Lanraplenib Sesquisuccinate Crystallization for Free Base Exclusion
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Solution Overview
Problem
Existing processes for preparing crystalline forms of Compound I sesquisuccinate result in impurities, particularly the free base form, affecting purity and stability, which is critical for pharmaceutical compositions used in treating diseases like cancer and autoimmune disorders.
Innovation Solution
A scalable process is developed to produce pure crystalline Compound I sesquisuccinate with specific X-ray powder diffraction peaks, excluding the free base form, by controlling the crystallization conditions using solvents like tetrahydrofuran and precise molar ratios of succinic acid and Compound I, followed by filtration and drying.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing processes are used to prepare crystalline forms of Compound I sesquisuccinate, then the manufacturing process can be implemented, but the purity is reduced due to formation of free base impurities
Solution Approach 1:
The patent applies parameter changes by precisely controlling the molar ratio of succinic acid to Compound I (within 1.8:1 to 2.2:1), temperature (20-40°C), and solvent composition (tetrahydrofuran with controlled water content). These parameter optimizations prevent free base impurity formation while maintaining high purity crystalline product.
Solution Approach 2:
The patent utilizes controlled phase transition during crystallization by adjusting temperature and solvent conditions to favor the formation of the desired sesquisuccinate crystal form over the free base form. The controlled cooling and crystallization process ensures pure product formation through selective phase transition.
2Stability of the object's composition
If crystalline forms with higher purity are produced through controlled crystallization, then the stability is improved, but the manufacturing process complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-dissolving succinic acid in tetrahydrofuran before adding Compound I, and by pre-controlling the water content of the solvent. This preliminary preparation ensures that the crystallization proceeds smoothly with minimal impurity formation, improving stability without requiring complex post-processing steps.
Solution Approach 2:
The patent implements feedback control by monitoring the crystallization process parameters (temperature, mixing rate, addition rate) and adjusting them based on observed crystal formation. This ensures optimal conditions are maintained throughout the process, achieving high stability while keeping the process manageable through real-time adjustments rather than complex pre-planning.
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
The process yields a composition with greater than 75% crystalline Compound I sesquisuccinate, ensuring high purity and stability, suitable for pharmaceutical use, particularly in immediate release formulations for treating conditions like acute myeloid leukemia.
Implementation Method 1
A scalable process is developed to produce pure crystalline Compound I sesquisuccinate with specific X-ray powder diffraction peaks
Implementation Method 2
by controlling the crystallization conditions using solvents like tetrahydrofuran
Implementation Method 3
followed by filtration and drying
Implementation Method 4
followed by filtration and drying
Data Source
AI summary
Described herein are high purity compositions of crystalline Compound I sesquisuccinate (Compound IA) and methods of preparing the same.