Risdiplam Crystalline Polymorphs for Stability and Dissolution
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Solution Overview
Problem
There is a need for additional solid state forms of Risdiplam, including crystalline polymorphs, to improve processing, handling, stability, and bioavailability for the treatment of spinal muscular atrophy (SMA).
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, which are prepared through processes involving solvent suspension and isolation, offering improved chemical and thermal stability, and can be combined with pharmaceutically acceptable excipients to form pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If new solid state forms of Risdiplam are developed, then chemical stability and dissolution profile are improved, but the complexity of the patent and formulation process increases
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline polymorphs (Forms 1-5) with different crystal structures and physical properties. Each polymorph represents a different parameter state of the same molecule, offering improved chemical stability and dissolution profiles while providing options to optimize formulation processes.
Solution Approach 2:
The patent creates composite pharmaceutical compositions by combining specific crystalline polymorphs of Risdiplam with pharmaceutically acceptable excipients. This allows the active ingredient to be paired with complementary materials that enhance stability, solubility, and bioavailability while managing formulation complexity.
2Manufacturing precision
If crystalline polymorphs are prepared through solvent suspension and isolation, then purity and crystallinity are improved, but the manufacturing time and process steps increase
Solution Approach 1:
The patent employs preliminary action by selecting and optimizing specific solvent systems and suspension conditions before crystallization. By pre-determining the appropriate solvents, temperatures, and isolation parameters for each polymorph form, the process achieves high crystallinity while minimizing unnecessary process steps and time.
3Productivity
If multiple solid state forms are developed, then bioavailability and dissolution profile are improved, but the difficulty of detecting and measuring different forms increases
Solution Approach 1:
The patent utilizes characteristic X-ray powder diffraction (XRPD) patterns and solid state 13C NMR spectra as unique identifiers for each crystalline polymorph form. These spectroscopic 'fingerprints' provide clear, distinguishable signals that facilitate easy detection, characterization, and quality control of different polymorphs despite their structural similarities.
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 crystalline polymorphs provide enhanced chemical stability, dissolution profile, and handling characteristics, enabling effective pharmaceutical formulations for treating SMA.
Implementation Method 1
characterized by specific X-ray powder diffraction patterns
Implementation Method 2
X-ray powder diffraction patterns
Implementation Method 3
solid state 13C NMR spectra
Data Source
AI summary
The present disclosure encompasses solid state forms of Risdiplam, including crystalline polymorphs of Risdiplam, processes for preparation thereof, and pharmaceutical compositions thereof.