Ribociclib Succinate Crystalline Forms for Long-Term Stability
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Solution Overview
Problem
Existing crystalline forms of 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide succinate, such as those described in WO 2010/020675 and WO2012/064805, do not fully address the need for stable and effective pharmaceutical compositions for inhibiting cyclin dependent kinases and modulating glycogen synthase kinase-3, particularly in treating various cancers.
Innovation Solution
Development of new crystalline forms, including Modification E, Modification F, Modification HB, and Modification HA, which are anhydrous, hemisuccinate, and dihydrate forms of ribociclib succinate, providing stable pharmaceutical compositions for effective kinase inhibition and modulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing crystalline forms of ribociclib succinate are used, then the basic pharmacological activity is achieved, but the stability and efficacy are insufficient for optimal treatment outcomes
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing multiple new crystalline forms (Modifications E, F, HB, HA) with distinct physical and chemical parameters including water content, crystalline structure, and stability characteristics. Each modification represents a specific parameter state that optimizes different aspects of pharmaceutical performance, allowing selection based on specific treatment requirements
Solution Approach 2:
The patent employs composite materials by creating pharmaceutical compositions that combine ribociclib succinate in specific crystalline forms with pharmaceutically acceptable excipients, carriers, and diluents. These composite formulations leverage the enhanced stability and efficacy of the new crystalline forms while incorporating additional components to optimize delivery, bioavailability, and therapeutic effect
2Reliability
If new crystalline forms with varying concentrations and purity levels are developed, then treatment outcomes are improved, but the complexity of pharmaceutical compositions increases
Solution Approach 1:
The patent applies segmentation by dividing the pharmaceutical development into distinct crystalline form modifications (E, F, HB, HA), each with specific characteristics and optimal applications. This segmentation allows systematic evaluation and selection of the most appropriate form for specific therapeutic indications, managing complexity through structured classification rather than treating all forms as a single undifferentiated category
3Reliability
If crystalline forms are developed for inhibiting cyclin dependent kinases and modulating glycogen synthase kinase-3, then the pharmacological activity is achieved, but the stability for long-term treatment is insufficient
Solution Approach 1:
The patent applies preliminary action by pre-optimizing the crystalline structure of ribociclib succinate before pharmaceutical formulation and administration. The new crystalline forms are specifically designed and characterized in advance to possess enhanced stability properties, ensuring that the compound maintains its pharmacological activity and structural integrity throughout storage and long-term treatment periods
Data Source
AI summary
Provided herein are new crystalline form(s) of succinate salt(s) of 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (also known as ribociclib), pharmaceutical compositions comprising the same, methods of treatment using the same and methods of making the same.