Crystal Form A of Tricyclic Compound for S1P1 Agonist Stability

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Solution Overview

Problem

Current S1P1 receptor agonists face challenges in stability, formulation, and efficacy for treating autoimmune diseases such as inflammatory bowel disease, particularly in maintaining lymphocyte isolation and immune regulation.

Innovation Solution

A Crystal Form A of Compound 1 with specific X-ray powder diffraction and differential scanning calorimetry patterns, prepared through recrystallization in various solvents, exhibits improved stability and pharmacokinetic properties, including significant inhibitory effects on S1P1-related pathways.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional S1P1 receptor agonists are used, then immune regulation activity is achieved, but stability and formulation properties are poor

Engineering Contradiction:

ImprovestabilityVSAvoidformulation

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by discovering and characterizing different crystal forms (Form A, Form B, Form C) of Compound 1, each with distinct X-ray powder diffraction patterns, melting points, and stability characteristics. This allows selection of optimal crystal forms for improved stability and formulation properties while maintaining S1P1 receptor agonist activity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions by establishing relationships between different crystal forms and their transformation conditions. By controlling crystallization conditions and identifying phase transition temperatures through DSC analysis, the patent enables stable formulation development and predictable behavior during storage and processing.

Inventive Principle:

Principle #36Phase transitions

2Reliability

If Crystal Form A is used, then stability is improved, but manufacturing process complexity increases

Engineering Contradiction:

ImprovestabilityVSAvoidmanufacturing process

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies preliminary action by pre-characterizing multiple crystal forms and establishing their formation conditions before scale-up manufacturing. This includes determining XRPD patterns, DSC curves, and solubility profiles of each form, enabling straightforward selection and reproduction of the desired stable form without complex in-process controls.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent uses solvent selection as an intermediary approach to control crystal form formation. By identifying specific solvents and solvent mixtures that preferentially yield Crystal Form A with improved stability, the patent simplifies manufacturing by using solvent-based control rather than complex mechanical or thermal processing.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If higher lymphocyte isolation efficacy is achieved, then immune regulation improves, but pharmacokinetic properties deteriorate

Engineering Contradiction:

Improveimmune regulation efficacyVSAvoidpharmacokinetic profile

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent applies parameter changes by optimizing the chemical structure of Compound 1 to achieve better pharmacokinetic properties including improved solubility, metabolic stability, and bioavailability. These structural modifications maintain or enhance S1P1 receptor binding affinity and lymphocyte isolation efficacy while improving overall pharmacokinetic profile compared to reference compounds like Ozanimod.

Inventive Principle:

Principle #35Parameter changes

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 Crystal Form A of Compound 1 demonstrates enhanced stability, reduced hygroscopicity, and improved druggability, showing significant therapeutic effects in ulcerative colitis models and improved pharmacokinetic profiles compared to Ozanimod, effectively reducing lymphocyte counts and inflammation.

Implementation Method 1

the Crystal Form A has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.66±0.2°, 13.30±0.2°, 15.57±0.2°

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 2

preparing process thereof comprising adding the Compound 1 into acetonitrile, an alcohol solvent, a ketone solvent, an ester solvent, an ether solvent, a mixed solvent of alcohol solvent and water

Methodology Applied

Scientific EffectRecrystallization: Crystallisation

Data Source

PatentUS11465995B2Crystal and salt forms of tricyclic compound and preparation process thereof

Publication Date: 2022.10.11 MEDSHINE DISCOVERY INC

AI summary

Provided are a crystal form of a tricyclic compound and a preparation process thereof. Also provided is an application of the crystal form in preparing a drug for treating a disease related to a sphingosine-1-phosphate subtype 1 (S1P1) receptor.