Risdiplam Crystalline Polymorphs for Stability and Processability

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

There is a need for additional solid state forms of Risdiplam, including crystalline polymorphs, to improve processing properties, stability, and bioavailability, which are not adequately addressed by existing forms.

Innovation Solution

The development of crystalline polymorphs of Risdiplam, such as Forms 1 to 5, characterized by specific X-ray powder diffraction patterns and solid state 13C NMR spectra, along with processes for their preparation, which can be used to create pharmaceutical compositions and formulations for treating spinal muscular atrophy (SMA).

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing solid state forms of Risdiplam are used, then the basic therapeutic function is achieved, but processing properties and stability are inadequate

Engineering Contradiction:

ImprovestabilityVSAvoidprocessing properties

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by discovering and characterizing multiple crystalline polymorphs (Forms 1-5) of Risdiplam, each with distinct crystal structures, melting points, and physical properties. By changing the crystalline form parameter, the patent achieves improved processing properties, stability, and solubility while maintaining the therapeutic function of the active ingredient.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite solid state forms by forming solvates and hydrates of Risdiplam with various solvents and water molecules. These composite structures incorporate host-guest interactions between the active ingredient and solvent molecules, resulting in materials with enhanced processing characteristics and stability profiles compared to the pure active ingredient.

Inventive Principle:

Principle #40Composite materials

2Manufacturing precision

If new solid state forms are developed to improve processing and stability, then manufacturing quality improves, but the complexity of characterizing and selecting appropriate forms increases

Engineering Contradiction:

Improveprocessing propertiesVSAvoidcharacterization complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent segments the complex problem of solid state characterization by systematically analyzing each polymorph and solvate form separately using multiple specialized techniques (XRPD, DSC, TGA, solid-state NMR, IR spectroscopy). This segmented approach allows thorough characterization of each form's unique properties without being overwhelmed by the complexity of the entire polymorph system.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs a universal multi-technique characterization framework that applies the same set of analytical methods (XRPD, DSC, TGA, NMR, IR) across all polymorph and solvate forms. This universal approach ensures consistent, comprehensive characterization of each form while streamlining the overall evaluation process through standardized protocols.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS12492214B2Solid state forms of Risdiplam and process for preparation thereof

Publication Date: 2025.12.09 ASSIA CHEM IND

AI summary

The present disclosure encompasses solid state forms of Risdiplam, including crystalline polymorphs of Risdiplam, processes for preparation thereof, and pharmaceutical compositions thereof.