Crystalline Forms of PDGFR Inhibitor for Pulmonary Arterial Hypertension
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Solution Overview
Problem
Current kinase receptor inhibitors, particularly PDGFR inhibitors, are not orally available and have off-target effects and dose-limiting side effects, necessitating the development of more potent and selective inhibitors for conditions like pulmonary arterial hypertension.
Innovation Solution
Development of novel crystalline forms of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide (Compound 1), specifically Form A and Form B, which are characterized by distinct XRPD patterns and DSC thermograms, offering enhanced solubility and stability for inhalation delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If crystalline forms of Compound 1 are developed, then solubility and stability are improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by developing specific crystalline forms (Form A and Form B) with distinct physical properties. Form A is characterized by specific XRPD peaks at 5.5, 7.8, 11.0, 12.3 and 15.6 degrees 2-theta, while Form B has peaks at 5.2, 6.1, 7.6, 11.5 and 12.3 degrees 2-theta. These parameter changes in crystal structure enable improved solubility and stability profiles for inhalation delivery.
Solution Approach 2:
The patent uses X-ray powder diffraction (XRPD) patterns as a signature or copy to identify and verify the specific crystalline forms. The characteristic diffractograms serve as diagnostic copies that confirm the presence of Form A or Form B, enabling quality control without requiring complex manufacturing processes.
2Reliability
If crystalline forms with enhanced solubility are produced, then bioavailability is improved, but process complexity increases
Solution Approach 1:
The patent changes the physical state parameter from amorphous to crystalline forms with specific lattice arrangements. Form A and Form B exhibit different solubility characteristics that can be optimized for inhalation delivery, improving bioavailability through controlled crystallization processes.
Solution Approach 2:
The patent replaces complex formulation approaches with crystallization-based processes. By controlling the formation of specific crystalline forms through straightforward recrystallization or precipitation methods, the patent achieves enhanced solubility and bioavailability without requiring complex delivery systems.
3Reliability
If selective PDGFR inhibition is achieved, then therapeutic efficacy is improved, but side effects increase
Solution Approach 1:
The patent changes the pharmacological parameter of selectivity by optimizing Compound 1 in its crystalline forms to achieve high potency and selectivity for PDGFRα and PDGFRβ. This parameter optimization enhances therapeutic efficacy while reducing off-target effects and dose-limiting side effects compared to previous kinase inhibitors.
Data Source
AI summary
Crystalline forms of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]-phenyl}-5-methylpyridine-3-carboxamide are provided. Pharmaceutical compositions and dosage forms containing the crystal forms are also provided, including related methods for modulating kinases generally, and specifically to treatment of PAH.