Ribociclib Succinate Polymorphs for High-Purity Crystallization
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Solution Overview
Problem
There is a need for novel polymorphic forms of Butanedioic acid-7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide that offer improved pharmaceutical performance characteristics, and existing processes for preparing Ribociclib yield low purity and efficiency.
Innovation Solution
Development of novel crystalline forms and acid addition salts of Ribociclib, such as crystalline forms-M, -S, -N, and -N1, and preparation processes using specific solvents and conditions to achieve high purity and yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing processes for preparing Ribociclib are used, then the preparation method is simple, but the purity and efficiency are low
Solution Approach 1:
The patent employs parameter changes by optimizing reaction conditions including temperature ranges (0-50°C), solvent selection (acetonitrile, ethyl acetate, isopropanol), pH control (pH 7-9 buffer), and concentration ratios to achieve high purity Ribociclib (≥98% HPLC purity) while maintaining process feasibility
Solution Approach 2:
The patent uses intermediary substances including buffers (phosphate buffer, acetate buffer), salts (sodium chloride, potassium chloride), and co-solvents to mediate the reaction process, enabling precise control of purity and yield while managing the complexity of the preparation process
2Productivity
If existing processes for preparing Ribociclib are used, then the preparation method is straightforward, but the yield and efficiency are low
Solution Approach 1:
The patent optimizes reaction parameters including temperature (0-50°C), reaction time (1-24 hours), solvent types and ratios, and pH levels to achieve high yield (70-90%) while maintaining process simplicity through systematic parameter control
Solution Approach 2:
The patent implements feedback control through monitoring reaction progress via HPLC analysis and adjusting conditions accordingly, including pH adjustment during reaction and optimization of crystallization conditions to maximize yield
3Reliability
If novel polymorphic forms are developed, then pharmaceutical performance is improved, but the development complexity increases
Solution Approach 1:
The patent develops four distinct crystalline polymorphic forms (Form-I, Form-II, Form-III, Form-IV) of Ribociclib succinate with different crystal structures and stability profiles, enabling selection of optimal forms for specific pharmaceutical applications while managing development complexity through systematic characterization
Solution Approach 2:
The patent segments the Ribociclib compound into multiple distinct polymorphic forms, each with unique properties (stability, solubility, bioavailability), allowing pharmaceutical developers to select the most appropriate form for specific therapeutic needs
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 novel crystalline forms and preparation processes result in highly pure Ribociclib compounds with enhanced pharmaceutical properties, suitable for various pharmaceutical compositions.
Implementation Method 1
the reaction mixture was cooled to 0-5° C. and stirred for 1-3 h. The resulting crystalline solid was collected by filtration
Implementation Method 2
The layers were separated and the organic layer was washed with water (3×50 mL) and brine (1×50 mL)
Implementation Method 3
The organic layer was concentrated under reduced pressure to obtain the title compound as a crystalline solid
Data Source
AI summary
The present invention relates to novel crystalline forms of butanedioic acid 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide of formula-la and process for preparation thereof.The present invention also relates to a process for the preparation of 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide.Further, the present application also relates to acid addition salts of 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide and process for the preparation thereof.