Ribociclib Succinate Crystal Forms for Humidity Stability
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Solution Overview
Problem
Existing Ribociclib succinate formulations exhibit hygroscopicity and instability under high humidity conditions, leading to moisture absorption and potential polymorphic changes, which affect processing, stability, and bioavailability.
Innovation Solution
Development of new crystalline forms of Ribociclib succinate, such as Form B, which demonstrates high stability and negligible hygroscopicity, along with processes for converting Ribociclib succinate to other solid state forms and salts, enhancing properties like chemical purity, solubility, and dissolution rate.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing Ribociclib succinate formulations are used, then the drug can be administered for breast cancer treatment, but the formulations exhibit hygroscopicity and instability under high humidity conditions leading to moisture absorption and polymorphic changes
Solution Approach 1:
The patent applies parameter changes by developing new crystalline forms (polymorphs) of Ribociclib succinate with different crystal structures that exhibit reduced hygroscopicity and improved stability. Specifically, Form II and Form III were identified as having superior stability characteristics compared to Form I, with Form II showing negligible hygroscopicity and Form III demonstrating enhanced stability under various humidity conditions. This resolves the contradiction by changing the physical state parameters of the drug substance while maintaining its therapeutic efficacy.
Solution Approach 2:
The patent employs composite materials by creating salt forms of Ribociclib with different counterions (succinate, mesylate, hydrochloride, oxalate, tosylate, sulfate, malate, maleate). These salt forms exhibit different hygroscopicity and stability profiles, allowing selection of the optimal salt form for specific formulation requirements. For example, Ribociclib mesylate and Ribociclib hydrochloride were found to have reduced hygroscopicity compared to the free base form, resolving the moisture absorption issue while maintaining drug efficacy.
2Ease of manufacture
If existing crystalline forms of Ribociclib succinate are used, then the drug maintains its therapeutic activity, but the processing and handling characteristics are suboptimal due to moisture sensitivity
Solution Approach 1:
The patent changes the crystal structure parameters by identifying and characterizing multiple polymorphic forms (Form I, Form II, Form III) with distinct XRPD patterns, melting points, and stability profiles. Form II was specifically identified as having optimal processing characteristics with negligible hygroscopicity and excellent stability, while Form III showed improved stability under high humidity conditions. This resolves the contradiction by providing crystalline forms that are both easy to process and stable.
Solution Approach 2:
The patent develops alternative salt forms that can be more easily manufactured and processed than the original succinate form. The new salt forms (mesylate, hydrochloride, oxalate, tosylate, sulfate, malate, maleate) offer improved processing characteristics and reduced moisture sensitivity, allowing for more robust manufacturing processes with fewer stability concerns during processing and storage.
3Reliability
If new solid state forms are developed, then improved stability and reduced hygroscopicity are achieved, but the formulation complexity increases
Solution Approach 1:
The patent systematically evaluates multiple polymorphic forms and salt forms based on defined parameters including hygroscopicity, stability, solubility, and processing characteristics. This structured approach allows for the identification of optimal forms (such as Form II and Form III) that provide improved stability without requiring complex formulation strategies. The selection criteria and characterization methods establish a clear framework that manages formulation complexity while achieving the desired stability improvements.
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 new crystalline forms provide improved stability, reduced moisture absorption, and enhanced processing characteristics, leading to better formulation and therapeutic efficacy for breast cancer treatment.
Implementation Method 1
Development of new crystalline forms of Ribociclib succinate, such as Form B, which demonstrates high stability and negligible hygroscopicity
Data Source
AI summary
The present disclosure relates to Ribociclib solid state forms, Ribociclib salts including Ribociclib succinate and solid state forms thereof, as well as processes for preparation thereof and pharmaceutical compositions thereof.