce Ixazomib Citrate, then production can be achieved, but mixtures with other forms are obtained, making it difficult to achieve pure and stable solid state forms
Solution Approach 1:
The patent modifies reaction parameters including acid catalysis conditions, solvent selection (specific ketones), temperature, and concentration ratios. These parameter changes direct the crystallization process to favor formation of a single stable polymorphic form rather than mixtures, thereby simultaneously improving purity and stability of the solid state form
Solution Approach 2:
The patent utilizes controlled phase transition during crystallization by adjusting reaction conditions to promote direct formation of the desired stable crystal form. By controlling the phase transition from solution to solid state through specific parameters (acid catalysis, solvent choice, temperature), the process avoids formation of metastable forms or mixtures, ensuring both purity and stability
3Ease of manufacture
If a one-phase system with catalytic acid and ketone solvent is used, then direct crystallization with low residual solvent is achieved, but the process requires specific reagents and conditions
Solution Approach 1:
The patent employs mineral acids that serve multiple functions: they catalyze the reaction, control pH, and facilitate crystallization. The ketone solvents also perform multiple roles as reaction medium, solvent for products, and crystallization promoter. This multi-functionality simplifies the overall process by reducing the number of separate steps and reagents needed, making the manufacturing process easier while maintaining adaptability
Data Source
AI summary
The present disclosure encompasses solid state forms of Ixazomib Citrate and pharmaceutical compositions thereof. Also disclosed are processes for preparation of Ixazomib Citrate.