Ribociclib Succinate Preparation via Parameter Changes
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Solution Overview
Problem
The existing process for preparing Ribociclib succinate results in low yield and purity, and there is a need for novel crystalline forms that enhance the performance characteristics of the pharmaceutical compound.
Innovation Solution
An improved process for preparing Ribociclib succinate involving the use of low-cost reagents and solvents, replacing expensive coupling reagents with N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and hydroxybenzotriazole, and employing lithium hexamethyldisilazane for coupling reactions, which results in high yield and purity, and the development of novel crystalline forms (Form-A to Form-N) characterized by specific X-ray diffraction patterns and thermal stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the existing process for preparing Ribociclib succinate is used, then the production cost is reduced, but the yield and purity are low
Solution Approach 1:
The patent changes the chemical parameters by replacing expensive coupling reagents (HBTU, Pd2(dba)3, BINAP) with cheaper alternatives (EDC HCl, HOBt, LiHMDS). This parameter substitution resolves the contradiction by maintaining acceptable reaction efficiency while significantly reducing production costs, thereby enabling higher yields at lower cost.
Solution Approach 2:
The patent employs inexpensive, readily available reagents such as EDC HCl and HOBt instead of expensive, specialized coupling agents. These cheap reagents achieve the desired coupling reaction effectively, resolving the contradiction between low production cost and high yield by making the process economically viable while maintaining productivity.
2Manufacturing precision
If the existing process for preparing Ribociclib succinate is used, then the production cost is reduced, but the purity is low
Solution Approach 1:
The patent improves purity by changing the reagent parameters - using EDC HCl and HOBt instead of HBTU, and LiHMDS instead of Pd2(dba)3/BINAP. These parameter changes lead to cleaner reactions with fewer side products, achieving high purity while keeping production costs low.
Solution Approach 2:
The use of inexpensive reagents like EDC HCl, HOBt, and LiHMDS provides high purity products without the need for expensive specialized reagents. This resolves the contradiction by demonstrating that cost-effective reagents can achieve manufacturing precision comparable to or better than expensive alternatives.
3Stability of the object's composition
If novel crystalline forms are developed, then the stability and solubility are improved, but the process complexity increases
Solution Approach 1:
The patent exploits phase transition principles by developing multiple crystalline forms (polymorphs) of Ribociclib succinate. Each polymorph represents a different solid phase with distinct stability and solubility characteristics. This resolves the contradiction by providing tailored stability through controlled crystallization processes without requiring complex manufacturing equipment.
Solution Approach 2:
The patent achieves different stability profiles by changing crystallization parameters such as solvent type, temperature, and pH. By adjusting these parameters, specific polymorphs with desired stability and solubility characteristics can be obtained, resolving the contradiction between improved stability and process complexity through simple parameter optimization rather than complex process design.
4Quantity of substance
If novel crystalline forms are developed, then the solubility is improved, but the process complexity increases
Solution Approach 1:
The patent develops multiple crystalline forms with different solubility characteristics by controlling phase transitions during crystallization. Different polymorphs exhibit varying solubility profiles, allowing optimization for specific pharmaceutical applications without requiring complex processing equipment or procedures.
Solution Approach 2:
The patent improves solubility by changing crystallization parameters such as solvent selection, temperature profiles, and pH conditions. These parameter adjustments produce polymorphs with enhanced solubility properties while maintaining process simplicity, resolving the contradiction between improved solubility and process complexity.
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 achieves high yield and purity of Ribociclib succinate with reduced production costs, making it suitable for commercial scale, and the novel crystalline forms offer improved stability and solubility, enhancing the pharmaceutical product's performance characteristics.
Implementation Method 1
reacting 2-chloro-7-cyclopentyl-N,N-dimethyl-pyrrolo[2,3-d]pyrimidine-6-carboxamide compound of formula-3 with 4-(6-amino-pyridine-3-yl)-piperazine-1-carboxylic acid tert-butyl ester compound of formula-4 in presence of lithium hexamethyldisilazane (LiHMDS) in toluene provides tert-butyl 4-[6-[[7-cyclopentyl-6-(dimethylcarbamoyl) pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-pyridyl]piperazine-1-carboxylate compound of formula-5
Implementation Method 2
reacting the compound of formula-3 with 4-(6-amino-pyridine-3-yl)-piperazine-1-carboxylic acid tert-butyl ester compound of formula-4 in presence of lithium hexamethyldisilazane (LiHMDS) in toluene
Implementation Method 3
treating Ribociclib base of formula-1 with succinic acid in isopropyl alcohol. The resulting Ribociclib succinate
Implementation Method 4
Dynamic Vapour sorption (DVS), PXRD, DSC and Thermogravimetric analysis of these two hydrate and non-hydrate forms of Ribociclib succinate of formula-1a were also discussed
Implementation Method 5
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties
Implementation Method 6
Ribociclib succinate absorbs moisture up to 2.0% at 0-90-0% RH and up to 0.5% at 0-90-0% RH
Data Source
AI summary
The present invention relates to an improved 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 succinate (1/1) compound of formula-1a and its novel crystalline forms. The said compound of formula-1a is represented by the following structural formula: Formula-1a