Amorphous and Crystalline IDO Inhibitor Forms for Bioavailability
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Solution Overview
Problem
There is a need for new solid forms of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide (Compound 1) with desirable chemical and physical properties, as well as reliable methods for their manufacture, purification, and formulation to facilitate commercialization, particularly for use as IDO inhibitors in cancer treatment.
Innovation Solution
The development of solid forms of Compound 1, including free base, monohydrate, and methanesulfonic acid salt forms, characterized by specific X-ray diffraction patterns and thermal behaviors, along with methods for their production and formulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If new solid forms of Compound 1 are developed, then stability and oral bioavailability are improved, but development complexity and manufacturing challenges increase
Solution Approach 1:
The patent applies parameter changes by developing multiple solid forms (amorphous and crystalline) of Compound 1 with different physical and chemical parameters. Specifically, it identifies and characterizes four distinct solid forms including amorphous Compound 1, crystalline Form 1, Form 2, and Form 3, each with unique X-ray diffraction patterns, thermal properties, and stability characteristics. This systematic exploration of parameter variations resolves the contradiction by finding optimal solid forms that improve stability and bioavailability while providing clear characterization methods for manufacturing control
Solution Approach 2:
The patent employs composite materials principles by creating specific hydrate forms (monohydrate) and solvate forms of Compound 1. These composite solid forms combine Compound 1 with water or other solvents in defined ratios and crystal structures, resulting in improved stability and handling properties. The detailed characterization of these composite forms including their specific XRPD patterns and thermal behaviors provides a foundation for reliable manufacturing
2Manufacturing precision
If multiple solid forms are characterized and manufactured, then product quality and bioavailability improve, but production time and processing complexity increase
Solution Approach 1:
The patent applies preliminary action by providing complete advance characterization of all four solid forms including their X-ray diffraction patterns, thermal properties, solubility characteristics, and stability data. This preliminary work establishes clear identification and control methods that enable manufacturers to quickly select and produce the appropriate form without extensive trial and error, thereby reducing production time while maintaining high product quality
Solution Approach 2:
The patent segments the Compound 1 product line into four distinct, well-characterized solid forms with unique identification characteristics. Each form is independently characterized with specific XRPD patterns, thermal profiles, and manufacturing parameters. This segmentation allows manufacturers to choose the most appropriate form for specific applications and scale production of individual forms efficiently without being constrained by the need to develop all forms simultaneously
Data Source
AI summary
The present disclosure relates to amorphous and crystalline forms of (R)—N-(4-chlorophenyl)-2-(1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide and its salts and hydrates, processes for their production, pharmaceutical compositions comprising them, and methods of treatment using them.