Belumosudil Crystalline Polymorphs and Salts for Stability
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Solution Overview
Problem
There is a need for additional solid state forms, including solvated forms, of Belumosudil and its salts to improve processing properties, stability, and bioavailability for pharmaceutical applications.
Innovation Solution
The development of crystalline polymorphs of Belumosudil, including Belumosudil Mesylate, Belumosudil Tosylate, and Belumosudil Besylate, along with processes for their preparation and pharmaceutical compositions thereof.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If additional solid state forms and salts of Belumosudil are developed, then stability and shelf-life are improved, but device complexity increases
Solution Approach 1:
The patent applies parameter changes by developing multiple solid state forms (polymorphs) and salt forms of Belumosudil, each with different physical and chemical properties. By changing the physical state parameters and chemical composition parameters, the invention achieves improved stability, solubility, and shelf-life while managing the complexity through systematic classification and characterization of these forms.
Solution Approach 2:
The patent creates composite material systems by combining Belumosudil with various counterions to form different salt compounds (e.g., mesylate, tosylate, besylate salts). These composite salt forms exhibit different physical properties compared to the free base, enabling improved formulation characteristics and stability while maintaining therapeutic activity.
2Productivity
If multiple crystalline polymorphs are developed, then bioavailability and handling characteristics are improved, but manufacturing precision requirements increase
Solution Approach 1:
The patent utilizes parameter changes in crystal structure, packing arrangement, and molecular orientation to generate different polymorphic forms with distinct bioavailability and handling properties. By controlling crystallization parameters such as temperature, pH, and solvent composition, the invention achieves desired physical properties while managing manufacturing precision through established crystallization techniques.
Solution Approach 2:
The patent creates multiple copies of the same molecular structure (Belumosudil) arranged in different crystalline patterns. Each polymorph represents a different spatial arrangement or 'copy' of the molecular structure, allowing the same active ingredient to exhibit different physical and pharmacological properties without changing the chemical composition.
3Ease of manufacture
If new solid state forms are discovered, then processing properties are improved, but loss of time in characterization and validation increases
Solution Approach 1:
The patent performs preliminary characterization and evaluation of new solid state forms during the development process, assessing properties such as solubility, dissolution rate, and stability before final formulation selection. By conducting these evaluations early and systematically, the invention identifies promising candidates that improve processing properties while minimizing time-consuming later-stage testing.
Solution Approach 2:
The patent implements feedback mechanisms where characterization data from newly discovered solid state forms is continuously evaluated and fed back into the formulation development process. This iterative feedback allows rapid identification of forms with desirable processing properties and adjustment of development priorities, reducing overall time loss through efficient resource allocation based on preliminary findings.
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
These crystalline polymorphs offer improved stability, handling characteristics, and bioavailability, enhancing the performance and shelf-life of Belumosudil-based pharmaceutical products.
Implementation Method 1
Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may produce a rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis ('TGA'), or differential scanning calorimetry ('DSC')), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum.
Implementation Method 2
Crystalline forms of Belumosudil are disclosed in International Publication No. WO 2021/129589.
Data Source
AI summary
The present disclosure encompasses solid state forms of Belumosudil, in embodiments crystalline polymorphs of Belumosudil or salts thereof, processes for preparation thereof, and pharmaceutical compositions thereof.